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  1. CT-1-CP-induced ventricular electrical remodeling in mice.

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    Chen, Shu-fen; Wei, Tao-zhi; Rao, Li-ya; Xu, Ming-guang; Dong, Zhan-ling

    2015-02-01

    The chronic effects of carboxyl-terminal polypeptide of Cardiotrophin-1 (CT-1-CP) on ventricular electrical remodeling were investigated. CT-1-CP, which contains 16 amino acids in sequence of the C-terminal of Cardiotrophin-1, was selected and synthesized, and then administered to Kunming mice (aged 5 weeks) by intraperitoneal injection (500 ng·g⁻¹·day⁻¹) (4 groups, n=10 and female: male=1:1 in each group) for 1, 2, 3 and 4 weeks, respectively. The control group (n=10, female: male=1:1) was injected by physiological saline for 4 weeks. The epicardial monophasic action potential (MAP) was recorded by using a contact-type MAP electrode placed vertically on the left ventricular (LV) epicardium surface, and the electrocardiogram (ECG) signal in lead II was monitored synchronously. ECG intervals (RR, PR, QRS and QT) and the amplitude of MAP (Am), the maximum upstroke velocity (Vmax), as well as action potential durations (APDs) at different repolarization levels (APD30, APD50, APD70, and APD90) of MAP were determined and analyzed in detail. There were no significant differences in RR and P intervals between CT-1-CP-treated groups and control group, but the PR segment and the QRS complex were greater in the former than in the latter (F=2.681 and 5.462 respectively, PCP-treated groups than in control group, the QT dispersion (QTd) of them was greater in the latter than in the former (F=3.090, PCP-treated groups and the prolongation of QT intervals increased gradually along with the time of exposure to CT-1-CP. The QRS complex had no significant change in control group, one-week and three-week CT-1-CP-treated groups, but prolonged significantly in two-week and four-week CT-1-CP-treated groups. Interestingly, the QTd after chest-opening was significantly greater than that before chest-opening in control group (t=5.242, PCP-treated groups. The mean MAP amplitude, Vmax and APD were greater in CT-1-CP-treated groups than those in control group, and became more obvious

  2. Electrophysiologic Remodeling of the Left Ventricle in Pressure Overload-Induced Right Ventricular Failure

    NARCIS (Netherlands)

    Hardziyenka, Maxim; Campian, Maria E.; Verkerk, Arie O.; Surie, Sulaiman; van Ginneken, Antoni C. G.; Hakim, Sara; Linnenbank, André C.; de Bruin-Bon, Rianne H. A. C. M.; Beekman, Leander; van der Plas, Mart N.; Remme, Carol A.; van Veen, Toon A. B.; Bresser, Paul; de Bakker, Jacques M. T.; Tan, Hanno L.

    2012-01-01

    Objectives The purpose of this study was to analyze the electrophysiologic remodeling of the atrophic left ventricle (LV) in right ventricular (RV) failure (RVF) after RV pressure overload. Background The LV in pressure-induced RVF develops dysfunction, reduction in mass, and altered gene

  3. Electrophysiologic remodeling of the left ventricle in pressure overload-induced right ventricular failure.

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    Hardziyenka, Maxim; Campian, Maria E; Verkerk, Arie O; Surie, Sulaiman; van Ginneken, Antoni C G; Hakim, Sara; Linnenbank, André C; de Bruin-Bon, H A C M Rianne; Beekman, Leander; van der Plas, Mart N; Remme, Carol A; van Veen, Toon A B; Bresser, Paul; de Bakker, Jacques M T; Tan, Hanno L

    2012-06-12

    The purpose of this study was to analyze the electrophysiologic remodeling of the atrophic left ventricle (LV) in right ventricular (RV) failure (RVF) after RV pressure overload. The LV in pressure-induced RVF develops dysfunction, reduction in mass, and altered gene expression, due to atrophic remodeling. LV atrophy is associated with electrophysiologic remodeling. We conducted epicardial mapping in Langendorff-perfused hearts, patch-clamp studies, gene expression studies, and protein level studies of the LV in rats with pressure-induced RVF (monocrotaline [MCT] injection, n = 25; controls with saline injection, n = 18). We also performed epicardial mapping of the LV in patients with RVF after chronic thromboembolic pulmonary hypertension (CTEPH) (RVF, n = 10; no RVF, n = 16). The LV of rats with MCT-induced RVF exhibited electrophysiologic remodeling: longer action potentials (APs) at 90% repolarization and effective refractory periods (ERPs) (60 ± 1 ms vs. 44 ± 1 ms; p < 0.001), and slower longitudinal conduction velocity (62 ± 2 cm/s vs. 70 ± 1 cm/s; p = 0.003). AP/ERP prolongation agreed with reduced Kcnip2 expression, which encodes the repolarizing potassium channel subunit KChIP2 (0.07 ± 0.01 vs. 0.11 ± 0.02; p < 0.05). Conduction slowing was not explained by impaired impulse formation, as AP maximum upstroke velocity, whole-cell sodium current magnitude/properties, and mRNA levels of Scn5a were unaltered. Instead, impulse transmission in RVF was hampered by reduction in cell length (111.6 ± 0.7 μm vs. 122.0 ± 0.4 μm; p = 0.02) and width (21.9 ± 0.2 μm vs. 25.3 ± 0.3 μm; p = 0.002), and impaired cell-to-cell impulse transmission (24% reduction in Connexin-43 levels). The LV of patients with CTEPH with RVF also exhibited ERP prolongation (306 ± 8 ms vs. 268 ± 5 ms; p = 0.001) and conduction slowing (53 ± 3 cm/s vs. 64 ± 3 cm/s; p = 0.005). Pressure-induced RVF is associated with electrophysiologic remodeling of the atrophic LV. Copyright

  4. Rapamycin attenuates hypoxia-induced pulmonary vascular remodeling and right ventricular hypertrophy in mice

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    Tillmanns Harald H

    2007-02-01

    Full Text Available Abstract Background Chronic hypoxia induces pulmonary arterial hypertension (PAH. Smooth muscle cell (SMC proliferation and hypertrophy are important contributors to the remodeling that occurs in chronic hypoxic pulmonary vasculature. We hypothesized that rapamycin (RAPA, a potent cell cycle inhibitor, prevents pulmonary hypertension in chronic hypoxic mice. Methods Mice were held either at normoxia (N; 21% O2 or at hypobaric hypoxia (H; 0.5 atm; ~10% O2. RAPA-treated animals (3 mg/kg*d, i.p. were compared to animals injected with vehicle alone. Proliferative activity within the pulmonary arteries was quantified by staining for Ki67 (positive nuclei/vessel and media area was quantified by computer-aided planimetry after immune-labeling for α-smooth muscle actin (pixel/vessel. The ratio of right ventricle to left ventricle plus septum (RV/[LV+S] was used to determine right ventricular hypertrophy. Results Proliferative activity increased by 34% at day 4 in mice held under H (median: 0.38 compared to N (median: 0.28, p = 0.028 which was completely blocked by RAPA (median HO+RAPA: 0.23, p = 0.003. H-induced proliferation had leveled off within 3 weeks. At this time point media area had, however, increased by 53% from 91 (N to 139 (H, p Conclusion Therapy with rapamycin may represent a new strategy for the treatment of pulmonary hypertension.

  5. Guanxin Danshen Formulation Protects against Myocardial Ischemia Reperfusion Injury-Induced Left Ventricular Remodeling by Upregulating Estrogen Receptor β

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    Xuehong Deng

    2017-11-01

    Full Text Available Background: Guanxin Danshen formulation (GXDSF is a traditional Chinese herbal recipe recorded in the Chinese Pharmacopeia since 1995 edition, which consists of Salviae miltiorrhizae Radix et Rhizoma, Notoginseng Radix et Rhizoma and Dalbergiae odoriferae Lignum. Our previous research suggested GXDSF had positive effect on cardiovascular disease. Therefore, the aim of this study was to elucidate the effects of GXDSF on myocardial ischemia reperfusion injury-induced left ventricular remodelling (MIRI-LVR.Methods: The effects of GXDSF on cardiac function were detected by haemodynamics and echocardiograms. The effects of GXDSF on biochemical parameters (AST, LDH and CK-MB were analyzed. Histopathologic examinations were performed to evaluate the effect of GXDSF on cardiac structure. In addition, the Traditional Chinese Medicine Systems Pharmacology (TCMSP database was used to predict the main target of GXDSF. Target validation was conducted by using western blots and immunofluorescent double staining assays.Results: We found that +dp/dt and LVSP were significantly elevated in the GXDSF-treated groups compared with the MIRI-LVR model group. Left ventricular ejection fraction (LVEF and left ventricular fractional shortening (LVFS were increased in the GXDSF-treated groups compared with the model group. All biochemical parameters (AST, LDH and CK-MB were considerably decreased in the GXDSF-treated groups compared with the model group. Fibrosis parameters (collagen I and III, α-SMA, and left ventricular fibrosis percentage were decreased to different degrees in the GXDSF-treated groups compared with the model group, and the collagen III/I ratio was elevated by the same treatments. TCMSP database prediction and western blot results indicated that estrogen receptor β (ERβ could be the main target of GXDSF. PHTPP, a selective antagonist of ERβ, could inhibit the expression of ERβ and the phosphorylation of PI3K and Akt in myocardial tissue induced by

  6. Early ventricular restraint after myocardial infarction: extent of the wrap determines the outcome of remodeling.

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    Enomoto, Yoshiharu; Gorman, Joseph H; Moainie, Sina L; Jackson, Benjamin M; Parish, Landi M; Plappert, Theodore; Zeeshan, Ahmad; St John-Sutton, Martin G; Gorman, Robert C

    2005-03-01

    Early infarct expansion initiates adverse remodeling, leads to left ventricular dilatation and portends a poor long-term outcome. Early mechanical prevention of infarct expansion has been proposed as a method to improve remodeling, but the extent of ventricular restraint necessary to optimize the salutary effect is not known. We tested the hypothesis that left ventricular restraint (wrap) is superior to infarct stiffening (patch). Infarction of 20% to 25% of the left ventricle was induced by coronary ligation in 69 sheep. Infarcts were either anteroapical (n = 33) or posterobasal (n = 36). Animals with each infarct received either no treatment (anteroapical, n = 26; posterobasal, n = 17), infarct stiffening with a localized Marlex mesh patch (posterobasal, n = 9) or left ventricular wrapping with Merseline mesh (anteroapical, n = 7; posterobasal, n = 10). End-systolic volume, end-diastolic volume, end-systolic muscle to cavity area ratio, left ventricular sphericity, ejection fraction, and degree of mitral regurgitation as determined by quantitative echocardiography were assessed before infarction and at 2, 5, and 8 weeks after infarction to evaluate the extent of left ventricular remodeling. Control animals in both groups experienced adverse remodeling. Anteroapical infarct animals developed large left ventricular aneurysms and the posterobasal infarct animals developed severe mitral regurgitation. Early infarct stiffening did not significantly improve any aspect of remodeling due to the posterobasal infarct. Early left ventricular wrapping significantly improved remodeling after both types of infarctions. Early left ventricular wrapping attenuates infarct expansion and has a salutary effect on remodeling. Simple infarct stiffening alone is not effective.

  7. Hydrogen gas attenuates embryonic gene expression and prevents left ventricular remodeling induced by intermittent hypoxia in cardiomyopathic hamsters.

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    Kato, Ryuji; Nomura, Atsuo; Sakamoto, Aiji; Yasuda, Yuki; Amatani, Koyuha; Nagai, Sayuri; Sen, Yoko; Ijiri, Yoshio; Okada, Yoshikatsu; Yamaguchi, Takehiro; Izumi, Yasukatsu; Yoshiyama, Minoru; Tanaka, Kazuhiko; Hayashi, Tetsuya

    2014-12-01

    The prevalence of sleep apnea is very high in patients with heart failure (HF). The aims of this study were to investigate the influence of intermittent hypoxia (IH) on the failing heart and to evaluate the antioxidant effect of hydrogen gas. Normal male Syrian hamsters (n = 22) and cardiomyopathic (CM) hamsters (n = 33) were exposed to IH (repeated cycles of 1.5 min of 5% oxygen and 5 min of 21% oxygen for 8 h during the daytime) or normoxia for 14 days. Hydrogen gas (3.05 vol/100 vol) was inhaled by some CM hamsters during hypoxia. IH increased the ratio of early diastolic mitral inflow velocity to mitral annulus velocity (E/e', 21.8 vs. 16.9) but did not affect the LV ejection fraction (EF) in normal Syrian hamsters. However, IH increased E/e' (29.4 vs. 21.5) and significantly decreased the EF (37.2 vs. 47.2%) in CM hamsters. IH also increased the cardiomyocyte cross-sectional area (672 vs. 443 μm(2)) and interstitial fibrosis (29.9 vs. 9.6%), along with elevation of oxidative stress and superoxide production in the left ventricular (LV) myocardium. Furthermore, IH significantly increased the expression of brain natriuretic peptide, β-myosin heavy chain, c-fos, and c-jun mRNA in CM hamsters. Hydrogen gas inhalation significantly decreased both oxidative stress and embryonic gene expression, thus preserving cardiac function in CM hamsters. In conclusion, IH accelerated LV remodeling in CM hamsters, at least partly by increasing oxidative stress in the failing heart. These findings might explain the poor prognosis of patients with HF and sleep apnea. Copyright © 2014 the American Physiological Society.

  8. Right ventricular remodeling in restrictive ventricular septal defect

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    Monreal, Gretel; Youtz, Dane J.; Phillips, Alistair B.; Eyman, Mahala E.; Gorr, Matthew W.; Velten, Christina; Lucchesi, Pamela A.; Wold, Loren E.; Gerhardt, Mark A.

    2014-01-01

    Restrictive ventricular septal defect (rVSD) presents with little/no hemodynamic aberrations despite a patent septal defect. Clinically, these patients are observed with the hope that the defect will functionally close over time without the need for surgical repair and development of heart failure. Without evidence supporting a definitive therapeutic strategy, rVSD patients may have increased risk of a poor outcome. We tested the hypothesis that rVSD results in subclinical RV diastolic dysfunction and molecular remodeling. Five pigs underwent surgical rVSD creation. Echocardiography, hemodynamics, myocyte contractility experiments, and proteomics/Western blot were performed 6-weeks post-rVSD and in controls. *p < 0.05. LV and RV hemodynamics in rVSD were comparable to controls. The tricuspid valve early/late diastolic inflow velocity ratio (TV E/A ratio) decreased from 1.6 ± 0.05 in controls to 1.0 ± 0.08* in rVSD, indicating RV diastolic dysfunction. rVSD RV myocytes showed abnormalities in contraction (departure velocity (Vd) − 51%*, Vd time +55%*) and relaxation (return velocity (Vr) −50%*, Vr time +62%*). Mitochondrial proteins (fatty acid, TCA cycle) increased 2-fold*, indicating heightened RV work. Desmin protein upregulated 285%* in rVSD RV myocardium, suggesting cytoskeletal remodeling. rVSD causes RV diastolic dysfunction, myocyte functional impairment, and mitochondrial/cytoskeletal protein upregulation in our model. Desmin upregulation may hinder sarcomeric organization/relaxation, representing a key subclinical early marker for future RV dysfunction. TV E/A measurements are a non-invasive modality to assess rVSD patients for diastolic dysfunction. Translational research applications may lead to fundamental changes in the clinical management of rVSD by providing evidence for early repair of the defect. PMID:20637777

  9. Modification of infarct material properties limits adverse ventricular remodeling.

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    Morita, Masato; Eckert, Chad E; Matsuzaki, Kanji; Noma, Mio; Ryan, Liam P; Burdick, Jason A; Jackson, Benjamin M; Gorman, Joseph H; Sacks, Michael S; Gorman, Robert C

    2011-08-01

    Infarct expansion after myocardial infarction (MI) is an important phenomenon that initiates and sustains adverse left ventricular (LV) remodeling. We tested the hypothesis that infarct modification by material-induced infarct stiffening and thickening limits infarct expansion and LV remodeling. Anteroapical infarction was induced in 21 sheep. Sheep were randomized to injection of saline (2.6 mL) or tissue filler material (2.6 mL) into the infarct within 3 hours of MI. Animals were monitored for 8 weeks with echocardiography to assess infarct expansion and global LV remodeling. Morphometric measurements were performed of excised hearts to quantify infarct thickness. Regional blood flow was assessed with colored microspheres. Infarct material properties were measured using biaxial tensile testing. Compared with controls at 8 weeks, treatment animals had less infarct expansion, reduced LV dilatation (LV systolic volumes: 60.8±4.3 vs 80.3±6.9 mL; p<0.05), greater ejection fraction (0.310±0.026 vs 0.276±0.013; p<0.05), thicker infarcts (5.5±0.2 vs 2.2±0.3 mm; p<0.05), and greater infarct blood flow (0.22±0.04 vs 0.11±0.03 mL/min/g; p<0.05). The longitudinal peak strain in the treatment group was less (0.05014±0.0141) than the control group (0.1024±0.0101), indicating increased stiffness of the treated infarcts. Durable infarct thickening and stiffening can be achieved by infarct biomaterial injection, resulting in the amelioration of infarct expansion and global LV remodeling. Further material optimization will allow for clinical translation of this novel treatment paradigm. Copyright © 2011 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.

  10. Surgical treatment of ischemic mitral regurgitation might not influence ventricular remodeling.

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    Enomoto, Yoshiharu; Gorman, Joseph H; Moainie, Sina L; Guy, T Sloane; Jackson, Benjamin M; Parish, Landi M; Plappert, Theodore; Zeeshan, Ahmad; St John-Sutton, Martin G; Gorman, Robert C

    2005-03-01

    Surgical treatment for ischemic mitral regurgitation has become more aggressive. However, no clinical study has demonstrated that surgical correction of chronic ischemic mitral regurgitation improves survival. We used 4 well-developed ovine models of postinfarction left ventricular remodeling to test the hypothesis that ischemic mitral regurgitation does not significantly contribute to postinfarction left ventricular remodeling. Infarction of 21% to 24% of the left ventricular mass was induced by means of coronary ligation in 77 sheep. Infarctions varied only by anatomic location in the left ventricle: anteroapical, n = 26; anterobasal, n = 16; laterobasal, n = 9; and posterobasal, n = 20. Six additional sheep had ring annuloplasty before posterobasal infarction. End-systolic and end-diastolic left ventricular volume, end-systolic muscle-to-cavity area ratio, left ventricular sphericity, ejection fraction, and degree of ischemic mitral regurgitation, as determined by means of quantitative echocardiography, were assessed before infarction and at 2, 5, and 8 weeks after infarction. All infarcts resulted in significant postinfarction remodeling and decreased ejection fraction. Anteroapical infarcts lead to left ventricular aneurysms. Only posterobasal infarcts caused severe and progressive ischemic mitral regurgitation. Remodeling because of posterobasal infarcts was not more severe than that caused by infarcts at other locations. Furthermore, prophylactic annuloplasty prevented the development of mitral regurgitation after posterobasal infarction but had no effect on remodeling. The extent of postinfarction remodeling is determined on the basis of infarct size and location. The development of ischemic mitral regurgitation might not contribute significantly to adverse remodeling. Ischemic mitral regurgitation is likely a manifestation rather than an important impetus for postinfarction remodeling.

  11. Passive ventricular remodeling in cardiac disease: Focus on heterogeneity

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    Elise L Kessler

    2014-12-01

    Full Text Available Passive ventricular remodeling is defined by the process of molecular ventricular adaptation to different forms of cardiac pathophysiology. It includes changes in tissue architecture, such as hypertrophy, fiber disarray, alterations in cell size and fibrosis. Besides that, it also includes molecular remodeling of gap junctions, especially those composed by Connexin43 proteins (Cx43 in the ventricles that affect cell-to-cell propagation of the electrical impulse, and changes in the sodium channels that modify excitability. All those alterations appear mainly in a heterogeneous manner, creating irregular and inhomogeneous electrical and mechanical coupling throughout the heart. This can predispose to reentry arrhythmias and adds to a further deterioration into heart failure. In this review, passive ventricular remodeling is described in Hypertrophic Cardiomyopathy (HCM, Dilated Cardiomyopathy (DCM, Ischemic Cardiomyopathy (ICM, and Arrhythmogenic Cardiomyopathy (ACM, with a main focus on the heterogeneity of those alterations mentioned above.

  12. Computer simulation of ECG manifestations of left ventricular electrical remodeling.

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    Bacharova, Ljuba; Szathmary, Vavrinec; Potse, Mark; Mateasik, Anton

    2012-01-01

    An increased QRS voltage is considered to be specific for the electrocardiogram (ECG) diagnosis of left ventricular hypertrophy (LVH). However, the QRS-complex patterns in patients with LVH cover a broader spectrum: increased QRS voltage, prolonged QRS duration, left axis deviation, and left anterior fascicular block- and left bundle branch block-like patterns, as well as pseudo-normal QRS patterns. The classical interpretation of the QRS patterns in LVH relates these changes to increased left ventricular mass (LVM) per se, while tending to neglect the modified active and passive electrical properties of the myocardium. However, it has been well documented that both active and passive electrical properties in LVH are altered. Using computer simulations, we have shown that an increased LVM is not the only determinant of QRS complex changes in LVH, as these changes could also be produced without changing the left ventricular mass, implying that these QRS patterns can be present in patients before their LVM exceeds the arbitrary upper normal limits. Our results link the experimental evidence on electrical remodeling with clinical interpretation of ECG changes in patients with LVH and stress the necessity of a complex interpretation of the QRS patterns considering both spatial and nonspatial determinants in terms of the spatial angle theory. We assume that hypertrophic electrical remodeling in combination with changes in left ventricular size and shape explains the variety of ECG patterns as well as the discrepancies between ECG and left ventricular mass. Copyright © 2012 Elsevier Inc. All rights reserved.

  13. Effect of paroxetine on left ventricular remodeling in an in vivo rat model of myocardial infarction.

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    Lassen, Thomas Ravn; Nielsen, Jan Møller; Johnsen, Jacob; Ringgaard, Steffen; Bøtker, Hans Erik; Kristiansen, Steen Buus

    2017-05-01

    Left ventricular (LV) remodeling following a myocardial infarction (MI) involves formation of reactive oxygen species (ROS). Paroxetine, a selective serotonin reuptake inhibitor, has an antioxidant effect in the vascular wall. We investigated whether paroxetine reduces myocardial ROS formation and LV remodeling following a MI. In a total of 32 Wistar rats, MI was induced by a 30-min ligation of the left anterior descending artery followed by 7- or 28-day reperfusion. During the 28 days of reperfusion, LV remodeling was evaluated by magnetic resonance imaging (MRI) and echocardiography (n = 20). After 28 days of reperfusion, the susceptibility to ventricular tachycardia was evaluated prior to sacrifice and histological assessment of myocyte cross-sectional area, fibrosis, and presence of myofibroblasts. Myocardial ROS formation was measured with dihydroethidium after 7 days of reperfusion in separate groups (n = 12). Diastolic LV volume, evaluated by MRI (417 ± 60 vs. 511 ± 64 µL, p paroxetine group than in controls. Furthermore, myocyte cross-sectional area was reduced in the paroxetine group compared with controls (277 ± 26 vs. 354 ± 23 mm(3), p paroxetine reduced the susceptibility to ventricular tachycardia (induced in 2/11 vs. 6/8 rats, p Paroxetine treatment following MI decreases LV remodeling and susceptibility to arrhythmias, probably by reducing ROS formation.

  14. Left ventricular failure produces profound lung remodeling and pulmonary hypertension in mice: heart failure causes severe lung disease.

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    Chen, Yingjie; Guo, Haipeng; Xu, Dachun; Xu, Xin; Wang, Huan; Hu, Xinli; Lu, Zhongbing; Kwak, Dongmin; Xu, Yawei; Gunther, Roland; Huo, Yuqing; Weir, E Kenneth

    2012-06-01

    Chronic left ventricular failure causes pulmonary congestion with increased lung weight and type 2 pulmonary hypertension. Understanding the molecular mechanisms for type 2 pulmonary hypertension and the development of novel treatments for this condition requires a robust experimental animal model and a good understanding of the nature of the resultant pulmonary remodeling. Here we demonstrate that chronic transverse aortic constriction causes massive pulmonary fibrosis and remodeling, as well as type 2 pulmonary hypertension, in mice. Thus, aortic constriction-induced left ventricular dysfunction and increased left ventricular end-diastolic pressure are associated with a ≤5.3-fold increase in lung wet weight and dry weight, pulmonary hypertension, and right ventricular hypertrophy. Interestingly, the aortic constriction-induced increase in lung weight was not associated with pulmonary edema but resulted from profound pulmonary remodeling with a dramatic increase in the percentage of fully muscularized lung vessels, marked vascular and lung fibrosis, myofibroblast proliferation, and leukocyte infiltration. The aortic constriction-induced left ventricular dysfunction was also associated with right ventricular hypertrophy, increased right ventricular end-diastolic pressure, and right atrial hypertrophy. The massive lung fibrosis, leukocyte infiltration, and pulmonary hypertension in mice after transverse aortic constriction clearly indicate that congestive heart failure also causes severe lung disease. The lung fibrosis and leukocyte infiltration may be important mechanisms in the poor clinical outcome in patients with end-stage heart failure. Thus, the effective treatment of left ventricular failure may require additional efforts to reduce lung fibrosis and the inflammatory response.

  15. [Cardiac dyssynchrony correlates with left ventricular remodeling after myocardial Infarction].

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    McNab, Paul; Castro, Pablo; Gabrielli, Luigi; Verdejo, Hugo; Quintana, Juan Carlos; Rodríguez, José A; Corbalán, Ramón

    2009-11-01

    Cardiac dyssynchrony is common in advanced heart failure (HF), but the changes in cardiac synchrony after myocardial infarction (MI) have not been adequately descríbed. To study the relationship between cardiac synchrony and left ventricular remodeling after acute myocardial infarction. Forty nine patients aged 59+/-10 years (77% men) with a first episode of a ST segment elevation MI, were studied. Scintigraphic left ventricular function and synchrony analyses were performed at baseline and after a six months follow-up. Determinations were compared with 33 healthy subjects. At baseline, patients with MIhad a decreased left ventricular ejection fraction (LVEF) and significant dyssynchrony, when compared with controls. LVEF was 36.4%+/-10%, left ventricular end-diastolic volume (LVEDV) 127+/-38 mL, interventricular delay (IEV) 29+/-35 miliseconds (ms), and intraventricular delay (IAV), 234+/-89 ms. After 6 months, LVEF significantly improved (38%+/-10%, p =0.042) without significant changes in LVEDV (129+/-32 mL, p =0.97), IEV (24+/-17, p =0.96) or IAV (231+/-97, p =0.34). At baseline there were significant correlations between IAV and LVEF, and between IAV and LVEDV (r =0.48, p =0.001 and r =0.41, p =0.004, respectively). These correlations remained significant after 6 months. There was a positive correlation between IAV and LVEDV changes at six months (r =0.403, p =0.04). The development of cardiac dyssynchrony correlates with adverse left ventricular remodeling after MI .

  16. Blockade of KCa3.1 Attenuates Left Ventricular Remodeling after Experimental Myocardial Infarction

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    Chen-Hui Ju

    2015-07-01

    Full Text Available Background/Aims: After myocardial infarction (MI, cardiac fibrosis greatly contributes to left ventricular remodeling and heart failure. The intermediate-conductance calcium-activated potassium Channel (KCa3.1 has been recently proposed as an attractive target of fibrosis. The present study aimed to detect the effects of KCa3.1 blockade on ventricular remodeling following MI and its potential mechanisms. Methods: Myocardial expression of KCa3.1 was initially measured in a mouse MI model by Western blot and real time-polymerase chain reaction. Then after treatment with TRAM-34, a highly selective KCa3.1 blocker, heart function and fibrosis were evaluated by echocardiography, histology and immunohistochemistry. Furthermore, the role of KCa3.1 in neonatal mouse cardiac fibroblasts (CFs stimulated by angiotensin II (Ang II was tested. Results: Myocardium expressed high level of KCa3.1 after MI. Pharmacological blockade of KCa3.1 channel improved heart function and reduced ventricular dilation and fibrosis. Besides, a lower prevalence of myofibroblasts was found in TRAM-34 treatment group. In vitro studies KCa3.1 was up regulated in CFs induced by Ang II and suppressed by its blocker.KCa3.1 pharmacological blockade attenuated CFs proliferation, differentiation and profibrogenic genes expression and may regulating through AKT and ERK1/2 pathways. Conclusion: Blockade of KCa3.1 is able to attenuate ventricular remodeling after MI through inhibiting the pro-fibrotic effects of CFs.

  17. Pattern and degree of left ventricular remodeling following a tailored surgical approach for hypertrophic obstructive cardiomyopathy

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    Ismail El-Hamamsy

    2012-07-01

    Full Text Available Background The role of a tailored surgical approach for hypertrophic cardiomyopathy (HCM on regional ventricular remodelling remains unknown. The aims of this study were to evaluate the pattern, extent and functional impact of regional ventricular remodelling after a tailored surgical approach. Conclusion Following a tailored surgical relief of outflow obstruction for HCM, there is a marked regional reverse LV remodelling. These changes could have a significant impact on overall ventricular dynamics and function.

  18. [Impact of chronic Chlamydia pneumoniae infection on left ventricular remodeling after myocardial infarction].

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    Marcinkowski, Marcin; Czarnecka, Danuta; Jastrzebski, Marek; Fedak, Danuta; Kawecka-Jaszcz, Kalina

    2006-01-01

    Postmyocardial infarction left ventricular remodeling is modified by inflammatory processes and structural changes in the myocardium. Chlamydia pneumoniae (Chp) causes chronic myocyte infection, affects apoptosis and TNF-alpha production, and may induce cross reactivity with alpha myosin. This is the way in which this intracellular pathogen may modulate remodeling on the cellular and organ level. The study was conducted in 101 patients with a first myocardial infarction in whom we evaluated the serological features of Chp infection using the ELISA method and echocardiographic left ventricular volume at 10 days and 10 weeks after the infarction. Patients with chronic Chp infection had a tendency toward higher end-diastolic volume at 10 weeks after the infarction (123 +/- 32.9 ml vs. 134 +/- 34.7 ml, p = 0.09). In order to better define this relationship we used ROC analysis and measured levels of antibodies: IgG = 117 EIU and IgA = 15.6 EIU by which we divided the patients into two subgroups. Those with IgG > or = 117 EIU and IgA > or = 15.6 EIU belong to the subgroup with chronic and active Chp infection. These patients had larger left ventricular end-diastolic volumes (155.8 vs. 123.1 ml, p = 0.0005) and end-systolic volumes (77.4 vs. 59.5 ml, p = 0.006) at 10 weeks after the infarction. Both subgroups were similar with respect to age, gender, history of arterial hypertension, systolic and diastolic blood pressure values, infarct site, reperfusion, infarct size, left ventricular ejection fraction and left ventricular contractility index. Type of reperfusion therapy and pharmacological treatment at 10 days and at 10 weeks did not differ, either. Chronic Chlamydia pneumonie infection modifies the course of left ventricular remodeling.

  19. Left ventricular remodeling and torsion dynamics in hypertensive patients.

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    Cameli, Matteo; Lisi, Matteo; Righini, Francesca Maria; Massoni, Alberto; Mondillo, Sergio

    2013-01-01

    Left ventricular (LV) torsion is a fundamental component of wall motion and plays an important role to optimize ventricular ejection fraction. The aim of our study was to calculate by speckle tracking echocardiography LV twist angle in patients with hypertension and LV remodeling, analyzing torsional indices in all patterns of hypertrophy, in comparison to torsional dynamics of age-matched healthy subjects. Hypertensive patients (n = 202) were divided in three groups, patients with concentric remodeling (n = 70), concentric hypertrophy (n = 68) and eccentric hypertrophy (n = 64), in relation to the echocardiographic measurements of relative wall thickness and LV mass, analyzing their torsional patterns by speckle tracking in comparison to age-matched control group. Compared to healthy controls, LV twist angle was increased in patients with hypertension and concentric remodeling (15.2° ± 1.9° vs. 11.0° ± 1.6°; p < 0.001), reaching the highest value in patients with concentric hypertrophy (19.4° ± 2.6°); instead LV twist angle presented depressed in the group of patients that presented eccentric hypertrophy (5.0° ± 1.1°). Regarding LV untwisting rate, it was higher in the concentric remodeling and concentric hypertrophy groups (-123.1°/s ± 12.1°/s and -145.1°/s ± 15.5°/s, respectively) in comparison with the controls (-90.0°/s ± 10.1°/s; p < 0.0001 for both). Instead, lower values of LV untwisting rate were observed in the eccentric remodeling group (-81.6°/s ± 8.1°/s), not significantly different to controls' values (p = 0.09). Enhanced LV twist angle appears to be a compensatory mechanism in hypertensive patients during the earlier stages of concentric remodeling and concentric hypertrophy; this hyper-torsion is inevitably loss in the more advanced stage of eccentric hypertrophy.

  20. Electrocardiographic evidence of ventricular repolarization remodelling during atrial fibrillation.

    Science.gov (United States)

    Tan, Hanno L; Smits, Jeroen P P; Loef, Arjan; Tanck, Michael W T; Hardziyenka, Maxim; Campian, Maria E

    2008-01-01

    Some atrial fibrillation (AF) patients develop excessive QTc prolongation and torsade de pointes when they take QTc-prolonging antiarrhythmic drugs (class IA/III) immediately after termination of AF. We hypothesized that this is caused by changes in ventricular repolarization during AF. We aimed to establish whether such 'ventricular repolarization remodelling' occurs. We studied all patients who visited our cardiac emergency room with AF and converted to sinus rhythm (SR) in a 30 months' period. We defined four groups: (i) no antiarrhythmic drugs, electrical cardioversion (n = 30), (ii) no antiarrhythmic drugs, spontaneous AF termination (n = 19), (iii) antiarrhythmic drugs, electrical cardioversion (n = 29), and (iv) antiarrhythmic drugs, spontaneous AF termination (n = 9). We studied QTc duration at SR before AF (SR(baseline)), immediately after termination of AF (SR(postAF)), and at follow-up (SR(followup): > or =7 days after SR(postAF)). Moreover, we studied determinants of QTc prolongation at SR(postAF). We found that, in all groups, QTc at SR(postAF) was significantly and transiently prolonged compared with SR(baseline). Although of limited magnitude on average (approximately 5%), the increase was substantial (approximately 15%) in some individuals. The only independent predictor of the magnitude of QTc prolongation was QTc duration at SR(baseline); this relation had a negative correlation. AF causes ventricular repolarization remodelling, resulting in QTc prolongation. QTc prolongation is substantial in some patients and may render these patients vulnerable to pro-arrhythmia from class IA/III antiarrhythmic drugs immediately after termination of AF.

  1. Atorvastatin Improves Ventricular Remodeling after Myocardial Infarction by Interfering with Collagen Metabolism.

    Science.gov (United States)

    Reichert, Karla; Pereira do Carmo, Helison Rafael; Galluce Torina, Anali; Diógenes de Carvalho, Daniela; Carvalho Sposito, Andrei; de Souza Vilarinho, Karlos Alexandre; da Mota Silveira-Filho, Lindemberg; Martins de Oliveira, Pedro Paulo; Petrucci, Orlando

    2016-01-01

    Therapeutic strategies that modulate ventricular remodeling can be useful after acute myocardial infarction (MI). In particular, statins may exert effects on molecular pathways involved in collagen metabolism. The aim of this study was to determine whether treatment with atorvastatin for 4 weeks would lead to changes in collagen metabolism and ventricular remodeling in a rat model of MI. Male Wistar rats were used in this study. MI was induced in rats by ligation of the left anterior descending coronary artery (LAD). Animals were randomized into three groups, according to treatment: sham surgery without LAD ligation (sham group, n = 14), LAD ligation followed by 10mg atorvastatin/kg/day for 4 weeks (atorvastatin group, n = 24), or LAD ligation followed by saline solution for 4 weeks (control group, n = 27). After 4 weeks, hemodynamic characteristics were obtained by a pressure-volume catheter. Hearts were removed, and the left ventricles were subjected to histologic analysis of the extents of fibrosis and collagen deposition, as well as the myocyte cross-sectional area. Expression levels of mediators involved in collagen metabolism and inflammation were also assessed. End-diastolic volume, fibrotic content, and myocyte cross-sectional area were significantly reduced in the atorvastatin compared to the control group. Atorvastatin modulated expression levels of proteins related to collagen metabolism, including MMP1, TIMP1, COL I, PCPE, and SPARC, in remote infarct regions. Atorvastatin had anti-inflammatory effects, as indicated by lower expression levels of TLR4, IL-1, and NF-kB p50. Treatment with atorvastatin for 4 weeks was able to attenuate ventricular dysfunction, fibrosis, and left ventricular hypertrophy after MI in rats, perhaps in part through effects on collagen metabolism and inflammation. Atorvastatin may be useful for limiting ventricular remodeling after myocardial ischemic events.

  2. Hydroxysafflor yellow A (HSYA) attenuates hypoxic pulmonary arterial remodelling and reverses right ventricular hypertrophy in rats.

    Science.gov (United States)

    Li, Lei; Dong, Pengda; Hou, Congjia; Cao, Fangyuan; Sun, Shouli; He, Fa; Song, Yanping; Li, Sen; Bai, Yuhua; Zhu, Daling

    2016-06-20

    Carthamus tinctorius L. is a traditional herbal medicine native to China with properties of promoting blood circulation and removing blood stasis, which is used for the treatment of cerebrovascular and cardiovascular diseases. Hydroxysafflor yellow A (HSYA) is the main constituent isolated from the flower of Carthamus tinctorius L. which is used as a marker substance in the quality control of Carthamus tinctorius L. in Chinese Pharmacopeia. This study is to investigate the hypertension attenuating effect of HSYA on hypoxia-induced pulmonary artery hypertension model rats, and the possible mechanism. The animal models were made by treating adult male Wistar rats (of the same age with the same weight of 200±25g) under hypoxia 24h per day for 9 days with or without administration of HSYA. The pulmonary arterial pressure of rats was measured after anesthetization; The right ventricular hypotrophy was evaluated by the right ventricular hypotrophy index (RVHI=[RV/(LV+S)]) as well as histomorphology assay with Hematoxylin and Eosin (HE) staining; The reducing of pulmonary artery remodelling was evaluated by histomorphology assay with HE staining; The proliferation of pulmonary artery smooth muscle cells (PASMCs) was evaluated by immunohistochemistry assays (PCNA and Ki67) and MTT assay. Cell cycle analysis and Weston-blot analysis were also performed in the study. HSYA reduced the mean right ventricular systolic pressure (RVSP) of rats with hypoxic pulmonary arterial hypertension (HPH) in a manner of concentration dependency. It significantly inhibited the PASMCs proliferation and attenuated the remodelling of the pulmonary artery and right ventricular hypertrophy. These findings suggested that HSYA protected against hypoxic induced pulmonary hypertension by reversing the remodelling of the pulmonary artery through inhibiting the proliferation and hypertrophy of PASMCs. This is in accordance with our previous finding that HSYA protects against the pulmonary artery

  3. Off-pump epicardial ventricular reconstruction restores left ventricular twist and reverses remodeling in an ovine anteroapical aneurysm model.

    Science.gov (United States)

    Cheng, Yanping; Aboodi, Michael S; Annest, Lon S; Wechsler, Andrew S; Kaluza, Greg L; Granada, Juan F; Yi, Geng-Hua

    2014-07-01

    The loss of normal apical rotation is associated with left ventricular (LV) remodeling and systolic dysfunction in patients with congestive heart failure after myocardial infarction. The objective of the present study was to evaluate the effect of epicardial ventricular reconstruction, an off-pump, less-invasive surgical reshaping technique, on myocardial strain, LV twist, and the potential alteration of myocardial fiber orientation in an ovine model of LV anteroapical aneurysm. LV anteroapical myocardial infarction was induced by coil embolization of the left anterior descending artery. Eight weeks after occlusion, epicardial ventricular reconstruction was performed using left thoracotomy under fluoroscopic guidance in 8 sheep to completely exclude the scar. The peak systolic longitudinal/circumferential strains and LV twist were evaluated using speckle tracking echocardiography before (baseline), after device implantation, and at 6 weeks of follow-up. Epicardial ventricular reconstruction was completed in all sheep without any complications. Immediately after device implantation, LV twist significantly increased (4.18 ± 1.40 vs baseline 1.97 ± 1.92; P = .02). The ejection fraction had increased 17% and LV end-systolic volume had decreased 40%. The global longitudinal strain increased from -5.3% to -9.1% (P anteroapical aneurysm model. Copyright © 2014 The American Association for Thoracic Surgery. Published by Mosby, Inc. All rights reserved.

  4. Cardiac fibroblast GSK-3β regulates ventricular remodeling and dysfunction in ischemic heart

    Science.gov (United States)

    Lal, Hind; Ahmad, Firdos; Zhou, Jibin; Yu, Justine E.; Vagnozzi, Ronald J.; Guo, Yuanjun; Yu, Daohai; Tsai, Emily J.; Woodgett, James; Gao, Erhe; Force, Thomas

    2014-01-01

    Background Myocardial infarction-induced remodeling includes chamber dilatation, contractile dysfunction, and fibrosis. Of these, fibrosis is the least understood. Following MI, activated cardiac fibroblasts (CFs) deposit extracellular matrix. Current therapies to prevent fibrosis are inadequate and new molecular targets are needed. Methods and Results Herein we report that GSK-3β is phosphorylated (inhibited) in fibrotic tissues from ischemic human and mouse heart. Using two fibroblast-specific GSK-3β knockout mouse models, we show that deletion of GSK-3β in CFs leads to fibrogenesis, left ventricular dysfunction and excessive scarring in the ischemic heart. Deletion of GSK-3β induces a pro-fibrotic myofibroblast phenotype in isolated CFs, in post-MI hearts, and in MEFs deleted for GSK-3β. Mechanistically, GSK-3β inhibits pro-fibrotic TGF-β1-SMAD-3 signaling via interactions with SMAD-3. Moreover, deletion of GSK-3β resulted in the suppression of SMAD-3 transcriptional activity. This pathway is central to the pathology since a small molecule inhibitor of SMAD-3 largely prevented fibrosis and limited LV remodeling. Conclusion These studies support targeting GSK-3β in myocardial fibrotic disorders and establish critical roles of CFs in remodeling and ventricular dysfunction. PMID:24899689

  5. Blood PGC-1α Concentration Predicts Myocardial Salvage and Ventricular Remodeling After ST-segment Elevation Acute Myocardial Infarction.

    Science.gov (United States)

    Fabregat-Andrés, Óscar; Ridocci-Soriano, Francisco; Estornell-Erill, Jordi; Corbí-Pascual, Miguel; Valle-Muñoz, Alfonso; Berenguer-Jofresa, Alberto; Barrabés, José A; Mata, Manuel; Monsalve, María

    2015-05-01

    Peroxisome proliferator-activated receptor gamma coactivator 1α (PGC-1α) is a metabolic regulator induced during ischemia that prevents cardiac remodeling in animal models. The activity of PGC-1α can be estimated in patients with ST-segment elevation acute myocardial infarction. The aim of the present study was to evaluate the value of blood PGC-1α levels in predicting the extent of necrosis and ventricular remodeling after infarction. In this prospective study of 31 patients with a first myocardial infarction in an anterior location and successful reperfusion, PGC-1α expression in peripheral blood on admission and at 72 hours was correlated with myocardial injury, ventricular volume, and systolic function at 6 months. Edema and myocardial necrosis were estimated using cardiac magnetic resonance imaging during the first week. At 6 months, infarct size and ventricular remodeling, defined as an increase > 10% of the left ventricular end-diastolic volume, was evaluated by follow-up magnetic resonance imaging. Myocardial salvage was defined as the difference between the edema and necrosis areas. Greater myocardial salvage was seen in patients with detectable PGC-1α levels at admission (mean [standard deviation (SD)], 18.3% [5.3%] vs 4.5% [3.9%]; P = .04). Induction of PGC-1α at 72 hours correlated with greater ventricular remodeling (change in left ventricular end-diastolic volume at 6 months, 29.7% [11.2%] vs 1.2% [5.8%]; P = .04). Baseline PGC-1α expression and an attenuated systemic response after acute myocardial infarction are associated with greater myocardial salvage and predict less ventricular remodeling. Copyright © 2014 Sociedad Española de Cardiología. Published by Elsevier España, S.L.U. All rights reserved.

  6. Integrated Mechanisms of CaMKII-dependent ventricular remodeling

    Directory of Open Access Journals (Sweden)

    Michael M Kreusser

    2014-03-01

    Full Text Available CaMKII has been shown to be activated during different cardiac pathological processes, and CaMKII-dependent mechanisms contribute to pathological cardiac remodeling, cardiac arrhythmias and contractile dysfunction during heart failure. Activation of CaMKII during cardiac stress results in a broad number of biological effects such as, on the one hand, acute effects due to phosphorylation of distinct cellular proteins as ion channels and calcium handling proteins and, on the other hand, integrative mechanisms by changing gene expression. This review focuses on transcriptional and epigenetic effects of CaMKII activation during chronic cardiac remodeling. Multiple mechanisms have been described how CaMKII mediates changes in cardiac gene expression. CaMKII has been shown to directly phosphorylate components of the cardiac gene regulation machinery. CaMKII phosphorylates several transcription factors such as CREB that induces the activation of specific gene programs. CaMKII activates transcriptional regulators also indirectly by phosphorylating histone deacetylases, especially HDAC4, which in turn inhibits transcription factors that drive cardiac hypertrophy, fibrosis and dysfunction. Recent studies demonstrate that CaMKII also phosphorylate directly histones, which may contribute to changes in gene expression. These findings of CaMKII-dependent gene regulation during cardiac remodeling processes suggest novel strategies for CaMKII-dependent transcriptional or epigenetic therapies to control cardiac gene expression and function. Manipulation of CaMKII-dependent signaling pathways in the settings of pathological cardiac growth, remodeling, and heart failure represents an auspicious therapeutic approach.

  7. Surgical ventricular remodeling: should we STICH or not?

    Science.gov (United States)

    Rao, Vivek

    2017-11-01

    The surgical management of patients with ischemic cardiomyopathy, especially those with left ventricular ejection fractions less than 20% has historically been controversial. The original trials of surgical revascularization versus medical therapy intentionally excluded those patients with an ejection fraction less than 35%. The significant advances in medical therapy for heart failure over the past 30 years (β-blockade, angiotensin converting enzyme inhibitors, internal cardiac defibrillator and so on) also mandated a reevaluation of the potential benefits of surgical revascularization in this high-risk subset. The purpose of this review is to examine the data from the Surgical Treatment for Ischemic Heart Failure (STICH) trial, initially reported in 2009 and 2011. Recent reports published in 2016 have now clearly defined the role of surgery over medical therapy for these patients. Furthermore, although the benefits of surgical ventricular reconstruction were once questioned by the results of STICH, further analyses identify that an appropriately selected patient who undergoes a technically adequate operation will derive benefit from surgical ventricular reconstruction. The conclusions from the various substudies examining STICH trial data now indicate that in surgical candidates with graftable coronary artery disease, surgical revascularization provides a reduction in overall mortality, cardiovascular deaths and hospitalizations, independent of symptoms, baseline left ventricular size or function and surprisingly, regardless of any viability or evidence of inducible ischemia.

  8. Prevalence and predictors of ventricular remodeling after anterior myocardial infarction in the era of modern medical therapy.

    Science.gov (United States)

    Farah, Elaine; Cogni, Ana Lucia; Minicucci, Marcos F; Azevedo, Paula S; Okoshi, Katashi; Matsubara, Beatriz B; Zanati, Silméia G; Haggeman, Rodrigo; Paiva, Sergio A R; Zornoff, Leonardo A M

    2012-05-01

    The consequences of aggressive therapy following a myocardial infarction (MI) on ventricular remodeling are not well established. Thus, the objective of this study was to analyze the prevalence, clinical characteristics, and predictors of left ventricular remodeling in the era of modern medical therapy. Clinical characteristics and echocardiographic data were analyzed in 66 consecutive patients with anterior infarction at admission and at 6-month follow-up. Ventricular remodeling was defined as an increase of 10% in ventricular end-systolic or end-diastolic diameter. In our study, 58% of patients presented with ventricular remodeling. Patients with remodeling possessed higher total plasma creatine kinase (CPK), MB-fraction (CPK-MB), heart rate, heart failure, shortness of breath, and reperfusion therapy than patients without remodeling. In contrast, patients with remodeling had a smaller ejection fraction, E-Wave deceleration time (EDT), and early (E' Wave) and late (A' Wave) diastolic mitral annulus velocity (average of septal and lateral walls), but a higher E/E' than patients without remodeling. Patients with remodeling used more diuretics, digoxin, oral anticoagulants and aldosterone antagonists than patients without remodeling. In the multivariate analyses, only E' Wave was an independent predictor of ventricular remodeling. Each 1 unit increase in the E' Wave was associated with a 59% increased odds of ventricular remodeling. In patients with anterior MI, despite contemporary treatment, ventricular remodeling is still a common event. In addition, diastolic function can have an important role as a predictor of remodeling in this scenario.

  9. Dilation and Hypertrophy: A Cell-Based Continuum Mechanics Approach Towards Ventricular Growth and Remodeling

    Science.gov (United States)

    Ulerich, J.; Göktepe, S.; Kuhl, E.

    This manuscript presents a continuum approach towards cardiac growth and remodeling that is capable to predict chronic maladaptation of the heart in response to changes in mechanical loading. It is based on the multiplicative decomposition of the deformation gradient into and elastic and a growth part. Motivated by morphological changes in cardiomyocyte geometry, we introduce an anisotropic growth tensor that can capture both hypertrophic wall thickening and ventricular dilation within one generic concept. In agreement with clinical observations, we propose wall thickening to be a stress-driven phenomenon whereas dilation is introduced as a strain-driven process. The features of the proposed approach are illustrated in terms of the adaptation of thin heart slices and in terms overload-induced dilation in a generic bi-ventricular heart model.

  10. Electrical remodeling and atrial dilation during atrial tachycardia are influenced by ventricular rate : Role of developing tachycardiomyopathy

    NARCIS (Netherlands)

    Schoonderwoerd, BA; Van Gelder, IC; Van Veldhuisen, DJ; Tieleman, RG; Grandjean, JG; Bel, KJ; Allessie, MA; Crijns, HJGM

    2001-01-01

    Atrial Remodeling in Tachycardiomyopathy. Introduction: Atrial fibrillation (AF) and congestive heart failure (CHF) are two clinical entities that often coincide. Our aim was to establish the influence of concomitant high ventricular rate and consequent development of CHF on electrical remodeling

  11. The relation between bradycardic dyssynchronous ventricular activation, remodeling and arrhythmogenesis

    NARCIS (Netherlands)

    Dunnink, A

    2016-01-01

    Sudden cardiac death (SCD) is a common cause of death and its incidence continues to rise. The occurrence of SCD is mainly due to development of malignant ventricular arrhythmias such as ventricular tachycardia or ventricular fibrillation. The underlying cause of SCD is almost always a complex

  12. Right ventricular relative wall thickness as a predictor of outcomes and of right ventricular reverse remodeling for patients with pulmonary hypertension

    OpenAIRE

    Sano, Hiroyuki; Tanaka, Hidekazu; Motoji, Yoshiki; Fukuda, Yuko; Mochizuki, Yasuhide; Hatani, Yutaka; Matsuzoe, Hiroki; Hatazawa, Keiko; Shimoura, Hiroyuki; Ooka, Junichi; Ryo-Koriyama, Keiko; Nakayama, Kazuhiko; Matsumoto, Kensuke; Emoto, Noriaki; Hirata, Ken-ichi

    2017-01-01

    Mid-term right ventricular (RV) reverse remodeling after treatment in patients with pulmonary hypertension (PH) is associated with long-term outcome as well as baseline RV remodeling. However, baseline factors influencing mid-term RV reverse remodeling after treatment and its prognostic capability remain unclear. We studied 54 PH patients. Mid-term RV remodeling was assessed in terms of the RV area, which was traced planimetrically at the end-systole (RVESA). RV reverse remodeling was defined...

  13. Pro- and anti-inflammatory cytokines in post-infarction left ventricular remodeling.

    Science.gov (United States)

    Zarrouk-Mahjoub, S; Zaghdoudi, M; Amira, Z; Chebi, H; Khabouchi, N; Finsterer, J; Mechmeche, R; Ghazouani, E

    2016-10-15

    Acute myocardial infarction (MI) leads to molecular, structural, geometric and functional changes in the heart during a process known as ventricular remodeling. Myocardial infarction is followed by an inflammatory response in which pro- and anti-inflammatory cytokines play a crucial role, particularly in left ventricular remodeling. This study aimed at evaluating serum concentrations of interleukin-8 (IL8), tumor-necrosis-factor-alpha (TNFα) and interleukin-10 (IL10), pro- and anti-inflammatory cytokines, and at correlating them with left ventricular remodeling as assessed by echocardiographic parameters. In a case-control study 30 MI patients were compared with 30 healthy controls. Serum concentrations of IL8, TNFα and IL10 were measured on day 2 and day 30 post-MI by chemiluminescence immunoassay and correlated with echocardiographic parameters. There was an increase of IL8, and TNFα together with a decrease of IL10 at both time points. IL8 was negatively correlated with the left ventricular end-diastolic diameter (LVEDD) and positively with left ventricular systolic volume. IL10 was negatively correlated with LVEDD and left atrial volume 30days post-MI. The increase of pro-inflammatory cytokines TNFα and IL8 was accompanied by decreased anti-inflammatory IL10. This imbalance between pro- and anti-inflammatory cytokines might contribute to the progression of left ventricular remodeling and may lead to heart failure. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  14. Nicorandil prevents right ventricular remodeling by inhibiting apoptosis and lowering pressure overload in rats with pulmonary arterial hypertension.

    Directory of Open Access Journals (Sweden)

    Xiang-Rong Zuo

    Full Text Available BACKGROUND: Most of the deaths among patients with severe pulmonary arterial hypertension (PAH are caused by progressive right ventricular (RV pathological remodeling, dysfunction, and failure. Nicorandil can inhibit the development of PAH by reducing pulmonary artery pressure and RV hypertrophy. However, whether nicorandil can inhibit apoptosis in RV cardiomyocytes and prevent RV remodeling has been unclear. METHODOLOGY/PRINCIPAL FINDINGS: RV remodeling was induced in rats by intraperitoneal injection of monocrotaline (MCT. RV systolic pressure (RVSP was measured at the end of each week after MCT injection. Blood samples were drawn for brain natriuretic peptide (BNP ELISA analysis. The hearts were excised for histopathological, ultrastructural, immunohistochemical, and Western blotting analyses. The MCT-injected rats exhibited greater mortality and less weight gain and showed significantly increased RVSP and RV hypertrophy during the second week. These worsened during the third week. MCT injection for three weeks caused pathological RV remodeling, characterized by hypertrophy, fibrosis, dysfunction, and RV mitochondrial impairment, as indicated by increased levels of apoptosis. Nicorandil improved survival, weight gain, and RV function, ameliorated RV pressure overload, and prevented maladaptive RV remodeling in PAH rats. Nicorandil also reduced the number of apoptotic cardiomyocytes, with a concomitant increase in Bcl-2/Bax ratio. 5-hydroxydecanoate (5-HD reversed these beneficial effects of nicorandil in MCT-injected rats. CONCLUSIONS/SIGNIFICANCE: Nicorandil inhibits PAH-induced RV remodeling in rats not only by reducing RV pressure overload but also by inhibiting apoptosis in cardiomyocytes through the activation of mitochondrial ATP-sensitive K(+ (mitoK(ATP channels. The use of a mitoK(ATP channel opener such as nicorandil for PAH-associated RV remodeling and dysfunction may represent a new therapeutic strategy for the amelioration of RV

  15. Myocardial connective tissue growth factor (CCN2/CTGF attenuates left ventricular remodeling after myocardial infarction.

    Directory of Open Access Journals (Sweden)

    Jørgen Gravning

    Full Text Available AIMS: Myocardial CCN2/CTGF is induced in heart failure of various etiologies. However, its role in the pathophysiology of left ventricular (LV remodeling after myocardial infarction (MI remains unresolved. The current study explores the role of CTGF in infarct healing and LV remodeling in an animal model and in patients admitted for acute ST-elevation MI. METHODS AND RESULTS: Transgenic mice with cardiac-restricted overexpression of CTGF (Tg-CTGF and non-transgenic littermate controls (NLC were subjected to permanent ligation of the left anterior descending coronary artery. Despite similar infarct size (area of infarction relative to area at risk 24 hours after ligation of the coronary artery in Tg-CTGF and NLC mice, Tg-CTGF mice disclosed smaller area of scar tissue, smaller increase of cardiac hypertrophy, and less LV dilatation and deterioration of LV function 4 weeks after MI. Tg-CTGF mice also revealed substantially reduced mortality after MI. Remote/peri-infarct tissue of Tg-CTGF mice contained reduced numbers of leucocytes, macrophages, and cells undergoing apoptosis as compared with NLC mice. In a cohort of patients with acute ST-elevation MI (n = 42 admitted to hospital for percutaneous coronary intervention (PCI serum-CTGF levels (s-CTGF were monitored and related to infarct size and LV function assessed by cardiac MRI. Increase in s-CTGF levels after MI was associated with reduced infarct size and improved LV ejection fraction one year after MI, as well as attenuated levels of CRP and GDF-15. CONCLUSION: Increased myocardial CTGF activities after MI are associated with attenuation of LV remodeling and improved LV function mediated by attenuation of inflammatory responses and inhibition of apoptosis.

  16. Diabetes Mellitus Associates with Increased Right Ventricular Afterload and Remodeling in Pulmonary Arterial Hypertension.

    Science.gov (United States)

    Whitaker, Morgan E; Nair, Vineet; Sinari, Shripad; Dherange, Parinita; Natarajan, Balaji; Trutter, Lindsey; Brittain, Evan L; Hemnes, Anna R; Austin, Eric; Patel, Kumar; Black, Stephen M; Garcia, Joe G N; Yuan, Jason X; Vanderpool, Rebecca; Rischard, Franz; Makino, Ayako; Bedrick, Edward J; Desai, Ankit A

    2018-02-05

    Diabetes mellitus is associated with left ventricular hypertrophy and dysfunction. Parallel studies have also reported associations between diabetes mellitus and right ventricle dysfunction and reduced survival in patients with pulmonary arterial hypertension. However, the impact of diabetes mellitus on the pulmonary vasculature has not been well-characterized. We hypothesized that diabetes mellitus and hyperglycemia could specifically influence right ventricular afterload and remodeling in patients with Group I pulmonary arterial hypertension, providing a link to their known susceptibility to right ventricular dysfunction. Using an adjusted model for age, gender, pulmonary vascular resistance, and medication use, associations of fasting blood glucose, glycated hemoglobin, and the presence of diabetes mellitus were evaluated with markers of disease severity in 162 patients with pulmonary arterial hypertension. A surrogate measure of increased pulmonary artery stiffness, elevated pulmonary arterial elastance (P=0.012), along with reduced log(pulmonary artery capacitance) (P=0.006) were significantly associated with the presence of diabetes mellitus in patients with pulmonary arterial hypertension in a fully adjusted model. Similar associations between pulmonary arterial elastance and capacitance were noted with both fasting blood glucose and glycated hemoglobin. Furthermore, right ventricular wall thickness on echocardiography was greater in pulmonary arterial hypertension patients with diabetes, supporting the link between right ventricular remodeling and diabetes. Cumulatively, these data demonstrate that an increase in right ventricular afterload, beyond pulmonary vascular resistance alone, may influence right ventricular remodeling and provide a mechanistic link between the susceptibility to right ventricular dysfunction in patients with both diabetes mellitus and pulmonary arterial hypertension. Copyright © 2018. Published by Elsevier Inc.

  17. Electrocardiographic evidence of ventricular repolarization remodelling during atrial fibrillation

    NARCIS (Netherlands)

    Tan, Hanno L.; Smits, Jeroen P. P.; Loef, Arjan; Tanck, Michael W. T.; Hardziyenka, Maxim; Campian, Maria E.

    2008-01-01

    Aims Some atria[ fibrillation (AF) patients develop excessive QTc prolongation and torsade de pointes when they take QTc-prolonging antiarrhythmic drugs (class IA/III) immediately after termination of AF We hypothesized that this is caused by changes in ventricular repolarization during AF We aimed

  18. [Effect of Sapindus saponins on myocardial inflammation and left ventricular remodeling in spontaneously hypertensive rats].

    Science.gov (United States)

    Chen, Ming; Chen, Zhi-Wu; Long, Zi-Jiang; Liu, Jin-Lin; Bian, Hai; Wang, Ya-Juan; Wang, Liang

    2013-02-01

    To investigate the effect of Sapindus saponins on myocardial inflammation and left ventricular remodeling in spontaneously hypertensive rats. Forty 16-week-old spontaneously hypertensive rats were randomly divided into five groups, placebo as model group, captopril tablets (27 mg/kg) as positive control, low-dose Sapindus saponins (27 mg/kg), medium-dose (54 mg/ kg) and high-dose (108 mg/kg) groups. And another eight healthy Wistar-Kyoto strain (WKY) rats were used as the normal group. The animals were treated for eight weeks, and the detection indexes were as follows: (1) Calculated left ventricular mass index (LVMI); (2) Observed the morphological changes on left ventricular myocardial tissue by HE staining; (3) Observed the collagen distribution in left ventricular myocardial by Masson staining; (4) Detected the protein expression of TGF-beta1 by immunohistochemical assay. Sapindus saponins could effectively reverse the left ventricular hypertrophy phenomenon in SHR, lowered LVMI, inhibited the myocardial cell hypertrophy and hyperplasia of collagen fibers, and blocked the expression level of TGF-beta1 in myocardial when compared with the SHR model group, there were significant differences (P Sapindus saponins can reserve the left ventricular remodeling in pathological conditions, its possible mechanism may be related to the inhibition of myocardial tissue inflammation factor of TGF-beta1.

  19. Concentric left ventricular remodeling and aortic stiffness: a comparison of obesity and hypertension.

    Science.gov (United States)

    Rider, Oliver J; Nethononda, Richard; Petersen, Steffen E; Francis, Jane M; Byrne, James P; Leeson, Paul; Clarke, Kieran; Neubauer, Stefan

    2013-09-10

    Increased thoracic ascending aortic stiffness is thought to contribute to concentric left ventricular hypertrophy and increased mortality, a pattern seen in hypertension. As such, aortic stiffness and increased left ventricular mass are candidates by which obesity increases cardiovascular risk. However, obesity is characterized predominantly by increased abdominal aortic stiffness and with eccentric left ventricular hypertrophy. We aimed to establish whether or not, in addition to these changes, there is also an element of concentric remodeling in obesity that was predicted by ascending aortic stiffness. 301 subjects underwent cardiovascular magnetic resonance imaging to measure regional aortic distensibility and left ventricular morphology. To compare obesity with hypertension, subjects were separated into groups by hypertensive status and body mass index. In comparison to normotensive subjects, hypertension was linked with concentric remodeling (a 17% increase in left ventricular mass:volume ratio (LVM:VR), (pObesity, in the absence of hypertension, was associated with elevated left ventricular mass when compared to normal weight normotensive subjects (by 27%, pobesity was, however, not correlated with ascending aortic distensibility when adjusted for mean arterial pressure (R=-0.14,pobesity there is a concentric element of hypertrophy that, unlike in hypertension, is not linked to increased ascending aortic stiffness. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

  20. ZP123 reduces energy required for defibrillation by preventing connexin43 remodeling during prolonged ventricular fibrillation in swine.

    Science.gov (United States)

    Yi, Shao-lei; Zhong, Jing-quan; Zhang, Jing; Su, Guo-ying; Li, Jing-sha; Liu, Hong-zhen; Zhang, Yun

    2012-01-01

    In ventricular fibrillation, the uncoupling of gap junctions slows conduction velocity and increases action-potential dispersion, which slows and diminishes defibrillation. We studied how the peptide ZP123, a gap-junction enhancer, might lower defibrillation-energy requirements during ventricular fibrillation in live pigs. We randomly assigned 33 pigs into 3 groups: ZP123 (receiving a 1-µg/kg bolus and 10 µg/kg/hr of ZP123), control (receiving saline solution), and sham (undergoing a sham operation). After a 30-min administration of agents, ventricular fibrillation was induced and left untreated for 8 min. Biphasic defibrillation of 50 J was increased by 50-J increments as necessary. Defibrillation-energy requirements were defined as the lowest energy required to achieve defibrillation. Electrocardiographic values were obtained before and after the administration of agents. Western blot and immunofluorescence analyses were performed on ventricular myocardial samples. All but one pig survived. The ZP123 treatment did not alter electrocardiographic variables. In the ZP123 group, the average required defibrillation energy was lower than that in the control group (327.28±269.6 vs 610±192.64 J; P=0.015), and the cumulative percentage of successful defibrillation at upper energy levels was higher (Pdefibrillation-energy requirements by preventing connexin43 remodeling during prolonged ventricular fibrillation.

  1. Coronary Artery Remodeling in a Model of Left Ventricular Pressure Overload Is Influenced by Platelets and Inflammatory Cells

    Science.gov (United States)

    Yang, Fanmuyi; Dong, Anping; Mueller, Paul; Caicedo, Jessica; Sutton, Alyssa Moore; Odetunde, Juliana; Barrick, Cordelia J.; Klyachkin, Yuri M.; Abdel-Latif, Ahmed; Smyth, Susan S.

    2012-01-01

    Left ventricular hypertrophy (LVH) is usually accompanied by intensive interstitial and perivascular fibrosis, which may contribute to arrhythmogenic sudden cardiac death. The mechanisms underlying the development of cardiac fibrosis are incompletely understood. To investigate the role of perivascular inflammation in coronary artery remodeling and cardiac fibrosis during hypertrophic ventricular remodeling, we used a well-established mouse model of LVH (transverse aortic constriction [TAC]). Three days after pressure overload, macrophages and T lymphocytes accumulated around and along left coronary arteries in association with luminal platelet deposition. Consistent with these histological findings, cardiac expression of IL-10 was upregulated and in the systemic circulation, platelet white blood cell aggregates tended to be higher in TAC animals compared to sham controls. Since platelets can dynamically modulate perivascular inflammation, we investigated the impact of thrombocytopenia on the response to TAC. Immunodepletion of platelets decreased early perivascular T lymphocytes' accumulation and altered subsequent coronary artery remodeling. The contribution of lymphocytes were examined in Rag1−/− mice, which displayed significantly more intimal hyperplasia and perivascular fibrosis compared to wild-type mice following TAC. Collectively, our studies support a role of early perivascular accumulation of platelets and T lymphocytes in pressure overload-induced inflammation. PMID:22916095

  2. Left ventricular remodeling in swine after myocardial infarction: a transcriptional genomics approach.

    Science.gov (United States)

    Kuster, Diederik W D; Merkus, Daphne; Kremer, Andreas; van Ijcken, Wilfred F J; de Beer, Vincent J; Verhoeven, Adrie J M; Duncker, Dirk J

    2011-11-01

    Despite the apparent appropriateness of left ventricular (LV) remodeling following myocardial infarction (MI), it poses an independent risk factor for development of heart failure. There is a paucity of studies into the molecular mechanisms of LV remodeling in large animal species. We took an unbiased molecular approach to identify candidate transcription factors (TFs) mediating the genetic reprogramming involved in post-MI LV remodeling in swine. Left ventricular tissue was collected from remote, non-infarcted myocardium, 3 weeks after MI-induction or sham-surgery. Microarray analysis identified 285 upregulated and 278 downregulated genes (FDR two-fold (p two-fold. Five TFs were identified in both TFBS and protein/DNA array analyses, which showed matching changes for COUP-TFII and glucocorticoid receptor (GR) only. Treatment of swine with the GR antagonist mifepristone after MI reduced the post-MI increase in LV mass, but LV dilation remained unaffected. Thus, using an unbiased approach to study post-MI LV remodeling in a physiologically relevant large animal model, we identified COUP-TFII and GR as potential key mediators of post-MI remodeling.

  3. Preventive effect of yuzu and hesperidin on left ventricular remodeling and dysfunction in rat permanent left anterior descending coronary artery occlusion model.

    Science.gov (United States)

    Yu, Hye Yon; Ahn, Ji Hun; Park, Se Won; Jung, Yi-Sook

    2015-01-01

    Left ventricular (LV) remodeling, which includes ventricular dilatation and increased interstitial fibrosis after myocardial infarction (MI), is the critical process underlying the progression to heart failure. Therefore, a novel approach for preventing LV remodeling after MI is highly desirable. Yuzu is a citrus plant originating in East Asia, and has a number of cardioprotective properties such as hesperidin. However, no study has proved whether yuzu can prevent LV remodeling. The aim of this study was to determine the effects of yuzu on heart failure (HF) and its potential impact on the LV remodeling process after MI. Our in vivo study using the permanent left anterior descending coronary artery (LAD) occlusion model demonstrate that one week pre-treatment with yuzu or its major metabolite hesperidin before LAD occlusion significantly attenuated cardiac dysfunction, myocyte apoptosis and inflammation. Not only yuzu but also hesperidin inhibited caspase-3 activity, myeloperoxidase expression, α-smooth muscle actin expression, and matrix metalloproteinase-2 activity in a permanent LAD occlusion rat model. To our knowledge, our findings provide the first evidence that yuzu and hesperidin prevent MI-induced ventricular dysfunction and structural remodeling of myocardium.

  4. Preventive Effect of Yuzu and Hesperidin on Left Ventricular Remodeling and Dysfunction in Rat Permanent Left Anterior Descending Coronary Artery Occlusion Model

    Science.gov (United States)

    Yu, Hye Yon; Ahn, Ji Hun; Park, Se Won; Jung, Yi-Sook

    2015-01-01

    Left ventricular (LV) remodeling, which includes ventricular dilatation and increased interstitial fibrosis after myocardial infarction (MI), is the critical process underlying the progression to heart failure. Therefore, a novel approach for preventing LV remodeling after MI is highly desirable. Yuzu is a citrus plant originating in East Asia, and has a number of cardioprotective properties such as hesperidin. However, no study has proved whether yuzu can prevent LV remodeling. The aim of this study was to determine the effects of yuzu on heart failure (HF) and its potential impact on the LV remodeling process after MI. Our in vivo study using the permanent left anterior descending coronary artery (LAD) occlusion model demonstrate that one week pre-treatment with yuzu or its major metabolite hesperidin before LAD occlusion significantly attenuated cardiac dysfunction, myocyte apoptosis and inflammation. Not only yuzu but also hesperidin inhibited caspase-3 activity, myeloperoxidase expression, α-smooth muscle actin expression, and matrix metalloproteinase-2 activity in a permanent LAD occlusion rat model. To our knowledge, our findings provide the first evidence that yuzu and hesperidin prevent MI-induced ventricular dysfunction and structural remodeling of myocardium. PMID:25559243

  5. Magnetic Resonance Imaging in the Assessment of Ventricular Remodeling and Viability

    OpenAIRE

    Jerosch-Herold, Michael; Kwong, Raymond Y.

    2008-01-01

    Cardiovascular MRI has effectively become a reference standard for quantifying ventricular volumes and function and for measuring the myocardial scar burden after myocardial infarction. Imaging of late gadolinium enhancement and microvascular obstruction carries strong prognostic information for identifying patients who would benefit from anti-remodeling therapy. The combination of gadolinium enhancement, perfusion, and cine imaging should make MRI the modality of choice in the assessment of ...

  6. High dose aspirin and left ventricular remodeling after myocardial infarction: aspirin and myocardial infarction.

    Science.gov (United States)

    Adamek, Anna; Hu, Kai; Bayer, Barbara; Wagner, Helga; Ertl, Georg; Bauersachs, Johann; Frantz, Stefan

    2007-07-01

    Proinflammatory proteins like inflammatory cytokines are implicated in myocardial depression and left ventricular remodeling after myocardial infarction. High-dose aspirin inhibits cytokine activation. Therefore, we tested the influence of high-dose aspirin treatment on left ventricular remodeling in mice after myocardial infarction. Mice were treated for 4 weeks with placebo or aspirin (120 mg/kg per day) by Alzet mini-osmotic pumps after ligation of the left anterior descending coronary artery. Serial transthoracic echocardiography was performed at days 1, 7, and 28. Over the 4 weeks, mortality was not different between the groups (placebo 30.8%, aspirin 30.8%). On echocardiography, animals after myocardial infarction exhibited left ventricular dilatation (week 4, end-systolic area, placebo sham 8.9 +/- 1.7 vs. placebo MI 15.9 +/- 2.5 mm(2)), which was not changed by aspirin treatment (week 4, end-systolic area, aspirin MI 14.5 +/- 1.3 mm(2), p= ns vs. placebo MI). The expression of the proinflammatory cytokines TNF and IL-1beta were markedly upregulated in mice with myocardial infarction on placebo. Cytokine expression was significantly reduced by aspirin treatment while collagen deposition was not influenced. Continuous aspirin treatment (120 mg/kg/d) reduces the expression of proinflammatory cytokines after myocardial infarction, but does not affect post-infarct cardiac remodeling and cardiac function.

  7. Acute aortocaval fistula: role of low perfusion pressure and subendocardial remodeling on left ventricular function.

    Science.gov (United States)

    Mazzo, Flávia R R; de Carvalho Frimm, Clovis; Moretti, Ana Iochabel S; Guido, Maria C; Koike, Marcia K

    2013-06-01

    The experimental model of aortocaval fistula is a useful model of cardiac hypertrophy in response to volume overload. In the present study it has been used to investigate the pathologic subendocardial remodeling associated with the development of heart failure during the early phases (day 1, 3, and 7) following volume overload. Compared with sham treated rats, aortocaval fistula rats showed lower systemic blood pressure and higher left ventricular end-diastolic pressure This resulted in lower coronary driving pressure and left ventricular systolic and diastolic dysfunction. Signs of myocyte necrosis, leukocyte cell infiltration, fibroplasia and collagen deposition appeared sequentially in the subendocardium where remodeling was more prominent than in the non-subendocardium. Accordingly, increased levels of TNF-alpha, IL-1 beta, and IL-6, and enhanced MMP-2 activity were all found in the subendocardium of rats with coronary driving pressure ≤ 60 mmHg. The coronary driving pressure was inversely correlated with MMP-2 activity in subendocardium in all time-points studied, and blood flow in this region showed positive correlation with systolic and diastolic function at day 7. Thus the predominant subendocardial remodeling that occurs in response to low myocardial perfusion pressure during the acute phases of aortocaval fistula contributes to early left ventricular dysfunction. © 2013 The Authors. International Journal of Experimental Pathology © 2013 International Journal of Experimental Pathology.

  8. Myocardial reverse remodeling after pressure unloading is associated with maintained cardiac mechanoenergetics in a rat model of left ventricular hypertrophy.

    Science.gov (United States)

    Ruppert, Mihály; Korkmaz-Icöz, Sevil; Li, Shiliang; Németh, Balázs Tamás; Hegedűs, Péter; Brlecic, Paige; Mátyás, Csaba; Zorn, Markus; Merkely, Béla; Karck, Matthias; Radovits, Tamás; Szabó, Gábor

    2016-09-01

    Pressure unloading represents the only effective therapy in increased afterload-induced left ventricular hypertrophy (LVH) as it leads to myocardial reverse remodeling (reduction of increased left ventricular mass, attenuated myocardial fibrosis) and preserved cardiac function. However, the effect of myocardial reverse remodeling on cardiac mechanoenergetics has not been elucidated. Therefore, we aimed to provide a detailed hemodynamic characterization in a rat model of LVH undergoing pressure unloading. Pressure overload was induced in Sprague-Dawley rats by abdominal aortic banding for 6 (AB 6th wk) or 12 wk (AB 12th wk). Sham-operated animals served as controls. Aortic debanding procedure was performed after the 6th experimental week (debanded 12th wk) to investigate the regression of LVH. Pressure unloading resulted in significant reduction of LVH (heart weight-to-tibial length ratio: 0.38 ± 0.01 vs. 0.58 ± 0.02 g/mm, cardiomyocyte diameter: 18.3 ± 0.1 vs. 24.1 ± 0.8 μm debanded 12th wk vs. AB 12th wk, P cardiac mechanoenergetics. Copyright © 2016 the American Physiological Society.

  9. Cardioprotective effect of polydatin on ventricular remodeling after myocardial infarction in coronary artery ligation rats.

    Science.gov (United States)

    Gao, Yan; Gao, Jianping; Chen, Changxun; Wang, Huilin; Guo, Juan; Wu, Rong

    2015-05-01

    The purpose of this study was to explore the effect of polydatin on ventricular remodeling after myocardial infarction in coronary artery ligation rats and to elucidate the underlying mechanisms. A rat model of ventricular remodeling after myocardial infarction was established by left coronary artery ligation. Rats with coronary artery ligation were randomly divided into five groups: control, plus 40 mg/kg captopril, plus 25 mg/kg polydatin, plus 50 mg/kg polydatin, and plus 100 mg/kg polydatin. The sham-operated group was used as a negative control. Rats were administered intragastrically with the corresponding drugs or drinking water for seven weeks. At the end of the treatment, the left ventricular weight index and heart weight index were assessed. The cross-sectional size of cardiomyocytes was measured by staining myocardium tissue with hematoxylin and eosin. Collagen content was counted by Sirius red in aqueous saturated picric acid. The concentrations of angiotensin I, angiotensin II, aldosterone, and endothelin 1 in myocardium or serum were determined by radioimmunoassay. Hydroxyproline and nitric oxide concentrations and glutathione peroxidase and catalase activities in serum were measured by ultraviolet spectrophotometry. Our results showed that seven weeks of polydatin treatment resulted in a significantly reduced left ventricular weight index, heart weight index, serum concentrations of hydroxyproline and aldosterone, an increased concentration of nitric oxide as well as enhanced activities of glutathione peroxidase and catalase. Myocardial angiotensin I, angiotensin II, and endothelin 1 levels were also reduced. The cardiomyocyte cross-sectional area and collagen deposition diminished. This study suggests that polydatin may attenuate ventricular remodeling after myocardial infarction in coronary artery ligation rats through restricting the excessive activation of the renin-angiotensin-aldosterone system and inhibiting peroxidation. Georg Thieme

  10. Age-related Ventricular Remodeling is an Independent Risk for Heart Failure Symptoms in Subjects With Preserved Systolic Function

    Directory of Open Access Journals (Sweden)

    Chung-Lieh Hung

    2011-03-01

    Conclusion: Cardiac structure, function, and various ventricular remodeling patterns were age-related. Such remodeling process is not only associated with a higher incidence of cardiovascular morbidities but also more likely to develop HF symptoms, which are independent of clinical variables and LV mass.

  11. Effects of losartan on ventricular remodeling in experimental infarction in rats

    Directory of Open Access Journals (Sweden)

    Zornoff Leonardo A. M.

    2000-01-01

    Full Text Available OBJECTIVE: To evaluate the effects of losartan on ventricular remodeling and on survival after myocardial infarction in rats. METHODS: After surgical occlusion of left coronary artery, 84 surviving male Wistar rats were divided into two groups: LO treated with losartan (20mg/kg/day, n=33 and NT (n=51, without medication. After 3 months, we analyzed mortality; ventricular to body mass ratio (VM /BM; myocardial hydroxyproline concentration (HOP; isovolumetric pressure, +dp/dt, -dp/dt, and diastolic volume/left ventricle mass ratio (VO/LV. RESULTS: Mortality was: LO = 22%, and NT = 47% (p0.05. The V0/LV values (median were 0.24 mL/g in group LO and 0.31 mL/g in group NT (p<0.05 compared to NT group. There were no differences between the groups for +dp/dt and -dp/dt parameters. CONCLUSION: 1- The use of losartan myocardial infarction causes an attenuation of ventricular remodeling, bringing about an increased survival, an attenuation of ventricular hypertrophy and dilation, and an improvement of the isovolumetric pressure; 2- the treatment does not modify the myocardial collagen concentration.

  12. Postnatal myocardium remodelling generates inhomogeneity in the architecture of the ventricular mass.

    Science.gov (United States)

    Jouk, Pierre-Simon; Truong, Ba Luu; Michalowicz, Gabrielle; Usson, Yves

    2017-11-28

    The 3D architecture of the ventricular mass is poorly known, although in vivo imaging techniques show the physiological inhomogeneity of ventricular walls mechanics. Polarized light imaging makes it possible to quantitatively analyse the myosin filament orientation. In this paper, we focus on the study the 3D architecture and regional isotropy of myocardial cells. Twenty normal human hearts, 10 from the perinatal period and 10 from the post-neonatal period were studied by polarized light microscopy. In each voxel of the ventricular mass (90 × 90 × 500 µm) the principal orientation segment was automatically and unambiguously extracted as well as a regional isotropy index (regional orientation tensor of the voxel neighbourhood). During the first months of postnatal age, the median regional isotropy values decreased in the ventricular mesh. This global decrease was not homogeneous across the ventricular walls. From the perinatal to the neonatal period, this decrease was more marked in the inner two-third of the lateral left ventricular wall and in the right part of the interventricular septum. There was a progressive post-neonatal appearance of a particularly inhomogeneous secondary arrangement of myocardial cells with alternation of thick low-RI and thin high-RI areas. This study has shown a postnatal change in ventricular myocardial architecture, which became more inhomogeneous. The cell rearrangements responsible for the inhomogeneity in ventricular myocardial architecture are revealed by a variation of the regional isotropy index. These major changes are probably an adaptive consequence of the major haemodynamic changes occurring after birth during the neonatal period that generates major parietal stress variations and parietal remodelling.

  13. Multidetector computed tomography predictors of late ventricular remodeling and function after acute myocardial infarction

    Energy Technology Data Exchange (ETDEWEB)

    Lessick, Jonathan, E-mail: j_lessick@rambam.health.gov.il [Cardiology Department, Rambam Health Care Campus, Haaliya Street, Haifa (Israel); Technion-IIT, Haaliya Street, Haifa (Israel); Abadi, Sobhi [Medical Imaging Department, Rambam Health Care Campus, Haaliya Street, Haifa (Israel); Agmon, Yoram [Cardiology Department, Rambam Health Care Campus, Haaliya Street, Haifa (Israel); Technion-IIT, Haaliya Street, Haifa (Israel); Keidar, Zohar [Nuclear Medicine Department, Rambam Health Care Campus, Haaliya Street, Haifa (Israel); Technion-IIT, Haaliya Street, Haifa (Israel); Carasso, Shemi; Aronson, Doron [Cardiology Department, Rambam Health Care Campus, Haaliya Street, Haifa (Israel); Technion-IIT, Haaliya Street, Haifa (Israel); Ghersin, Eduard [Department of Diagnostic Radiology, University of Miami, Miller School of Medicine, Miami, FL (United States); Rispler, Shmuel [Cardiology Department, Rambam Health Care Campus, Haaliya Street, Haifa (Israel); Technion-IIT, Haaliya Street, Haifa (Israel); Sebbag, Anat [Cardiology Department, Rambam Health Care Campus, Haaliya Street, Haifa (Israel); Israel, Ora [Nuclear Medicine Department, Rambam Health Care Campus, Haaliya Street, Haifa (Israel); Technion-IIT, Haaliya Street, Haifa (Israel); Hammerman, Haim; Roguin, Ariel [Cardiology Department, Rambam Health Care Campus, Haaliya Street, Haifa (Israel); Technion-IIT, Haaliya Street, Haifa (Israel)

    2012-10-15

    Background: Despite advent of rapid arterial revascularization as 1st line treatment for acute myocardial infarction (AMI), incomplete restoral of flow at the microvascular level remains a problem and is associated with adverse prognosis, including pathological ventricular remodeling. We aimed to study the association between multidetector row computed tomography (MDCT) perfusion defects and ventricular remodeling post-AMI. Methods: In a prospective study, 20 patients with ST-elevation AMI, treated by primary angioplasty, underwent arterial and late phase MDCT as well as radionuclide scans to study presence, size and severity of myocardial perfusion defects. Contrast echocardiography was performed at baseline and at 4 months follow-up to evaluate changes in myocardial function and remodeling. Results: Early defects (ED), late defects (LD) and late enhancement (LE) were detected in 15, 7 and 16 patients, respectively and radionuclide defects in 15 patients. The ED area (r = 0.74), and LD area (r = 0.72), and to a lesser extent LE area (r = 0.62) correlated moderately well with SPECT summed rest score. By univariate analysis, follow-up end-systolic volume index and ejection fraction were both significantly related to ED and LD size and severity, but not to LE size or severity. By multivariate analysis, end-systolic volume index was best predicted by LD area (p < 0.05) and ejection fraction by LD enhancement ratio. Conclusions: LD size and severity on MDCT are most closely associated with pathological ventricular remodeling after AMI and may thus play a role in early identification and treatment of this condition.

  14. Right ventricular failure following chronic pressure overload is associated with reduction in left ventricular mass: evidence for atrophic remodeling.

    Science.gov (United States)

    Hardziyenka, Maxim; Campian, Maria E; Reesink, Herre J; Surie, Sulaiman; Bouma, Berto J; Groenink, Maarten; Klemens, Christine A; Beekman, Leander; Remme, Carol A; Bresser, Paul; Tan, Hanno L

    2011-02-22

    We sought to study whether patients with right ventricular failure (RVF) secondary to chronic thromboembolic pulmonary hypertension (CTEPH) have reduced left ventricular (LV) mass, and whether LV mass reduction is caused by atrophy. The LV in patients with CTEPH is underfilled (unloaded). LV unloading may cause atrophic remodeling that is associated with diastolic and systolic dysfunction. We studied LV mass using cardiac magnetic resonance imaging (MRI) in 36 consecutive CTEPH patients (before/after pulmonary endarterectomy [PEA]) and 11 healthy volunteers selected to match age and sex of patients. We studied whether LV atrophy is present in monocrotaline (MCT)-injected rats with RVF or controls by measuring myocyte dimensions and performing in situ hybridization. At baseline, CTEPH patients with RVF had significantly lower LV free wall mass indexes than patients without RVF (35 ± 6 g/m(2) vs. 44 ± 7 g/m(2), p = 0.007) or volunteers (42 ± 6 g/m(2), p = 0.006). After PEA, LV free wall mass index increased (from 38 ± 6 g/m(2) to 44 ± 9 g/m(2), p = 0.001), as right ventricular (RV) ejection fraction improved (from 31 ± 8% to 56 ± 12%, p < 0.001). Compared with controls, rats with RVF had reduced LV free wall mass and smaller LV free wall myocytes. Expression of atrial natriuretic peptide was higher, whereas that of α-myosin heavy chain and sarcoplasmic reticulum calcium ATPase-2 were lower in RVF than in controls, both in RV and LV. RVF in patients with CTEPH is associated with reversible reduction in LV free wall mass. In a rat model of RVF, myocyte shrinkage due to atrophic remodeling contributed to reduction in LV free wall mass. Copyright © 2011 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

  15. Early repair of moderate ischemic mitral regurgitation reverses left ventricular remodeling: a functional and molecular study.

    Science.gov (United States)

    Beeri, Ronen; Yosefy, Chaim; Guerrero, J Luis; Abedat, Suzan; Handschumacher, Mark D; Stroud, Robert E; Sullivan, Suzanne; Chaput, Miguel; Gilon, Dan; Vlahakes, Gus J; Spinale, Francis G; Hajjar, Roger J; Levine, Robert A

    2007-09-11

    Mitral regurgitation (MR) doubles postmyocardial infarction (MI) mortality. We have shown that moderate MR augments remodeling in an apical MI model (no intrinsic MR) with independent left ventricle-to-left atrial MR-type flow. We hypothesized that repairing moderate MR 1 month after MI reverses this remodeling. Anteroapical MIs were created in 18 sheep, and a left ventricle-to-left atrial shunt implanted in 12 (regurgitant fraction, 30%). Six sheep had the shunt closed at 1 month (repair group). Sheep were compared at baseline, and at 1 and 3 months. Sheep in the MI+MR (unrepaired) and repaired groups remodeled during the first month (120% increased left ventricular end-systolic volume [ESV; P<0.01]), but shunt closure reversed remodeling at 3 months, with end-diastolic volume (EDV) and ESV 135% and 128% of baseline versus 220% and 280% without repair (P<0.001). At 3 months, dP/dt and preload-recruitable stroke work were relatively maintained in the repaired and MI-only groups versus nearly 50% decreases without repair. Prohypertrophic gp130 and antiapoptotic pAkt increased followed by exhaustion below baseline without repair, but remained elevated at 3 months with repair or MI only. With repair, matrix metalloproteinase-2 decreased to < or = 50% that without repair in remote and border zones at 3 months, and the matrix metalloproteinase inhibitor TIMP-4 increased dramatically. Early repair of moderate MR in the setting of apical MI substantially reverses the otherwise progressive remodeling process, with reduced left ventricular volumes, relatively maintained contractility, persistently activated intracellular signals promoting hypertrophy and opposing apoptosis, and reduced matrix proteolytic activity. These findings are of interest for the current controversy regarding potential benefits of repair of MR after MI.

  16. Correlation of Ventricular Arrhythmogenesis with Neuronal Remodeling of Cardiac Postganglionic Parasympathetic Neurons in the Late Stage of Heart Failure after Myocardial Infarction

    Science.gov (United States)

    Zhang, Dongze; Tu, Huiyin; Wang, Chaojun; Cao, Liang; Muelleman, Robert L.; Wadman, Michael C.; Li, Yu-Long

    2017-01-01

    Introduction: Ventricular arrhythmia is a major cause of sudden cardiac death in patients with chronic heart failure (CHF). Our recent study demonstrates that N-type Ca2+ currents in intracardiac ganglionic neurons are reduced in the late stage of CHF rats. Rat intracardiac ganglia are divided into the atrioventricular ganglion (AVG) and sinoatrial ganglion. Only AVG nerve terminals innervate the ventricular myocardium. In this study, we tested the correlation of electrical remodeling in AVG neurons with ventricular arrhythmogenesis in CHF rats. Methods and Results: CHF was induced in male Sprague-Dawley rats by surgical ligation of the left coronary artery. The data from 24-h continuous radiotelemetry ECG recording in conscious rats showed that ventricular tachycardia/fibrillation (VT/VF) occurred in 3 and 14-week CHF rats but not 8-week CHF rats. Additionally, as an index for vagal control of ventricular function, changes of left ventricular systolic pressure (LVSP) and the maximum rate of left ventricular pressure rise (LV dP/dtmax) in response to vagal efferent nerve stimulation were blunted in 14-week CHF rats but not 3 or 8-week CHF rats. Results from whole-cell patch clamp recording demonstrated that N-type Ca2+ currents in AVG neurons began to decrease in 8-week CHF rats, and that there was also a significant decrease in 14-week CHF rats. Correlation analysis revealed that N-type Ca2+ currents in AVG neurons negatively correlated with the cumulative duration of VT/VF in 14-week CHF rats, whereas there was no correlation between N-type Ca2+ currents in AVG neurons and the cumulative duration of VT/VF in 3-week CHF. Conclusion: Malignant ventricular arrhythmias mainly occur in the early and late stages of CHF. Electrical remodeling of AVG neurons highly correlates with the occurrence of ventricular arrhythmias in the late stage of CHF. PMID:28533740

  17. Correlation of Ventricular Arrhythmogenesis with Neuronal Remodeling of Cardiac Postganglionic Parasympathetic Neurons in the Late Stage of Heart Failure after Myocardial Infarction

    Directory of Open Access Journals (Sweden)

    Dongze Zhang

    2017-05-01

    Full Text Available Introduction: Ventricular arrhythmia is a major cause of sudden cardiac death in patients with chronic heart failure (CHF. Our recent study demonstrates that N-type Ca2+ currents in intracardiac ganglionic neurons are reduced in the late stage of CHF rats. Rat intracardiac ganglia are divided into the atrioventricular ganglion (AVG and sinoatrial ganglion. Only AVG nerve terminals innervate the ventricular myocardium. In this study, we tested the correlation of electrical remodeling in AVG neurons with ventricular arrhythmogenesis in CHF rats.Methods and Results: CHF was induced in male Sprague-Dawley rats by surgical ligation of the left coronary artery. The data from 24-h continuous radiotelemetry ECG recording in conscious rats showed that ventricular tachycardia/fibrillation (VT/VF occurred in 3 and 14-week CHF rats but not 8-week CHF rats. Additionally, as an index for vagal control of ventricular function, changes of left ventricular systolic pressure (LVSP and the maximum rate of left ventricular pressure rise (LV dP/dtmax in response to vagal efferent nerve stimulation were blunted in 14-week CHF rats but not 3 or 8-week CHF rats. Results from whole-cell patch clamp recording demonstrated that N-type Ca2+ currents in AVG neurons began to decrease in 8-week CHF rats, and that there was also a significant decrease in 14-week CHF rats. Correlation analysis revealed that N-type Ca2+ currents in AVG neurons negatively correlated with the cumulative duration of VT/VF in 14-week CHF rats, whereas there was no correlation between N-type Ca2+ currents in AVG neurons and the cumulative duration of VT/VF in 3-week CHF.Conclusion: Malignant ventricular arrhythmias mainly occur in the early and late stages of CHF. Electrical remodeling of AVG neurons highly correlates with the occurrence of ventricular arrhythmias in the late stage of CHF.

  18. Correlation of Ventricular Arrhythmogenesis with Neuronal Remodeling of Cardiac Postganglionic Parasympathetic Neurons in the Late Stage of Heart Failure after Myocardial Infarction.

    Science.gov (United States)

    Zhang, Dongze; Tu, Huiyin; Wang, Chaojun; Cao, Liang; Muelleman, Robert L; Wadman, Michael C; Li, Yu-Long

    2017-01-01

    Introduction: Ventricular arrhythmia is a major cause of sudden cardiac death in patients with chronic heart failure (CHF). Our recent study demonstrates that N-type Ca(2+) currents in intracardiac ganglionic neurons are reduced in the late stage of CHF rats. Rat intracardiac ganglia are divided into the atrioventricular ganglion (AVG) and sinoatrial ganglion. Only AVG nerve terminals innervate the ventricular myocardium. In this study, we tested the correlation of electrical remodeling in AVG neurons with ventricular arrhythmogenesis in CHF rats. Methods and Results: CHF was induced in male Sprague-Dawley rats by surgical ligation of the left coronary artery. The data from 24-h continuous radiotelemetry ECG recording in conscious rats showed that ventricular tachycardia/fibrillation (VT/VF) occurred in 3 and 14-week CHF rats but not 8-week CHF rats. Additionally, as an index for vagal control of ventricular function, changes of left ventricular systolic pressure (LVSP) and the maximum rate of left ventricular pressure rise (LV dP/dtmax) in response to vagal efferent nerve stimulation were blunted in 14-week CHF rats but not 3 or 8-week CHF rats. Results from whole-cell patch clamp recording demonstrated that N-type Ca(2+) currents in AVG neurons began to decrease in 8-week CHF rats, and that there was also a significant decrease in 14-week CHF rats. Correlation analysis revealed that N-type Ca(2+) currents in AVG neurons negatively correlated with the cumulative duration of VT/VF in 14-week CHF rats, whereas there was no correlation between N-type Ca(2+) currents in AVG neurons and the cumulative duration of VT/VF in 3-week CHF. Conclusion: Malignant ventricular arrhythmias mainly occur in the early and late stages of CHF. Electrical remodeling of AVG neurons highly correlates with the occurrence of ventricular arrhythmias in the late stage of CHF.

  19. Coronary flow reserve in the remote myocardium predicts left ventricular remodeling following acute myocardial infarction.

    Science.gov (United States)

    Cheng, Rongchao; Wei, Guoqian; Yu, Longhao; Su, Zhendong; Wei, Li; Bai, Xiuping; Tian, Jiawei; Li, Xueqi

    2014-07-01

    Coronary flow reserve (CFR) in the non-infarcted myocardium is often impaired following acute myocardial infarction (AMI). However, the clinical significance of CFR in the non-infarcted myocardium is not fully understood. The objective of the present study was to assess whether a relationship exists between CFR and left ventricular remodeling following AMI. We enrolled 18 consecutive patients undergoing coronary intervention. Heart function was analyzed using real-time myocardial contrast echocardiography at one week and six months after coronary angioplasty. Ten subjects were enrolled as the control group and were examined using the same method at the same time to assess CFR. Cardiac troponin I (cTnI) levels were routinely analyzed to estimate peak concentration. CFR was 1.55±0.11 in the infarcted zone and 2.05±0.31 in the remote zone (p2.05). The levels of cTnI were higher in Group I compared to Group II on admission (36.40 vs. 21.38, p<0.05). Furthermore, left ventricular end diastolic volume was higher in Group I compared to Group II at six months following coronary angioplasty. Microvascular dysfunction is commonly observed in the remote myocardium. The CFR value accurately predicts adverse ventricular remodeling following AMI.

  20. Verapamil induced ventricular hypertrophy in conscious dogs.

    Science.gov (United States)

    French, W J; Garner, D; Adomian, G E; Averill, W; Laks, M M

    1989-08-01

    Verapamil is used clinically in the treatment of various cardiac diseases including hypertrophic cardiomyopathy. Its long term effects on ventricular mass are not well known. In 11 conscious dogs heart rate, aortic and left ventricular pressures, cardiac output, a methoxamine induced stress ventricular function test and left ventriculography were performed. These variables were measured prior to and following a mean 7.2 month infusion of verapamil at 0.005 or 0.01 mg.kg-1.min-1 using a subcutaneously implanted pump. Resting haemodynamic variables and left ventricular ejection fraction [60(SD 6) v 55(6)%] were unchanged between baseline and chronic verapamil studies, but the slope of the methoxamine induced stress ventricular function test decreased from 3.9(0.8) to 2.1 (1.3). After verapamil was discontinued the mean slope of the stress ventricular function test returned to the baseline 4.0(1.7). Total ventricular weight increased 22% from 176.1(17.5) g.m-2 in controls to 215.6(29.5) g.m-2 (p less than 0.01) in the verapamil animals. The right ventricular weight increased 25% from 46(5.9) to 57.6(9.1) g.m-2 (p less than 0.01); the septum weight increased 26% from 42.5(4.1) to 53.7(7.2) g.m-2 (p less than 0.001); and the left ventricular free wall weight increased 19% from 87.4(9.8) to 103.9(15.7) g.m-2 (p less than 0.01). The increase in ventricular weights was not due to fibrosis or oedema since hydroxyproline contents and wet/dry ratios were not increased. In conclusion, a chronic infusion of verapamil in conscious dogs caused no change in resting haemodynamic variables but produced reversible depression of stress ventricular function and biventricular and septal hypertrophy.

  1. Remote Zone Extracellular Volume and Left Ventricular Remodeling in Survivors of ST-Elevation Myocardial Infarction.

    Science.gov (United States)

    Carberry, Jaclyn; Carrick, David; Haig, Caroline; Rauhalammi, Samuli M; Ahmed, Nadeem; Mordi, Ify; McEntegart, Margaret; Petrie, Mark C; Eteiba, Hany; Hood, Stuart; Watkins, Stuart; Lindsay, Mitchell; Davie, Andrew; Mahrous, Ahmed; Ford, Ian; Sattar, Naveed; Welsh, Paul; Radjenovic, Aleksandra; Oldroyd, Keith G; Berry, Colin

    2016-08-01

    The natural history and pathophysiological significance of tissue remodeling in the myocardial remote zone after acute ST-elevation myocardial infarction (STEMI) is incompletely understood. Extracellular volume (ECV) in myocardial regions of interest can now be measured with cardiac magnetic resonance imaging. Patients who sustained an acute STEMI were enrolled in a cohort study (BHF MR-MI [British Heart Foundation Magnetic Resonance Imaging in Acute ST-Segment Elevation Myocardial Infarction study]). Cardiac magnetic resonance was performed at 1.5 Tesla at 2 days and 6 months post STEMI. T1 modified Look-Locker inversion recovery mapping was performed before and 15 minutes after contrast (0.15 mmol/kg gadoterate meglumine) in 140 patients at 2 days post STEMI (mean age: 59 years, 76% male) and in 131 patients at 6 months post STEMI. Remote zone ECV was lower than infarct zone ECV (25.6±2.8% versus 51.4±8.9%; P<0.001). In multivariable regression, left ventricular ejection fraction was inversely associated with remote zone ECV (P<0.001), and diabetes mellitus was positively associated with remote zone ECV (P=0.010). No ST-segment resolution (P=0.034) and extent of ischemic area at risk (P<0.001) were multivariable associates of the change in remote zone ECV at 6 months (ΔECV). ΔECV was a multivariable associate of the change in left ventricular end-diastolic volume at 6 months (regression coefficient [95% confidence interval]: 1.43 (0.10-2.76); P=0.036). ΔECV is implicated in the pathophysiology of left ventricular remodeling post STEMI, but because the effect size is small, ΔECV has limited use as a clinical biomarker of remodeling. URL: https://www.clinicaltrials.gov. Unique identifier: NCT02072850. © 2016 The Authors.

  2. Sarcomeric lesions and remodeling proximal to intercalated disks in overload-induced cardiac hypertrophy.

    Science.gov (United States)

    Kebir, Sied; Orfanos, Zacharias; Schuld, Julia; Linhart, Markus; Lamberz, Christian; van der Ven, Peter F M; Schrickel, Jan; Kirfel, Gregor; Fürst, Dieter O; Meyer, Rainer

    2016-10-15

    Pressure overload induces cardiac remodeling involving both the contractile machinery and intercalated disks (IDs). Filamin C (FlnC) and Xin actin-binding repeat-containing proteins (XIRPs) are multi-adapters localizing in IDs of higher vertebrates. Knockout of the gene encoding Xin (Xirp1) in mice leads to a mild cardiac phenotype with ID mislocalization. In order to amplify this phenotype, we performed transverse aortic constriction (TAC) on control and Xirp1-deficient mice. TAC induced similar left ventricular hypertrophy in both genotypes, suggesting that the lack of Xin does not lead to higher susceptibility to cardiac overload. However, in both genotypes, FlnC appeared in "streaming" localizations across multiple sarcomeres proximal to the IDs, suggesting a remodeling response. Furthermore, FlnC-positive areas of remodeling, reminiscent of sarcomeric lesions previously described for skeletal muscles (but so far unreported in the heart), were also observed. These adaptations reflect a similarly strong effect of the pressure induced by TAC in both genotypes. However, 2 weeks post-operation TAC-treated knockout hearts had reduced levels of connexin43 and slightly increased incidents of ventricular tachycardia compared to their wild-type (WT) counterparts. Our findings highlight the FlnC-positive sarcomeric lesions and ID-proximal streaming as general remodeling responses in cardiac overload-induced hypertrophy. Copyright © 2016 Elsevier Inc. All rights reserved.

  3. High fat diet aggravates atrial and ventricular remodeling of hypertensive heart disease in aging rats.

    Science.gov (United States)

    Shiou, Yi-Lin; Huang, I-Chieh; Lin, Hsin-Ting; Lee, Hsiang-Chun

    2017-09-06

    Left ventricular hypertrophy is a major cause of heart failure in aging population. This study is to determine whether an excess dietary fat is lipotoxic or lipoprotein to the hypertrophic aging heart. At 44-week-old, a normal chow (12% fat) was replaced a high-fat diet (HFD; 45% fat) for randomly selective spontaneously hypertensive rats (SHR + HFD, n = 6) and Wistar-Kyoto rats (WKY + HFD, n = 6, normotensive control). Others (SHR, n = 11; WKY, n = 10) were continuously fed with normal diets. After 27 weeks, electrocardiogram, echocardiography, and femoral arterial catheterization were performed before rats being sacrificed for molecular biology analyses. HFD aggravated cardiac atrial, ventricular dilation and hypertrophy in SHR (LV mass: SHR + HFD 2026.0 ± 424.9 vs SHR 1449 ± 461.1 mg, unpaired t test P heart disease in aging rats was aggravated by HFD with worse atrial, ventricular remodeling and associated with left ventricular systolic function impairment. Copyright © 2017. Published by Elsevier B.V.

  4. Renin-angiotensin-aldosterone genotype influences ventricular remodeling in infants with single ventricle.

    Science.gov (United States)

    Mital, Seema; Chung, Wendy K; Colan, Steven D; Sleeper, Lynn A; Manlhiot, Cedric; Arrington, Cammon B; Cnota, James F; Graham, Eric M; Mitchell, Michael E; Goldmuntz, Elizabeth; Li, Jennifer S; Levine, Jami C; Lee, Teresa M; Margossian, Renee; Hsu, Daphne T

    2011-05-31

    We investigated the effect of polymorphisms in the renin-angiotensin-aldosterone system (RAAS) genes on ventricular remodeling, growth, renal function, and response to enalapril in infants with single ventricle. Single ventricle infants enrolled in a randomized trial of enalapril were genotyped for polymorphisms in 5 genes: angiotensinogen, angiotensin-converting enzyme, angiotensin II type 1 receptor, aldosterone synthase, and chymase. Alleles associated with renin-angiotensin-aldosterone system upregulation were classified as risk alleles. Ventricular mass, volume, somatic growth, renal function using estimated glomerular filtration rate, and response to enalapril were compared between patients with ≥2 homozygous risk genotypes (high risk), and those with SCPC) and at age 14 months. Of 230 trial subjects, 154 were genotyped: Thirty-eight were high risk, and 116 were low risk. Ventricular mass and volume were elevated in both groups pre-SCPC. Ventricular mass and volume decreased and estimated glomerular filtration rate increased after SCPC in the low-risk (PSCPC surgery, less improvement in renal function, and impaired somatic growth, the latter especially in patients receiving enalapril. Renin-angiotensin-aldosterone system genotype may identify a high-risk subgroup of single ventricle patients who fail to fully benefit from volume-unloading surgery. Follow-up is warranted to assess long-term impact. http://www.clinicaltrials.gov. Unique identifier: NCT00113087.

  5. Adverse impact of diabetes mellitus on left ventricular remodelling in patients with chronic primary mitral regurgitation.

    Science.gov (United States)

    Ernande, Laura; Beaudoin, Jonathan; Piro, Victoria; Meziani, Souhila; Scherrer-Crosbie, Marielle

    2018-01-03

    Diabetes mellitus (DM) has an impact on left ventricular (LV) geometry and function, and is associated with worsening of pressure-overload LV remodelling; however, its impact on volume-overload LV remodelling is unknown. The objective of the study was to examine the association between DM and LV remodelling in patients with chronic mitral regurgitation (MR) caused by mitral valve prolapse. During a median follow-up of 3.26 [interquartile range 1.59-6.06] years, we evaluated the evolution of echocardiographic variables in 375 consecutive patients, including 61 (16%) patients with DM. The main endpoint was LV remodelling evaluated by LV end-diastolic diameter (LVEDD) and LV mass index increase. LV end-systolic diameter (LVESD) and ejection fraction (LVEF) were also evaluated. Patients with DM increased their LVEDD more than patients without DM (1.98±4.1 vs 0.15±4.54mm/year of follow-up; P=0.002). LVEF remained stable in the two groups. After adjustment for potential confounders, including age, sex, hypertension, body mass index, MR severity, medications and follow-up duration, DM remained independently associated with LVEDD increase (β=2.30; P<0.001). When comparing patients with DM with patients without DM matched for age, sex and LVEDD at baseline, DM was independently associated with increased LVEDD (β=2.14; P=0.002), LV mass index (β=10.7; P=0.004) and LVESD (β=2.07; P=0.01). DM is associated with worsening of LV remodelling in patients with moderate or severe chronic MR caused by mitral valve prolapse. Copyright © 2018 Elsevier Masson SAS. All rights reserved.

  6. Myocardial infarction and left ventricular remodeling: results of the CEDIM trial. Carnitine Ecocardiografia Digitalizzata Infarto Miocardico.

    Science.gov (United States)

    Colonna, P; Iliceto, S

    2000-02-01

    Left ventricular dilatation after acute myocardial infarction (MI) is a powerful predictor of progressive functional deterioration, culminating in heart failure and death. The most important determinants of post-MI left ventricular remodeling are the size of the infarct, the degree of residual stenosis in the infarct-related artery, and the viability of the infarct zone. In addition to reperfusion therapy and angiotensin-converting enzyme inhibition, metabolic intervention with L-carnitine may represent a therapeutic approach for preventing left ventricular dilatation and preserving cardiac function. Ongoing studies with early metabolic intervention with carnitine in the acute phase of infarction may prove successful in protecting the microcirculation against ischemic damage and enhancing its ability to respond to blood flow resumption. The results of the multicenter, randomized, double-blind Carnitine Ecocardiografia Digitalizzata Infarto Miocardico (CEDIM) trial suggest that the early and long-term administration of L-carnitine attenuates progressive left ventricular dilatation after acute anterior MI. Results show significant, consistent reductions in end-diastolic volume and end-systolic volume in patients who received L-carnitine compared with placebo. The ongoing CEDIM-2 trial (projected 4000 patients with acute MI) will assess the efficacy of L-carnitine in reducing the combined incidence of death and heart failure at 6 months. In addition to standard reperfusion therapy and angiotensin-converting enzyme inhibition, metabolic intervention with L-carnitine may be a therapeutic approach for preventing left ventricular dilatation and preserving cardiac function by limiting infarct size, decreasing residual stenosis in the infarct-related artery, and increasing viability of the infarct zone.

  7. Left ventricular remodelling changes without concomitant loss of myocardial fat after long-term dietary intervention.

    Science.gov (United States)

    Andersson, Jonas; Mellberg, Caroline; Otten, Julia; Ryberg, Mats; Rinnström, Daniel; Larsson, Christel; Lindahl, Bernt; Hauksson, Jon; Johansson, Bengt; Olsson, Tommy

    2016-08-01

    Accumulation of myocardial triglycerides (MTG) is associated with impaired left ventricular (LV) remodelling and function in obese and diabetic subjects. The role of MTG accumulation in development of heart failure in this group of patients is unknown. Short-term studies suggest that diets that lead to weight loss could mobilize MTG, with a favourable effect on cardiac remodelling. In a 24-month, randomized, investigator-blinded study, we assessed the effect of two different diets and subsequent weight loss on cardiac function and MTG in postmenopausal women. Sixty-eight healthy postmenopausal women with body mass index [BMI] ≥27kg/m(2) were randomized to an ad libitum Palaeolithic diet (PD) or a Nordic Nutrition Recommendation (NNR) diet for 24months. Morphology, cardiac function, and MTG levels were measured using magnetic resonance (MR) scanning, including proton spectroscopy at baseline and 6 and 24months. Despite mean weight losses of 4.9 (1.0) kg (NNR) and 7.8 (1.1) kg (PD), the MTG content did not change over time (p=0.98 in the NNR and p=0.11 in the PD group at 24months). Reduced left ventricular mass was observed in both diet groups over 24months. Blood pressure was reduced at 6months, but returned to baseline levels at 24months. End diastolic volume, stroke volume, and cardiac output decreased over time. No differences between diet groups were observed. Diet intervention and moderate weight loss over 24months improved LV remodelling but did not alter MTG levels in overweight/obese postmenopausal women. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  8. Is gender responsible for everything? The relationship between sex and right ventricular remodeling in metabolic syndrome.

    Science.gov (United States)

    Tadic, Marijana V; Ivanovic, Branislava A; Petrovic, Milan

    2013-08-01

    The aim of this study was to examine the impact of metabolic syndrome (MS) on right ventricular (RV) remodeling in different genders. The study included 341 subjects (216 subjects with MS and 125 controls). MS was defined by the presence of ≥ 3 ATP-NCEP-III criteria. All subjects underwent complete two-dimensional echocardiography. RV structure, diastolic, and global function were significantly impaired in MS subjects, in both genders. The multiple regression analysis of MS parameters showed that systolic blood pressure (BP) and waist circumference were independently associated with RV wall thickness in women, whereas the only independent predictor in men was systolic BP. The multivariate logistic regression analysis revealed that increased BP, impaired fasting glucose, and dyslipidemia were a combination of MS risk factors related with RV hypertrophy solely in women. Increased systolic BP, impaired fasting glucose, and abdominal obesity were independently associated with tricuspid E/e' in women, whereas increased systolic BP was the only independent predictor in men. Impaired fasting glucose, abdominal obesity, and dyslipidemia were a combination of MS criteria, which was independently associated with RV diastolic dysfunction only in women. Different parameters of MS are responsible for RV remodeling in women and men. The metabolic parameters of MS are more important for RV remodeling in women. © 2013, Wiley Periodicals, Inc.

  9. Predictors of left ventricular remodeling after ST-elevation myocardial infarction.

    Science.gov (United States)

    Hendriks, Tom; Hartman, Minke H T; Vlaar, Pieter J J; Prakken, Niek H J; van der Ende, Yldau M Y; Lexis, Chris P H; van Veldhuisen, Dirk J; van der Horst, Iwan C C; Lipsic, Erik; Nijveldt, Robin; van der Harst, Pim

    2017-09-01

    Adverse left ventricular (LV) remodeling after acute ST-elevation myocardial infarction (STEMI) is associated with morbidity and mortality. We studied clinical, biochemical and angiographic determinants of LV end diastolic volume index (LVEDVi), end systolic volume index (LVESVi) and mass index (LVMi) as global LV remodeling parameters 4 months after STEMI, as well as end diastolic wall thickness (EDWT) and end systolic wall thickness (ESWT) of the non-infarcted myocardium, as compensatory remote LV remodeling parameters. Data was collected in 271 patients participating in the GIPS-III trial, presenting with a first STEMI. Laboratory measures were collected at baseline, 2 weeks, and 6-8 weeks. Cardiovascular magnetic resonance imaging (CMR) was performed 4 months after STEMI. Linear regression analyses were performed to determine predictors. At baseline, patients were 21% female, median age was 58 years. At 4 months, mean LV ejection fraction (LVEF) was 54 ± 9%, mean infarct size was 9.0 ± 7.9% of LVM. Strongest univariate predictors (all p infarcted myocardium.

  10. Myocardial remodeling and bioelectric changes in tachycardia-induced heart failure in dogs

    Energy Technology Data Exchange (ETDEWEB)

    Song, B.; Wang, B.N.; Chen, D.N.; Luo, Z.G. [Department of Cardiovascular Medicine, The First Affiliated Hospital, Anhui Medical University, HeFei, Anhui Province (China)

    2013-09-06

    In this study, electrical and structural remodeling of ventricles was examined in tachycardia-induced heart failure (HF). We studied two groups of weight-matched adult male mongrel dogs: a sham-operated control group (n=5) and a pacing group (n=5) that underwent ventricular pacing at 230 bpm for 3 weeks. Clinical symptoms of congestive HF were observed in both groups. Their hemodynamic parameters were determined and the severity of the HF was evaluated by M-mode echocardiography. Changes in heart morphology were observed by scanning electron and light microscopy. Ventricular action potential duration (APD), as well as the 50 and 90% APD were measured in both groups. All dogs exhibited clinical symptoms of congestive HF after rapid right ventricular pacing for 3 weeks. These data indicate that rapid, right ventricular pacing produces a useful experimental model of low-output HF in dogs, characterized by biventricular pump dysfunction, biventricular cardiac dilation, and non-ischemic impairment of left ventricular contractility. Electrical and structural myocardial remodeling play an essential role in congestive HF progression, and should thus be prevented.

  11. Impact of Aortic Valve Replacement on Left Ventricular Remodeling in Patients with Severe Aortic Stenosis and Severe Left Ventricular Dysfunction

    Directory of Open Access Journals (Sweden)

    Abderrahmane Bakkali

    2016-12-01

    Full Text Available Objective: The aim of this study was to evaluate the effect of aortic valve replacement on left ventricular function and remodeling among patients with severe aortic stenosis and severe left ventricular dysfunction. Methods: In this retrospective bicentric study extended over a 15-year period, 61 consecutive patients underwent isolated AVR for severe AS associated to reduced LV function. The mean age was 58.21 ± 12.50 years and 83.60 % were men. 70.50% of patients were in class III or IV NYHA. The mean left ventricular ejection fraction (LVEF was 32.9 ± 5.6.The mean LVEDD and LVESD were respectively 63.6 ± 9.2 and 50.2 ± 8.8 mm. The mean calculated logistic EuroScore was 12.2 ±4.5. Results: The hospital mortality was 11.5%. Morbidity was marked mainly by low output syndrome in 40.8% of cases. After a median follow-up of 38 months we have recorded 3 deaths. Almost all survivors were in class I and II of NYHA. The mean LV end-diastolic and end-systolic diameters decreased significantly at late postoperative stage. The mean LV ejection fraction increased significantly from 32.9 ± 5.6 to 38.2 ± 9.3 and to 50.3 ± 9.6 in early and late postoperative stages, respectively. Multivariate linear regression analysis found that increased early postoperative LVEF (β= 0.44, 95% CI [0.14; 0.75], p=0.006 and low mean transprosthesis gradient (β=-0.72, 95% CI [-1.42; -0.02], p= 0.04 were the independent predictors of left ventricular systolic function recovery. Conclusion: Patients with aortic valve stenosis and impaired LV systolic function benefited from AVR as regard improvement of LV function parameters and regression of the LV diameters .This improvement depends mainly on early postoperative LVEF and mean transprosthesis gradient.

  12. Left ventricular remodeling leads to heart failure in mice with cardiac-specific overexpression of VEGF-B167: echocardiography and magnetic resonance imaging study.

    Science.gov (United States)

    Lottonen-Raikaslehto, Line; Rissanen, Riina; Gurzeler, Erika; Merentie, Mari; Huusko, Jenni; Schneider, Jurgen E; Liimatainen, Timo; Ylä-Herttuala, Seppo

    2017-03-01

    Cardiac-specific overexpression of vascular endothelial growth factor (VEGF)-B 167 is known to induce left ventricular hypertrophy due to altered lipid metabolism, in which ceramides accumulate to the heart and cause mitochondrial damage. The aim of this study was to evaluate and compare different imaging methods to find the most sensitive way to diagnose at early stage the progressive left ventricular remodeling leading to heart failure. Echocardiography and cardiovascular magnetic resonance imaging were compared for imaging the hearts of transgenic mice with cardiac-specific overexpression of VEGF-B 167 and wild-type mice from 5 to 14 months of age at several time points. Disease progression was verified by molecular biology methods and histology. We showed that left ventricular remodeling is already ongoing at the age of 5 months in transgenic mice leading to heart failure by the age of 14 months. Measurements from echocardiography and cardiovascular magnetic resonance imaging revealed similar changes in cardiac structure and function in the transgenic mice. Changes in histology, gene expressions, and electrocardiography supported the progression of left ventricular hypertrophy. Longitudinal relaxation time in rotating frame (T 1 ρ ) in cardiovascular magnetic resonance imaging could be suitable for detecting severe fibrosis in the heart. We conclude that cardiac-specific overexpression of VEGF-B 167 leads to left ventricular remodeling at early age and is a suitable model to study heart failure development with different imaging methods. © 2017 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of The Physiological Society and the American Physiological Society.

  13. Xenon and isoflurane reduce left ventricular remodeling after myocardial infarction in the rat.

    Science.gov (United States)

    Roehl, Anna B; Funcke, Sandra; Becker, Michael M; Goetzenich, Andreas; Bleilevens, Christian; Rossaint, Rolf; Steendijk, Paul; Hein, Marc

    2013-06-01

    Xenon and isoflurane are known to have cardioprotective properties. We tested the hypothesis that these anesthetics positively influence myocardial remodeling 28 days after experimental perioperative myocardial infarction and compared their effects. A total of 60 male Sprague-Dawley rats were subjected to 60 min of coronary artery occlusion and 120 min of reperfusion. Prior to ischemia, the animals were randomized for the different narcotic regimes (0.6 vol% isoflurane, 70 vol% xenon, or intraperitoneal injection of s-ketamine). Acute injury was quantified by echocardiography and troponin I. After 4 weeks, left ventricular function was assessed by conductance catheter to quantify hemodynamic compromise. Cardiac remodeling was characterized by quantification of dilatation, hypertrophy, fibrosis, capillary density, apoptosis, and expression of fetal genes (α/β myosin heavy chains, α-skeletal actin, periostin, and sarco/endoplasmic reticulum Ca2+-ATPase). Whereas xenon and isoflurane impeded the acute effects of ischemia-reperfusion on hemodynamics and myocardial injury at a comparable level, differences were found after 4 weeks. Xenon in contrast to isoflurane or ketamine anesthetized animals demonstrated a lower remodeling index (0.7 ± 0.1 vs. 0.9 ± 0.3 and 1.0 ± 0.3g/ml), better ejection fraction (62 ± 9 vs. 49 ± 7 and 35 ± 6%), and reduced expression of β-myosin heavy chain and periostin. The effects on hypertrophy, fibrosis, capillary density, and apoptosis were comparable. Compared to isoflurane and s-ketamine, xenon limited progressive adverse cardiac remodeling and contractile dysfunction 28 days after perioperative myocardial infarction.

  14. Left ventricular remodeling and fibrosis: Sex differences and relationship with diastolic function in hypertrophic cardiomyopathy

    Energy Technology Data Exchange (ETDEWEB)

    Chen, You-Zhou [Department of Cardiology, State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Disease, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing (China); Qiao, Shu-Bin, E-mail: qsbfw@sina.com [Department of Cardiology, State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Disease, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing (China); Hu, Feng-Huan; Yuan, Jian-Song; Yang, Wei-Xian; Cui, Jin-Gang [Department of Cardiology, State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Disease, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing (China); Zhang, Yan [Department of Radiology, State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Disease, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing (China); Zhang, Chang-Lin [Department of Cardiology, State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Disease, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing (China)

    2015-08-15

    Highlights: • There are significant differences in LV remodeling and fibrosis as divided by sex. • Women have worse diastolic dysfunction compared to men measured by CMR. • LV remodeling and fibrosis correlate with markers of diastolic dysfunction. - Abstract: Objectives: We investigated sex differences in left ventricular (LV) remodeling and fibrosis and their relationship with LV diastolic dysfunction by cardiovascular magnetic resonance (CMR). Methods: CMR imaging was performed simultaneously in 152 age-matched patients (76 men, 76 women; mean age: 49 ± 9 years) without LV systolic dysfunction. LV remodeling index (LVRI) was calculated as the ratio of LV mass and end-diastolic volume. Diastolic function indexes including peak filling rate (PFR) and time to PFR (tPFR) were evaluated. Extent of late gadolinium enhancement (LGE) was measured. Results: LVRI and extent of LGE were greater in women compared with men (1.48 ± 0.22 vs. 1.36 ± 0.28 g/ml; 13.15 ± 2.48 vs. 11.35 ± 2.34 g, respectively, both P < 0.001). Women had lower PFR and higher tPFR (both P < 0.001) than men. LVRI and the extent of LGE showed significant relationships with parameters of diastolic function in both sex. In a multivariate analysis, LVRI remained a strong independent predictor of PFR and TPFR in women (β = −0.272, P = 0.032; β = 0.348, P = 0.016, respectively), and in men (β = −0.374, P < 0.001; β = 0.660, P < 0.001, respectively). Furthermore, the extent of LGE also remained an independent predictor of PFR in women (β = −0.283, P = 0.033) and men (β = −0.492, P < 0.001). Conclusions: There are prominent sex differences in LV remodeling and myocardial fibrosis. We suggest that the effects of LV remodeling and fibrosis may lead to diastolic dysfunction with greater susceptibility to worse clinical outcome in women.

  15. [Effect of metformin on ventricular remodeling in patients with primary hypertension and type 2 diabetes mellitus].

    Science.gov (United States)

    Wu, Yueyang; Zhao, Wei; Zhang, Youyi; Feng, Xinheng; Li, Zhaoping; Gao, Wei

    2015-11-24

    To explore the effects of metformin on left ventricular remodeling in patients with primary hypertension and type 2 diabetes mellitus, and to investigate the effects of hypertension duration and duration of drug administration on metformin's cardiac action. The clinical and echocardiographic data of 176 patients with primary hypertension and type 2 diabetes mellitus who were admitted to department of cardiology from January to December 2012 were retrospectively analyzed. The follow-up period was 6 to 24 months (the median follow-up time was 11 months). The patients were classified into two groups according to the usage of metformin: metformin group (n=84) and control group (n=92). The clinical data and echocardiography findings were evaluated both at baseline and follow-up. Subgroup analyses were used to assess the effects of hypertension duration and duration of drug medication on metfomin's action. At baseline, there was no significant difference in interventricular septum depth (IVSD), left ventricular posterior wall depth (LVPWD), and left ventricular mass index (LVMI) between the two groups. At the follow-up period, IVSD (P=0.001), LVPWD (P=0.04) and LVMI (P=0.01) were lower in metformin group. Multiple linear regression indicated that metformin had significant influence on LVPWD (P=0.02) and LVMI (P=0.04). At the follow-up period, LVMI was lower in two metformin subgroups. Additionally, LVMI was lower in the group which the patients took metformin for more than one year than that in control group (P=0.04). For patients whose hypertension duration was not shorter than 5 years, IVSD (P=0.01) and LVMI (P=0.02) were lower in metformin group at the follow-up period, compared with control group. Metformin may attenuate hypertrophy of left ventricular in patients with primary hypertension and type 2 diabetes mellitus. In patients with longer hypertension duration and longer duration of metformin use, metformin may show more obvious effects.

  16. Changes in pulmonary arterial wall mechanical properties and lumenal architecture with induced vascular remodeling

    Science.gov (United States)

    Molthen, Robert C.; Heinrich, Amy E.; Haworth, Steven T.; Dawson, Christopher A.

    2004-04-01

    To explore and quantify pulmonary arterial remodeling we used various methods including micro-CT, high-resolution 3-dimensional x-ray imaging, to examine the structure and function of intact pulmonary vessels in isolated rat lungs. The rat is commonly used as an animal model for studies of pulmonary hypertension (PH) and the accompanying vascular remodeling, where vascular remodeling has been defined primarily by changes in the vessel wall composition in response to hypertension inducing stimuli such as chronic hypoxic exposure (CHE) or monocrotaline (MCT) injection. Little information has been provided as to how such changes affect the vessel wall mechanical properties or the lumenal architecture of the pulmonary arterial system that actually account for the hemodynamic consequences of the remodeling. In addition, although the link between primary forms of pulmonary hypertension and inherited genetics is well established, the role that genetic coding plays in hemodynamics and vascular remodeling is not. Therefore, we are utilizing Fawn-Hooded (FH), Sprague-Dawley (SD) and Brown Norway (BN)rat strains along with unique imaging methods to parameterize both vessel distensibility and lumenal morphometry using a principal pulmonary arterial pathway analysis based on self-consistency. We have found for the hypoxia model, in addition to decreased body weight, increased hematocrit, increased right ventricular hypertrophy, the distensibility of the pulmonary arteries is shown to decrease significantly in the presence of remodeling.

  17. Interaction of Left Ventricular Remodeling and Regional Dyssynchrony on Long-Term Prognosis after Cardiac Resynchronization Therapy

    DEFF Research Database (Denmark)

    Tayal, Bhupendar; Sogaard, Peter; Delgado-Montero, Antonia

    2017-01-01

    BACKGROUND: Left ventricular (LV) remodeling in heart failure (HF) manifested by chamber dilatation is associated with worse clinical outcomes. However, the impact of LV dilatation on the association of measures of dyssynchrony with long-term prognosis and resynchronization potential after cardiac...

  18. Relationship of malnutrition, n-terminal pro-b-type natriuretic peptide and ventricular remodeling in patients on maintenance hemodialysis

    Directory of Open Access Journals (Sweden)

    Yu-Ji Lee

    2012-06-01

    In conclusion, malnutrition in HD patients is accompanied by volume overload and associated with increased log NT–proBNP levels independent of volume status, and these levels are independently associated with increased LVMI. This suggests that malnutrition may affect ventricular remodeling or dysfunction in HD patients.

  19. Effect of the direct renin inhibitor aliskiren on left ventricular remodelling following myocardial infarction with systolic dysfunction

    DEFF Research Database (Denmark)

    Solomon, Scott D; Shin, Sung Hee; Shah, Amil

    2011-01-01

    Direct renin inhibitors provide an alternative approach to inhibiting the renin-angiotensin-aldosterone system (RAAS) at the most proximal, specific, and rate-limiting step. We tested the hypothesis that direct renin inhibition would attenuate left ventricular remodelling in patients following...

  20. Effect of the direct renin inhibitor aliskiren on left ventricular remodelling following myocardial infarction with systolic dysfunction

    DEFF Research Database (Denmark)

    Solomon, Scott D; Shin, Sung Hee; Shah, Amil

    2011-01-01

    Direct renin inhibitors provide an alternative approach to inhibiting the renin-angiotensin-aldosterone system (RAAS) at the most proximal, specific, and rate-limiting step. We tested the hypothesis that direct renin inhibition would attenuate left ventricular remodelling in patients following ac...

  1. Prediction of Left Ventricular Remodeling after a Myocardial Infarction: Role of Myocardial Deformation: A Systematic Review and Meta-Analysis.

    Directory of Open Access Journals (Sweden)

    Olivier Huttin

    Full Text Available Left ventricular (LV adverse or reverse remodeling after ST-segment elevation myocardial infarction (MI is the best outcome to assess the benefit of revascularization. Speckle tracking echocardiography (STE may accurately identify early deformation impairment, while also being predictive of LV remodeling during follow-up. This systematic analysis aimed to provide a comprehensive review of current findings on STE as a predictor of LV remodeling after MI.PubMed databases were searched through December 2014 to identify studies in adults targeting the association between LV remodeling and STE. Meta-regression was performed for longitudinal analysis.A total of 23 prospective studies (3066 patients were found eligible. Eleven studies reported an association between STE and adverse remodeling and twelve studies with reverse remodeling. Using peak systolic longitudinal strain, the most accurate cut-off to predict adverse remodeling and reverse remodeling ranged from -12.8% to -10.2% and from -13.7% to -9.5%, respectively. In smaller studies, assessment of circumferential strain and torsion showed additive value in predicting remodeling. Meta-regression analysis revealed that longitudinal STE was associated with adverse remodeling (pooled univariable OR = 1.27, 1.17-1.38, p<0.001; pooled multivariable OR = 1.38, 1.13-1.70, p = 0.002 while pooled ORs of longitudinal STE only tended to predict reverse remodeling (pooled OR = 0.75, 0.54-1.06, p = 0.09.This systematic review suggests that STE is associated with changes in LV volume or function regardless of underlying mechanisms and deformation direction. Meta-regression demonstrates a strong association between peak longitudinal systolic strain and adverse remodeling. Added STE predictive value over other clinical, biological and imaging variables remains to be proven.

  2. Moderate exercise training improves survival and ventricular remodeling in an animal model of left ventricular volume overload.

    Science.gov (United States)

    Lachance, Dominic; Plante, Eric; Bouchard-Thomassin, Andrée-Anne; Champetier, Serge; Roussel, Elise; Drolet, Marie-Claude; Arsenault, Marie; Couet, Jacques

    2009-09-01

    Exercise training has beneficial effects in patients with heart failure, although there is still no clear evidence that it may impact on their survival. There are no data regarding the effects of exercise in subjects with chronic left ventricular (LV) volume overload. Using a rat model of severe aortic valve regurgitation (AR), we studied the effects of long-term exercise training on survival, development of heart failure, and LV myocardial remodeling. One hundred sixty male adult rats were divided in 3 groups: sham sedentary (n=40), AR sedentary (n=80), and AR trained (n=40). Training consisted in treadmill running for up to 30 minutes, 5 times per week for 9 months, at a maximal speed of 20 m/minute. All sham-operated animals survived the entire course of the protocol. After 9 months, 65% of trained animals were alive compared with 46% of sedentary ones (P=0.05). Ejection fractions remained in the normal range (all above 60%) and LV masses between AR groups were similar. There was significantly less LV fibrosis in the trained group and lower LV filling pressures and improved echocardiographic diastolic parameters. Heart rate variability was also improved by exercise. Our data show that moderate endurance training is safe, does not increase the rate of developing heart failure, and most importantly, improves survival in this animal model of chronic LV volume overload. Exercise improved LV diastolic function, heart rate variability, and reduced myocardial fibrosis.

  3. Effect of candesartan treatment on left ventricular remodeling after aortic valve replacement for aortic stenosis

    DEFF Research Database (Denmark)

    Dahl, Jordi S; Videbaek, Lars; Poulsen, Mikael K

    2010-01-01

    In hypertension, angiotensin receptor blockers can augment regression of left ventricular (LV) hypertrophy. It is not known whether this also is the case after aortic valve replacement (AVR) for severe aortic stenosis (AS). To test the hypothesis that treatment with candesartan in addition...... to conventional treatment is able to augment LV and left atrial (LA) reverse remodeling in patients with AS undergoing AVR, we studied 114 patients scheduled for AVR. Patients were randomized to treatment with candesartan 32 mg 1 time/day or conventional therapy immediately after AVR. Patients were followed...... group had greater improvement in longitudinal LV systolic function assessed by tissue Doppler S' wave (0.6 +/- 0.1-cm/s increase in control group vs 1.4 +/- 0.1 cm/s in candesartan group, p = 0.01, p for trend = 0.02) and a decrease in LA volume (p for trend = 0.01). Treatment had no effect on diastolic...

  4. [Occupational stress as a factor of left ventricular myocardial remodeling in people with normal arterial pressure].

    Science.gov (United States)

    Sorokin, A V; Prazdnov, A S; Korovina, O V

    2007-01-01

    The authors studied correlations between occupational stress, caused by high tension at work, and disturbances in 24-hour arterial pressure (AP), lipid level, and left ventricular (LM) myocardial remodeling in locomotive engineers with normal AP. Two hundred and five locomotive engineers with NAP (according to 2004 classification by Russian Scientific Society of Cardiologists) aged 20 to 45 years were included in this cross-sectional study; the subjects present a whole sample of the locomotive crew of Chelyabinsk railway station. The control group consisted of III persons working eight fixed working hours a day whose work was not associated with high tension (turners and metalworkers). The examination of the both groups included bifunctional 24-hour AP and ECG monitoring during the subjects'days off, Echo CG, measurement of blood lipids, and measurement of table salt sensitivity threshold. Also evaluated were the prevalence of horizontal and vertical family background of arterial hypertension, excessive body weight, hypokinesia, and smoking. The study demonstrated that the prevalence of the chief factors of chronic non-infectious diseases as well as the values of office and 24-hour systolic and diastolic arterial pressure (SAD; DAD) were the same in both groups. At the same time, the locomotive engineers with normal AP had unfavorable hemodynamic AP profile (24-hour SAD index (p = 0.008) was lower indicating insufficient SAD decrease at night; the speed of morning SAD and DAD increase was elevated 1.5 to 2 times; heart rate was higher as well) which can be considered signs of hypersympathicotonia. By comparison with the controls, the locomotive engineers had more pronounced morphofunctional changes in the left ventricular (LV), myocardium; LV mass was greater, and LV myocardial hypertrophy was more frequent in this group (17.9 and 1.8%, respectively). The data demonstrate the contribution of occupational stress-related non-hemodynamic factors to myocardial

  5. Effect of ivabradine on left ventricular remodelling after reperfused myocardial infarction: A pilot study.

    Science.gov (United States)

    Gerbaud, Edouard; Montaudon, Michel; Chasseriaud, Warren; Gilbert, Stephen; Cochet, Hubert; Pucheu, Yann; Horovitz, Alice; Bonnet, Jacques; Douard, Hervé; Coste, Pierre

    2014-01-01

    Heart rate is a major determinant of myocardial oxygen demand; in ST-segment elevation myocardial infarction (STEMI), patients treated with primary percutaneous intervention (PPCI), heart rate at discharge correlates with mortality. Ivabradine is a pure heart rate-reducing agent that has no effect on blood pressure and contractility, and can reverse left ventricular (LV) remodelling in patients with heart failure. To evaluate whether ivabradine, when added to current guideline-based therapy, improves LV remodelling in STEMI patients treated with PPCI. This paired-cohort study included 124 patients between June 2011 and July 2012. Ivabradine (5mg twice daily) was given promptly after PPCI, along with beta-blockers, to obtain a heart rate<60 beats per minute (ivabradine group). This group was matched with STEMI patients treated in line with current guidelines, including beta-blockers (bisoprolol), according to age, sex, infarct-related coronary artery, ischaemia time and infarct size determined by initial cardiac magnetic resonance imaging (CMR) (control group). Statistical analyses were performed according to an intention-to-continue treatment principle. CMR data at 3 months were available for 122 patients. Heart rate was lower in the ivabradine group than in the control group during the initial CMR (P=0.02) and the follow-up CMR (P=0.006). At the follow-up CMR, there was a smaller increase in LV end-diastolic volume index in the ivabradine group than in the control group (P=0.04). LV end-systolic volume index remained unchanged in the ivabradine group, but increased in the control group (P=0.01). There was a significant improvement in LV ejection fraction in the ivabradine group compared with in the control group (P=0.04). In successfully reperfused STEMI patients, ivabradine may improve LV remodelling when added to current guideline-based therapy. Copyright © 2013 Elsevier Masson SAS. All rights reserved.

  6. Factors affecting left ventricular remodeling after valve replacement for aortic stenosis. An overview

    Directory of Open Access Journals (Sweden)

    Mhagna Zen

    2006-06-01

    Full Text Available Abstract Although a small percentage of patients with critical aortic stenosis do not develop left ventricle hypertrophy, increased ventricular mass is widely observed in conditions of increased afterload. There is growing epidemiological evidence that hypertrophy is associated with excess cardiac mortality and morbidity not only in patients with arterial hypertension, but also in those undergoing aortic valve replacement. Valve replacement surgery relieves the aortic obstruction and prolongs the life of many patients, but favorable or adverse left ventricular remodeling is affected by a large number of factors whose specific roles are still a subject of debate. Age, gender, hemodynamic factors, prosthetic valve types, myocyte alterations, interstitial structures, blood pressure control and ethnicity can all influence the process of left ventricle mass regression, and myocardial metabolism and coronary artery circulation are also involved in the changes occurring after aortic valve replacement. The aim of this overview is to analyze these factors in the light of our experience, elucidate the important question of prosthesis-patient mismatch by considering the method of effective orifice area, and discuss surgical timings and techniques that can improve the management of patients with aortic valve stenosis and maximize the probability of mass regression.

  7. Identification of Candidate Genes Potentially Relevant to Chamber-Specific Remodeling in Postnatal Ventricular Myocardium

    Directory of Open Access Journals (Sweden)

    Mario Torrado

    2010-01-01

    Full Text Available Molecular predisposition of postnatal ventricular myocardium to chamber-dependent (concentric or eccentric remodeling remains largely elusive. To this end, we compared gene expression in the left (LV versus right ventricle (RV in newborn piglets, using a differential display reverse transcription-PCR (DDRT-PCR technique. Out of more than 5600 DDRT-PCR bands, a total of 153 bands were identified as being differentially displayed. Of these, 96 bands were enriched in the LV, whereas the remaining 57 bands were predominant in the RV. The transcripts, displaying over twofold LV-RV expression differences, were sequenced and identified by BLAST comparison to known mRNA sequences. Among the genes, whose expression was not previously recognized as being chamber-dependent, we identified a small cohort of key regulators of muscle cell growth/proliferation (MAP3K7IP2, MSTN, PHB2, APOBEC3F and gene expression (PTPLAD1, JMJD1C, CEP290, which may be relevant to the chamber-dependent predisposition of ventricular myocardium to respond differentially to pressure (LV and volume (RV overloads after birth. In addition, our data demonstrate chamber-dependent alterations in expression of as yet uncharacterized novel genes, which may also be suitable candidates for association studies in animal models of LV/RV hypertrophy.

  8. Featured Article: Cardioprotective effects of lysyl oxidase inhibition against volume overload-induced extracellular matrix remodeling

    Science.gov (United States)

    El Hajj, Elia C; El Hajj, Milad C; Ninh, Van K

    2015-01-01

    A hallmark of heart failure (HF) is adverse extracellular matrix (ECM) remodeling, which is regulated by the collagen cross-linking enzyme, lysyl oxidase (LOX). In this study, we evaluate the efficacy of LOX inhibition to prevent adverse left ventricular (LV) remodeling and dysfunction using an experimental model of HF. Sprague–Dawley rats were subjected to surgically induced volume overload (VO) by creation of aortocaval fistula (ACF). A LOX inhibitor, beta-aminopropionitrile (BAPN; 100 mg/kg/day), was administered to rats with ACF or sham surgery at eight weeks postsurgery. Echocardiography was used to assess progressive alterations in cardiac ventricular structure and function. Left ventricular (LV) catheterization was used to assess alterations in contractility, stiffness, LV pressure and volume, and other indices of cardiac function. The LV ECM alterations were assessed by: (a) histological staining of collagen, (b) protein expression of collagen types I and III, (c) hydroxyproline assay, and (d) cross-linking assay. LOX inhibition attenuated VO-induced increases in cardiac stress, and attenuated increases in interstitial myocardial collagen, total collagen, and protein levels of collagens I and III. Both echocardiography and catheterization measurements indicated improved cardiac function post-VO in BAPN treated rats vs. untreated. Inhibition of LOX attenuated VO-induced decreases in LV stiffness and cardiac function. Overall, our data indicate that LOX inhibition was cardioprotective in the volume overloaded heart. PMID:26582054

  9. Predictors of the left ventricular dysfunction induced by ventricular arrhythmia

    Directory of Open Access Journals (Sweden)

    А. І. Vytryhovskiy

    2016-08-01

    Full Text Available The most powerful predictor of life-threatening arrhythmia risk is a combination of low heart rate variability with low ejection fraction (EF of the left ventricle. Aim. To identify predictors of left ventricle dysfunction which is induced by ventricular arrhythmia. Materials and methods. To diagnose structural changes of left ventricular functional capacity and reserves in patients with previous myocardial infarction and patients with high and very high cardiovascular risk by SCORE scale and for establishment the relationship between morphological heart changes and pathological phenomenon of heart turbulence echocardiography and study of heart rate turbulence variability were performed. 603 patients were selected for the research. All patients were divided into groups: group 1 – patients with coronary heart disease, but without associated risk factors, such as smoking, obesity, metabolic syndrome; group 2 – patients who smoke tobacco more than 2 years (very high cardiovascular risk by scale SCORE; group 3 – patients with metabolic syndrome without coronary heart disease or arterial hypertension (very high cardiovascular risk by scale SCORE. The control group consisted of 149 persons. Results. The feature of structural changes in patients with myocardial infarction and in patients with a high cardiovascular risk by SCORE with heart rate turbulence compared with cases without НRT is considerably thickening of the left interventricular septum in systole. Based on this, it can be argued that the emergence of ventricular arrhythmia and accordingly phenomenon of heart rate turbulence in patients with existing cardiovascular diseases and risk factors has both morphological and functional character. Significant difference of echocardioscopy parameters in patients with postinfarction cardiosclerosis and risk factors by the SCORE system was established by index of intraventricular septum thickness in systole, and in persons with high risk – in

  10. Preliminary study of beta-blocker therapy on modulation of interleukin-33/ST2 signaling during ventricular remodeling after acute myocardial infarction.

    Science.gov (United States)

    Xia, Jinggang; Qu, Yang; Yin, Chunlin; Xu, Dong

    2017-01-01

    This study aimed to evaluate the role of b-blocker therapy on modulating interleukin (IL)-33/ST2 (interleukin-1 receptor-like 1) signaling during ventricular remodeling related to heart failure (HF) after acute myocardial infarction (AMI). Sprague-Dawley rats that survived surgery to induce AMI were randomly divided into the placebo group and the b-blocker treatment group. A sham group was used as a control. Left ventricular (LV) function variables, the myocardial infarct size, fibrosis and IL-33/ST2 protein expression was measured. Compared with the placebo group, b-blocker treatment significantly improved LV function and reduced infarct size (p blocker treatment (p > 0.05), however, treatment with b-blocker enhanced IL-33/ST2 signaling, with lower expression of sST2 (p blocker therapy might play a beneficial role in the modula-tion of IL-33/ST2 signaling during ventricular remodeling. These results may be helpful in identifying IL-33/ST2 systems as putative b-blocker targets at an early stage after AMI. (Cardiol J 2017; 24, 2: 188-194).

  11. Repeated sauna therapy attenuates ventricular remodeling after myocardial infarction in rats by increasing coronary vascularity of noninfarcted myocardium.

    Science.gov (United States)

    Sobajima, Mitsuo; Nozawa, Takashi; Shida, Takuya; Ohori, Takashi; Suzuki, Takayuki; Matsuki, Akira; Inoue, Hiroshi

    2011-08-01

    Repeated sauna therapy (ST) increases endothelial nitric oxide synthase (eNOS) activity and improves cardiac function in heart failure as well as peripheral blood flow in ischemic limbs. The present study investigates whether ST can increase coronary vascularity and thus attenuate cardiac remodeling after myocardial infarction (MI). We induced MI by ligating the left coronary artery of Wistar rats. The rats were placed in a far-infrared dry sauna at 41°C for 15 min and then at 34°C for 20 min once daily for 4 wk. Cardiac hemodynamic, histopathological, and gene analyses were performed. Despite the similar sizes of MI between the ST and non-ST groups (51.4 ± 0.3 vs. 51.1 ± 0.2%), ST reduced left ventricular (LV) end-diastolic (9.7 ± 0.4 vs. 10.7 ± 0.5 mm, P myocardial atrial natriuretic peptide mRNA levels. Vascular density was reduced in the noninfarcted myocardium of non-ST rats, and the density of cells positive for CD31 and for α-smooth muscle actin was decreased. These decreases were attenuated in ST rats compared with non-ST rats and associated with increases in myocardial eNOS and vascular endothelial growth factor mRNA levels. In conclusion, ST attenuates cardiac remodeling after MI, at least in part, through improving coronary vascularity in the noninfarcted myocardium. Repeated ST might serve as a novel noninvasive therapy for patients with MI.

  12. Absence of cystatin C involvement in ventricular remodelling and heart failure.

    Science.gov (United States)

    Pérez-Calvo, J I; Castiella Muruzábal, T; Búcar Barjud, M; Josa Laorden, C; Sánchez Marteles, M; Lacambra Blasco, I; Asensio López, M C; Pascual Figal, D A

    2016-03-01

    Cystatin C (CysC) is a protease encoded by housekeeping genes. Although its prognostic value in heart failure (HF) is well known, it is debatable whether this value is due to the greater accuracy of CysC in calculating the glomerular filtration rate or to its involvement in pathological ventricular remodelling. The aim of this study was to determine whether CysC expression changes in the myocardium of foetuses of different ages and in the myocardium of adults with various cardiovascular diseases, as well as to analyse the correlation between its serum concentrations and cardiac structure and morphology in a patient group with HF. We analysed the correlations (Pearson's r and Spearman's test) between the serum CysC levels and echocardiographic parameters of 351 patients with HF. We also performed immunohistochemical staining for CysC, metalloproteinase-9 (MMP-9) and desmin in 9 cardiac tissue samples from autopsies of 4 foetuses of different gestational ages and 5 healthy adults or adults with cardiovascular disease. For the patients with HF, there was no correlation between the CysC concentrations and the cardiac parameters measured by 2D echocardiography. The immunohistochemistry showed a weak background staining for CysC in all samples, regardless of age and the presence or absence of cardiovascular diseases. Our results suggest that CysC does not have a significant role in the pathological remodelling of the left ventricle in HF. Copyright © 2015 Elsevier España, S.L.U. y Sociedad Española de Medicina Interna (SEMI). All rights reserved.

  13. Heme oxygenase-1 (HO-1) inhibits postmyocardial infarct remodeling and restores ventricular function.

    Science.gov (United States)

    Liu, Xiaoli; Pachori, Alok S; Ward, Christopher A; Davis, J Paul; Gnecchi, Massimiliano; Kong, Deling; Zhang, Lunan; Murduck, Jared; Yet, Shaw-Fang; Perrella, Mark A; Pratt, Richard E; Dzau, Victor J; Melo, Luis G

    2006-02-01

    We reported previously that predelivery of the anti-oxidant gene heme oxygenase-1 (HO-1) to the heart by adeno associated virus (AAV) markedly reduces injury after acute myocardial infarction (MI). However, the effect of HO-1 gene delivery on postinfarction recovery has not been investigated. In the current study, we assessed the effect of HO-1 gene delivery on post-MI left ventricle (LV) remodeling and function using echocardiographic imaging and histomorphometric approaches. Two groups of Sprague-Dawley rats were injected with 4 x 10(11) particles of AAV-LacZ (control) or AAV-hHO-1 in the LV wall. Eight wk after gene transfer, the animals were subjected to 30 min of ischemia by ligation of left anterior descending artery (LAD) followed by reperfusion. Echocardiographic measurements were obtained in a blinded fashion prior and at 1.5 and 3 months after I/R. Ejection fraction (EF) was reduced by 13% and 40% in the HO-1 and LacZ groups, respectively at 1.5 months after MI. Three months after MI, EF recovered fully in the HO-1, but only partially in the LacZ-treated animals. Post-MI LV dimensions were markedly increased and the anterior wall was markedly thinned in the LacZ-treated animals compared with the HO-1-treated animals. Significant myocardial scarring and fibrosis were observed in the LacZ-group in association with elevated levels of interstitial collagen I and III and MMP-2 activity. Post-MI myofibroblast accumulation was reduced in the HO-1-treated animals, and retroviral overexpression of HO-1 reduced proliferation of isolated cardiac fibroblasts. Our data indicate that rAAV-HO-1 gene transfer markedly reduces fibrosis and ventricular remodeling and restores LV function and chamber dimensions after myocardial infarction.

  14. Metabolic Gene Remodeling and Mitochondrial Dysfunction in Failing Right Ventricular Hypertrophy due to Pulmonary Arterial Hypertension

    Science.gov (United States)

    Gomez-Arroyo, Jose; Mizuno, Shiro; Szczepanek, Karol; Van Tassell, Benjamin; Natarajan, Ramesh; dos Remedios, Cristobal G.; Drake, Jennifer I.; Farkas, Laszlo; Kraskauskas, Donatas; Wijesinghe, Dayanjan S.; Chalfant, Charles E.; Bigbee, John; Abbate, Antonio; Lesnefsky, Edward J.; Bogaard, Harm J.; Voelkel, Norbert F.

    2013-01-01

    Background Right ventricular dysfunction (RVD) is the most frequent cause of death in patients with pulmonary arterial hypertension. Whereas abnormal energy substrate utilization has been implicated in the development of chronic left heart failure, data describing such metabolic remodeling in RVD remain incomplete. Thus, we sought to characterize metabolic gene expression changes and mitochondrial dysfunction in functional and dysfunctional RV hypertrophy. Methods and Results Two different rat models of RV hypertrophy were studied. The model of RVD (SU5416/hypoxia) exhibited a significantly decreased gene expression of PPAR-gamma coactivator-1 alpha (PGC-1α), PPAR-α and ERR-α. The expression of multiple PCG-1α target genes required for fatty acid oxidation (FAO) was similarly decreased. Decreased PGC-1α expression was also associated with a net loss of mitochondrial protein and oxidative capacity. Reduced mitochondrial number was associated with a downregulation of TFAM and other genes required for mitochondrial biogenesis. Electron microscopy demonstrated that in RVD tissue, mitochondria had abnormal shape and size. Lastly, respirometric analysis demonstrated that mitochondria isolated from RVD-tissue had a significantly reduced ADP-stimulated (state 3) rate for complex I. Conversely, functional RV hypertrophy in the pulmonary artery banding (PAB) model showed normal expression of PGC-1α, whereas the expression of FAO genes was either preserved or unregulated. Moreover, PAB-RV tissue exhibited preserved TFAM expression and mitochondrial respiration despite elevated RV pressure-overload. Conclusions Right ventricular dysfunction, but not functional RV hypertrophy in rats, demonstrates a gene expression profile compatible with a multilevel impairment of fatty acid metabolism and significant mitochondrial dysfunction, partially independent of chronic pressure-overload. PMID:23152488

  15. Right ventricular relative wall thickness as a predictor of outcomes and of right ventricular reverse remodeling for patients with pulmonary hypertension.

    Science.gov (United States)

    Sano, Hiroyuki; Tanaka, Hidekazu; Motoji, Yoshiki; Fukuda, Yuko; Mochizuki, Yasuhide; Hatani, Yutaka; Matsuzoe, Hiroki; Hatazawa, Keiko; Shimoura, Hiroyuki; Ooka, Junichi; Ryo-Koriyama, Keiko; Nakayama, Kazuhiko; Matsumoto, Kensuke; Emoto, Noriaki; Hirata, Ken-Ichi

    2017-03-01

    Mid-term right ventricular (RV) reverse remodeling after treatment in patients with pulmonary hypertension (PH) is associated with long-term outcome as well as baseline RV remodeling. However, baseline factors influencing mid-term RV reverse remodeling after treatment and its prognostic capability remain unclear. We studied 54 PH patients. Mid-term RV remodeling was assessed in terms of the RV area, which was traced planimetrically at the end-systole (RVESA). RV reverse remodeling was defined as a relative decrease in the RVESA of at least 15% at 10.2 ± 9.4 months after treatment. Long-term follow-up was 5 years. Adverse events occurred in ten patients (19%) and mid-term RV reverse remodeling after treatment was observed in 37 (69%). Patients with mid-term RV reverse remodeling had more favorable long-term outcomes than those without (log-rank: p = 0.01). Multivariate logistic regression analysis showed that RV relative wall thickness (RV-RWT), as calculated as RV free-wall thickness/RV basal linear dimension at end-diastole, was an independent predictor of mid-term RV reverse remodeling (OR 1.334; 95% CI, 1.039-1.713; p = 0.03). Moreover, patients with RV-RWT ≥0.21 showed better long-term outcomes than did those without (log-rank p = 0.03), while those with RV-RWT ≥0.21 and mid-term RV reverse remodeling had the best long-term outcomes. Patients with RV-RWT <0.21 and without mid-term RV reverse remodeling, on the other hand, had worse long-term outcomes than other sub-groups. In conclusions, RV-RWT could predict mid-term RV reverse remodeling after treatment in PH patients, and was associated with long-term outcomes. Our finding may have clinical implications for better management of PH patients.

  16. Thymoquinone attenuates monocrotaline-induced pulmonary artery hypertension via inhibiting pulmonary arterial remodeling in rats.

    Science.gov (United States)

    Zhu, Ning; Zhao, Xuyong; Xiang, Yijia; Ye, Shiyong; Huang, Jie; Hu, Wuming; Lv, Linchun; Zeng, Chunlai

    2016-10-15

    Pulmonary artery remodeling induced by excess proliferation, migration and apoptosis resistance of pulmonary arterial smooth muscle cells (PASMCs) is a key component in pulmonary artery hypertension (PAH). Thymoquinone (TQ) triggers cancer cells apoptosis through multiple mechanisms. In addition, TQ inhibits migration of human nonsmall-cell lung cancer cells and human glioblastoma cells. In the current study, we investigated effects of TQ on MCT-induced PAH in rats and its underlying mechanisms. After 2weeks of monocrotaline injection (MCT, 60mg/kg), Male Sprague-Dawley rats received TQ (8mg/kg, 12mg/kg, 16mg/kg) or olive oil per day for 2weeks. Hemodynamic changes, right ventricular hypertrophy, and lung morphological features were examined 4weeks later. In addition, TUNEL, PCNA, α-SMA, Bax and Bcl-2 were detected by immunohistochemistry staining. Bax, Bcl-2, cleaved caspase-3, cleaved poly (ADP-ribose) polymerase (PARP) MMP2, MMP9 and activation of p38MAPK and NF-κB were assessed by Western blot. MCT-induced an increase in pulmonary blood pressure and right ventricular hypertrophy, which were attenuated by TQ treatment. TQ also blocked MCT-induced pulmonary arterial remodeling, proliferation of PASMCs, elevation of MMP2 and downregulation of ratio of Bax/Bcl-2, cleaved caspase-3 and cleaved PARP. Furthermore, TQ inhibited MCT-induced activation of p38MAPK and NF-κB. TQ ameliorates MCT-induced pulmonary artery hypertension by inhibiting pulmonary arterial remodeling partially via p38MAPK/NF-κB signaling pathway in rats. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  17. Predictors of ventricular remodelling in patients with reperfused acute myocardial infarction and left ventricular dysfunction candidates for bone marrow cell therapy: insights from the BONAMI trial

    Energy Technology Data Exchange (ETDEWEB)

    Manrique, Alain [Nuclear Medicine, CHU de Caen, Caen (France); Universite de Caen Normandie, EA 4650, Caen (France); CHU de Caen et GIP Cyceron, Caen cedex 6 (France); Lemarchand, Patricia; Delasalle, Beatrice; Lamirault, Guillaume; Trochu, Jean-Noel; Le Tourneau, Thierry [L' Institut du thorax, INSERM, UMR1087, Nantes (France); CNRS, UMR 6291, Nantes (France); Universite de Nantes, Nantes (France); CHU de Nantes, Nantes (France); Lairez, Olivier; Roncalli, Jerome [Institut CARDIOMET-Toulouse, Cardiac Imaging Center, CIC Biotherapies, CHU de Toulouse, Toulouse (France); Sportouch-Duckan, Catherine; Piot, Christophe [Universite Montpellier, Institut de Genomique Fonctionnelle, INSERM U661, CNRS UMR 5203, Montpellier (France); Clinique du Millenaire, Montpellier (France); Le Corvoisier, Philippe [Hopital Henri Mondor, INSERM, Centre d' Investigation Clinique 1430 et U955 equipe 3, Creteil (France); Neuder, Yannick [CHU de Grenoble, Pole Thorax et Vaisseaux, Grenoble (France); Richardson, Marjorie [CHRU Lille, Service d' Explorations Fonctionnelles Cardiovasculaires, Hopital Cardiologique, Lille (France); Lebon, Alain [CHU de Caen, Service de Cardiologie, Caen (France); Teiger, Emmanuel [Hopital Henri Mondor, AP-HP, Unite de Cardiologie Interventionnelle et Federation de Cardiologie, Creteil (France); Hossein-Foucher, Claude [Hopital Salengro CHRU de Lille, Service de Medecine Nucleaire, Lille (France); Universite de Lille 2, UFR de Medecine, Lille (France)

    2016-04-15

    Few data are available regarding the relation of left ventricular (LV) mechanical dyssynchrony to remodelling after acute myocardial infarction (MI) and stem cell therapy. We evaluated the 1-year time course of both LV mechanical dyssynchrony and remodelling in patients enrolled in the BONAMI trial, a randomized, multicenter controlled trial assessing cell therapy in patients with reperfused MI. Patients with acute MI and ejection fraction (EF) ≤ 45 % were randomized to cell therapy or to control and underwent thallium single-photon emission computed tomography (SPECT), radionuclide angiography, and echocardiography at baseline, 3 months, and 1 year. Eighty-three patients with a comprehensive 1-year follow-up were included. LV dyssynchrony was assessed by the standard deviation (SD) of the LV phase histogram using radionuclide angiography. Remodelling was defined as a 20 % increase in LV end-systolic volume index (LVESVI) at 1 year. At baseline, LVEF, wall motion score index, and perfusion defect size were significantly impaired in the 43 patients (52 %) with LV remodelling (all p < 0.001), without significant increase in LV mechanical dyssynchrony. During follow-up, there was a progressive increase in LV SD (p = 0.01). Baseline independent predictors of LV remodelling were perfusion SPECT defect size (p = 0.001), LVEF (p = 0.01) and a history of hypertension (p = 0.043). Bone marrow cell therapy did not affect the time-course of LV remodelling and dyssynchrony. LV remodelling 1 year after reperfused MI is associated with progressive LV dyssynchrony and is related to baseline infarct size and ejection fraction, without impact of cell therapy on this process. (orig.)

  18. Are the metabolic syndrome, blood pressure pattern, and their interaction responsible for the right ventricular remodeling?

    Science.gov (United States)

    Tadic, Marijana; Ivanovic, Branislava; Celic, Vera; Cuspidi, Cesare

    2013-08-01

    The aim of our study was to define the relationship between the metabolic syndrome (MS), nondipping pattern, and their interaction on right ventricular (RV) structural and functional changes in untreated hypertensive patients. This cross-sectional study included 318 recently diagnosed hypertensive patients. MS was defined by the presence of at least 3 National Cholesterol Education Program's Adult Treatment Panel III criteria. All patients underwent 24-h ambulatory blood pressure monitoring and a complete two-dimensional echocardiography examination. MS was found in 144 (45%) hypertensive patients and the nondipping pattern was detected in 147 (46%) patients. Hypertensive patients with MS had higher 24-h and night-time blood pressure levels in comparison with non-MS patients with the same nocturnal blood pressure pattern. RV wall thickness was significantly increased and RV diastolic function was significantly deteriorated in nondippers (with and without MS), but still more impaired in MS patients. MS, nondipping pattern, and their interaction had a huge impact on RV wall thickness, parameters of RV diastolic function (E/At, E/e't, e'/a't), as well as RV global function estimated by the myocardial performance index. Among the MS criteria, only fasting glucose level and abdominal obesity were associated independently with RV hypertrophy, diastolic, and global dysfunction. MS, nondipping pattern, and their interaction significantly impact RV structure, diastolic, and global function. Fasting glucose level and abdominal obesity are the most important MS criteria for RV remodeling in arterial hypertension.

  19. Tomato (Lycopersicon esculentum) or lycopene supplementation attenuates ventricular remodeling after myocardial infarction through different mechanistic pathways.

    Science.gov (United States)

    Pereira, Bruna L B; Reis, Patrícia P; Severino, Fábio E; Felix, Tainara F; Braz, Mariana G; Nogueira, Flávia R; Silva, Renata A C; Cardoso, Ana C; Lourenço, Maria A M; Figueiredo, Amanda M; Chiuso-Minicucci, Fernanda; Azevedo, Paula S; Polegato, Bertha F; Okoshi, Katashi; Fernandes, Ana A H; Paiva, Sergio A R; Zornoff, Leonardo A M; Minicucci, Marcos F

    2017-08-01

    The objective of this study was to evaluate the influence of tomato or lycopene supplementation on cardiac remodeling after myocardial infarction (MI). Male Wistar rats were assigned to four groups: the sham group (animals that underwent simulated surgery) that received a standard chow (S; n=18), the infarcted group that received a standard chow (MI; n=13), the infarcted group supplemented with lycopene (1 mg of lycopene/kg body weight/day) (MIL; n=16) and the infarcted group supplemented with tomato (MIT; n=16). After 3 months, morphological, functional and biochemical analyses were performed. The groups MIL and MIT showed decreased interstitial fibrosis induced by infarction. Tomato supplementation attenuated the hypertrophy induced by MI. In addition, tomato and lycopene improved diastolic dysfunction evaluated by echocardiographic and isolated heart studies, respectively. The MI group showed higher levels of cardiac TNF-α compared to the MIL and MIT groups. Decreased nuclear factor E2-related factor 2 was measured in the MIL group. Lipid hydroperoxide levels were higher in the infarcted groups; however, the MIT group had a lower concentration than did the MI group [S=223±20.8, MI=298±19.5, MIL=277±26.6, MIT=261±28.8 (nmol/g); n=8; Ptomato or lycopene supplementation attenuated the cardiac remodeling process and improved diastolic function after MI. However, the effect of lycopene and tomato supplementation occurred through different mechanistic pathways. Copyright © 2017 Elsevier Inc. All rights reserved.

  20. Pregnancy-induced remodeling of heart valves.

    Science.gov (United States)

    Pierlot, Caitlin M; Moeller, Andrew D; Lee, J Michael; Wells, Sarah M

    2015-11-01

    Recent studies have demonstrated remodeling of aortic and mitral valves leaflets under the volume loading and cardiac expansion of pregnancy. Those valves' leaflets enlarge with altered collagen fiber architecture, content, and cross-linking and biphasic changes (decreases, then increases) in extensibility during gestation. This study extends our analyses to right-sided valves, with additional compositional measurements for all valves. Valve leaflets were harvested from nonpregnant heifers and pregnant cows. Leaflet structure was characterized by leaflet dimensions, and ECM composition was determined using standard biochemical assays. Histological studies assessed changes in cellular and ECM components. Leaflet mechanical properties were assessed using equibiaxial mechanical testing. Collagen thermal stability and cross-linking were assessed using denaturation and hydrothermal isometric tension tests. Pulmonary and tricuspid leaflet areas increased during pregnancy by 35 and 55%, respectively. Leaflet thickness increased by 20% only in the pulmonary valve and largely in the fibrosa (30% thickening). Collagen crimp length was reduced in both the tricuspid (61%) and pulmonary (42%) valves, with loss of crimped area in the pulmonary valve. Thermomechanics showed decreased collagen thermal stability with surprisingly maintained cross-link maturity. The pulmonary leaflet exhibited the biphasic change in extensibility seen in left side valves, whereas the tricuspid leaflet mechanics remained largely unchanged throughout pregnancy. The tricuspid valve exhibits a remodeling response during pregnancy that is significantly diminished from the other three valves. All valves of the heart remodel in pregnancy in a manner distinct from cardiac pathology, with much similarity valve to valve, but with interesting valve-specific responses in the aortic and tricuspid valves. Copyright © 2015 the American Physiological Society.

  1. Severity of structural and functional right ventricular remodeling depends on training load in an experimental model of endurance exercise.

    Science.gov (United States)

    Sanz-de la Garza, Maria; Rubies, Cira; Batlle, Montserrat; Bijnens, Bart H; Mont, Lluis; Sitges, Marta; Guasch, Eduard

    2017-09-01

    Arrhythmogenic right ventricular (RV) remodeling has been reported in response to regular training, but it remains unclear how exercise intensity affects the presence and extent of such remodeling. We aimed to assess the relationship between RV remodeling and exercise load in a long-term endurance training model. Wistar rats were conditioned to run at moderate (MOD; 45 min, 30 cm/s) or intense (INT; 60 min, 60 cm/s) workloads for 16 wk; sedentary rats served as controls. Cardiac remodeling was assessed with standard echocardiographic and tissue Doppler techniques, sensor-tip pressure catheters, and pressure-volume loop analyses. After MOD training, both ventricles similarly dilated (~16%); the RV apical segment deformation, but not the basal segment deformation, was increased [apical strain rate (SR): -2.9 ± 0.5 vs. -3.3 ± 0.6 s -1 , SED vs. MOD]. INT training prompted marked RV dilatation (~26%) but did not further dilate the left ventricle (LV). A reduction in both RV segments' deformation in INT rats (apical SR: -3.3 ± 0.6 vs. -3.0 ± 0.4 s -1 and basal SR: -3.3 ± 0.7 vs. -2.7 ± 0.6 s -1 , MOD vs. INT) led to decreased global contractile function (maximal rate of rise of LV pressure: 2.53 ± 0.15 vs. 2.17 ± 0.116 mmHg/ms, MOD vs. INT). Echocardiography and hemodynamics consistently pointed to impaired RV diastolic function in INT rats. LV systolic and diastolic functions remained unchanged in all groups. In conclusion, we showed a biphasic, unbalanced RV remodeling response with increasing doses of exercise: physiological adaptation after MOD training turns adverse with INT training, involving disproportionate RV dilatation, decreased contractility, and impaired diastolic function. Our findings support the existence of an exercise load threshold beyond which cardiac remodeling becomes maladaptive. NEW & NOTEWORTHY Exercise promotes left ventricular eccentric hypertrophy with no changes in systolic or diastolic function in healthy rats. Conversely, right

  2. Right ventricular failure following chronic pressure overload is associated with reduction in left ventricular mass: evidence for atrophic remodeling

    NARCIS (Netherlands)

    Hardziyenka, Maxim; Campian, Maria E.; Reesink, Herre J.; Surie, Sulaiman; Bouma, Berto J.; Groenink, Maarten; Klemens, Christine A.; Beekman, Leander; Remme, Carol A.; Bresser, Paul; Tan, Hanno L.

    2011-01-01

    We sought to study whether patients with right ventricular failure (RVF) secondary to chronic thromboembolic pulmonary hypertension (CTEPH) have reduced left ventricular (LV) mass, and whether LV mass reduction is caused by atrophy. The LV in patients with CTEPH is underfilled (unloaded). LV

  3. Natural reversal of pulmonary vascular remodeling and right ventricular remodeling in SU5416/hypoxia-treated Sprague-Dawley rats.

    Directory of Open Access Journals (Sweden)

    Makhosazane Zungu-Edmondson

    Full Text Available Pulmonary arterial hypertension (PAH is a lethal disease and improved therapeutic strategies are needed. Increased pulmonary arterial pressure, due to vasoconstriction and vascular remodeling, causes right ventricle (RV failure and death in patients. The treatment of Sprague-Dawley rats with SU5416 injection and exposure to chronic hypoxia for three weeks followed by maintenance in normoxia promote progressive and severe PAH with pathologic features that resemble human PAH. At 5-17 weeks after the SU5416 injection, PAH is developed with pulmonary vascular remodeling as well as RV hypertrophy and fibrosis. The present study investigated subsequent events that occur in these PAH animals.At 35 weeks after the SU5416 injection, rats still maintained high RV pressure, but pulmonary vascular remodeling was significantly reduced. Metabolomics analysis revealed that lungs of normal rats and rats from the 35-week time point had different metabolomics profiles. Despite the maintenance of high RV pressure, fibrosis was resolved at 35-weeks. Masson's trichrome stain and Western blotting monitoring collagen 1 determined 12% fibrosis in the RV at 17-weeks, and this was decreased to 5% at 35-weeks. The level of myofibroblasts was elevated at 17-weeks and normalized at 35-weeks.These results suggest that biological systems possess natural ways to resolve pulmonary and RV remodeling. The resolution of RV fibrosis appears to involve the reduction of myofibroblast-dependent collagen synthesis. Understanding these endogenous mechanisms should help improve therapeutic strategies to treat PAH and RV failure.

  4. Acute left ventricular remodeling following myocardial infarction: coupling of regional healing with remote extracellular matrix expansion.

    Science.gov (United States)

    Chan, William; Duffy, Stephen J; White, David A; Gao, Xiao-Ming; Du, Xiao-Jun; Ellims, Andris H; Dart, Anthony M; Taylor, Andrew J

    2012-09-01

    This prospective study aimed to assess regional and temporal patterns of extracellular matrix (ECM) changes post-myocardial infarction (MI). A fundamental process in the development of ischemic left ventricular (LV) dysfunction is LV remodeling, characterized by structural and functional abnormalities throughout the myocardium including the noninfarcted (remote) myocardium and interstitium. Contrast-enhanced cardiac magnetic resonance (CMR) was performed on MI patients acutely (mean: 5 days post-MI, n = 25) and repeated subacutely (mean: 139 days post-MI, n = 21), and was also performed in a separate group of 15 patients with chronic MI (mean: 2,580 days post-MI, n = 15). Twenty volunteers without a history of MI acted as controls. CMR was used to evaluate LV morphology and function, with post-contrast T1 mapping to semiquantitatively assess changes in the ECM. Putative mediators of myocardial inflammation and fibrosis, including macrophage migration inhibitory factor (MIF), were also measured. Age, sex, and diabetic and hypertensive status did not differ between MI groups and controls. Compared with controls, patients early post-acute MI demonstrated reduced LV ejection fraction (50.25 ± 7.29% vs. 66.7 ± 6.2% [controls], p infarction early post-acute MI, compared with controls, demonstrated reduced systolic thickening (60 ± 5.0% vs. 106 ± 7.6%, p ≤ 0.0002), and lower post-contrast myocardial T1 times suggestive of ECM expansion (437 ± 113 ms vs. 549 ± 119 ms, p = 0.01). In a subgroup analysis between early post-acute MI and controls of similar age and sex, the remote sector post-contrast myocardial T1 times remained significantly shorter post-acute MI compared with controls (420 ± 121 ms vs. 529 ± 113 ms, p = 0.03). Serum levels of MIF inversely correlated with global myocardial T1 time in patients early post-acute MI (r = -0.6, p = 0.01), suggesting a coupling of regional healing with acute LV remodeling. Within a week of acute MI, the remote myocardium

  5. Left ventricular remodeling in the post-infarction heart: a review of cellular, molecular mechanisms, and therapeutic modalities.

    Science.gov (United States)

    Gajarsa, Jason J; Kloner, Robert A

    2011-01-01

    As more patients survive myocardial infarctions, the incidence of heart failure increases. After an infarction, the human heart undergoes a series of structural changes, which are governed by cellular and molecular mechanisms in a pathological metamorphosis termed "remodeling." This review will discuss the current developments in our understanding of these molecular and cellular events in remodeling and the various pharmacological, cellular and device therapies used to treat, and potentially retard, this condition. Specifically, this paper will examine the neurohormonal activity of the renin-angiotensin-aldosterone axis and its molecular effects on the heart. The emerging understanding of the extra-cellular matrix and the various active molecules within it, such as the matrix metalloproteinases, elicits new appreciation for their role in cardiac remodeling and as possible future therapeutic targets. Cell therapy with stem cells is another recent therapy with great potential in improving post-infarcted hearts. Lastly, the cellular and molecular effects of left ventricular assist devices on remodeling will be reviewed. Our increasing knowledge of the cellular and molecular mechanisms underlying cardiac remodeling enables us not only to better understand how our more successful therapies, like angiotensin-converting enzyme inhibitors, work, but also to explore new therapies of the future.

  6. Acute effect of static exercise in patients with aortic regurgitation assessed by cardiovascular magnetic resonance: role of left ventricular remodelling.

    Science.gov (United States)

    Alegret, Josep M; Martinez-Micaelo, Neus; La Gerche, Andre; Franco-Bonafonte, Luis; Rubio-Pérez, Francisco; Calvo, Nahum; Montero, Manuel

    2017-04-01

    In patients with aortic regurgitation (AR), the effect of static exercise (SE) on global ventricular function and AR severity has not been previously studied. Resting and SE cardiovascular magnetic resonance (CMR) were prospectively performed in 23 asymptomatic patients with AR. During SE, we observed a decrease in regurgitant volume in both end-diastolic (EDV) and end-systolic (ESV) volume in both ventricles, as well as a slight decrease in LV ejection fraction (EF). Interestingly, responses varied depending on the degree of LV remodelling. Among patients with a greater degree of LV remodelling, we observed a decrease in LVEF (56 ± 4 % at rest vs 48 ± 7 % during SE, p = 0.001) as a result of a lower decrease in LVESV (with respect to LVEDV. Among patients with a lower degree of LV remodelling, LVEF remained unchanged. RVEF remained unchanged in both groups. In patients with AR, SE provoked a reduction in preload, LV stroke volume, and regurgitant volume. In those patients with higher LV remodelling, we observed a decrease in LVEF, suggesting a lower LV contractile reserve. • In patients with aortic regurgitation, static exercise reduced preload volume. • In patients with aortic regurgitation, static exercise reduced stroke volume. • In patients with aortic regurgitation, static exercise reduced regurgitant volume. • In patients with greater remodelling, static exercise unmasked a lower contractile reserve. • Effect of static exercise on aortic regurgitation was assessed by cardiac MR.

  7. Genetic Dissection of Cardiac Remodeling in an Isoproterenol-Induced Heart Failure Mouse Model.

    Directory of Open Access Journals (Sweden)

    Jessica Jen-Chu Wang

    2016-07-01

    Full Text Available We aimed to understand the genetic control of cardiac remodeling using an isoproterenol-induced heart failure model in mice, which allowed control of confounding factors in an experimental setting. We characterized the changes in cardiac structure and function in response to chronic isoproterenol infusion using echocardiography in a panel of 104 inbred mouse strains. We showed that cardiac structure and function, whether under normal or stress conditions, has a strong genetic component, with heritability estimates of left ventricular mass between 61% and 81%. Association analyses of cardiac remodeling traits, corrected for population structure, body size and heart rate, revealed 17 genome-wide significant loci, including several loci containing previously implicated genes. Cardiac tissue gene expression profiling, expression quantitative trait loci, expression-phenotype correlation, and coding sequence variation analyses were performed to prioritize candidate genes and to generate hypotheses for downstream mechanistic studies. Using this approach, we have validated a novel gene, Myh14, as a negative regulator of ISO-induced left ventricular mass hypertrophy in an in vivo mouse model and demonstrated the up-regulation of immediate early gene Myc, fetal gene Nppb, and fibrosis gene Lgals3 in ISO-treated Myh14 deficient hearts compared to controls.

  8. Impact of chronic use of cibenzoline on left ventricular pressure gradient and left ventricular remodeling in patients with hypertrophic obstructive cardiomyopathy.

    Science.gov (United States)

    Hamada, Mareomi; Ikeda, Shuntaro; Ohshima, Kiyotaka; Nakamura, Masayuki; Kubota, Norio; Ogimoto, Akiyoshi; Shigematsu, Yuji

    2016-03-01

    Cibenzoline, a class Ia antiarrhythmic drug, is useful for reducing the left ventricular pressure gradient (LVPG) in patients with hypertrophic obstructive cardiomyopathy (HOCM). However, chronic effects of cibenzoline on LVPG and left ventricular (LV) remodeling are unknown. Forty-one patients with HOCM participated in this study. Echocardiographic, electrocardiographic, and brain natriuretic peptide (BNP) data collected before and after cibenzoline treatment were compared. From the relation between LVPG and plasma concentration of cibenzoline, an efficacious plasma concentration of cibenzoline was estimated. The mean follow-up period was 74.2±47.1 months. The LVPG decreased from 104.8±62.6mmHg to 27.6±30.5mmHg (pcomplications. Copyright © 2015. Published by Elsevier Ltd.

  9. nNOS is involved in cardiac remodeling induced by chronic ethanol consumption.

    Science.gov (United States)

    Silva, Susana M; Silva, Sérgio; Meireles, Manuela; Leal, Sandra

    2015-03-02

    Chronic ethanol consumption has deleterious effects on the cardiovascular system by directly damaging the myocardial structure and/or by neurohormonal activation. Moreover, nitric oxide (NO) derived from neuronal NO synthase (nNOS) seems to be important to balance the harmful effects of ethanol consumption, because it influences several aspects of cardiac physiology and attenuates pathological cardiac remodeling. However, the impact of chronic ethanol consumption on nNOS expression is unknown. We address this subject in the present study by evaluating whether chronic ethanol consumption induces cardiac remodeling and hypertension, and if these changes are associated with alterations in the expression of nNOS. Male Wistar rats were examined after ingesting a 20% alcohol solution for 6 months. Blood alcohol concentration and brain natriuretic peptide (BNP) levels were measured. The cardiac remodeling was assessed by histomorphometric analysis and the nNOS expression was evaluated by immunofluorescence and western blot analysis. Our results show that chronic ethanol consumption induces cardiac remodeling, namely thinning of left ventricular wall, cardiomyocyte hypertrophy and increased fibrosis, and elevations of arterial blood pressure. They also show that in rats fed with ethanol for 6 months, the circulating BNP levels had decreased as well as the expression of nNOS in left ventricle cardiomyocytes. These findings suggest that the effects of chronic ethanol consumption on BNP levels and/or on nNOS expression in cardiomyocytes may contribute to aggravate the cardiac remodeling and leads to progression of cardiomyopathy. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

  10. Selective class I histone deacetylase inhibition suppresses hypoxia-induced cardiopulmonary remodeling through an antiproliferative mechanism.

    Science.gov (United States)

    Cavasin, Maria A; Demos-Davies, Kim; Horn, Todd R; Walker, Lori A; Lemon, Douglas D; Birdsey, Nicholas; Weiser-Evans, Mary C M; Harral, Julie; Irwin, David C; Anwar, Adil; Yeager, Michael E; Li, Min; Watson, Peter A; Nemenoff, Raphael A; Buttrick, Peter M; Stenmark, Kurt R; McKinsey, Timothy A

    2012-03-02

    Histone deacetylase (HDAC) inhibitors are efficacious in models of hypertension-induced left ventricular heart failure. The consequences of HDAC inhibition in the context of pulmonary hypertension with associated right ventricular cardiac remodeling are poorly understood. This study was performed to assess the utility of selective small-molecule inhibitors of class I HDACs in a preclinical model of pulmonary hypertension. Rats were exposed to hypobaric hypoxia for 3 weeks in the absence or presence of a benzamide HDAC inhibitor, MGCD0103, which selectively inhibits class I HDACs 1, 2, and 3. The compound reduced pulmonary arterial pressure more dramatically than tadalafil, a standard-of-care therapy for human pulmonary hypertension that functions as a vasodilator. MGCD0103 improved pulmonary artery acceleration time and reduced systolic notching of the pulmonary artery flow envelope, which suggests a positive impact of the HDAC inhibitor on pulmonary vascular remodeling and stiffening. Similar results were obtained with an independent class I HDAC-selective inhibitor, MS-275. Reduced pulmonary arterial pressure in MGCD0103-treated animals was associated with blunted pulmonary arterial wall thickening because of suppression of smooth muscle cell proliferation. Right ventricular function was maintained in MGCD0103-treated animals. Although the class I HDAC inhibitor only modestly reduced right ventricular hypertrophy, it had multiple beneficial effects on the right ventricle, which included suppression of pathological gene expression, inhibition of proapoptotic caspase activity, and repression of proinflammatory protein expression. By targeting distinct pathogenic mechanisms, isoform-selective HDAC inhibitors have potential as novel therapeutics for pulmonary hypertension that will complement vasodilator standards of care.

  11. Lung irradiation induces pulmonary vascular remodelling resembling pulmonary arterial hypertension.

    Science.gov (United States)

    Ghobadi, G; Bartelds, B; van der Veen, S J; Dickinson, M G; Brandenburg, S; Berger, R M F; Langendijk, J A; Coppes, R P; van Luijk, P

    2012-04-01

    Pulmonary arterial hypertension (PAH) is a commonly fatal pulmonary vascular disease that is often diagnosed late and is characterised by a progressive rise in pulmonary vascular resistance resulting from typical vascular remodelling. Recent data suggest that vascular damage plays an important role in the development of radiation-induced pulmonary toxicity. Therefore, the authors investigated whether irradiation of the lung also induces pulmonary hypertension. Different sub-volumes of the rat lung were irradiated with protons known to induce different levels of pulmonary vascular damage. Early loss of endothelial cells and vascular oedema were observed in the irradiation field and in shielded parts of the lung, even before the onset of clinical symptoms. 8 weeks after irradiation, irradiated volume-dependent vascular remodelling was observed, correlating perfectly with pulmonary artery pressure, right ventricle hypertrophy and pulmonary dysfunction. The findings indicate that partial lung irradiation induces pulmonary vascular remodelling resulting from acute pulmonary endothelial cell loss and consequential pulmonary hypertension. Moreover, the close resemblance of the observed vascular remodelling with vascular lesions in PAH makes partial lung irradiation a promising new model for studying PAH.

  12. Effect of prolonged inotropic stimulation on ventricular remodeling during healing after myocardial infarction in the dog: mechanistic insights.

    Science.gov (United States)

    Jugdutt, B I; Khan, M I; Jugdutt, S J; Blinston, G E

    1996-06-01

    We hypothesized that positive inotropic stimulation during healing after myocardial infarction might increase contractile pull on the infarct segment, increase expansion and promote ventricular dilation. The effect of prolonged inotropic stimulation on left ventricular remodeling during healing after myocardial infarction has not been studied. The effects of 6 weeks of inotropic stimulation on in vivo changes in left ventricular topography, function and mass (serial two-dimensional echocardiograms), hemodynamic variables, postmortem topography (planimetry) and collagen (hydroxyproline content) were studied in 36 chronically instrumented dogs randomized, 2 days after small anterior infarction, to digoxin (0.125 mg daily) and no digoxin (control group). Heart rate and arterial and left atrial pressures were similar in the two groups, but the first derivative of left ventricular pressure (peak dP/dt), systolic thickening of the noninfarct wall and systolic thinning of the infarct wall were higher in the digoxin group during the 6 weeks. At 6 weeks, infarct scar size and collagen content were similar in both groups, but the digoxin group had more infarct expansion and thinning. Between 2 days and 6 weeks, the digoxin group showed more in vivo diastolic infarct expansion, thinning and bulging; more aneurysm but less global dilation and increase in mass; and no change in ejection fraction. The effects of inotropic stimulation on remodeling were more marked in infarcts with 100% than 85% transmurality. Prolonged inotropic stimulation with digoxin during healing after small anterior infarction increases infarct bulging without decreasing infarct collagen content and preserves global ventricular size, mass and systolic function.

  13. Serotonin Potentiates Transforming Growth Factor-beta3 Induced Biomechanical Remodeling in Avian Embryonic Atrioventricular Valves

    Science.gov (United States)

    Buskohl, Philip R.; Sun, Michelle L.; Thompson, Robert P.; Butcher, Jonathan T.

    2012-01-01

    Embryonic heart valve primordia (cushions) maintain unidirectional blood flow during development despite an increasingly demanding mechanical environment. Recent studies demonstrate that atrioventricular (AV) cushions stiffen over gestation, but the molecular mechanisms of this process are unknown. Transforming growth factor-beta (TGFβ) and serotonin (5-HT) signaling modulate tissue biomechanics of postnatal valves, but less is known of their role in the biomechanical remodeling of embryonic valves. In this study, we demonstrate that exogenous TGFβ3 increases AV cushion biomechanical stiffness and residual stress, but paradoxically reduces matrix compaction. We then show that TGFβ3 induces contractile gene expression (RhoA, aSMA) and extracellular matrix expression (col1α2) in cushion mesenchyme, while simultaneously stimulating a two-fold increase in proliferation. Local compaction increased due to an elevated contractile phenotype, but global compaction appeared reduced due to proliferation and ECM synthesis. Blockade of TGFβ type I receptors via SB431542 inhibited the TGFβ3 effects. We next showed that exogenous 5-HT does not influence cushion stiffness by itself, but synergistically increases cushion stiffness with TGFβ3 co-treatment. 5-HT increased TGFβ3 gene expression and also potentiated TGFβ3 induced gene expression in a dose-dependent manner. Blockade of the 5HT2b receptor, but not 5-HT2a receptor or serotonin transporter (SERT), resulted in complete cessation of TGFβ3 induced mechanical strengthening. Finally, systemic 5-HT administration in ovo induced cushion remodeling related defects, including thinned/atretic AV valves, ventricular septal defects, and outflow rotation defects. Elevated 5-HT in ovo resulted in elevated remodeling gene expression and increased TGFβ signaling activity, supporting our ex-vivo findings. Collectively, these results highlight TGFβ/5-HT signaling as a potent mechanism for control of biomechanical remodeling of

  14. Serotonin potentiates transforming growth factor-beta3 induced biomechanical remodeling in avian embryonic atrioventricular valves.

    Directory of Open Access Journals (Sweden)

    Philip R Buskohl

    Full Text Available Embryonic heart valve primordia (cushions maintain unidirectional blood flow during development despite an increasingly demanding mechanical environment. Recent studies demonstrate that atrioventricular (AV cushions stiffen over gestation, but the molecular mechanisms of this process are unknown. Transforming growth factor-beta (TGFβ and serotonin (5-HT signaling modulate tissue biomechanics of postnatal valves, but less is known of their role in the biomechanical remodeling of embryonic valves. In this study, we demonstrate that exogenous TGFβ3 increases AV cushion biomechanical stiffness and residual stress, but paradoxically reduces matrix compaction. We then show that TGFβ3 induces contractile gene expression (RhoA, aSMA and extracellular matrix expression (col1α2 in cushion mesenchyme, while simultaneously stimulating a two-fold increase in proliferation. Local compaction increased due to an elevated contractile phenotype, but global compaction appeared reduced due to proliferation and ECM synthesis. Blockade of TGFβ type I receptors via SB431542 inhibited the TGFβ3 effects. We next showed that exogenous 5-HT does not influence cushion stiffness by itself, but synergistically increases cushion stiffness with TGFβ3 co-treatment. 5-HT increased TGFβ3 gene expression and also potentiated TGFβ3 induced gene expression in a dose-dependent manner. Blockade of the 5HT2b receptor, but not 5-HT2a receptor or serotonin transporter (SERT, resulted in complete cessation of TGFβ3 induced mechanical strengthening. Finally, systemic 5-HT administration in ovo induced cushion remodeling related defects, including thinned/atretic AV valves, ventricular septal defects, and outflow rotation defects. Elevated 5-HT in ovo resulted in elevated remodeling gene expression and increased TGFβ signaling activity, supporting our ex-vivo findings. Collectively, these results highlight TGFβ/5-HT signaling as a potent mechanism for control of biomechanical

  15. Carbon monoxide pollution promotes cardiac remodeling and ventricular arrhythmia in healthy rats.

    Science.gov (United States)

    Andre, Lucas; Boissière, Julien; Reboul, Cyril; Perrier, Romain; Zalvidea, Santiago; Meyer, Gregory; Thireau, Jérôme; Tanguy, Stéphane; Bideaux, Patrice; Hayot, Maurice; Boucher, François; Obert, Philippe; Cazorla, Olivier; Richard, Sylvain

    2010-03-15

    Epidemiologic studies associate atmospheric carbon monoxide (CO) pollution with adverse cardiovascular outcomes and increased cardiac mortality risk. However, there is a lack of data regarding cellular mechanisms in healthy individuals. To investigate the chronic effects of environmentally relevant CO levels on cardiac function in a well-standardized healthy animal model. Wistar rats were exposed for 4 weeks to filtered air (CO pollution. Myocardial function was assessed by echocardiography and analysis of surface ECG and in vitro by measuring the excitation-contraction coupling of single left ventricular cardiomyocytes. Chronic CO pollution promoted left ventricular interstitial and perivascular fibrosis, with no change in cardiomyocyte size, and had weak, yet significant, effects on in vivo cardiac function. However, both contraction and relaxation of single cardiomyocytes were markedly altered. Several changes occurred, including decreased Ca(2+) transient amplitude and Ca(2+) sensitivity of myofilaments and increased diastolic intracellular Ca(2+) subsequent to decreased SERCA-2a expression and impaired Ca(2+) reuptake. CO pollution increased the number of arrhythmic events. Hyperphosphorylation of Ca(2+)-handling and sarcomeric proteins, and reduced responses to beta-adrenergic challenge were obtained, suggestive of moderate CO-induced hyperadrenergic state. Chronic CO exposure promotes a pathological phenotype of cardiomyocytes in the absence of underlying cardiomyopathy. The less severe phenotype in vivo suggests a role for compensatory mechanisms. Arrhythmia propensity may derive from intracellular Ca(2+) overload.

  16. Contribution of Impaired Parasympathetic Activity to Right Ventricular Dysfunction and Pulmonary Vascular Remodeling in Pulmonary Arterial Hypertension.

    Science.gov (United States)

    da Silva Gonçalves Bos, Denielli; Van Der Bruggen, Cathelijne E; Kurakula, Kondababu; Sun, Xiao-Qing; Casali, Karina R; Casali, Adenauer G; Rol, Nina; Szulcek, Robert; Dos Remedios, Cris; Guignabert, Christophe; Tu, Ly; Dorfmuller, Peter; Humbert, Marc; Wijnker, Paul J M; Kuster, Diederik W D; van der Velden, Jolanda; Goumans, Marie-José; Bogaard, Harm-Jan; Vonk-Noordegraaf, Anton; de Man, Frances S; Handoko, M Louis

    2017-11-22

    Background -Beneficial effects of parasympathetic stimulation have been reported in left heart failure, however, whether it would be beneficial for pulmonary arterial hypertension (PAH) remains to be explored. Here, we investigated the relationship between parasympathetic activity and right ventricular (RV) function in PAH-patients, and the potential therapeutic effects of pyridostigmine (PYR), an oral drug stimulating the parasympathetic activity through acetylcholinesterase (AchE) inhibition, in experimental pulmonary hypertension (PH). Methods -Heart rate recovery (HRR) after maximal cardiopulmonary exercise test was used as a surrogate for parasympathetic activity. RV ejection fraction (RVEF) was assessed in 112 PAH-patients. Expression of nicotinic (α-7nAchR) and muscarinic (m2AchR) receptors, and AchE activity were evaluated in RV (n=11) and lungs (n=7) from PAH-patients undergoing heart/lung transplantation and compared with tissue obtained from controls. In addition, we investigated the effects of PYR (40 mg/kg/day) in experimental PH. PH was induced in male rats by SU5416 (25 mg/kg; s.c.) injection followed by 4 weeks of hypoxia. In a subgroup sympathetic/parasympathetic modulation was assessed by power spectral analysis. At week 6, PH status was confirmed by echocardiography, and rats were randomized to vehicle or treatment (both n=12). At the end-of-study, echocardiography was repeated, with additional RV pressure-volume measurements, along with lung, RV histological and protein analyses. Results -PAH-patients with lower RVEF (<41%) had a significantly reduced HRR in comparison to patients with higher RVEF. In PAH RV-samples, α-7nAchR was increased and AchE activity was reduced versus controls. No difference in m2AchR expression was observed. Chronic PYR-treatment in PH-rats normalized the cardiovascular autonomic function, demonstrated by an increase in parasympathetic activity and baroreflex sensitivity. PYR improved survival, increased RV

  17. Pentoxifylline Attenuates Cardiac Remodeling Induced by Tobacco Smoke Exposure

    Energy Technology Data Exchange (ETDEWEB)

    Minicucci, Marcos; Oliveira, Fernando; Santos, Priscila; Polegato, Bertha; Roscani, Meliza; Fernandes, Ana Angelica; Lustosa, Beatriz; Paiva, Sergio; Zornoff, Leonardo; Azevedo, Paula, E-mail: paulasa@fmb.unesp.br [Faculdade de Medicina de Botucatu, Universidade Estadual Paulista, São Paulo, SP (Brazil)

    2016-05-15

    Tobacco smoke exposure is an important risk factor for cardiac remodeling. Under this condition, inflammation, oxidative stress, energy metabolism abnormalities, apoptosis, and hypertrophy are present. Pentoxifylline has anti‑inflammatory, anti-apoptotic, anti-thrombotic and anti-proliferative properties. The present study tested the hypothesis that pentoxifylline would attenuate cardiac remodeling induced by smoking. Wistar rats were distributed in four groups: Control (C), Pentoxifylline (PX), Tobacco Smoke (TS), and PX-TS. After two months, echocardiography, invasive blood pressure measurement, biochemical, and histological studies were performed. The groups were compared by two-way ANOVA with a significance level of 5%. TS increased left atrium diameter and area, which was attenuated by PX. In the isolated heart study, TS lowered the positive derivate (+dp/dt), and this was attenuated by PX. The antioxidants enzyme superoxide dismutase and glutathione peroxidase were decreased in the TS group; PX recovered these activities. TS increased lactate dehydrogenase (LDH) and decreased 3-hydroxyacyl Coenzyme A dehydrogenases (OH-DHA) and citrate synthase (CS). PX attenuated LDH, 3-OH-DHA and CS alterations in TS-PX group. TS increased IL-10, ICAM-1, and caspase-3. PX did not influence these variables. TS induced cardiac remodeling, associated with increased inflammation, oxidative stress, apoptosis, and changed energy metabolism. PX attenuated cardiac remodeling by reducing oxidative stress and improving cardiac bioenergetics, but did not act upon cardiac cytokines and apoptosis.

  18. Myocardial contractile reserve predicts left ventricular reverse remodeling and cardiac events in dilated cardiomyopathy.

    Science.gov (United States)

    Morimoto, Ryota; Okumura, Takahiro; Hirashiki, Akihiro; Ishii, Hideki; Ichii, Takeo; Aoki, Soichiro; Furusawa, Kenji; Hiraiwa, Hiroaki; Kondo, Toru; Watanabe, Naoki; Kano, Naoaki; Fukaya, Kenji; Sawamura, Akinori; Takeshita, Kyosuke; Bando, Yasuko K; Murohara, Toyoaki

    2017-10-01

    Catecholamine sensitivity estimated using a dobutamine stress test (DST) is recognized as a measure of the beta-adrenergic myocardial contractile reserve, which is involved with left ventricular reverse remodeling (LV-RR). We investigated whether the prognostic ability of the DST for LV-RR could predict cardiac events. There was a total of 192 enrolled patients with dilated cardiomyopathy (DCM). DCM was defined as a LV ejection fraction (LV-EF) ≤45% and LV end-diastolic dimension (LVDd) ≥55mm. One hundred patients were subjected to micromanometer-based measurement of the maximal first derivative of LV pressure (LVdP/dtmax), an index of LV contractility, at baseline and following the infusion of dobutamine (10μg/kg/min) via a pigtail catheter. Percentage changes in LVdP/dtmax from the baseline to peak values under dobutamine stress (ΔLVdP/dtmax) were also calculated. After excluding 17 patients who received cardiac resynchronization therapy within 3 months of undergoing DST (n=15) and who did not receive follow-up echocardiography (n=2), 83 patients were enrolled (52.5±12.3 years). During the follow-up period (4.7±2.6 years), LV-RR was recognized in 49 of 83 patients (59.0%). A multivariate logistic regression analysis revealed that ΔLVdP/dtmax (hazard ratio: 1.024, p=0.007) and the symptom duration (hazard ratio: 0.977, p=0.003) were independent predictors of LV-RR. A receiver operating characteristic curve analysis revealed a ΔLVdP/dtmax cut-off value of 75.1% for LV-RR and a significantly lower cardiac event rate in the ΔLVdP/dtmax≥75.1% group (p=0.045). ΔLVdP/dtmax estimated using DST was a useful predictor of LV-RR and cardiac events in patients with DCM. Copyright © 2017 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.

  19. Impact of Atrial Fibrillation Ablation on Left Ventricular Filling Pressure and Left Atrial Remodeling

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    Simone Nascimento dos Santos

    2014-12-01

    Full Text Available Background: Left ventricular (LV diastolic dysfunction is associated with new-onset atrial fibrillation (AF, and the estimation of elevated LV filling pressures by E/e' ratio is related to worse outcomes in patients with AF. However, it is unknown if restoring sinus rhythm reverses this process. Objective: To evaluate the impact of AF ablation on estimated LV filling pressure. Methods: A total of 141 patients underwent radiofrequency (RF ablation to treat drug-refractory AF. Transthoracic echocardiography was performed 30 days before and 12 months after ablation. LV functional parameters, left atrial volume index (LAVind, and transmitral pulsed and mitral annulus tissue Doppler (e' and E/e' were assessed. Paroxysmal AF was present in 18 patients, persistent AF was present in 102 patients, and long-standing persistent AF in 21 patients. Follow-up included electrocardiographic examination and 24-h Holter monitoring at 3, 6, and 12 months after ablation. Results: One hundred seventeen patients (82.9% were free of AF during the follow-up (average, 18 ± 5 months. LAVind reduced in the successful group (30.2 mL/m2 ± 10.6 mL/m2 to 22.6 mL/m2 ± 1.1 mL/m2, p < 0.001 compared to the non-successful group (37.7 mL/m2 ± 14.3 mL/m2 to 37.5 mL/m2 ± 14.5 mL/m2, p = ns. Improvement of LV filling pressure assessed by a reduction in the E/e' ratio was observed only after successful ablation (11.5 ± 4.5 vs. 7.1 ± 3.7, p < 0.001 but not in patients with recurrent AF (12.7 ± 4.4 vs. 12 ± 3.3, p = ns. The success rate was lower in the long-standing persistent AF patient group (57% vs. 87%, p = 0.001. Conclusion: Successful AF ablation is associated with LA reverse remodeling and an improvement in LV filling pressure.

  20. Impact of Atrial Fibrillation Ablation on Left Ventricular Filling Pressure and Left Atrial Remodeling

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    Santos, Simone Nascimento dos, E-mail: simonens@cardiol.br [Instituto Brasília de Arritmia- Universidade de Brasília, DF (Brazil); Faculdade de Medicina (UnB), Brasília, DF (Brazil); Henz, Benhur Davi; Zanatta, André Rodrigues; Barreto, José Roberto; Loureiro, Kelly Bianca; Novakoski, Clarissa; Santos, Marcus Vinícius Nascimento dos; Giuseppin, Fabio F.; Oliveira, Edna Maria; Leite, Luiz Roberto [Instituto Brasília de Arritmia- Universidade de Brasília, DF (Brazil)

    2014-12-15

    Left ventricular (LV) diastolic dysfunction is associated with new-onset atrial fibrillation (AF), and the estimation of elevated LV filling pressures by E/e' ratio is related to worse outcomes in patients with AF. However, it is unknown if restoring sinus rhythm reverses this process. To evaluate the impact of AF ablation on estimated LV filling pressure. A total of 141 patients underwent radiofrequency (RF) ablation to treat drug-refractory AF. Transthoracic echocardiography was performed 30 days before and 12 months after ablation. LV functional parameters, left atrial volume index (LAVind), and transmitral pulsed and mitral annulus tissue Doppler (e' and E/e') were assessed. Paroxysmal AF was present in 18 patients, persistent AF was present in 102 patients, and long-standing persistent AF in 21 patients. Follow-up included electrocardiographic examination and 24-h Holter monitoring at 3, 6, and 12 months after ablation. One hundred seventeen patients (82.9%) were free of AF during the follow-up (average, 18 ± 5 months). LAVind reduced in the successful group (30.2 mL/m{sup 2} ± 10.6 mL/m{sup 2} to 22.6 mL/m{sup 2} ± 1.1 mL/m{sup 2}, p < 0.001) compared to the non-successful group (37.7 mL/m{sup 2} ± 14.3 mL/m{sup 2} to 37.5 mL/m{sup 2} ± 14.5 mL/m{sup 2}, p = ns). Improvement of LV filling pressure assessed by a reduction in the E/e' ratio was observed only after successful ablation (11.5 ± 4.5 vs. 7.1 ± 3.7, p < 0.001) but not in patients with recurrent AF (12.7 ± 4.4 vs. 12 ± 3.3, p = ns). The success rate was lower in the long-standing persistent AF patient group (57% vs. 87%, p = 0.001). Successful AF ablation is associated with LA reverse remodeling and an improvement in LV filling pressure.

  1. Role of circulating angiotensin converting enzyme 2 in left ventricular remodeling following myocardial infarction: a prospective controlled study.

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    José T Ortiz-Pérez

    Full Text Available Angiotensin-converting enzyme 2 (ACE2 cleaves Angiotensin-II to Angiotensin-(1-7, a cardioprotective peptide. Serum soluble ACE2 (sACE2 activity is raised in chronic heart failure, suggesting a compensatory role in left ventricular dysfunction. Our aim was to study the relationship between sACE2 activity, infarct size, left ventricular systolic function and remodeling following ST-elevation myocardial infarction (STEMI. A contrast-enhanced cardiac magnetic resonance study was performed acutely in 95 patients with first STEMI and repeated at 6 months to measure LV end-diastolic volume index, ejection fraction and infarct size. Baseline sACE2 activities, measured by fluorescent enzymatic assay 24 to 48 hours and at 7 days from admission, were compared to that obtained in 22 matched controls. Patients showed higher sACE2 at baseline than controls (104.4 [87.4-134.8] vs 74.9 [62.8-87.5] RFU/µl/hr, p<0.001. At seven days, sACE2 activity significantly increased from baseline (115.5 [92.9-168.6] RFU/µl/hr, p<0.01. An inverse correlation between sACE2 activity with acute and follow-up ejection fraction was observed (r = -0.519, p<0.001; r = -0.453, p = 0.001, respectively. Additionally, sACE2 directly correlated with infarct size (r = 0.373, p<0.001. Both, infarct size (β = -0.470 [95%CI:-0.691:-0.248], p<0.001 and sACE2 at 7 days (β = -0.025 [95%CI:-0.048:-0.002], p = 0.030 were independent predictors of follow-up ejection fraction. Patients with sACE2 in the upper tertile had a 4.4 fold increase in the incidence of adverse left ventricular remodeling (95% confidence interval: 1.3 to 15.2, p = 0.027. In conclusion, serum sACE2 activity rises in relation to infarct size, left ventricular systolic dysfunction and is associated with the occurrence of left ventricular remodeling.

  2. Compatibility of Astragalus and Salvia extract inhibits myocardial fibrosis and ventricular remodeling by regulation of protein kinase D1 protein

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    Mao, Bingyu; Nuan, Liu; Yang, Lei; Zeng, Xiaotao

    2015-01-01

    Aims: This study is to determine the effect of astragalus and salvia extract on the alteration of myocardium in a rat model of myocardial infarction. Methods: A total of 40 male Sprague-Dawley rats were randomly divided into the sham-operated group, the control group, the Astragalus group, the Salvia group, and the compatibility of Astragalus and Salvia and group. The cardiac functions were determined at 8 weeks after treatment. Hematoxylin-eosin staining was performed to observe the morphology and arrangement of cardiomyocytes. Masson’s trichrome staining was performed to investigate the distribution of myocardial interstitial collagen. Immunohistochemical staining was performed to determine the expression ofprotein kinase D1 in myocardial tissues. Results: In the sham-operated group, the Astragalus group, the Salvia group, and the compatibility of Astragalus and Salvia group, the left ventricular systolic pressure and the maximum rate of left ventricular pressure were significantly increased while the left ventricular end diastolic pressure were significantly decreased when compared with those in the control group (P Salvia group. Contents of collagen fibers in myocardial tissues were decreased in the compatibility of Astragalus and Salvia group (P Salvia group. Conclusions: Compatibility of Astragalus and Salvia extract may inhibit myocardial fibrosis and ventricular remodeling by regulation of protein kinase D1 protein in a rat model of myocardial infarction. PMID:26064267

  3. Left ventricular remodeling and the athlete’s heart, irrespective of quality load training

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    Giorgio Galanti

    2016-11-01

    Full Text Available Abstract Background Regular physical exercise determines a progressive increase of the cardiac mass known as adaptive hypertrophy. Up to now, two morphological echocardiographic heart patterns of athletes have been described by Morganroth in 1975: predominant augmentation of wall thickness, and major cavity size in chamber dimensions in the case of prevalent static or dynamic components. The aim of the study was to follow up the impact of physical training on heart morphology and function in a group of elite soccer and rugby players for at least five years. Method From January 1993 to December 2015 a group of 250 elite soccer players and 114 rugby players were examined: 78 soccer players and 60 rugby players were followed up for 5 years. They were matched with a control group. Results LV dimensions and LVMi were significantly higher in the athletes than in the inactive subjects (LVMi : 123.45; LVMi: 81.5 vs 94.36 g/m2 respectively. After the five-year follow up the athletes showed no significant modifications in cardiac dimensions: (LVDd from 52.00 ± mm to 52.90 ± mm; LVSd increased from 31.58 ± mm to 32.33 ± mm; Left Ventricular CMI from 120.77 to 121.45 g/m2;p = NS in soccer; from 50.43 ± mm to 52.22 ± mm; Left Ventricular Systolic diameter increased from 32.51 ± mm to 32.8 ± mm; Left Ventricular Mass index from 81,5 to 87,4 g/m2;p = NS and no significant enhancement of the aortic root diameter was observed (Aortic root: from 27.39 mm to 31.64 mm in soccer players; from 30,68 mm to 30.95 mm. Conclusions No significant differences were found among the athletes practicing sports with different workload components, and resistance training. In trained athletes the dimensions of the LV chamber and LVMi are generally within the upper limits of the normal range. After a five-year follow-up, the dimensions of the chambers of the heart remain within the normal range, despite being within the the

  4. Molecular mechanism of obesity-induced "metabolic" tissue remodeling.

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    Tanaka, Miyako; Itoh, Michiko; Ogawa, Yoshihiro; Suganami, Takayoshi

    2017-10-31

    Chronic inflammation is a common molecular basis underlying a variety of chronic diseases. Accumulating evidence has also suggested that chronic inflammation contributes to the pathogenesis of obesity and diabetes, which have been considered as a metabolic disease. For the last several decades, there was a dramatic progress in the underlying mechanism of adipose tissue dysfunction induced by obesity. Tissue remodeling is one of the histological features of chronic inflammation, in which stromal cells dramatically change in number and cell type. Indeed, adipose tissue remodeling is induced by various stromal cells and results in the impairment of adipose tissue function such as adipocytokine production and lipid storage, which leads to systemic metabolic disorder. In addition to adipose tissue, liver is another example of obesity-induced tissue remodeling. In this review, we will discuss how obesity induces interstitial fibrosis in adipose tissue and liver, particularly focusing on the role of macrophages. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

  5. Impaired glutathione redox system paradoxically suppresses angiotensin II-induced vascular remodeling.

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    Izawa, Kazuma; Okada, Motoi; Sumitomo, Kazuhiro; Nakagawa, Naoki; Aizawa, Yoshiaki; Kawabe, Junichi; Kikuchi, Kenjiro; Hasebe, Naoyuki

    2014-01-01

    Angiotensin II (AII) plays a central role in vascular remodeling via oxidative stress. However, the interaction between AII and reduced glutathione (GSH) redox status in cardiovascular remodeling remains unknown. In vivo: The cuff-induced vascular injury model was applied to Sprague Dawley rats. Then we administered saline or a GSH inhibitor, buthionine sulfoximine (BSO, 30 mmol/L in drinking water) for a week, subsequently administered 4 more weeks by osmotic pump with saline or AII (200 ng/kg/minute) to the rats. In vitro: Incorporation of bromodeoxyuridine (BrdU) was measured to determine DNA synthesis in cultured rat vascular smooth muscle cells (VSMCs). BSO reduced whole blood GSH levels. Systolic blood pressure was increased up to 215 ± 4 mmHg by AII at 4 weeks (pAII and BSO alone, and was markedly enhanced by AII+BSO. The left ventricular weight to body weight ratio was significantly increased in AII and AII+BSO as compared to controls (2.52 ± 0.08, 2.50 ± 0.09 and 2.10 ± 0.07 mg/g respectively, pAII, significantly increased in AII+BSO. The anti-single-stranded DNA staining revealed increasing apoptotic cells in the neointima of injured arteries in BSO groups. BrdU incorporation in cultured VSMCs with AII was increased dose-dependently. Furthermore it was totally abolished by BSO and was reversed by GSH monoethyl ester. We demonstrated that a vast oxidative stress in impaired GSH redox system totally abolished AII-induced vascular, not cardiac remodeling via enhancement of apoptosis in the neointima and suppression of cell growth in the media. The drastic suppression of remodeling may result in fragile vasculature intolerable to mechanical stress by AII.

  6. Intra-coronary administration of cyclosporine limits infarct size, attenuates remodeling and preserves left ventricular function in porcine acute anterior infarction.

    Science.gov (United States)

    Sheu, Jiunn-Jye; Chua, Sarah; Sun, Cheuk-Kwan; Chang, Li-Teh; Yen, Chia-Hung; Wu, Chiung-Jen; Fu, Morgan; Yip, Hon-Kan

    2011-02-17

    We tested whether intra-coronary administration of cyclosporine effectively preserves left ventricular (LV) function in porcine acute anterior wall infarction (AMI). Eighteen male mini-pigs were randomized into groups 1 (control), 2 (AMI alone), and 3 (AMI with cyclosporine treatment). AMI was induced by ligating middle left anterior descending artery (LAD). Fifteen minutes after ligation, saline and cyclosporine (2.5 mg) combination was injected into LAD beyond ligation in groups 2 and 3, respectively. Echocardiography was performed after 14 days, followed by animal sacrifice. Larger infarcted area (IA) was noted in group 2 than in group 3 (p infarct size, attenuates LV remodeling and preserves LV function. Copyright © 2009. Published by Elsevier Ireland Ltd.

  7. Lysyl oxidase overexpression accelerates cardiac remodeling and aggravates angiotensin II-induced hypertrophy.

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    Galán, María; Varona, Saray; Guadall, Anna; Orriols, Mar; Navas, Miquel; Aguiló, Silvia; de Diego, Alicia; Navarro, María A; García-Dorado, David; Rodríguez-Sinovas, Antonio; Martínez-González, José; Rodriguez, Cristina

    2017-09-01

    Lysyl oxidase (LOX) controls matrix remodeling, a key process that underlies cardiovascular diseases and heart failure; however, a lack of suitable animal models has limited our knowledge with regard to the contribution of LOX to cardiac dysfunction. Here, we assessed the impact of LOX overexpression on ventricular function and cardiac hypertrophy in a transgenic LOX (TgLOX) mouse model with a strong cardiac expression of human LOX. TgLOX mice exhibited high expression of the transgene in cardiomyocytes and cardiofibroblasts, which are associated with enhanced LOX activity and H2O2 production and with cardiofibroblast reprogramming. LOX overexpression promoted an age-associated concentric remodeling of the left ventricle and impaired diastolic function. Furthermore, LOX transgenesis aggravated angiotensin II (Ang II)-induced cardiac hypertrophy and dysfunction, which triggered a greater fibrotic response that was characterized by stronger collagen deposition and cross-linking and high expression of fibrotic markers. In addition, LOX transgenesis increased the Ang II-induced myocardial inflammatory infiltrate, exacerbated expression of proinflammatory markers, and decreased that of cardioprotective factors. Mechanistically, LOX overexpression enhanced oxidative stress and potentiated the Ang II-mediated cardiac activation of p38 MAPK while reducing AMPK activation. Our findings suggest that LOX induces an age-dependent disturbance of diastolic function and aggravates Ang II-induced hypertrophy, which provides novel insights into the role of LOX in cardiac performance.-Galán, M., Varona, S., Guadall, A., Orriols, M., Navas, M., Aguiló, S., de Diego, A., Navarro, M. A., García-Dorado, D., Rodríguez-Sinovas, A., Martínez-González, J., Rodriguez, C. Lysyl oxidase overexpression accelerates cardiac remodeling and aggravates angiotensin II-induced hypertrophy. © FASEB.

  8. Role of chymase in cigarette smoke-induced pulmonary artery remodeling and pulmonary hypertension in hamsters

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    Yang Ting

    2010-03-01

    Full Text Available Abstract Background Cigarette smoking is an important risk factor for pulmonary arterial hypertension (PAH in chronic obstructive pulmonary disease (COPD. Chymase has been shown to function in the enzymatic production of angiotensin II (AngII and the activation of transforming growth factor (TGF-β1 in the cardiovascular system. The aim of this study was to determine the potential role of chymase in cigarette smoke-induced pulmonary artery remodeling and PAH. Methods Hamsters were exposed to cigarette smoke; after 4 months, lung morphology and tissue biochemical changes were examined using immunohistochemistry, Western blotting, radioimmunoassay and reverse-transcription polymerase chain reaction. Results Our results show that chronic cigarette smoke exposure significantly induced elevation of right ventricular systolic pressures (RVSP and medial hypertrophy of pulmonary arterioles in hamsters, concurrent with an increase of chymase activity and synthesis in the lung. Elevated Ang II levels and enhanced TGF-β1/Smad signaling activation were also observed in smoke-exposed lungs. Chymase inhibition with chymostatin reduced the cigarette smoke-induced increase in chymase activity and Ang II concentration in the lung, and attenuated the RVSP elevation and the remodeling of pulmonary arterioles. Chymostatin did not affect angiotensin converting enzyme (ACE activity in hamster lungs. Conclusions These results suggest that chronic cigarette smoke exposure can increase chymase activity and expression in hamster lungs. The capability of activated chymase to induce Ang II formation and TGF-β1 signaling may be part of the mechanism for smoking-induced pulmonary vascular remodeling. Thus, our study implies that blockade of chymase might provide benefits to PAH smokers.

  9. Exercise training attenuates right ventricular remodeling in rats with pulmonary arterial stenosis

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    Brunno Lemes

    2016-12-01

    Full Text Available Introduction: Pulmonary arterial stenosis (PAS is a congenital defect that causes outflow tract obstruction of the right ventricle (RV. Currently, negative issues are reported in the PAS management: not all patients may be eligible to surgeries; there is often the need for another surgery during passage to adulthood; patients with mild stenosis may have later cardiac adverse repercussions. Thus, the search for approaches to counteract the long-term PAS effects showed to be a current target. At the study herein, we evaluated the cardioprotective role of exercise training in rats submitted to PAS for 9 weeks. Methods & Results: Exercise resulted in improved physical fitness and systolic RV function. Exercise also blunted concentric cavity changes, diastolic dysfunction, and fibrosis induced by PAS. Exercise additional benefits were also reported in a pro-survival signal, in which there were increased Akt1 activity and normalized myocardial apoptosis. These findings were accompanied by microRNA-1 downregulation and microRNA-21 upregulation. Moreover, exercise was associated with a higher myocardial abundance of the sarcomeric protein α-MHC and proteins that modulate calcium handling - ryanodine receptor and Serca 2, supporting the potential role of exercise in improving myocardial performance. Conclusion: Our results represent the first demonstration that exercise can attenuate the RV remodeling in an experimental PAS. The cardioprotective effects were associated with positive modulation of RV function, survival signaling pathway, apoptosis, and proteins involved in the regulation of myocardial contractility.

  10. Antifibrillatory effects of renal denervation on ventricular fibrillation in a canine model of pacing-induced heart failure.

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    Luo, Qingzhi; Jin, Qi; Zhang, Ning; Huang, Shangwei; Han, Yanxin; Lin, Changjian; Ling, Tianyou; Chen, Kang; Pan, Wenqi; Wu, Liqun

    2018-01-01

    What is the central question of this study? In the present study, we investigated the effects of renal denervation on the vulnerability to ventricular fibrillation and the ventricular electrical properties in a rapid pacing-induced heart failure canine model. What is the main finding and its importance? Renal denervation significantly attenuated the process of heart failure and improved left ventricular systolic dysfunction, stabilized ventricular electrophysiological properties and decreased the vulnerability of the heart to ventricular fibrillation during heart failure. Thus, renal denervation can attenuate ventricular electrical remodelling and exert a potential antifibrillatory action in a pacing-induced heart failure canine model. In this study, we investigated the effects of renal denervation (RDN) on the vulnerability to ventricular fibrillation (VF) and the ventricular electrical properties in a canine model of pacing-induced heart failure (HF). Eighteen beagles were divided into the following three groups: control (n = 6), HF (n = 6) and HF+RDN (n = 6). Heart failure was induced by rapid right ventricular pacing. Renal denervation was performed simultaneously with the pacemaker implantation in the HF+RDN group. A 64-unipolar basket catheter was used to perform global endocardial mapping of the left ventricle. The restitution properties and dispersion of refractoriness were estimated from the activation recovery intervals (ARIs) by a pacing protocol. The VF threshold (VFT) was defined as the maximal pacing cycle length required to induce VF using a specific pacing protocol. The defibrillation threshold (DFT) was measured by an up-down algorithm. Renal denervation partly restored left ventricular systolic function and attenuated the process of HF. Compared with the control group, the VFT in the HF group was decreased by 27% (106 ± 8.0 versus 135 ± 10 ms, P Renal denervation significantly flattened the ventricular ARI restitution curve by 15% (1

  11. [Effect of sesamin on pulmonary vascular remodeling in rats with monocrotaline-induced pulmonary hypertension].

    Science.gov (United States)

    Li, Xian-wei; Gao, Yun-xing; Li, Shu; Yang, Jie-ren

    2015-04-01

    To observe the effect of sesamin (Ses) on pulmonary vascular remodeling in rats with monocrotaline ( MCT)-induced pulmonary hypertension (PH). Totally 48 male Sprague-Dawley (SD) rats were fed adaptively for one week and then divided into the normal control group, the MCT group, the MCT +Ses (50 mg x kg(-1)) group and the MCT + Ses (100 mg x kg(-1)) group, with 12 rats in each group. The PH rat model was induced through the subcutaneous injection with MCT(60 mg x kg(-1)). After the administration for four weeks, efforts were made to measure the right ventricular systolic pressure( RVSP) and mean pulmonary artery pressure (mPAP) through right jugular vein catheterization, and isolate right ventricle( RV) and left ventricle( LV) +septum (S) and measure their length to calculate RV/ ( LV + S) and ratio of RV to tibial length. Pathologic changes in arterioles were observed by HE staining. Masson's trichrome stain was used to demonstrate changes in collagen deposition of arterioles. The alpha-smooth muscle actin (alpha-SMA) expression in pulmonary arteries was measured by immunohistochemisty. The total antioxidative capacity (T-AOC) and malondialdehyde (MDA) content in pulmonary arteries were determined by the colorimetric method. The protein expressions of collagen I, NOX2 and NOX4 were analyzed by Real-time PCR and Western blot. After the administration for 4 weeks, Ses could attenuate RVSP and mPAP induced by MCT, RV/ (LV + S) and ratio of RV to Tibial length, alpha-SMA and collagen I expressions and remodeling of pulmonary vessels and right ventricle. Meanwhile, Ses could obviously inhibit the expressions of NOX2, NOX4 and MDA content and increase T-AOC. Sesamin could ameliorate pulmonary vascular remodeling induced by monocrotaline in PH rats. Its mechanism may be related to expressions of NOX2 and NOX4 expression and reduction in oxidative stress injury.

  12. Correlation of Ventricular Arrhythmogenesis with Neuronal Remodeling of Cardiac Postganglionic Parasympathetic Neurons in the Late Stage of Heart Failure after Myocardial Infarction

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    Zhang, Dongze; Tu, Huiyin; Wang, Chaojun; Cao, Liang; Muelleman, Robert L.; Wadman, Michael C; Li, Yu-Long

    2017-01-01

    Introduction: Ventricular arrhythmia is a major cause of sudden cardiac death in patients with chronic heart failure (CHF). Our recent study demonstrates that N-type Ca2+ currents in intracardiac ganglionic neurons are reduced in the late stage of CHF rats. Rat intracardiac ganglia are divided into the atrioventricular ganglion (AVG) and sinoatrial ganglion. Only AVG nerve terminals innervate the ventricular myocardium. In this study, we tested the correlation of electrical remodeling in AVG ...

  13. Intermittent Hypoxia-Induced Cardiovascular Remodeling Is Reversed by Normoxia in a Mouse Model of Sleep Apnea.

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    Castro-Grattoni, Anabel L; Alvarez-Buvé, Roger; Torres, Marta; Farré, Ramon; Montserrat, Josep M; Dalmases, Mireia; Almendros, Isaac; Barbé, Ferran; Sánchez-de-la-Torre, Manuel

    2016-06-01

    Intermittent hypoxia (IH) is the principal injurious factor involved in the cardiovascular morbidity and mortality associated with OSA. The gold standard for treatment is CPAP, which eliminates IH and appears to reduce cardiovascular risk. There is no experimental evidence on the reversibility of cardiovascular remodeling after IH withdrawal. The objective of the present study is to assess the reversibility of early cardiovascular structural remodeling induced by IH after resumption of normoxic breathing in a novel recovery animal model mimicking OSA treatment. We investigated cardiovascular remodeling in C57BL/6 mice exposed to IH for 6 weeks vs the normoxia group and its spontaneous recovery after 6 subsequent weeks under normoxia. Aortic expansive remodeling was induced by IH, with intima-media thickening and without lumen perimeter changes. Elastic fiber network disorganization, fragmentation, and estrangement between the end points of disrupted fibers were increased by IH. Extracellular matrix turnover was altered, as visualized by collagen and mucoid interlaminar accumulation. Furthermore, left ventricular perivascular fibrosis was increased by IH, whereas cardiomyocytes size was unaffected. These cardiovascular remodeling events induced by IH were normalized after recovery in normoxia, mimicking CPAP treatment. The early structural cardiovascular remodeling induced by IH was normalized after IH removal, revealing a novel recovery model for studying the effects of OSA treatment. Our findings suggest the clinical relevance of early detection and effective treatment of OSA in patients to prevent the natural course of cardiovascular diseases. Copyright © 2016 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.

  14. Effect of chemokine receptor CXCR4 on hypoxia-induced pulmonary hypertension and vascular remodeling in rats

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    Hales Charles A

    2011-02-01

    Full Text Available Abstract Background CXCR4 is the receptor for chemokine CXCL12 and reportedly plays an important role in systemic vascular repair and remodeling, but the role of CXCR4 in development of pulmonary hypertension and vascular remodeling has not been fully understood. Methods In this study we investigated the role of CXCR4 in the development of pulmonary hypertension and vascular remodeling by using a CXCR4 inhibitor AMD3100 and by electroporation of CXCR4 shRNA into bone marrow cells and then transplantation of the bone marrow cells into rats. Results We found that the CXCR4 inhibitor significantly decreased chronic hypoxia-induced pulmonary hypertension and vascular remodeling in rats and, most importantly, we found that the rats that were transplanted with the bone marrow cells electroporated with CXCR4 shRNA had significantly lower mean pulmonary pressure (mPAP, ratio of right ventricular weight to left ventricular plus septal weight (RV/(LV+S and wall thickness of pulmonary artery induced by chronic hypoxia as compared with control rats. Conclusions The hypothesis that CXCR4 is critical in hypoxic pulmonary hypertension in rats has been demonstrated. The present study not only has shown an inhibitory effect caused by systemic inhibition of CXCR4 activity on pulmonary hypertension, but more importantly also has revealed that specific inhibition of the CXCR4 in bone marrow cells can reduce pulmonary hypertension and vascular remodeling via decreasing bone marrow derived cell recruitment to the lung in hypoxia. This study suggests a novel therapeutic approach for pulmonary hypertension by inhibiting bone marrow derived cell recruitment.

  15. Review in Translational Cardiology: MicroRNAs and Myocardial Fibrosis in Aortic Valve Stenosis, a Deep Insight on Left Ventricular Remodeling.

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    Iacopo, Fabiani; Lorenzo, Conte; Calogero, Enrico; Matteo, Passiatore; Riccardo, Pugliese Nicola; Veronica, Santini; Valentina, Barletta; Riccardo, Liga; Cristian, Scatena; Maria, Mazzanti Chiara; Vitantonio, Di Bello

    2016-01-01

    MicroRNAs (miRNAs) are a huge class of noncoding RNAs that regulate protein-encoding genes (degradation/inhibition of translation). miRNAs are nowadays recognized as regulators of biological processes underneath cardiovascular disorders including hypertrophy, ischemia, arrhythmias, and valvular disease. In particular, circulating miRNAs are promising biomarkers of pathology. This review gives an overview of studies in aortic valve stenosis (AS), exclusively considering myocardial remodeling processes. We searched through literature (till September 2016), all studies and reviews involving miRNAs and AS (myocardial compartment). Although at the beginning of a new era, clear evidences exist on the potential diagnostic and prognostic implementation of miRNAs in the clinical setting. In particular, for AS, miRNAs are modulators of myocardial remodeling and hypertrophy. In our experience, here presented in summary, the principal findings of our research were a confirm of the pathophysiological role in AS of miRNA-21, in particular, the interdependence between textural miRNA-21 and fibrogenic stimulus induced by an abnormal left ventricular pressure overload. Moreover, circulating miRNA-21 (biomarker) levels are able to reflect the presence of significant myocardial fibrosis (MF). Thus, the combined evaluation of miRNA-21, a marker of MF, and hypertrophy, together with advanced echocardiographic imaging (two-dimensional speckle tracking), could fulfill many existing gaps, renewing older guidelines paradigms, also allowing a better risk prognostic and diagnostic strategies.

  16. Reverse left ventricular remodeling is more likely in non ischemic cardiomyopathy patients upgraded to biventricular stimulation after chronic right ventricular pacing

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    Morales Maria-Aurora

    2011-12-01

    Full Text Available Abstract Background Chronic right ventricular (RV apical pacing may lead to left ventricular (LV dyssynchrony and LV dysfunction. In heart failure due to RV pacing, upgrading to biventricular stimulation (CRT can improve NYHA Class and LV function. A proportion of patients do not respond to upgrading. Aim was to assess whether etiology of LV dysfunction accounts for responses to CRT in RV-paced patients. Methods Sixty-two patients treated by CRT, under RV pacing from 50.2 ± 5.4 months, were studied. Cause of LV dysfunction was non-ischemic (NIC in 28 and ischemic cardiomyopathy (IC in 34 patients. Clinical and conventional echocardiographic parameters were available within 1 month before RV pacing, within 1 month before CRT and at 12 ± 2 months of follow-up (FU. Results Decreased LVEF (from 37.0 ± 8.8 to 25.6 ± 6.1%, p 10% decrease in LVESD was observed in 24 patients: 5 with IC, 19 with NIC (p 10% decrease in LVESD remained highly significant (p Conclusions CRT improves functional class even after long-lasting pacing. Reverse remodeling is evident in a small population, more likely with NIC.

  17. Comparison of the Young-Laplace law and finite element based calculation of ventricular wall stress: implications for postinfarct and surgical ventricular remodeling.

    Science.gov (United States)

    Zhang, Zhihong; Tendulkar, Amod; Sun, Kay; Saloner, David A; Wallace, Arthur W; Ge, Liang; Guccione, Julius M; Ratcliffe, Mark B

    2011-01-01

    Both the Young-Laplace law and finite element (FE) based methods have been used to calculate left ventricular wall stress. We tested the hypothesis that the Young-Laplace law is able to reproduce results obtained with the FE method. Magnetic resonance imaging scans with noninvasive tags were used to calculate three-dimensional myocardial strain in 5 sheep 16 weeks after anteroapical myocardial infarction, and in 1 of those sheep 6 weeks after a Dor procedure. Animal-specific FE models were created from the remaining 5 animals using magnetic resonance images obtained at early diastolic filling. The FE-based stress in the fiber, cross-fiber, and circumferential directions was calculated and compared to stress calculated with the assumption that wall thickness is very much less than the radius of curvature (Young-Laplace law), and without that assumption (modified Laplace). First, circumferential stress calculated with the modified Laplace law is closer to results obtained with the FE method than stress calculated with the Young-Laplace law. However, there are pronounced regional differences, with the largest difference between modified Laplace and FE occurring in the inner and outer layers of the infarct borderzone. Also, stress calculated with the modified Laplace is very different than stress in the fiber and cross-fiber direction calculated with FE. As a consequence, the modified Laplace law is inaccurate when used to calculate the effect of the Dor procedure on regional ventricular stress. The FE method is necessary to determine stress in the left ventricle with postinfarct and surgical ventricular remodeling. Copyright © 2011 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.

  18. Comparison of Young Laplace law and finite element based calculation of ventricular wall stress: Implications for post infarct and surgical ventricular remodeling

    Science.gov (United States)

    Zhang, Zhihong; Tendulkar, Amod; Sun, Kay; Stander, Nielen; Saloner, David A.; Wallace, Arthur W.; Ge, Liang; Guccione, Julius M.; Ratcliffe, Mark B.

    2010-01-01

    Objectives Both the Young Laplace law and finite element (FE) based methods have been used to calculate left ventricular (LV) wall stress. We tested the hypothesis that the Young Laplace law is able to reproduce results obtained with FE method. Methods Magnetic resonance (MRI) images with non-invasive tags were used to calculate 3D myocardial strain in five sheep 16 weeks after anteroapical myocardial infarction and in one of those sheep 6 weeks after a Dor procedure. Animal specific FE models were created from the remaining five animals using MRI images obtained at early diastolic filling. FE based stress in the fiber, cross fiber and circumferential directions was calculated and compared to stress calculated with (Young Laplace law) and without (Modified Laplace) the assumption that wall thickness is very much less than the radius of curvature. Results First,circumferential stress calculated with the Modified Laplace law is closer to results obtained with the FE method than stress calculated with the Young Laplace law. However, there are pronounced regional differences with the largest difference between Modified Laplace and FE occurring especially in the inner and outer layers of the infarct borderzone. Also, stress calculated with Modified Laplace is very different than stress in the fiber and cross fiber direction calculated with FE. As a consequence, the Modified Laplace law is inaccurate when used to calculate the effect of the Dor procedure on regional ventricular stress. Conclusion The FE method is necessary to determine stress in the LV with post infarct and surgical ventricular remodeling. PMID:21172505

  19. Myocardial infarction induces structural and functional remodelling of the intrinsic cardiac nervous system.

    Science.gov (United States)

    Rajendran, Pradeep S; Nakamura, Keijiro; Ajijola, Olujimi A; Vaseghi, Marmar; Armour, J Andrew; Ardell, Jeffrey L; Shivkumar, Kalyanam

    2016-01-15

    following MI. The neuronal response was differentially decreased to ventricular vs. atrial pacing post-MI (63% in control vs. 44% in MI to ventricular pacing; P < 0.01). MI induced morphological and phenotypic changes within the ICNS. The alteration of afferent neural signals, and remodelling of convergent neurons, represents a 'neural signature' of ischaemic heart disease. © 2015 The Authors. The Journal of Physiology © 2015 The Physiological Society.

  20. Cardiac structure and function, remodeling, and clinical outcomes among patients with diabetes after myocardial infarction complicated by left ventricular systolic dysfunction, heart failure, or both

    DEFF Research Database (Denmark)

    Shah, Amil M; Hung, Chung-Lieh; Shin, Sung Hee

    2011-01-01

    The mechanisms responsible for the increased risk of heart failure (HF) post-myocardial infarction (MI) may differ between patients with versus without diabetes. We hypothesized that after high-risk MI, patients with diabetes would demonstrate patterns of remodeling that are suggestive of reduced...... ventricular compliance and that are associated with an increased risk of death or HF....

  1. Differences in left ventricular remodelling in patients with aortic stenosis treated with transcatheter aortic valve replacement with corevalve prostheses compared to surgery with porcine or bovine biological prostheses

    DEFF Research Database (Denmark)

    Ngo, Thuc Anh; Hassager, Christian; Thyregod, Hans Gustav Hørsted

    2018-01-01

    Aims: Patients with severe aortic stenosis (AS) can be considered for treatment with either transcatheter (TAVR) or surgical aortic valve replacement (SAVR). The purpose of this study was to compare left ventricular (LV) remodeling in patients with AS after treatment with TAVR or SAVR. Methods an...

  2. Aortic stenosis with abnormal eccentric left ventricular remodeling secondary to hypothyroidism in a Bourdeaux Mastiff

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    Guilherme Augusto Minozzo

    Full Text Available ABSTRACT: This paper describes a case of congenital aortic stenosis with eccentric left ventricular hypertrophy associated with hypothyroidism in a 1-year-old Bourdeaux Mastiff dog. The dog had ascites, apathy, alopecic and erythematous skin lesions in different parts of the body. A two-dimensional echocardiogram revealed aortic valve stenosis, with poststenotic dilation in the ascending aorta. The same exam showed eccentric hypertrophy and dilation of the left ventricle during systole and diastole. Aortic stenosis usually results in concentric left ventricular hypertrophy instead of eccentric hypertrophy; and therefore, this finding was very unusual. Hypothyroidism, which is uncommon in young dogs, may be incriminated as the cause of ventricular dilation, making this report even more interesting. Because hypothyroidism would only result in dilatation, the eccentric hypertrophy was attributed to pressure overload caused by aortic stenosis. Thus, cardiac alterations of this case represent a paradoxical association of both diseases.

  3. Focal myocardial infarction induces global remodeling of cardiac sympathetic innervation: neural remodeling in a spatial context.

    Science.gov (United States)

    Ajijola, Olujimi A; Yagishita, Daigo; Patel, Krishan J; Vaseghi, Marmar; Zhou, Wei; Yamakawa, Kentaro; So, Eileen; Lux, Robert L; Mahajan, Aman; Shivkumar, Kalyanam

    2013-10-01

    Myocardial infarction (MI) induces neural and electrical remodeling at scar border zones. The impact of focal MI on global functional neural remodeling is not well understood. Sympathetic stimulation was performed in swine with anteroapical infarcts (MI; n = 9) and control swine (n = 9). A 56-electrode sock was placed over both ventricles to record electrograms at baseline and during left, right, and bilateral stellate ganglion stimulation. Activation recovery intervals (ARIs) were measured from electrograms. Global and regional ARI shortening, dispersion of repolarization, and activation propagation were assessed before and during sympathetic stimulation. At baseline, mean ARI was shorter in MI hearts than control hearts (365 ± 8 vs. 436 ± 9 ms, P < 0.0001), dispersion of repolarization was greater in MI versus control hearts (734 ± 123 vs. 362 ± 32 ms(2), P = 0.02), and the infarcted region in MI hearts showed longer ARIs than noninfarcted regions (406 ± 14 vs. 365 ± 8 ms, P = 0.027). In control animals, percent ARI shortening was greater on anterior than posterior walls during right stellate ganglion stimulation (P = 0.0001), whereas left stellate ganglion stimulation showed the reverse (P = 0.0003). In infarcted animals, this pattern was completely lost. In 50% of the animals studied, sympathetic stimulation, compared with baseline, significantly altered the direction of activation propagation emanating from the intramyocardial scar during pacing. In conclusion, focal distal anterior MI alters regional and global pattern of sympathetic innervation, resulting in shorter ARIs in infarcted hearts, greater repolarization dispersion, and altered activation propagation. These conditions may underlie the mechanisms by which arrhythmias are initiated when sympathetic tone is enhanced.

  4. Progression of Left Ventricular Dysfunction and Remodelling under Optimal Medical Therapy in CHF Patients: Role of Individual Genetic Background.

    Science.gov (United States)

    Rigolli, Marzia; Cicoira, Mariantonietta; Bergamini, Corinna; Chiampan, Andrea; Rossi, Andrea; Vassanelli, Corrado

    2011-01-05

    Background. Neurohormonal systems play an important role in chronic heart failure (CHF). Due to interindividual heterogeneity in the benefits of therapy, it may be hypothesized that polymorphisms of neurohormonal systems may affect left ventricular (LV) remodelling and systolic function. We aimed to assess whether genetic background of maximally treated CHF patients predicts variations in LV systolic function and volumes. Methods and Results. We prospectively studied 131 CHF outpatients on optimal treatment for at least six months. Echocardiographic evaluations were performed at baseline and after 12 months. Genotype analysis for ACE I/D, β1adrenergic receptor (AR) Arg389Gly, β2AR Arg16Gly, and β2AR Gln27Glu polymorphisms was performed. No differences in baseline characteristics were detected among subgroups. ACE II was a significant predictor of improvement of LV end-diastolic and end-systolic volume (P = .003 and P = .002, respectively) but not of LV ejection fraction (LVEF); β1AR389 GlyGly was related to improvement of LVEF (P = .02) and LV end-systolic volume (P = .01). The predictive value of polymorphisms remained after adjustment for other clinically significant predictors (P < .05 for all). Conclusions. ACE I/D and β1AR Arg389Gly polymorphisms are independent predictors of reverse remodeling and systolic function recovery in CHF patients under optimal treatment.

  5. Progression of Left Ventricular Dysfunction and Remodelling under Optimal Medical Therapy in CHF Patients: Role of Individual Genetic Background

    Directory of Open Access Journals (Sweden)

    Marzia Rigolli

    2011-01-01

    Full Text Available Background. Neurohormonal systems play an important role in chronic heart failure (CHF. Due to interindividual heterogeneity in the benefits of therapy, it may be hypothesized that polymorphisms of neurohormonal systems may affect left ventricular (LV remodelling and systolic function. We aimed to assess whether genetic background of maximally treated CHF patients predicts variations in LV systolic function and volumes. Methods and Results. We prospectively studied 131 CHF outpatients on optimal treatment for at least six months. Echocardiographic evaluations were performed at baseline and after 12 months. Genotype analysis for ACE I/D, β1adrenergic receptor (AR Arg389Gly, β2AR Arg16Gly, and β2AR Gln27Glu polymorphisms was performed. No differences in baseline characteristics were detected among subgroups. ACE II was a significant predictor of improvement of LV end-diastolic and end-systolic volume (=.003 and =.002, respectively but not of LV ejection fraction (LVEF; β1AR389 GlyGly was related to improvement of LVEF (=.02 and LV end-systolic volume (=.01. The predictive value of polymorphisms remained after adjustment for other clinically significant predictors (<.05 for all. Conclusions. ACE I/D and β1AR Arg389Gly polymorphisms are independent predictors of reverse remodeling and systolic function recovery in CHF patients under optimal treatment.

  6. Acute Reverse Remodelling After Transcatheter Aortic Valve Implantation: A Link Between Myocardial Fibrosis and Left Ventricular Mass Regression.

    Science.gov (United States)

    Dobson, Laura Elizabeth; Musa, Tarique A; Uddin, Akhlaque; Fairbairn, Timothy A; Swoboda, Peter P; Erhayiem, Bara; Foley, James; Garg, Pankaj; Haaf, Philip; Fent, Graham J; Malkin, Christopher J; Blackman, Daniel J; Plein, Sven; Greenwood, John P

    2016-12-01

    Despite the wealth of data showing the positive effects on cardiac reverse remodelling in the long-term, the immediate effects of transcatheter aortic valve implantation (TAVI) on the left ventricle are yet to be comprehensively described using cardiovascular magnetic resonance imaging. Also, the link between myocardial fibrosis and acute left ventricular (LV) mass regression is unknown. Fifty-seven patients with severe aortic stenosis awaiting TAVI underwent paired cardiovascular magnetic resonance scans before and early after the procedure (4 [interquartile range, 3-5] days). LV mass, volume, and function were measured. Late gadolinium enhancement (LGE) imaging was performed to assess for the presence of and pattern of myocardial fibrosis. After the procedure, 53 (95%) patients experienced an immediate (10.1 ± 7.1%) reduction in indexed LV mass (LVMi) from 76 ± 15.5 to 68.4 ± 14.7 g/m(2) (P reverse remodelling occurs immediately after TAVI, with significant LV mass regression in the total population and an improvement in LVEF in those with preexisting LV impairment. Those without myocardial fibrosis at baseline experience greater LV mass regression than those with fibrosis. Copyright © 2016 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.

  7. Atorvastatin therapy during the peri-infarct period attenuates left ventricular dysfunction and remodeling after myocardial infarction.

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    Xian-Liang Tang

    Full Text Available Although statins impart a number of cardiovascular benefits, whether statin therapy during the peri-infarct period improves subsequent myocardial structure and function remains unclear. Thus, we evaluated the effects of atorvastatin on cardiac function, remodeling, fibrosis, and apoptosis after myocardial infarction (MI. Two groups of rats were subjected to permanent coronary occlusion. Group II (n = 14 received oral atorvastatin (10 mg/kg/d daily for 3 wk before and 4 wk after MI, while group I (n = 12 received equivalent doses of vehicle. Infarct size (Masson's trichrome-stained sections was similar in both groups. Compared with group I, echocardiographic left ventricular ejection fraction (LVEF and fractional area change (FAC were higher while LV end-diastolic volume (LVEDV and LV end-systolic and end-diastolic diameters (LVESD and LVEDD were lower in treated rats. Hemodynamically, atorvastatin-treated rats exhibited significantly higher dP/dt(max, end-systolic elastance (Ees, and preload recruitable stroke work (PRSW and lower LV end-diastolic pressure (LVEDP. Morphometrically, infarct wall thickness was greater in treated rats. The improvement of LV function by atorvastatin was associated with a decrease in hydroxyproline content and in the number of apoptotic cardiomyocyte nuclei. We conclude that atorvastatin therapy during the peri-infarct period significantly improves LV function and limits adverse LV remodeling following MI independent of a reduction in infarct size. These salubrious effects may be due in part to a decrease in myocardial fibrosis and apoptosis.

  8. Heart failure with anemia: novel findings on the roles of renal disease, interleukins, and specific left ventricular remodeling processes.

    Science.gov (United States)

    O'Meara, Eileen; Rouleau, Jean L; White, Michel; Roy, Karine; Blondeau, Lucie; Ducharme, Anique; Neagoe, Paul-Eduard; Sirois, Martin G; Lavoie, Joël; Racine, Normand; Liszkowski, Mark; Madore, François; Tardif, Jean-Claude; de Denus, Simon

    2014-09-01

    Anemia is a highly prevalent and strong independent prognostic marker in heart failure (HF), yet this association is not completely understood. Whether anemia is simply a marker of disease severity and concomitant chronic kidney disease or represents the activation of other detrimental pathways remains uncertain. We sought to determine which pathophysiological pathways are exacerbated in patients with HF, reduced ejection fraction (HFrEF) and anemia in comparison with those without anemia. In a prospective study involving 151 patients, selected biomarkers were analyzed, each representing proposed contributive mechanisms in the pathophysiology of anemia in HF. We compared clinical, echocardiographic, and circulating biomarkers profiles among patients with HFrEF and anemia (group 1), HFrEF without anemia (group 2), and chronic kidney disease with preserved EF, without established HF (chronic kidney disease control group 3). We demonstrate here that many processes other than those related to chronic kidney disease are involved in the anemia-HF relationship. These are linked to the pathophysiological mechanisms pertaining to left ventricular systolic dysfunction and remodeling, systemic inflammation and volume overload. We found that levels of interleukin-6 and interleukin-10, specific markers of cardiac remodeling (procollagen type III N-terminal peptide, matrix metalloproteinase-2, tissue inhibitor of matrix metalloproteinase 1, left atrial volume), myocardial stretch (NT-proBNP [N-terminal probrain natriuretic peptide]), and myocyte death (troponin T) are related to anemia in HFrEF. Anemia is strongly associated not only with markers of more advanced and active heart disease but also with the level of renal dysfunction in HFrEF. Increased myocardial remodeling, inflammation, and volume overload are the hallmarks of patients with anemia and HF. http://www.clinicaltrials.gov. Unique identifier: NCT00834691. © 2014 American Heart Association, Inc.

  9. Low coronary driving pressure early in the course of myocardial infarction is associated with subendocardial remodelling and left ventricular dysfunction

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    Koike, Marcia Kiyomi; De Carvalho Frimm, Clovis; Cúri, Mariana

    2007-01-01

    Subendocardial remodelling of the left ventricular (LV) non-infarcted myocardium has been poorly investigated. Previously, we have demonstrated that low coronary driving pressure (CDP) early postinfarction was associated with the subsequent development of remote subendocardial fibrosis. The present study aimed at examining the role of CDP in LV remodelling and function following infarction. Haemodynamics were performed in Wistar rats immediately after myocardial infarction (MI group) or sham surgery (SH group) and at days 1, 3, 7 and 28. Heart tissue sections were stained with HE, Sirius red and immunostained for α-actin. Two distinct LV regions remote to infarction were examined: subendocardium (SE) and interstitium (INT). Myocyte necrosis, leucocyte infiltration, myofibroblasts and collagen volume fraction were determined. Compared with SH, MI showed lower CDP and LV systolic and diastolic dysfunction. Necrosis was evident in SE at day 1. Inflammation and fibroplasia predominated in SE as far as day 7. Fibrosis was restricted to SE from day 3 on. Inflammation occurred in INT at days 1 and 3, but at a lower grade than in SE. CDP correlated inversely with SE necrosis (r = −0.65, P = 0.003, at day 1), inflammation (r = −0.76, P < 0.001, at day 1), fibroplasia (r = −0.47, P = 0.04, at day 7) and fibrosis (r = −0.83, P < 0.001, at day 28). Low CDP produced progressive LV expansion. Necrosis at day 1, inflammation at days 3 and 7, and fibroplasia at day 7 correlated inversely with LV function. CDP is a key factor to SE integrity and affects LV remodelling and function following infarction. PMID:17696909

  10. Molecular Remodeling of Left and Right Ventricular Myocardium in Chronic Anthracycline Cardiotoxicity and Post-Treatment Follow Up

    Science.gov (United States)

    Lenčová-Popelová, Olga; Jirkovský, Eduard; Mazurová, Yvona; Lenčo, Juraj; Adamcová, Michaela; Šimůnek, Tomáš; Geršl, Vladimír; Štěrba, Martin

    2014-01-01

    Chronic anthracycline cardiotoxicity is a serious clinical issue with well characterized functional and histopathological hallmarks. However, molecular determinants of the toxic damage and associated myocardial remodeling remain to be established. Furthermore, details on the different propensity of the left and right ventricle (LV and RV, respectively) to the cardiotoxicity development are unknown. Hence, the aim of the investigation was to study molecular changes associated with remodeling of the LV and RV in chronic anthracycline cardiotoxicity and post-treatment follow up. The cardiotoxicity was induced in rabbits with daunorubicin (3 mg/kg/week for 10 weeks) and animals were sacrificed either at the end of the treatment or after an additional 10 weeks. Daunorubicin induced severe and irreversible cardiotoxicity associated with LV dysfunction and typical morphological alterations, whereas the myocardium of the RV showed only mild changes. Both ventricles also showed different expression of ANP after daunorubicin treatment. Daunorubicin impaired the expression of several sarcomeric proteins in the LV, which was not the case of the RV. In particular, a significant drop was found in titin and thick filament proteins at both mRNA and protein level and this might be connected with persistent LV down-regulation of GATA-4. In addition, the LV was more affected by treatment-induced perturbations in calcium handling proteins. LV cardiomyocytes showed marked up-regulation of desmin after the treatment and vimentin was mainly induced in LV fibroblasts, whereas only weaker changes were observed in the RV. Remodeling of extracellular matrix was almost exclusively found in the LV with particular induction of collagen I and IV. Hence, the present study describes profound molecular remodeling of myocytes, non-myocyte cells and extracellular matrix in response to chronic anthracycline treatment with marked asymmetry between LV and RV. PMID:24804796

  11. Molecular remodeling of left and right ventricular myocardium in chronic anthracycline cardiotoxicity and post-treatment follow up.

    Directory of Open Access Journals (Sweden)

    Olga Lenčová-Popelová

    Full Text Available Chronic anthracycline cardiotoxicity is a serious clinical issue with well characterized functional and histopathological hallmarks. However, molecular determinants of the toxic damage and associated myocardial remodeling remain to be established. Furthermore, details on the different propensity of the left and right ventricle (LV and RV, respectively to the cardiotoxicity development are unknown. Hence, the aim of the investigation was to study molecular changes associated with remodeling of the LV and RV in chronic anthracycline cardiotoxicity and post-treatment follow up. The cardiotoxicity was induced in rabbits with daunorubicin (3 mg/kg/week for 10 weeks and animals were sacrificed either at the end of the treatment or after an additional 10 weeks. Daunorubicin induced severe and irreversible cardiotoxicity associated with LV dysfunction and typical morphological alterations, whereas the myocardium of the RV showed only mild changes. Both ventricles also showed different expression of ANP after daunorubicin treatment. Daunorubicin impaired the expression of several sarcomeric proteins in the LV, which was not the case of the RV. In particular, a significant drop was found in titin and thick filament proteins at both mRNA and protein level and this might be connected with persistent LV down-regulation of GATA-4. In addition, the LV was more affected by treatment-induced perturbations in calcium handling proteins. LV cardiomyocytes showed marked up-regulation of desmin after the treatment and vimentin was mainly induced in LV fibroblasts, whereas only weaker changes were observed in the RV. Remodeling of extracellular matrix was almost exclusively found in the LV with particular induction of collagen I and IV. Hence, the present study describes profound molecular remodeling of myocytes, non-myocyte cells and extracellular matrix in response to chronic anthracycline treatment with marked asymmetry between LV and RV.

  12. Thermally induced osteocyte damage initiates a remodelling signaling cascade.

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    Eimear B Dolan

    Full Text Available Thermal elevations experienced by bone during orthopaedic procedures, such as cutting and drilling, exothermal reactions from bone cement, and thermal therapies such as tumor ablation, can result in thermal damage leading to death of native bone cells (osteocytes, osteoblasts, osteoclasts and mesenchymal stem cells. Osteocytes are believed to be the orchestrators of bone remodeling, which recruit nearby osteoclast and osteoblasts to control resorption and bone growth in response to mechanical stimuli and physical damage. However, whether heat-induced osteocyte damage can directly elicit bone remodelling has yet to be determined. This study establishes the link between osteocyte thermal damage and the remodeling cascade. We show that osteocytes directly exposed to thermal elevations (47°C for 1 minute become significantly apoptotic and alter the expression of osteogenic genes (Opg and Cox2. The Rankl/Opg ratio is consistently down-regulated, at days 1, 3 and 7 in MLO-Y4s heat-treated to 47°C for 1 minute. Additionally, the pro-osteoblastogenic signaling marker Cox2 is significantly up-regulated in heat-treated MLO-Y4s by day 7. Furthermore, secreted factors from heat-treated MLO-Y4s administered to MSCs using a novel co-culture system are shown to activate pre-osteoblastic MSCs to increase production of the pro-osteoblastic differentiation marker, alkaline phosphatase (day 7, 14, and calcium deposition (day 21. Most interestingly, an initial pro-osteoclastogenic signaling response (increase Rankl and Rankl/Opg ratio at day 1 followed by later stage pro-osteoblastogenic signaling (down-regulation in Rankl and the Rankl/Opg ratio and an up-regulation in Opg and Cox2 by day 7 was observed in non-heat-treated MLO-Y4s in co-culture when these were exposed to the biochemicals produced by heat-treated MLO-Y4s. Taken together, these results elucidate the vital role of osteocytes in detecting and responding to thermal damage by means of thermally

  13. Benefit of cardiopoietic mesenchymal stem cell therapy on left ventricular remodelling: results from the Congestive Heart Failure Cardiopoietic Regenerative Therapy (CHART-1) study.

    Science.gov (United States)

    Teerlink, John R; Metra, Marco; Filippatos, Gerasimos S; Davison, Beth A; Bartunek, Jozef; Terzic, Andre; Gersh, Bernard J; Povsic, Thomas J; Henry, Timothy D; Alexandre, Bertrand; Homsy, Christian; Edwards, Christopher; Seron, Aymeric; Wijns, William; Cotter, Gad

    2017-11-01

    Left ventricular (LV) reverse remodelling is an important marker of improved outcomes in patients with advanced heart failure (HF). We examined the impact of the intramyocardial administration of bone-marrow-derived, lineage-directed, autologous cardiopoietic mesenchymal stem cells (C3BS-CQR-1) on LV remodelling in patients with advanced HF enrolled in the CHART-1 study. Patients (n=351) with symptomatic advanced HF secondary to ischaemic heart disease, and reduced LV ejection fraction (LVEF CHART-1, intramyocardial administration of cardiopoietic stem cells led to reverse remodelling as evidenced by significant progressive decreases in LVEDV and LVESV through the 52 weeks of follow-up. Further studies are needed to explore the dose response with regard to cell number and injected volume, and reverse remodelling. © 2017 The Authors. European Journal of Heart Failure © 2017 European Society of Cardiology.

  14. Biomass fuel smoke exposure was associated with adverse cardiac remodeling and left ventricular dysfunction in Peru.

    Science.gov (United States)

    Burroughs Peña, M S; Velazquez, E J; Rivera, J D; Alenezi, F; Wong, C; Grigsby, M; Davila-Roman, V G; Gilman, R H; Miranda, J J; Checkley, W

    2017-07-01

    While household air pollution from biomass fuel combustion has been linked to cardiovascular disease, the effects on cardiac structure and function have not been well described. We sought to determine the association between biomass fuel smoke exposure and cardiac structure and function by transthoracic echocardiography. We identified a random sample of urban and rural residents living in the high-altitude region of Puno, Peru. Daily biomass fuel use was self-reported. Participants underwent transthoracic echocardiography. Multivariable linear regression was used to examine the relationship of biomass fuel use with echocardiographic measures of cardiac structure and function, adjusting for age, sex, height, body mass index, diabetes, physical activity, and tobacco use. One hundred and eighty-seven participants (80 biomass fuel users and 107 non-users) were included in this analysis (mean age 59 years, 58% women). After adjustment, daily exposure to biomass fuel smoke was associated with increased left ventricular internal diastolic diameter (P=.004), left atrial diameter (P=.03), left atrial area (four-chamber) (P=.004) and (two-chamber) (P=.03), septal E' (P=.006), and lateral E' (P=.04). Exposure to biomass fuel smoke was also associated with worse global longitudinal strain in the two-chamber view (P=.01). Daily biomass fuel use was associated with increased left ventricular size and decreased left ventricular systolic function by global longitudinal strain. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  15. Remodelling of cardiac sympathetic re-innervation with thoracic spinal cord stimulation improves left ventricular function in a porcine model of heart failure.

    Science.gov (United States)

    Liao, Song-Yan; Liu, Yuan; Zuo, Mingliang; Zhang, Yuelin; Yue, Wensheng; Au, Ka-Wing; Lai, Wing-Hon; Wu, Yangsong; Shuto, Chika; Chen, Peter; Siu, Chung-Wah; Schwartz, Peter J; Tse, Hung-Fat

    2015-12-01

    Thoracic spinal cord stimulation (SCS) has been shown to improve left ventricular ejection fraction (LVEF) in heart failure (HF). Nevertheless, the optimal duration (intermittent vs. continuous) of stimulation and the mechanisms of action remain unclear. We performed chronic thoracic SCS at the level of T1-T3 (50 Hz, pulse width 0.2 ms) in 30 adult pigs with HF induced by myocardial infarction and rapid ventricular pacing for 4 weeks. All the animals were treated with daily oral metoprolol succinate (25 mg) plus ramipril (2.5 mg), and randomized to a control group (n = 10), intermittent SCS (4 h ×3, n = 10) or continuous SCS (24 h, n = 10) for 10 weeks. Serial measurements of LVEF and +dP/dt and serum levels of norepinephrine and B-type natriuretic peptide (BNP) were measured. After sacrifice, immunohistological studies of myocardial sympathetic and parasympathetic nerve sprouting and innervation were performed. Echocardiogram revealed a significant increase in LVEF and +dP/dt at 10 weeks in both the intermittent and continuous SCS group compared with controls (P < 0.05). In both SCS groups, there was diffuse sympathetic nerve sprouting over the infarct, peri-infarct, and normal regions compared with only the peri-infarct and infarct regions in the control group. In addition, sympathetic innervation at the peri-infarct and infarct regions was increased following SCS, but decreased in the control group. Myocardium norepinephrine spillover and serum BNP at 10 weeks was significantly decreased only in the continuous SCS group (P < 0.05). In a porcine model of HF, SCS induces significant remodelling of cardiac sympathetic innervation over the peri-infarct and infarct regions and is associated with improved LV function and reduced myocardial norepinephrine spillover. Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2015. For permissions please email: journals.permissions@oup.com.

  16. Very mild hypothermia during ischemia and reperfusion improves postinfarction ventricular remodeling.

    Science.gov (United States)

    Hamamoto, Hirotsugu; Sakamoto, Hiroaki; Leshnower, Bradley G; Parish, Landi M; Kanemoto, Shinya; Hinmon, Robin; Plappert, Theodore; Miyamoto, Shinji; St John-Sutton, Martin G; Gorman, Joseph H; Gorman, Robert C

    2009-01-01

    Mild hypothermia (anteroapical infarct followed by 3 hours of reperfusion. Temperature was maintained at either 39.5 degrees C (n = 11), 38.5 degrees C (n = 7), 37.5 degrees C (n = 7), 36.5 degrees C (n = 7), or 35.5 degrees C (n = 6) for the entire period of ischemia and reperfusion. The area at risk (AR) and infarct size as a percentage of AR (I/AR) were determined with a double staining and planimetry technique. In the second phase of the study, chronic post-infarction remodeling was assessed in animals with nonreperfused infarcts (n = 6), 1 hour of ischemia followed by reperfusion at 39.5 degrees C (n = 6) and 1 hour of ischemia followed by reperfusion at 37.5 degrees C (n = 6). Remodeling was determined at 8 weeks after infarction using echocardiography. The I/AR in the 39.5 degrees C, 38.5 degrees C, 37.5 degrees C, 36.5 degrees C, and the 35.5 degrees C groups was 71.8 +/- 3.0%, 63.1 +/- 1.9%, 49.4 +/- 1.4%, 38.7 +/- 1.4%, and 21.7 +/- 2.2%, respectively (p < 0.05 between all groups). In the chronic study LV end systolic volume at 8 weeks after infarction was 81 +/- 8 mL in the nonreperfused group, 57 +/- 4 mL in the 39.5 degrees C reperfusion group, and 41 +/- 3 mL in the 37.5 degrees C reperfusion group (p < 0.05 for between group differences). Subtle degrees of hypothermia can significantly improve immediate myocardial salvage and long-term LV remodeling after infarct reperfusion.

  17. [MRT assessment of metabolic and thrombolytic therapy effects on postinfarction left ventricular remodeling].

    Science.gov (United States)

    Tarasov, N I; Kokov, A N; Barbarash, L S

    2006-01-01

    To examine effects of trimetasidine on morphofunctional indices of the left ventricle (LV) in myocardial infarction (MI) patients on combined treatment. Seventy five patients with primary macrofocal MI were randomized into 2 groups. Patients of group 1 (n = 38) received a combination of bisoprolol (beta-blocker) with enalapril (ACE inhibitor) in individual doses under control of blood pressure and blood creatinine level. Group 2 (n = 37) patients received the same combination of drugs and, in addition, trimetasidine in a dose 70 mg/day from postmyocardial day 7-10 for 6 months. Two subgroups from the groups were given systemic thrombolytic therapy (STLT) with streptokinase. MRT and cine-MRT of the heart were made for measurement of LV morphofunctional parameters. Low-field MRT of the heart in MI patients treated with adjuvant STLT (1500000 U within 6 hours after MI onset) and trimetasidine (preductal MB) in a dose 70 mg/day from the disease day 7-10 registered a significant inhibition of pathological LV postinfarction remodeling: a decrease of body surface indexed LV end diastolic volume by 10.3%, systolic volume--by 15.4%, LV myocardial tension--by 14.0%, sphericity index--by 7.1%; an increase in the index of relative wall thickness by 5.3%, cardiac index--by 9.2% compared to the group treated without trimetasidine. 6-month therapy with trimetasidine of MI patients leads to a significant regress of morphofunctional changes accompanying LV remodeling. Pathological LV postinfarction remodeling inhibits significantly in MI patients combined treatment of whom included STLT (streptokinase in a dose 1500,000 U within 6 hours after acute MI onset and trimetasidine in a dose 70 mg/day on postmyocardial infarction day 7-10).

  18. Mitochondrial Remodeling in Chicken Induced Pluripotent Stem-Like Cells.

    Science.gov (United States)

    Choi, Hyun Woo; Kim, Jong Soo; Choi, Sol; Ju Hong, Yean; Byun, Sung June; Seo, Han Geuk; Do, Jeong Tae

    2016-03-15

    Chicken pluripotent stem cells (PSCs), such as embryonic stem cells and blastoderm cells, have been used to study development and differentiation in chicken. However, chicken PSCs are not widely used because they are hard to maintain in long-term culture. Recent reports suggest that chicken somatic cells can be reprogrammed to pluripotent state by defined factors to form induced pluripotent stem cells (iPSCs). These chicken iPSCs showed pluripotent differentiation potential and could be maintained in long-term culture. However, intracytoplasmic remodeling during reprogramming of chicken cells remains largely unknown. In this study, we generated chicken iPS-like cells (ciPSLCs) from chicken embryonic fibroblasts using a retroviral expression system encoding human reprogramming factors. These ciPSLCs could be maintained for more than 10 passages and expressed the endogenous chicken pluripotency markers, cNonog and cSox2. Moreover, the ciPSLCs showed higher nucleus to cytoplasm ratio and contained globular mitochondria with immature cristae. This morphology was similar to that of mammalian PSCs, but different from that of avian somatic cells, which showed lower nucleus to cytoplasm ratio and mature mitochondria. These results suggest that intracytoplasmic organelles in differentiated somatic cells could be successfully remodeled into the pluripotent state during reprogramming in chicken.

  19. Impaired glutathione redox system paradoxically suppresses angiotensin II-induced vascular remodeling.

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    Kazuma Izawa

    Full Text Available BACKGROUND: Angiotensin II (AII plays a central role in vascular remodeling via oxidative stress. However, the interaction between AII and reduced glutathione (GSH redox status in cardiovascular remodeling remains unknown. METHODS: In vivo: The cuff-induced vascular injury model was applied to Sprague Dawley rats. Then we administered saline or a GSH inhibitor, buthionine sulfoximine (BSO, 30 mmol/L in drinking water for a week, subsequently administered 4 more weeks by osmotic pump with saline or AII (200 ng/kg/minute to the rats. In vitro: Incorporation of bromodeoxyuridine (BrdU was measured to determine DNA synthesis in cultured rat vascular smooth muscle cells (VSMCs. RESULTS: BSO reduced whole blood GSH levels. Systolic blood pressure was increased up to 215 ± 4 mmHg by AII at 4 weeks (p<0.01, which was not affected by BSO. Superoxide production in vascular wall was increased by AII and BSO alone, and was markedly enhanced by AII+BSO. The left ventricular weight to body weight ratio was significantly increased in AII and AII+BSO as compared to controls (2.52 ± 0.08, 2.50 ± 0.09 and 2.10 ± 0.07 mg/g respectively, p<0.05. Surprisingly, the co-treatment of BSO totally abolished these morphological changes. Although the vascular circumferential wall stress was well compensated in AII, significantly increased in AII+BSO. The anti-single-stranded DNA staining revealed increasing apoptotic cells in the neointima of injured arteries in BSO groups. BrdU incorporation in cultured VSMCs with AII was increased dose-dependently. Furthermore it was totally abolished by BSO and was reversed by GSH monoethyl ester. CONCLUSIONS: We demonstrated that a vast oxidative stress in impaired GSH redox system totally abolished AII-induced vascular, not cardiac remodeling via enhancement of apoptosis in the neointima and suppression of cell growth in the media. The drastic suppression of remodeling may result in fragile vasculature intolerable to mechanical

  20. Interspecific differences in hypoxia-induced gill remodeling in carp.

    Science.gov (United States)

    Dhillon, Rashpal S; Yao, Lili; Matey, Victoria; Chen, Bo-Jian; Zhang, An-Jie; Cao, Zhen-Dong; Fu, Shi-Jian; Brauner, Colin J; Wang, Yuxiang S; Richards, Jeffrey G

    2013-01-01

    The gills of many fish, but in particular those of crucian carp (Carassius carassius) and goldfish (Carassius auratus), are capable of extensive remodeling in response to changes in oxygen (O2), temperature, and exercise. In this study, we investigated the interspecific variation in hypoxia-induced gill modeling and hypoxia tolerance in 10 closely related groups of cyprinids (nine species, with two strains of Cyprinus carpio). There was significant variation in hypoxia tolerance, measured as the O2 tension (P(O2)) at which fish lost equilibrium (LOEcrit), among the 10 groups of carp. In normoxia, there was a significant, phylogenetically independent relationship between mass-specific gill surface area and LOEcrit, with the more hypoxia-tolerant carp having smaller gills than their less hypoxia-tolerant relatives. All groups of carp, except the Chinese bream (Megalobrama pellegrini), increased mass-specific gill surface area in response to 48 h of exposure to hypoxia (0.7 kPa) through reductions in the interlamellar cell mass (ILCM) volume. The magnitude of the hypoxia-induced reduction in the ILCM was negatively correlated with LOEcrit (and thus positively correlated with hypoxia tolerance), independent of phylogeny. The hypoxia-induced changes in gill morphology resulted in reduced variation in mass-specific gill surface area among species and eliminated the relationship between LOEcrit and mass-specific gill surface area. While behavioral responses to hypoxia differed among the carp groups, there were no significant relationships between hypoxia tolerance and the Po2 at which aquatic surface respiration (ASR) was initiated or the total number of ASR events observed during progressive hypoxia. Our results are the first to show that the extent of gill remodeling in cyprinids is associated with hypoxia tolerance in a phylogenetically independent fashion.

  1. Erythrocyte Stiffness during Morphological Remodeling Induced by Carbon Ion Radiation

    Science.gov (United States)

    Zhang, Baoping; Liu, Bin; Zhang, Hong; Wang, Jizeng

    2014-01-01

    The adverse effect induced by carbon ion radiation (CIR) is still an unavoidable hazard to the treatment object. Thus, evaluation of its adverse effects on the body is a critical problem with respect to radiation therapy. We aimed to investigate the change between the configuration and mechanical properties of erythrocytes induced by radiation and found differences in both the configuration and the mechanical properties with involving in morphological remodeling process. Syrian hamsters were subjected to whole-body irradiation with carbon ion beams (1, 2, 4, and 6 Gy) or X-rays (2, 4, 6, and 12 Gy) for 3, 14 and 28 days. Erythrocytes in peripheral blood and bone marrow were collected for cytomorphological analysis. The mechanical properties of the erythrocytes were determined using atomic force microscopy, and the expression of the cytoskeletal protein spectrin-α1 was analyzed via western blotting. The results showed that dynamic changes were evident in erythrocytes exposed to different doses of carbon ion beams compared with X-rays and the control (0 Gy). The magnitude of impairment of the cell number and cellular morphology manifested the subtle variation according to the irradiation dose. In particular, the differences in the size, shape and mechanical properties of the erythrocytes were well exhibited. Furthermore, immunoblot data showed that the expression of the cytoskeletal protein spectrin-α1 was changed after irradiation, and there was a common pattern among its substantive characteristics in the irradiated group. Based on these findings, the present study concluded that CIR could induce a change in mechanical properties during morphological remodeling of erythrocytes. According to the unique characteristics of the biomechanical categories, we deduce that changes in cytomorphology and mechanical properties can be measured to evaluate the adverse effects generated by tumor radiotherapy. Additionally, for the first time, the current study provides a new

  2. Cardiomyopathy induced by incessant fascicular ventricular tachycardia.

    Science.gov (United States)

    Velázquez-Rodríguez, Enrique; Rodríguez-Piña, Horacio; Pacheco-Bouthillier, Alex; Deras-Mejía, Luz María

    2013-01-01

    A 12-year-old girl with symptoms of fatigue, decreased exercise tolerance and progressive dyspnea (New York Heart Association functional class III) with a possible diagnosis of dilated cardiomyopathy secondary to viral myocarditis. Because of incessant wide QRS tachycardia refractory to antiarrhythmic drugs, she was referred for electrophysiological study. The diagnosis was idiopathic left ventricular tachycardia involving the posterior fascicle of the left bundle branch. After successful treatment with radiofrequency catheter ablation guided by a Purkinje potential radiological and echocardiographic evaluation showed complete reversal of left ventricular function in the first 3 months and no recurrence of arrhythmia during 2 years of follow up. Copyright © 2012 Instituto Nacional de Cardiología Ignacio Chávez. Published by Masson Doyma México S.A. All rights reserved.

  3. Relationship between infarct size and severity measured by gated SPECT and long-term left ventricular remodelling after acute myocardial infarction

    Energy Technology Data Exchange (ETDEWEB)

    Berti, Valentina; Sciagra, Roberto; Pupi, Alberto [University of Florence, Nuclear Medicine Unit, Department of Clinical Physiopathology, Florence (Italy); Acampa, Wanda; Ricci, Francesca; Gallicchio, Rosj; Cuocolo, Alberto [University Federico II and Institute of Biostructures and Bioimages of the National Council of Research, Department of Biomorphological and Functional Sciences, Naples (Italy); Cerisano, Giampaolo [Careggi Hospital, Division of Cardiology, Florence (Italy); Vigorito, Carlo [University Federico II, Department of Clinical Medicine, Cardiovascular and Immunological Sciences, Cardiac Rehabilitation Unit, Naples (Italy)

    2011-06-15

    After acute myocardial infarction (AMI), left ventricular (LV) remodelling may occur despite successful reperfusion. This study aimed to investigate by gated single photon emission computed tomography (SPECT) the long-term evolution of myocardial perfusion and LV function after AMI and to identify the predictors of LV remodelling. Sixty-eight AMI patients successfully treated by primary percutaneous coronary intervention underwent {sup 99m}Tc-sestamibi gated SPECT at 1 month (baseline) and over 6-month follow-up after the acute event. LV remodelling was defined as 20% increase in LV end-diastolic volume at follow-up. At baseline, patients with remodelling (n = 14) showed larger (infarct size 29.3 {+-} 7.8%) and more transmural (infarct severity 0.28 {+-} 0.10) infarctions, and reduced LV ejection fraction (35.4 {+-} 5.6%), but similar LV volume indexes, compared to patients without remodelling (n = 54) (infarct size 20.8 {+-} 14.4%, p < 0.05, infarct severity 0.40 {+-} 0.11, p < 0.001, ejection fraction 44.5 {+-} 9.2, p < 0.001). At stepwise multivariate regression analysis, infarct severity showed the best predictive value for predicting LV remodelling (F = 5.54, p < 0.05). Using the thresholds identified by receiver-operating characteristic curve analysis, infarct size and severity detected patients with remodelling with 75% accuracy and 95% negative predictive value. Infarct resorption (defined as the defect size difference between follow-up and baseline) was comparable between patients with (-4.4 {+-} 8.4%) and without remodelling (-6.8 {+-} 9.4%) (p = NS). Perfusion parameters assessed by gated SPECT in the subacute phase after successfully treated AMI correlate with changes in functional parameters at long-term follow-up. Infarct severity is more effective than infarct size, but both are helpful for predicting LV remodelling. (orig.)

  4. The association of sleep disordered breathing with left ventricular remodeling in CAD patients: a cross-sectional study.

    Science.gov (United States)

    Alonderis, Audrius; Raskauskiene, Nijole; Gelziniene, Vaidute; Mickuviene, Narseta; Brozaitiene, Julija

    2017-09-18

    There is still insufficient knowledge on the potential effect of mild to moderate sleep-disordered breathing (SDB) that is widely prevalent, often asymptomatic, and largely undiagnosed in patients with stable coronary artery disease (CAD). SDB affects 34% of men and 17% of women aged between 30 and 70. The objective of this study was to evaluate the association between SDB and left ventricular (LV) hypertrophy as well as structural remodeling in stable CAD patients. The study was based on a cross-sectional design. Echocardiography and polysomnography was performed in 772 patients with CAD and with untreated sleep apnea. All study participants underwent testing by Epworth Sleepiness Scale questionnaire. Their mean age, NYHA and left ventricular ejection fraction were, respectively: 57 ± 9 years, 2.1 ± 0.5 and 51 ± 8%, and 76% were men. Sleep apnea (SA) was defined as an apnea-hypopnea-index (AHI) ≥5 events/h, and, non-SA, as an AHI CAD patients with SA. The patients with SA had significantly higher values of both interventricular septal thickness and posterior wall thickness. Multiple logistic regression analysis showed that even mild sleep apnea was an independent predictor for LVH by wall thickness criteria and concentric LVH (OR = 1.5; 95% CI 1.04-2.2 and OR = 1.9; 1.3-2.9 respectively). We concluded that unrecognized sleep apnea was highly prevalent among patients with stable CAD, and the majority of those patients did not report daytime sleepiness. Mild to moderate sleep apnea was associated with increased LV wall thickness, LV mass, and with higher prevalence of concentric LV hypertrophy independently of coexisting obesity, hypertension, diabetes mellitus or advancing age.

  5. Therapeutic impact of dietary vitamin D supplementation for preventing right ventricular remodeling and improving survival in pulmonary hypertension.

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    Hiroaki Tanaka

    Full Text Available Pulmonary hypertension (PH, caused by elevated pulmonary vascular resistance, leads to right heart failure and ultimately death. Vitamin D deficiency can predispose individuals to hypertension and left ventricular dysfunction; however, it remains unknown how serum vitamin D level is related to PH and right ventricular (RV dysfunction.Serum 25-hydroxyvitamin D [25(OHD] levels were assessed in PH patients for an association with disease severity. To examine whether vitamin D supplementation could prevent the development of pulmonary vascular remodeling and RV dysfunction in PH, a rat model of PH was fed either normal chow or a high vitamin D diet.The majority (95.1% of PH patients had 25(OHD levels in the insufficiency range, which is associated with increased mean pulmonary artery pressure, increased pulmonary vascular resistance, and decreased cardiac output in PH patients. Vitamin D supplementation significantly increased serum 25(OHD levels and improved survival in PH rats. Interestingly, while the supplemented rats retained the typical increases in medial thickness of the muscular pulmonary arteries and RV systolic pressure, RV cardiomyocyte hypertrophy and B-type natriuretic peptide expression was significantly attenuated.Vitamin D deficiency is frequently seen in patients diagnosed with PH and low serum levels of 25(OHD are associated with severity of PH and RV dysfunction. Vitamin D supplementation in PH rats improved survival via ameliorating pathological RV hypertrophy. These findings suggest an insufficient intake of vitamin D might potentially accelerate RV dysfunction, leading to a crucial clinical impact of vitamin D supplementation in PH.

  6. Relationship between infarct tissue characteristics and left ventricular remodeling in patients with versus without early revascularization for acute myocardial infarction as assessed with contrast-enhanced cardiovascular magnetic resonance imaging

    NARCIS (Netherlands)

    Olimulder, Marlon; Olimulder, M.A.G.M.; Galjee, M.A.; Wagenaar, L.J.; van Es, J.; van der Palen, Jacobus Adrianus Maria; von Birgelen, Clemens

    2012-01-01

    Left ventricular (LV) remodeling following myocardial infarction (MI) is the result of complex interactions between various factors, including presence or absence of early revascularization. The impact of early revascularization on the relationship between infarct tissue characteristics and LV

  7. Residual Stress Impairs Pump Function After Surgical Ventricular Remodeling: A Finite Element Analysis.

    Science.gov (United States)

    Pantoja, Joe Luis; Zhang, Zhihong; Tartibi, Mehrzad; Sun, Kay; Macmillan, Warrick; Guccione, Julius M; Ge, Liang; Ratcliffe, Mark B

    2015-12-01

    Surgical ventricular restoration (Dor procedure) is generally thought to reduce left ventricular (LV) myofiber stress (FS) but to adversely affect pump function. However, the underlying mechanism is unclear. The goal of this study was to determine the effect of residual stress (RS) on LV FS and pump function after the Dor procedure. Previously described finite element models of the LV based on magnetic resonance imaging data obtained in 5 sheep 16 weeks after anteroapical myocardial infarction were used. Simulated polyethylene terephthalate fiber (Dacron) patches that were elliptical and 25% of the infarct opening area were implanted using a virtual suture technique (VIRTUAL-DOR). In each case, diastole and systole were simulated, and RS, FS, LV volumes, systolic and diastolic function, and pump (Starling) function were calculated. VIRTUAL-DOR was associated with significant RS that was tensile (2.89 ± 1.31 kPa) in the remote myocardium and compressive (234.15 ± 65.53 kPa) in the border zone. VIRTUAL-DOR+RS (compared with VIRTUAL-DOR-NO-RS) was associated with further reduction in regional diastolic and systolic FS, with the greatest change in the border zone (43.5-fold and 7.1-fold, respectively; p < 0.0001). VIRTUAL-DOR+RS was also associated with further reduction in systolic and diastolic volumes (7.9%; p = 0.0606, and 10.6%; p = 0.0630, respectively). The resultant effect was a further reduction in pump function after VIRTUAL-DOR+RS. Residual stress that occurs after the Dor procedure is positive (tensile) in the remote myocardium and negative (compressive) in the border zone and associated with reductions in FS and LV volumes. The resultant effect is a further reduction in LV pump (Starling) function. Copyright © 2015 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.

  8. TNF-Like Weak Inducer of Apoptosis Aggravates Left Ventricular Dysfunction after Myocardial Infarction in Mice

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    Kai-Uwe Jarr

    2014-01-01

    Full Text Available Background. TNF-like weak inducer of apoptosis (TWEAK has recently been shown to be potentially involved in adverse cardiac remodeling. However, neither the exact role of TWEAK itself nor of its receptor Fn14 in this setting is known. Aim of the Study. To analyze the effects of sTWEAK on myocardial function and gene expression in response to experimental myocardial infarction in mice. Results. TWEAK directly suppressed the expression of PGC-1α and genes of oxidative phosphorylation (OXPHOS in cardiomyocytes. Systemic sTWEAK application after MI resulted in reduced left ventricular function and increased mortality without changes in interstitial fibrosis or infarct size. Molecular analysis revealed decreased phosphorylation of PI3K/Akt and ERK1/2 pathways associated with reduced expression of PGC-1α and PPARα. Likewise, expression of OXPHOS genes such as atp5O, cycs, cox5b, and ndufb5 was also reduced. Fn14 -/- mice showed significantly improved left ventricular function and PGC-1α levels after MI compared to their respective WT littermates (Fn14 +/+. Finally, inhibition of intrinsic TWEAK with anti-TWEAK antibodies resulted in improved left ventricular function and survival. Conclusions. TWEAK exerted maladaptive effects in mice after myocardial infarction most likely via direct effects on cardiomyocytes. Analysis of the potential mechanisms revealed that TWEAK reduced metabolic adaptations to increased cardiac workload by inhibition of PGC-1α.

  9. Molecular Mechanisms of Retinoid Receptors in Diabetes-Induced Cardiac Remodeling

    Directory of Open Access Journals (Sweden)

    Jing Pan

    2014-06-01

    Full Text Available Diabetic cardiomyopathy (DCM, a significant contributor to morbidity and mortality in diabetic patients, is characterized by ventricular dysfunction, in the absence of coronary atherosclerosis and hypertension. There is no specific therapeutic strategy to effectively treat patients with DCM, due to a lack of a mechanistic understanding of the disease process. Retinoic acid, the active metabolite of vitamin A, is involved in a wide range of biological processes, through binding and activation of nuclear receptors: retinoic acid receptors (RAR and retinoid X receptors (RXR. RAR/RXR-mediated signaling has been implicated in the regulation of glucose and lipid metabolism. Recently, it has been reported that activation of RAR/RXR has an important role in preventing the development of diabetic cardiomyopathy, through improving cardiac insulin resistance, inhibition of intracellular oxidative stress, NF-κB-mediated inflammatory responses and the renin-angiotensin system. Moreover, downregulated RAR/RXR signaling has been demonstrated in diabetic myocardium, suggesting that impaired RAR/RXR signaling may be a trigger to accelerate diabetes-induced development of DCM. Understanding the molecular mechanisms of retinoid receptors in the regulation of cardiac metabolism and remodeling under diabetic conditions is important in providing the impetus for generating novel therapeutic approaches for the prevention and treatment of diabetes-induced cardiac complications and heart failure.

  10. Thymosin Beta 4 protects mice from monocrotaline-induced pulmonary hypertension and right ventricular hypertrophy.

    Directory of Open Access Journals (Sweden)

    Chuanyu Wei

    Full Text Available Pulmonary hypertension (PH is a progressive vascular disease of pulmonary arteries that impedes ejection of blood by the right ventricle. As a result there is an increase in pulmonary vascular resistance and pulmonary arterial pressure causing right ventricular hypertrophy (RVH and RV failure. The pathology of PAH involves vascular cell remodeling including pulmonary arterial endothelial cell (PAEC dysfunction and pulmonary arterial smooth muscle cell (PASMC proliferation. Current therapies are limited to reverse the vascular remodeling. Investigating a key molecule is required for development of new therapeutic intervention. Thymosin beta-4 (Tβ4 is a ubiquitous G-actin sequestering protein with diverse biological function and promotes wound healing and modulates inflammatory responses. However, it remains unknown whether Tβ4 has any protective role in PH. The purpose of this study is to evaluate the whether Tβ4 can be used as a vascular-protective agent. In monocrotaline (MCT-induced PH mouse model, we showed that mice treated with Tβ4 significantly attenuated the systolic pressure and RVH, compared to the MCT treated mice. Our data revealed for the first time that Tβ4 selectively targets Notch3-Col 3A-CTGF gene axis in preventing MCT-induced PH and RVH. Our study may provide pre-clinical evidence for Tβ4 and may consider as vasculo-protective agent for the treatment of PH induced RVH.

  11. Dietary nitrite supplementation attenuates cardiac remodeling in l-NAME-induced hypertensive rats.

    Science.gov (United States)

    Sonoda, Kunihiro; Ohtake, Kazuo; Uchida, Hiroyuki; Ito, Junta; Uchida, Masaki; Natsume, Hideshi; Tamada, Hazuki; Kobayashi, Jun

    2017-07-01

    Loss of nitric oxide (NO) bioavailability underlies the development of hypertensive heart disease. We investigated the effects of dietary nitrite on N(G)-nitro-l-arginine methyl ester (l-NAME)-induced hypertension. Sprague-Dawley rats were divided into five groups: an untreated control group, an l-NAME-treated group, and three other l-NAME-treated groups supplemented with 10 mg/L or 100 mg/L of nitrite or 100 mg/L of captopril in drinking water. After the 8-week experimental period, mean arterial blood pressure was measured, followed by sampling of blood and heart tissue for assessment of nitrite/nitrate levels in the plasma and heart, the plasma level of angiotensin II (AT II), and the heart transcriptional levels of AT II type 1 receptor (AT1R), transforming growth factor-β1 (TGF-β1), and connective tissue proteins such as type 1 collagen and fibronectin. Heart tissue was analyzed by histopathological morphometry, including assessments of ventricular and coronary vascular hypertrophy and fibrosis, as well as immunohistochemistry analyses of myocardial expression of AT1R. l-NAME treatment reduced the plasma nitrate level and led to the development of hypertension, with increased plasma levels of AT II and increased heart transcriptional levels of AT1R and TGF-β1-mediated connective tissue proteins, showing myocardial and coronary arteriolar hypertrophy and fibrosis. However, dietary nitrite supplementation inhibited TGF-β1-mediated cardiac remodeling by suppressing AT II and AT1R. These results suggest that dietary nitrite levels achievable via a daily high-vegetable diet could improve hypertensive heart disease by inhibiting AT II-AT1R-mediated cardiac remodeling. Copyright © 2017 Elsevier Inc. All rights reserved.

  12. Traditional Formula, Modern Application: Chinese Medicine Formula Sini Tang Improves Early Ventricular Remodeling and Cardiac Function after Myocardial Infarction in Rats

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    Jiangang Liu

    2014-01-01

    Full Text Available Sini Tang (SNT is a traditional Chinese herbal formula consisting of four different herbs: the root of Aconitum carmichaelii, the bark of Cinnamomum cassia, the rhizome of Zingiber officinale, and the root of Glycyrrhiza uralensis. This study aims to evaluate the improvement of early ventricular remodeling and cardiac function in myocardial infarction (MI rats by SNT. A MI model was established by ligation of the left anterior descending coronary artery. Following treatment for 4 weeks, ultrasonic echocardiography was performed. Myocardial histopathological changes were observed using haematoxylin and eosin staining. Collagens (type I and type III, transforming growth factor-β1 (TGF-β1, and Toll-like receptors (TLR-2 and TLR-4 were measured in plasma, serum, and myocardial tissue. SNT treatment decreased the infarct size, the left ventricular cavity area/heart cavity area ratio, and the left ventricle dimension at end systole and increased the left ventricular ejection fraction. SNT reduced the levels of TLR-2 and TLR-4 in myocardial tissue significantly and decreased the collagens content in serum and in myocardial tissue. SNT could partially reduce the level of TGF-β1 in serum and in myocardial tissue. Our data suggest that the Chinese medicine formula SNT has the potential to improve early ventricular remodeling and cardiac function after MI.

  13. Cardio-protecteffect of qiliqiangxin capsule on left ventricular remodeling, dysfunction and apoptosis in heart failure rats after chronic myocardial infarction.

    Science.gov (United States)

    Liang, Tuo; Zhang, Yuhui; Yin, Shijie; Gan, Tianyi; An, Tao; Zhang, Rongcheng; Wang, Yunhong; Huang, Yan; Zhou, Qiong; Zhang, Jian

    2016-01-01

    Qiliqiangxin (QL) capsule is a traditional Chinese medicine which has been approved for the treatment of chronic heart failure. Evidences proved that QL capsules further reduced the NT-proBNP levels and improved left ventricular ejection fraction in CHF patients but the evidence supporting its underlying mechanism is still unclear. Myocardial infarction (MI) -Heart failure (HF) Sprague-Dawley ratsmodel and neonatal rat cardiac myocytes (NRCMs) were used. Animals were assigned into 4 groups, normal group (n=6), shame-operation group (n=6), MI rats 4 weeks after left anterior descending coronary artery ligation were randomized into vehicle group (n=8), QL group (n=8). QL significantly attenuated cardiac dysfunction and ventricle remodeling as echocardiography and hemodynamic measurements showed improvement in left ventricular ejection fraction, fractional shortening, ±dp/dt and left ventricular end diastolic and systolic diameters in QL treated group compared with the vehicle group. Improvements ininterstitial fibrosisand mitochondrial structures were also exhibited by Sirius Red staining, RT-PCR and electron microscopy. QL treatment improved apoptosis and VEGF expression in rats marginal infract area. Complementary experiments analyzed the improved apoptosis and up-regulate of VEGF in ischemia-hypoxia cultivated NRCMs is in an Akt dependent manner and can be reversed by Akt inhibitor. QL capsule can improve cardiac dysfunction and ventricular remodeling in MI-HF ratsmodel, this cardiac protective efficacy may be concerned with attenuated apoptosis and cardiac fibrosis. Up-regulated VEGF expression and Akt phosphorylation may take part in this availability.

  14. Design and rationale of a multicentre, randomised, double-blind, placebo-controlled clinical trial to evaluate the effect of vitamin D on ventricular remodelling in patients with anterior myocardial infarction: the VITamin D in Acute Myocardial Infarction (VITDAMI) trial

    OpenAIRE

    Tu??n, Jos?; Gonz?lez-Hern?ndez, Ignacio; Llanos-Jim?nez, Luc?a; Alonso-Mart?n, Joaqu?n; Escudier-Villa, Juan M; Tar?n, Nieves; Crist?bal, Carmen; Sanz, Petra; Pello, Ana M; Ace?a, ?lvaro; Carda, Roc?o; Orejas, Miguel; Tom?s, Marta; Beltr?n, Paula; Calero Rueda, Marta

    2016-01-01

    Introduction Decreased plasma vitamin D (VD) levels are linked to cardiovascular damage. However, clinical trials have not demonstrated a benefit of VD supplements on left ventricular (LV) remodelling. Anterior ST-elevation acute myocardial infarction (STEMI) is the best human model to study the effect of treatments on LV remodelling. We present a proof-of-concept study that aims to investigate whether VD improves LV remodelling in patients with anterior STEMI. Methods and analysis The VITami...

  15. Dominant negative Ras attenuates pathological ventricular remodeling in pressure overload cardiac hypertrophy

    Science.gov (United States)

    Ramos-Kuri, Manuel; Rapti, Kleopatra; Mehel, Hind; Zhang, Shihong; Dhandapany, Perundurai S.; Liang, Lifan; García-Carrancá, Alejandro; Bobe, Regis; Fischmeister, Rodolphe; Adnot, Serge; Lebeche, Djamel; Hajjar, Roger J.; Lipskaia, Larissa; Chemaly, Elie R.

    2015-01-01

    The importance of the oncogene Ras in cardiac hypertrophy is well appreciated. The hypertrophic effects of the constitutively active mutant Ras-Val12 are revealed by clinical syndromes due to the Ras mutations and experimental studies. We examined the possible anti-hypertrophic effect of Ras inhibition in vitro using rat neonatal cardiomyocytes (NRCM) and in vivo in the setting of pressure-overload left ventricular (LV) hypertrophy (POH) in rats. Ras functions were modulated via adenovirus directed gene transfer of active mutant Ras-Val12 or dominant negative mutant N17-DN-Ras (DN-Ras). Ras-Val12 expression in vitro activates NFAT resulting in pro-hypertrophic and cardio-toxic effects on NRCM beating and Z-line organization. In contrast, the DN-Ras was antihypertrophic on NRCM, inhibited NFAT and exerted cardio-protective effects attested by preserved NRCM beating and Z line structure. Additional experiments with silencing H-Ras gene strategy corroborated the antihypertrophic effects of siRNA-H-Ras on NRCM. In vivo, with the POH model, both Ras mutants were associated with similar hypertrophy two weeks after simultaneous induction of POH and Ras-mutant gene transfer. However, LV diameters were higher and LV fractional shortening lower in the Ras-Val12 group compared to control and DN-Ras. Moreover, DN-Ras reduced the cross-sectional area of cardiomyocytes in vivo, and decreased the expression of markers of pathologic cardiac hypertrophy. In isolated adult cardiomyocytes after 2 weeks of POH and Ras-mutant gene transfer, DN-Ras improved sarcomere shortening and calcium transients compared to Ras-Val12. Overall, DN-Ras promotes a more physiological form of hypertrophy, suggesting an interesting therapeutic target for pathological cardiac hypertrophy. PMID:26260012

  16. Right ventricular remodeling in idiopathic and scleroderma-associated pulmonary arterial hypertension: two distinct phenotypes

    Science.gov (United States)

    Mathai, Stephen C.; Tedford, Ryan J.; Damico, Rachel L.; Corona-Villalobos, Cecilia; Kolb, Todd M.; Chaisson, Neal F.; Harris, Traci Housten; Zimmerman, Stefan L.; Kamel, Ihab R.; Kass, David A.; Hassoun, Paul M.

    2015-01-01

    Abstract Patients with scleroderma (SSc)–associated pulmonary arterial hypertension (PAH) have worse survival than patients with idiopathic PAH (IPAH). We hypothesized that the right ventricle (RV) adapts differently in SSc-PAH versus IPAH. We used cardiac magnetic resonance imaging (cMRI) and hemodynamic characteristics to assess the relationship between RV morphology and RV load in patients with SSc-PAH and IPAH. In 53 patients with PAH (35 with SSc-PAH and 18 with IPAH) diagnosed by right heart catheterization (RHC), we examined cMRIs obtained within 48 hours of RHC and compared RV morphology between groups. Regression analysis was used to assess the association between diagnosis (IPAH vs. SSc-PAH) and RV measurements after adjusting for age, sex, race, body mass index (BMI), left ventricular (LV) mass, and RV load. There were no significant differences in unadjusted comparisons of cMRI measurements between the two groups. Univariable regression showed RV mass index (RVMI) was linearly associated with measures of RV load in both the overall cohort and within each group. Multivariable linear regression models revealed a significant interaction between disease type and RVMI adjusting for pulmonary vascular resistance (PVR), age, sex, race, BMI, and LV mass. This model showed a decreased slope in the relationship between RVMI and PVR in the SSc-PAH group compared with the IPAH group. RVMI varies linearly with measures of RV load. After adjusting for multiple potential confounders, patients with SSc-PAH demonstrated significantly less RV hypertrophy with increasing PVR than patients with IPAH. This difference in adaptive hypertrophy may in part explain previously observed decreased contractility and poorer survival in SSc-PAH. PMID:26064458

  17. Peripheral nerve injury induces adult brain neurogenesis and remodelling.

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    Rusanescu, Gabriel; Mao, Jianren

    2017-02-01

    Unilateral peripheral nerve chronic constriction injury (CCI) has been widely used as a research model of human neuropathic pain. Recently, CCI has been shown to induce spinal cord adult neurogenesis, which may contribute to the chronic increase in nociceptive sensitivity. Here, we show that CCI also induces rapid and profound asymmetrical anatomical rearrangements in the adult rodent cerebellum and pons. This remodelling occurs throughout the hindbrain, and in addition to regions involved in pain processing, also affects other sensory modalities. We demonstrate that these anatomical changes, partially reversible in the long term, result from adult neurogenesis. Neurogenic markers Mash1, Ngn2, doublecortin and Notch3 are widely expressed in the rodent cerebellum and pons, both under normal and injured conditions. CCI-induced hindbrain structural plasticity is absent in Notch3 knockout mice, a strain with impaired neuronal differentiation, demonstrating its dependence on adult neurogenesis. Grey matter and white matter structural changes in human brain, as a result of pain, injury or learned behaviours have been previously detected using non-invasive neuroimaging techniques. Because neurogenesis-mediated structural plasticity is thought to be restricted to the hippocampus and the subventricular zone, such anatomical rearrangements in other parts of the brain have been thought to result from neuronal plasticity or glial hypertrophy. Our findings suggest the presence of extensive neurogenesis-based structural plasticity in the adult mammalian brain, which may maintain a memory of basal sensory levels, and act as an adaptive mechanism to changes in sensory inputs. © 2016 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.

  18. Loperamide Induced Life Threatening Ventricular Arrhythmia

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    Ankit Upadhyay

    2016-01-01

    Full Text Available Loperamide is over-the-counter antidiarrheal agent acting on peripherally located μ opioid receptors. It is gaining popularity among drug abusers as opioid substitute. We report a case of a 46-year-old male that was presented after cardiac arrest. After ruling out ischemia, cardiomyopathy, pulmonary embolism, central nervous system pathology, sepsis, and other drug toxicity, we found out that patient was using around 100 mg of Loperamide to control his chronic diarrhea presumably because of irritable bowel syndrome for last five years and consumed up to 200 mg of Loperamide daily for last two days before the cardiac arrest. We hypothesize that the patient’s QTc prolongation and subsequent cardiac arrest are due to Loperamide toxicity. Patient experienced gradual resolution of tachyarrhythmia and gradual decrease in QTc interval during hospitalization which supports the evidence of causal relationship between Loperamide overdose and potentially fatal arrhythmias. It also provided the clue that patient may have congenital long QT syndrome which was unmasked by Loperamide causing ventricular arrhythmias. This case adds one more pearl in the literature to support that Loperamide overdose related cardiac toxicity does exist and it raises concerns over Loperamide abuse in the community.

  19. Anti-inflammatory, Antithrombotic and Cardiac Remodeling Preventive Effects of Eugenol in Isoproterenol-Induced Myocardial Infarction in Wistar Rat.

    Science.gov (United States)

    Mnafgui, Kais; Hajji, Raouf; Derbali, Fatma; Gammoudi, Anis; Khabbabi, Gaddour; Ellefi, Hedi; Allouche, Noureddine; Kadri, Adel; Gharsallah, Neji

    2016-10-01

    This study aimed to evaluate the antithrombotic, anti-inflammatory and anti-cardiac remodeling properties of eugenol in isoproterenol-induced myocardial infarction in rats. Male Wistar rats were randomly divided into four groups, control, iso [100 mg/kg body weight was injected subcutaneously into rats at an interval of 24 h for 2 days (6th and 7th day) to induce MI] and pretreated animals with clopidogrel (0.2 mg/kg) and eugenol (50 mg/kg) orally for 7 days and intoxicated with isoproterenol (Iso + Clop) and (Iso + EG) groups. Isoproterenol-induced myocardial infarcted rats showed notable changes in the ECG pattern, increase in heart weight index, deterioration in the hemodynamic function and rise in plasma level of troponin-T, CK-MB and LDH and ALT by 316, 74, 172 and 45 %, respectively, with histological myocardium necrosis and cells inflammatory infiltration. In addition, significant increases in plasma levels of inflammatory biomarkers such as fibrinogen, α1, α2, β1, β2 and γ globulins with decrease level of albumin were observed in infarcted rats as compared to normal ones. Else, the angiotensin-converting enzyme (ACE) activity in plasma, kidney and heart of the isoproterenol-induced rats was significantly increased by 34, 47 and 93 %, respectively, as compared to normal group. However, the administration of eugenol induced a clear improvement in cardiac biomarkers injury, reduced inflammatory mediators proteins, increased heart activities of superoxide dismutase and glutathione peroxidase with reduce in thiobarbituric acid-reactive substances content and inhibition of ventricular remodeling process through inhibition of ACE activity. Overall, eugenol evidences high preventive effects from cardiac remodeling process.

  20. Increased Serum Levels of Fetal Tenascin-C Variants in Patients with Pulmonary Hypertension: Novel Biomarkers Reflecting Vascular Remodeling and Right Ventricular Dysfunction?

    Science.gov (United States)

    Rohm, Ilonka; Grün, Katja; Müller, Linda Marleen; Kretzschmar, Daniel; Fritzenwanger, Michael; Yilmaz, Atilla; Lauten, Alexander; Jung, Christian; Schulze, P Christian; Berndt, Alexander; Franz, Marcus

    2017-11-08

    Pulmonary vascular remodeling is a pathophysiological feature that common to all classes of pulmonary hypertension (PH) and right ventricular dysfunction, which is the major prognosis-limiting factor. Vascular, as well as cardiac tissue remodeling are associated with a re-expression of fetal variants of cellular adhesion proteins, including tenascin-C (Tn-C). We analyzed circulating levels of the fetal Tn-C splicing variants B⁺ and C⁺ Tn-C in serum of PH patients to evaluate their potential as novel biomarkers reflecting vascular remodeling and right ventricular dysfunction. Serum concentrations of B⁺ and C⁺ Tn-C were determined in 80 PH patients and were compared to 40 healthy controls by enzyme-linked immunosorbent assay. Clinical, laboratory, echocardiographic, and functional data were correlated with Tn-C levels. Serum concentrations of both Tn-C variants were significantly elevated in patients with PH (p C and echocardiographic parameters, including systolic pulmonary artery pressure (B⁺ Tn-C: r = 0.31, p C⁺ Tn-C: r = 0.26, p = 0.006) and right atrial area (B⁺ Tn-C: r = 0.46, p C⁺ Tn-C: r = 0.49, p C: r = 0.45, p C⁺ Tn-C: r = 0.42, p C variants and 6-minute walk distance as a functional parameter (B⁺ Tn-C: r = -0.54, p C⁺ Tn-C: r = -0.43, p C, but not C⁺ Tn-C, was found to be an independent predictor of pulmonary hypertension. Both fetal Tn-C variants may represent novel biomarkers that are capable of estimating both pulmonary vascular remodeling and right ventricular load. The potential beneficial impact of Tn-C variants for risk stratification in patients with PH needs further investigation.

  1. Maternal smoking during pregnancy induces airway remodelling in mice offspring

    NARCIS (Netherlands)

    Blacquiere, M. J.; Timens, W.; Melgert, B. N.; Geerlings, M.; Postma, D. S.; Hylkema, M. N.

    Children from smoking mothers have an increased risk of developing asthma for reasons largely unknown. The effects of maternal smoking during pregnancy on remodelling, allergic airway inflammation and hyperresponsiveness in offspring were investigated in an experimental asthma model. Mice were

  2. Left Ventricular Architecture, Long-Term Reverse Remodeling, and Clinical Outcome in Mild Heart Failure With Cardiac Resynchronization: Results From the REVERSE Trial.

    Science.gov (United States)

    St John Sutton, Martin; Linde, Cecilia; Gold, Michael R; Abraham, William T; Ghio, Stefano; Cerkvenik, Jeffrey; Daubert, Jean-Claude

    2017-03-01

    This study sought to determine the effects of abnormal left ventricular (LV) architecture on cardiac remodeling and clinical outcomes in mild heart failure (HF). Cardiac resynchronization therapy (CRT) is an established treatment for HF that improves survival in part by favorably remodeling LV architecture. LV shape is a dynamic component of LV architecture on which contractile function depends. Transthoracic 2-dimensional echocardiography was used to quantify changes in LV architecture over 5 years of follow-up of patients with mild HF from the REVERSE study. REVERSE was a prospective study of patients with large hearts (LV end-diastolic dimension ≥55 mm), LV ejection fraction 120 ms randomly assigned to CRT-ON (n = 419) and CRT-OFF (n = 191). CRT-OFF patients were excluded from this analysis. LV dimensions, volumes, mass index, and LV ejection fraction were calculated. LV architecture was assessed using the sphericity index, as follows: (LV end-diastolic volume)/(4/3 × π × r 3 ) × 100%. LV architecture improved over time and demonstrated significant associations between LV shape, age, sex, and echocardiography metrics. Changes in LV architecture were strongly correlated with changes in LV end-systolic volume index and LV end-diastolic volume index (both p 15% occurred in more than two-thirds of patients, which indicates considerable reverse remodeling. We demonstrated that change in LV architecture in patients with mild HF with CRT is associated with structural and functional remodeling. Mean LV filling pressure was elevated, and the inability to lower it was an additional predictor of HF hospitalization or death. (Resynchronization Reverses Remodeling in Systolic Left Ventricular Dysfunction [REVERSE]; NCT00271154). Copyright © 2017 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

  3. Identifying non-inducible ventricular tachycardia origin utilizing defibrillator electrograms.

    Science.gov (United States)

    Tschabrunn, Cory M; Anter, Elad; Marchlinski, Francis E

    2013-04-01

    Developing an ablation strategy when the clinical arrhythmia cannot be induced is a challenge. A 72-year-old man is transferred to our facility for ventricular tachycardia (VT) storm. Endocardial and epicardial voltage mapping was normal and program stimulation failed to induce any arrhythmias. Implantable cardioverter-defibrillators (ICD) electrograms (EGMs) were recorded while pacing and compared to the stored clinical events. Ablation lesions were delivered across a narrow area of matching ICD EGM pace maps. The patient has remained arrhythmia free for 11 months. ICD EGMs may be useful in facilitating successful VT ablation when the clinical arrhythmia cannot be induced in the EP lab.

  4. Downregulation of β-Adrenoceptors in Isoproterenol-Induced Cardiac Remodeling through HuR.

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    Qian Yin

    Full Text Available β-adrenergic receptors (β-ARs play an important role in cardiac remodeling, which is the key pathological process in various heart diseases and leads to heart failure. However, the regulation of β-AR expression in remodeling hearts is still unclear. This study aims to clarify the possible mechanisms underlying the regulation of β1- and β2-AR expression in cardiac remodeling. The rat model of cardiac remodeling was established by subcutaneous injection of isoproterenol(ISO at the dose of 0.25 mg·kg(-1·d(-1 for 7 days. We found that the expression of β1- and β2-ARs decreased in the remodeling heart. The mechanisms may include the inhibition of DNA transcription and the increase of mRNA degradation. cAMP-response element binding protein(CREB is a well-known transcription factor of β-AR. However, the expression and activation of CREB was not changed in the remodeling heart. Further, human Antigen-R (HuR, a RNA binding protein, which binds to the 3'-untranslated region of the β-AR mRNA and promotes RNA degradation, was increased in the remodeling model. And in vitro, HuR deficiency reversed the reduction of β-AR mRNA induced by ISO. Therefore, the present findings indicate that HuR, but not CREB, is responsible for the reduction of β-AR expression in ISO induced cardiac remodeling.

  5. Effect of loading-dose ticagrelor on coronary blood flow, left ventricular remodeling and myocardial enzyme spectrum in patients with acute myocardial infarction after interventional therapy

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    Xiao-Rui Xie

    2016-12-01

    Full Text Available Objective: To study the effect of loading-dose ticagrelor on coronary blood flow, left ventricular remodeling and myocardial enzyme spectrum in patients with acute myocardial infarction after interventional therapy. Methods: A total of 86 patients with acute myocardial infarction who received emergency PCI in our hospital between May 2013 and May 2016 were selected and randomly divided into two groups, ticagrelor group received perioperative ticagrelor therapy and clopidogrel group received perioperative clopidogrel therapy. After PCI, coronary blood flow reperfusion was evaluated, serum myocardial remodeling indexes and myocardial enzymes were determined, and cardiac color Doppler ultrasonography was conducted to determine the cardiac function indexes. Results: TIMI grading and TMPG grading of ticagrelor group after PCI were significantly higher than those of clopidogrel group; serum MMP9, BNP, CITP, PICP, PIIINP, CK, CK-MB, cTnI and cTnT content of ticagrelor group 24h after operation were significantly lower than those of clopidogrel group; LVEDD, LVSED and LVMI of ticagrelor group 2 weeks after operation were significantly lower than those of clopidogrel group while LVEF was significantly higher than that of clopidogrel group. Conclusion: Peri-PCI loading-dose ticagrelor can improve coronary blood perfusion and reduce ventricular remodeling and myocardial injury in patients with acute myocardial infarction.

  6. Bronchoconstriction Induces TGF-β Release and Airway Remodelling in Guinea Pig Lung Slices.

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    Tjitske A Oenema

    Full Text Available Airway remodelling, including smooth muscle remodelling, is a primary cause of airflow limitation in asthma. Recent evidence links bronchoconstriction to airway remodelling in asthma. The mechanisms involved are poorly understood. A possible player is the multifunctional cytokine TGF-β, which plays an important role in airway remodelling. Guinea pig lung slices were used as an in vitro model to investigate mechanisms involved in bronchoconstriction-induced airway remodelling. To address this aim, mechanical effects of bronchoconstricting stimuli on contractile protein expression and TGF-β release were investigated. Lung slices were viable for at least 48 h. Both methacholine and TGF-β1 augmented the expression of contractile proteins (sm-α-actin, sm-myosin, calponin after 48 h. Confocal fluorescence microscopy showed that increased sm-myosin expression was enhanced in the peripheral airways and the central airways. Mechanistic studies demonstrated that methacholine-induced bronchoconstriction mediated the release of biologically active TGF-β, which caused the increased contractile protein expression, as inhibition of actin polymerization (latrunculin A or TGF-β receptor kinase (SB431542 prevented the methacholine effects, whereas other bronchoconstricting agents (histamine and KCl mimicked the effects of methacholine. Collectively, bronchoconstriction promotes the release of TGF-β, which induces airway smooth muscle remodelling. This study shows that lung slices are a useful in vitro model to study mechanisms involved in airway remodelling.

  7. Disruption of TGF-β signaling in smooth muscle cell prevents flow-induced vascular remodeling

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    Gao, Fu [Department of Vascular Surgery, Peking University People’s Hospital, Beijing (China); Chambon, Pierre [Institut de Génétique et de Biologie Moléculaire et Cellulaire (CNRS UMR7104, INSERM U596, ULP, Collége de France) and Institut Clinique de la Souris, ILLKIRCH, Strasbourg (France); Tellides, George [Department of Surgery, Interdepartmental Program in Vascular Biology and Therapeutics, Yale University School of Medicine, New Haven, CT (United States); Kong, Wei [Department of Physiology and Pathophysiology, Basic Medical College of Peking University, Beijing (China); Zhang, Xiaoming, E-mail: rmygxgwk@163.com [Department of Vascular Surgery, Peking University People’s Hospital, Beijing (China); Li, Wei [Department of Vascular Surgery, Peking University People’s Hospital, Beijing (China)

    2014-11-07

    Highlights: • TGF-β signaling in SMC contributes to the flow-induced vascular remodeling. • Disruption of TGF-β signaling in SMC can prevent this process. • Targeting SM-specific Tgfbr2 could be a novel therapeutic strategy for vascular remodeling. - Abstract: Transforming growth factor-β (TGF-β) signaling has been prominently implicated in the pathogenesis of vascular remodeling, especially the initiation and progression of flow-induced vascular remodeling. Smooth muscle cells (SMCs) are the principal resident cells in arterial wall and are critical for arterial remodeling. However, the role of TGF-β signaling in SMC for flow-induced vascular remodeling remains unknown. Therefore, the goal of our study was to determine the effect of TGF-β pathway in SMC for vascular remodeling, by using a genetical smooth muscle-specific (SM-specific) TGF-β type II receptor (Tgfbr2) deletion mice model. Mice deficient in the expression of Tgfbr2 (MyhCre.Tgfbr2{sup f/f}) and their corresponding wild-type background mice (MyhCre.Tgfbr2{sup WT/WT}) underwent partial ligation of left common carotid artery for 1, 2, or 4 weeks. Then the carotid arteries were harvested and indicated that the disruption of Tgfbr2 in SMC provided prominent inhibition of vascular remodeling. And the thickening of carotid media, proliferation of SMC, infiltration of macrophage, and expression of matrix metalloproteinase (MMP) were all significantly attenuated in Tgfbr2 disruption mice. Our study demonstrated, for the first time, that the TGF-β signaling in SMC plays an essential role in flow-induced vascular remodeling and disruption can prevent this process.

  8. IcarisideII improves left ventricular remodeling in spontaneously hypertensive rats by inhibiting the ASK1-JNK/p38 signaling pathway.

    Science.gov (United States)

    Wu, Yuting; Qian, Zhiqiang; Fu, Shu; Yue, Yun; Li, Yeli; Sun, Ruimin; Huang, Bo; Yang, Danli

    2017-11-21

    Inhibition or removal of excess reactive oxygen species can effectively protect cellular function or reduce cell death because oxidative stress is the main cause of cellular damage in many diseases. The flavonoid compound IcarisideII having a slight inhibitory effect on PDE5, is the main active components of epimedium in vivo and has a wide range of pharmacological effects on oxidation and apoptosis. However, whether IcarisideII has the same protective effect on ventricular remodeling in spontaneously hypertensive rats (SHR) is unknown. We found that compared with WKY rats, SHRs exhibited noticeable arterial hypertension. Additionally, echocardiography showed that the diameter of the left ventricle was enlarged, wall thickness was increased, and ejection fraction and short axis shortening rate were reduced. H&E staining demonstrated that SHR cells were disordered and noticeably hypertrophic. Masson trichrome staining revealed significant myocardial fibrosis in the myocardium. Tunel staining indicated that 4.39 times the percent of apoptotic cells were present in SHRs compared to WKY rats. In our study, intra-gastric administration of IcarisideII decreased blood pressure, promoted heart function recovery and improved ventricular remodeling in SHRs. Additionally, it reduced myocardial fibrosis, inhibited myocardial apoptosis, decreased the generation of reactive oxygen species and improved SOD activity. IcarisideII down-regulated the activation of the oxidative stress associated proteins ASK1, p38 and JNK; inhibited the expression of p53, Bax and cleaved-caspase3 in the mitochondrial apoptosis pathway; and up-regulated the expression of Bcl-2. In conclusion, this study indicates that IcarisideII can inhibit myocardial apoptosis and improve left ventricular remodeling in SHRs. It can be inferred that this mechanism may be related to the inhibition of the ASK1-JNK/p38 signaling pathway. Copyright © 2017 Elsevier B.V. All rights reserved.

  9. Metabolic remodeling in moderate synchronous versus dyssynchronous pacing-induced heart failure: integrated metabolomics and proteomics study.

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    Junko Shibayama

    Full Text Available Heart failure (HF is accompanied by complex alterations in myocardial energy metabolism. Up to 40% of HF patients have dyssynchronous ventricular contraction, which is an independent indicator of mortality. We hypothesized that electromechanical dyssynchrony significantly affects metabolic remodeling in the course of HF. We used a canine model of tachypacing-induced HF. Animals were paced at 200 bpm for 6 weeks either in the right atrium (synchronous HF, SHF or in the right ventricle (dyssynchronous HF, DHF. We collected biopsies from left ventricular apex and performed comprehensive metabolic pathway analysis using multi-platform metabolomics (GC/MS; MS/MS; HPLC and LC-MS/MS label-free proteomics. We found important differences in metabolic remodeling between SHF and DHF. As compared to Control, ATP, phosphocreatine (PCr, creatine, and PCr/ATP (prognostic indicator of mortality in HF patients were all significantly reduced in DHF, but not SHF. In addition, the myocardial levels of carnitine (mitochondrial fatty acid carrier and fatty acids (12:0, 14:0 were significantly reduced in DHF, but not SHF. Carnitine parmitoyltransferase I, a key regulatory enzyme of fatty acid ß-oxidation, was significantly upregulated in SHF but was not different in DHF, as compared to Control. Both SHF and DHF exhibited a reduction, but to a different degree, in creatine and the intermediates of glycolysis and the TCA cycle. In contrast to this, the enzymes of creatine kinase shuttle were upregulated, and the enzymes of glycolysis and the TCA cycle were predominantly upregulated or unchanged in both SHF and DHF. These data suggest a systemic mismatch between substrate supply and demand in pacing-induced HF. The energy deficit observed in DHF, but not in SHF, may be associated with a critical decrease in fatty acid delivery to the ß-oxidation pipeline, primarily due to a reduction in myocardial carnitine content.

  10. Metabolic remodeling in moderate synchronous versus dyssynchronous pacing-induced heart failure: integrated metabolomics and proteomics study.

    Science.gov (United States)

    Shibayama, Junko; Yuzyuk, Tatiana N; Cox, James; Makaju, Aman; Miller, Mickey; Lichter, Justin; Li, Hui; Leavy, Jane D; Franklin, Sarah; Zaitsev, Alexey V

    2015-01-01

    Heart failure (HF) is accompanied by complex alterations in myocardial energy metabolism. Up to 40% of HF patients have dyssynchronous ventricular contraction, which is an independent indicator of mortality. We hypothesized that electromechanical dyssynchrony significantly affects metabolic remodeling in the course of HF. We used a canine model of tachypacing-induced HF. Animals were paced at 200 bpm for 6 weeks either in the right atrium (synchronous HF, SHF) or in the right ventricle (dyssynchronous HF, DHF). We collected biopsies from left ventricular apex and performed comprehensive metabolic pathway analysis using multi-platform metabolomics (GC/MS; MS/MS; HPLC) and LC-MS/MS label-free proteomics. We found important differences in metabolic remodeling between SHF and DHF. As compared to Control, ATP, phosphocreatine (PCr), creatine, and PCr/ATP (prognostic indicator of mortality in HF patients) were all significantly reduced in DHF, but not SHF. In addition, the myocardial levels of carnitine (mitochondrial fatty acid carrier) and fatty acids (12:0, 14:0) were significantly reduced in DHF, but not SHF. Carnitine parmitoyltransferase I, a key regulatory enzyme of fatty acid ß-oxidation, was significantly upregulated in SHF but was not different in DHF, as compared to Control. Both SHF and DHF exhibited a reduction, but to a different degree, in creatine and the intermediates of glycolysis and the TCA cycle. In contrast to this, the enzymes of creatine kinase shuttle were upregulated, and the enzymes of glycolysis and the TCA cycle were predominantly upregulated or unchanged in both SHF and DHF. These data suggest a systemic mismatch between substrate supply and demand in pacing-induced HF. The energy deficit observed in DHF, but not in SHF, may be associated with a critical decrease in fatty acid delivery to the ß-oxidation pipeline, primarily due to a reduction in myocardial carnitine content.

  11. The PDE4 inhibitor CHF-6001 and LAMAs inhibit bronchoconstriction-induced remodeling in lung slices.

    Science.gov (United States)

    Kistemaker, Loes E M; Oenema, Tjitske A; Baarsma, Hoeke A; Bos, I Sophie T; Schmidt, Martina; Facchinetti, Fabrizio; Civelli, Maurizio; Villetti, Gino; Gosens, Reinoud

    2017-09-01

    Combination therapy of PDE4 inhibitors and anticholinergics induces bronchoprotection in COPD. Mechanical forces that arise during bronchoconstriction may contribute to airway remodeling. Therefore, we investigated the impact of PDE4 inhibitors and anticholinergics on bronchoconstriction-induced remodeling. Because of the different mechanism of action of PDE4 inhibitors and anticholinergics, we hypothesized functional interactions of these two drug classes. Guinea pig precision-cut lung slices were preincubated with the PDE4 inhibitors CHF-6001 or roflumilast and/or the anticholinergics tiotropium or glycopyorrolate, followed by stimulation with methacholine (10 μM) or TGF-β1 (2 ng/ml) for 48 h. The inhibitory effects on airway smooth muscle remodeling, airway contraction, and TGF-β release were investigated. Methacholine-induced protein expression of smooth muscle-myosin was fully inhibited by CHF-6001 (0.3-100 nM), whereas roflumilast (1 µM) had smaller effects. Tiotropium and glycopyrrolate fully inhibited methacholine-induced airway remodeling (0.1-30 nM). The combination of CHF-6001 and tiotropium or glycopyrrolate, in concentrations partially effective by themselves, fully inhibited methacholine-induced remodeling in combination. CHF-6001 did not affect airway closure and had limited effects on TGF-β1-induced remodeling, but rather, it inhibited methacholine-induced TGF-β release. The PDE4 inhibitor CHF-6001, and to a lesser extent roflumilast, and the LAMAs tiotropium and glycopyrrolate inhibit bronchoconstriction-induced remodeling. The combination of CHF-6001 and anticholinergics was more effective than the individual compounds. This cooperativity might be explained by the distinct mechanisms of action inhibiting TGF-β release and bronchoconstriction. Copyright © 2017 the American Physiological Society.

  12. Lung irradiation induces pulmonary vascular remodelling resembling pulmonary arterial hypertension

    NARCIS (Netherlands)

    Ghobadi, G.; Bartelds, B.; van der Veen, S. J.; Dickinson, M. G.; Brandenburg, S.; Berger, R. M. F.; Langendijk, J. A.; Coppes, R. P.; van Luijk, P.

    Background Pulmonary arterial hypertension (PAH) is a commonly fatal pulmonary vascular disease that is often diagnosed late and is characterised by a progressive rise in pulmonary vascular resistance resulting from typical vascular remodelling. Recent data suggest that vascular damage plays an

  13. Increased reactive oxygen species, metabolic maladaptation, and autophagy contribute to pulmonary arterial hypertension-induced ventricular hypertrophy and diastolic heart failure.

    Science.gov (United States)

    Rawat, Dhawjbahadur K; Alzoubi, Abdallah; Gupte, Rakhee; Chettimada, Sukrutha; Watanabe, Makino; Kahn, Andrea G; Okada, Takao; McMurtry, Ivan F; Gupte, Sachin A

    2014-12-01

    Pulmonary arterial hypertension (PAH) is a debilitating and deadly disease with no known cure. Heart failure is a major comorbidity and a common cause of the premature death of patients with PAH. Increased asymmetrical right ventricular hypertrophy and septal wall thickening compress the left ventricular cavity and elicit diastolic heart failure. In this study, we used the Sugen5416/hypoxia/normoxia-induced PAH rat to determine whether altered pyridine nucleotide signaling in the failing heart contributes to 1) increased oxidative stress, 2) changes in metabolic phenotype, 3) autophagy, and 4) the PAH-induced failure. We found that increased reactive oxygen species, metabolic maladaptation, and autophagy contributed to the pathogenesis of right ventricular remodeling and hypertrophy that lead to left ventricular diastolic dysfunction. In addition, arterial elastance increased in PAH rats. Glucose-6-phosphate dehydrogenase is a major source of pyridine molecule (nicotinamide adenine dinucleotide phosphate), which is a substrate for nicotinamide adenine dinucleotide phosphate oxidases in the heart. Dehydroepiandrosterone, a 17-ketosteroid that reduces pulmonary hypertension and right ventricular hypertrophy, inhibited glucose-6-phosphate dehydrogenase, decreased oxidative stress, increased glucose oxidation and acetyl-coA, and reduced autophagy in the hearts of PAH rats. It also decreased arterial stiffness and improved left ventricular diastolic function. These findings demonstrate that pyridine nucleotide signaling, at least partly, mediates PAH-induced diastolic heart failure, and that reduction of glucose-6-phosphate dehydrogenase-derived nicotinamide adenine dinucleotide phosphate is beneficial to improve left ventricle diastolic function. © 2014 American Heart Association, Inc.

  14. Automated Extracellular Volume Fraction Mapping Provides Insights Into the Pathophysiology of Left Ventricular Remodeling Post-Reperfused ST-Elevation Myocardial Infarction.

    Science.gov (United States)

    Bulluck, Heerajnarain; Rosmini, Stefania; Abdel-Gadir, Amna; White, Steven K; Bhuva, Anish N; Treibel, Thomas A; Fontana, Marianna; Gonzalez-Lopez, Esther; Reant, Patricia; Ramlall, Manish; Hamarneh, Ashraf; Sirker, Alex; Herrey, Anna S; Manisty, Charlotte; Yellon, Derek M; Kellman, Peter; Moon, James C; Hausenloy, Derek J

    2016-07-11

    Whether the remote myocardium of reperfused ST-segment elevation myocardial infarction (STEMI) patients plays a part in adverse left ventricular (LV) remodeling remains unclear. We aimed to use automated extracellular volume fraction (ECV) mapping to investigate whether changes in the ECV of the remote (ECVR emote) and infarcted myocardium (ECVI nfarct) impacted LV remodeling. Forty-eight of 50 prospectively recruited reperfused STEMI patients completed a cardiovascular magnetic resonance at 4±2 days and 40 had a follow-up scan at 5±2 months. Twenty healthy volunteers served as controls. Mean segmental values for native T1, T2, and ECV were obtained. Adverse LV remodeling was defined as ≥20% increase in LV end-diastolic volume. ECVR emote was higher on the acute scan when compared to control (27.9±2.1% vs 26.4±2.1%; P=0.01). Eight patients developed adverse LV remodeling and had higher ECVR emote acutely (29.5±1.4% vs 27.4±2.0%; P=0.01) and remained higher at follow-up (28.6±1.5% vs 26.6±2.1%; P=0.02) compared to those without. Patients with a higher ECVR emote and a lower myocardial salvage index (MSI) acutely were significantly associated with adverse LV remodeling, independent of T1Remote, T1Core and microvascular obstruction, whereas a higher ECVI nfarct was significantly associated with worse wall motion recovery. ECVR emote was increased acutely in reperfused STEMI patients. Those with adverse LV remodeling had higher ECVR emote acutely, and this remained higher at follow-up than those without adverse LV remodeling. A higher ECVR emote and a lower MSI acutely were significantly associated with adverse LV remodeling whereas segments with higher ECVI nfarct were less likely to recover wall motion. © 2016 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell.

  15. Selective Class I HDAC Inhibition Suppresses Hypoxia-Induced Cardiopulmonary Remodeling Through an Anti-Proliferative Mechanism

    Science.gov (United States)

    Cavasin, Maria A.; Demos-Davies, Kim; Horn, Todd R.; Walker, Lori A.; Lemon, Douglas D.; Birdsey, Nicholas; Weiser-Evans, Mary C. M.; Harral, Jules; Irwin, David C.; Anwar, Adil; Yeager, Michael E.; Li, Min; Watson, Peter A.; Nemenoff, Raphael A.; Buttrick, Peter M.; Stenmark, Kurt R.; McKinsey, Timothy A.

    2012-01-01

    Rationale Histone deacetylase (HDAC) inhibitors are efficacious in models of hypertension-induced left ventricular (LV) heart failure. The consequences of HDAC inhibition in the context of pulmonary hypertension (PH) with associated right ventricular (RV) cardiac remodeling are poorly understood. Objective This study was performed to assess the utility of selective small molecule inhibitors of class I HDACs in a pre-clinical model of PH. Methods and Results Rats were exposed to hypobaric hypoxia for 3 weeks in the absence or presence of a benzamide HDAC inhibitor, MGCD0103, which selectively inhibits class I HDACs −1, −2 and −3. The compound reduced pulmonary arterial pressure (PAP) more dramatically than tadalafil, a standard-of-care therapy for human PH that functions as a vasodilator. MGCD0103 improved pulmonary artery (PA) acceleration time (PAAT) and reduced systolic notching of the PA flow envelope, suggesting a positive impact of the HDAC inhibitor on pulmonary vascular remodeling and stiffening. Similar results were obtained with an independent class I HDAC-selective inhibitor, MS-275. Reduced PAP in MGCD0103-treated animals was associated with blunted pulmonary arterial wall thickening due to suppression of smooth muscle cell proliferation. RV function was maintained in MGCD0103 treated animals. Although the class I HDAC inhibitor only modestly reduced RV hypertrophy, it had multiple beneficial effects on the RV, which included suppression of pathological gene expression, inhibition of pro-apoptotic caspase activity, and repression of pro-inflammatory protein expression. Conclusions By targeting distinct pathogenic mechanisms, isoform-selective HDAC inhibitors have potential as novel therapeutics for PH that will complement vasodilator standards-of-care. PMID:22282194

  16. FIBROBLAST CYTOSKELETAL REMODELING INDUCED BY TISSUE STRETCH INVOLVES ATP SIGNALING

    OpenAIRE

    Langevin, HM; Fujita, T.; Bouffard, NA; Takano, T; Koptiuch, C; Badger, GJ; Nedergaard, M

    2013-01-01

    Fibroblasts in whole areolar connective tissue respond to static stretching of the tissue by expanding and remodeling their cytoskeleton within minutes both ex vivo and in vivo. This study tested the hypothesis that the mechanism of fibroblast expansion in response to tissue stretch involves extracellular ATP signaling. In response to tissue stretch ex vivo, ATP levels in the bath solution increased significantly, and this increase was sustained for 20 minutes, returning to baseline at 60 min...

  17. A Computational Model for Simulating Spaceflight Induced Bone Remodeling

    Science.gov (United States)

    Pennline, James A.; Mulugeta, Lealem

    2014-01-01

    An overview of an initial development of a model of bone loss due to skeletal unloading in weight bearing sites is presented. The skeletal site chosen for the initial application of the model is the femoral neck region because hip fractures can be debilitating to the overall performance health of astronauts. The paper begins with the motivation for developing such a model of the time course of change in bone in order to understand the mechanism of bone demineralization experienced by astronauts in microgravity, to quantify the health risk, and to establish countermeasures. Following this, a general description of a mathematical formulation of the process of bone remodeling is discussed. Equations governing the rate of change of mineralized bone volume fraction and active osteoclast and osteoblast are illustrated. Some of the physiology of bone remodeling, the theory of how imbalance in remodeling can cause bone loss, and how the model attempts to capture this is discussed. The results of a preliminary validation analysis that was carried out are presented. The analysis compares a set of simulation results against bone loss data from control subjects who participated in two different bed rest studies. Finally, the paper concludes with outlining the current limitations and caveats of the model, and planned future work to enhance the state of the model.

  18. Changes in Systemic Hemodynamics in Hypertensive Patients with Diabetes Mellitus Type 2 Depending on the Type of Left Ventricular Remodeling

    Directory of Open Access Journals (Sweden)

    E.Yu. Gura

    2014-04-01

    The correlations with the main indicators of the intracardiac systemic hemodynamics confirm a single pathogenetic mechanism of the cardiovascular remodeling in patients with hypertension combined with type 2 diabetes.

  19. Endoplasmic reticulum stress sensor protein kinase R-like endoplasmic reticulum kinase (PERK) protects against pressure overload-induced heart failure and lung remodeling.

    Science.gov (United States)

    Liu, Xiaoyu; Kwak, Dongmin; Lu, Zhongbing; Xu, Xin; Fassett, John; Wang, Huan; Wei, Yidong; Cavener, Douglas R; Hu, Xinli; Hall, Jennifer; Bache, Robert J; Chen, Yingjie

    2014-10-01

    Studies have reported that development of congestive heart failure is associated with increased endoplasmic reticulum stress. Double stranded RNA-activated protein kinase R-like endoplasmic reticulum kinase (PERK) is a major transducer of the endoplasmic reticulum stress response and directly phosphorylates eukaryotic initiation factor 2α, resulting in translational attenuation. However, the physiological effect of PERK on congestive heart failure development is unknown. To study the effect of PERK on ventricular structure and function, we generated inducible cardiac-specific PERK knockout mice. Under unstressed conditions, cardiac PERK knockout had no effect on left ventricular mass, or its ratio to body weight, cardiomyocyte size, fibrosis, or left ventricular function. However, in response to chronic transverse aortic constriction, PERK knockout mice exhibited decreased ejection fraction, increased left ventricular fibrosis, enhanced cardiomyocyte apoptosis, and exacerbated lung remodeling in comparison with wild-type mice. PERK knockout also dramatically attenuated cardiac sarcoplasmic reticulum Ca(2+)-ATPase expression in response to aortic constriction. Our findings suggest that PERK is required to protect the heart from pressure overload-induced congestive heart failure. © 2014 American Heart Association, Inc.

  20. Induced Pluripotent Stem Cells-Derived Mesenchymal Stem Cells Attenuate Cigarette Smoke-Induced Cardiac Remodeling and Dysfunction

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    Yingmin Liang

    2017-07-01

    Full Text Available The strong relationship between cigarette smoking and cardiovascular disease (CVD has been well-documented, but the mechanisms by which smoking increases CVD risk appear to be multifactorial and incompletely understood. Mesenchymal stem cells (MSCs are regarded as an important candidate for cell-based therapy in CVD. We hypothesized that MSCs derived from induced pluripotent stem cell (iPSC-MSCs or bone marrow (BM-MSCs might alleviate cigarette smoke (CS-induced cardiac injury. This study aimed to investigate the effects of BM-MSCs or iPSC-MSCs on CS-induced changes in serum and cardiac lipid profiles, oxidative stress and inflammation as well as cardiac function in a rat model of passive smoking. Male Sprague-Dawley rats were randomly selected for exposure to either sham air (SA as control or 4% CS for 1 h per day for 56 days. On day 29 and 43, human adult BM-MSCs, iPSC-MSCs or PBS were administered intravenously to CS-exposed rats. Results from echocardiography, serum and cardiac lipid profiles, cardiac antioxidant capacity, cardiac pro- and anti-inflammatory cytokines and cardiac morphological changes were evaluated at the end of treatment. iPSC-MSC-treated group showed a greater effect in the improvement of CS-induced cardiac dysfunction over BM-MSCs-treated group as shown by increased percentage left ventricular ejection fraction and percentage fractional shortening, in line with the greater reversal of cardiac lipid abnormality. In addition, iPSC-MSCs administration attenuated CS-induced elevation of cardiac pro-inflammatory cytokines as well as restoration of anti-inflammatory cytokines and anti-oxidative markers, leading to ameliorate cardiac morphological abnormalities. These data suggest that iPSC-MSCs on one hand may restore CS-induced cardiac lipid abnormality and on the other hand may attenuate cardiac oxidative stress and inflammation via inhibition of CS-induced NF-κB activation, leading to improvement of cardiac remodeling and

  1. The impact of trans-catheter aortic valve replacement induced left-bundle branch block on cardiac reverse remodeling.

    Science.gov (United States)

    Dobson, Laura E; Musa, Tarique A; Uddin, Akhlaque; Fairbairn, Timothy A; Bebb, Owen J; Swoboda, Peter P; Haaf, Philip; Foley, James; Garg, Pankaj; Fent, Graham J; Malkin, Christopher J; Blackman, Daniel J; Plein, Sven; Greenwood, John P

    2017-02-22

    Left bundle branch block (LBBB) is common following trans-catheter aortic valve replacement (TAVR) and has been linked to increased mortality, although whether this is related to less favourable cardiac reverse remodeling is unclear. The aim of the study was to investigate the impact of TAVR induced LBBB on cardiac reverse remodeling. 48 patients undergoing TAVR for severe aortic stenosis were evaluated. 24 patients with new LBBB (LBBB-T) following TAVR were matched with 24 patients with a narrow post-procedure QRS (nQRS). Patients underwent cardiovascular magnetic resonance (CMR) prior to and 6 m post-TAVR. Measured cardiac reverse remodeling parameters included left ventricular (LV) size, ejection fraction (LVEF) and global longitudinal strain (GLS). Inter- and intra-ventricular dyssynchrony were determined using time to peak radial strain derived from CMR Feature Tracking. In the LBBB-T group there was an increase in QRS duration from 96 ± 14 to 151 ± 12 ms (P < 0.001) leading to inter- and intra-ventricular dyssynchrony (inter: LBBB-T 130 ± 73 vs nQRS 23 ± 86 ms, p < 0.001; intra: LBBB-T 118 ± 103 vs. nQRS 13 ± 106 ms, p = 0.001). Change in indexed LV end-systolic volume (LVESVi), LVEF and GLS was significantly different between the two groups (LVESVi: nQRS -7.9 ± 14.0 vs. LBBB-T -0.6 ± 10.2 ml/m 2 , p = 0.02, LVEF: nQRS +4.6 ± 7.8 vs LBBB-T -2.1 ± 6.9%, p = 0.002; GLS: nQRS -2.1 ± 3.6 vs. LBBB-T +0.2 ± 3.2%, p = 0.024). There was a significant correlation between change in QRS and change in LVEF (r = -0.434, p = 0.002) and between change in QRS and change in GLS (r = 0.462, p = 0.001). Post-procedure QRS duration was an independent predictor of change in LVEF and GLS at 6 months. TAVR-induced LBBB is associated with less favourable cardiac reverse remodeling at medium term follow up. In view of this, every effort should be made to prevent TAVR-induced LBBB

  2. Hydrochlorothiazide modulates ischemic heart failure-induced cardiac remodeling via inhibiting angiotensin II type 1 receptor pathway in rats.

    Science.gov (United States)

    Luo, Jinghong; Chen, Xuanlan; Luo, Chufan; Lu, Guihua; Peng, Longyun; Gao, Xiuren; Zuo, Zhiyi

    2017-04-01

    Our previous study indicates that hydrochlorothiazide inhibits transforming growth factor (TGF)-β/Smad signaling pathway, improves cardiac function and reduces fibrosis. We determined whether these effects were common among the diuretics and whether angiotensin II receptor type 1 (AT1) signaling pathway played a role in these effects. Heart failure was produced by ligating the left anterior descending coronary artery in adult male Sprague Dawley rats. Two weeks after the ligation, 70 rats were randomly divided into five groups: sham-operated group, control group, valsartan group (80 mg/kg/d), hydrochlorothiazide group (12.5 mg/kg/d) and furosemide group (20 mg/kg/d). In addition, neonatal rat ventricular fibroblasts were treated with angiotensin II. After eight-week drug treatment, hydrochlorothiazide group and valsartan group but not furosemide group had improved cardiac function (ejection fraction was 49.4±2.1%, 49.5±1.8% and 39.9±1.9%, respectively, compared with 40.1±2.2% in control group), reduced cardiac interstitial fibrosis and collagen volume fraction (9.7±1.2%, 10.0±1.3% and 14.1±0.8%, respectively, compared with 15.9±1.1% in control group), and decreased expression of AT1, TGF-β and Smad2 in the cardiac tissues. In addition, hydrochlorothiazide reduced plasma angiotensin II and aldosterone levels. Furthermore, hydrochlorothiazide inhibited angiotensin II-induced TGF-β1 and Smad2 protein expression in the neonatal rat ventricular fibroblasts. Our study indicates that the cardiac function and remodeling improvement after ischemic heart failure may not be common among the diuretics. Hydrochlorothiazide may reduce the left ventricular wall stress and angiotensin II signaling pathway to provide these beneficial effects. © 2016 John Wiley & Sons Ltd.

  3. Impact of Remote Ischemic Postconditioning during Primary Percutaneous Coronary Intervention on Left Ventricular Remodeling after Anterior Wall ST-Segment Elevation Myocardial Infarction: A Single-Center Experience.

    Science.gov (United States)

    Elbadawi, Ayman; Awad, Omar; Raymond, Ramy; Badran, Haytham; Mostafa, Ahmad E; Saad, Marwan

    2017-12-01

    The role of remote ischemic postconditioning (RIPostC) in improving left ventricular (LV) remodeling after primary percutaneous coronary intervention (PCI) is not well established. To determine the efficacy and safety of RIPostC in improving LV remodeling and cardiovascular outcomes after primary PCI for anterior ST-elevation myocardial infarction (STEMI). Seventy-one patients with anterior STEMI were randomized to primary PCI with RIPostC protocol ( n  = 36) versus conventional primary PCI ( n  = 35). Primary outcomes included LV remodeling and LV ejection fraction (LVEF) at 6 month follow-up using transthoracic echocardiography. Secondary outcomes included infarct size, ST-segment resolution (STR) ≥70%, Thrombolysis in Myocardial Infarction (TIMI) flow grade, and myocardial blush grade (MBG). Major adverse cardiac events (MACEs) were also assessed at 6 months. Safety outcome included incidence of acute kidney injury (AKI) postprimary PCI. Sixty patients completed the study. At 6 months, there was no significant decrease in the incidence of LV remodeling with RIPostC group ( p  = 0.42). Similarly, RIPostC failed to show significant improvement in LVEF. However, STR ≥ 70% after primary PCI was achieved more in the RIPostC group ( p  = 0.04), with a trend toward less AKI in the RIPostC group ( p  = 0.08). All other secondary end points, including MACEs at 6 months, were similar in both groups. RIPostC might be associated with better STR after reperfusion as well as less incidence of AKI in patients undergoing primary PCI for anterior wall STEMI, indicating potential benefit in those patients. Whether this role can be translated to better outcomes after primary PCI warrants further investigation.

  4. Inhibition of nitric oxide synthases abrogates pregnancy-induced uterine vascular expansive remodeling.

    Science.gov (United States)

    Osol, George; Barron, Carolyn; Gokina, Natalia; Mandala, Maurizio

    2009-01-01

    It was the aim of this study to test the hypothesis that hypertension and/or inhibition of nitric oxide (NO) synthases alters uterine vascular remodeling during pregnancy. Using a model of hypertension (NO synthase inhibition with L-NAME) in nonpregnant and pregnant rats, comparisons were made with age-matched controls, as well as with animals receiving hydralazine along with L-NAME to maintain normotension in the presence of NO synthase inhibition. Circumferential and axial remodeling of large (main uterine, MUA) and small (premyometrial radial) arteries were quantified and compared. L-NAME treatment prevented expansive circumferential remodeling of the MUA; cotreatment with hydralazine was without effect. Circumferential remodeling of smaller premyometrial radial arteries was also significantly attenuated in hypertensive pregnant animals, while premyometrial radial arteries from rats receiving hydralazine with L-NAME were of intermediate diameter. Neither hypertension nor NO synthase inhibition had any effect on the substantial (200-300%) axial growth of MUA or premyometrial radial arteries. NO plays a major role in facilitating pregnancy-induced expansive remodeling in the uterine circulation, particularly in larger arteries. Some beneficial effects of hydralazine on expansive circumferential remodeling were noted in smaller radial vessels, and these may be linked to its prevention of systemic hypertension and/or to local effects on the arterial wall. Neither NO synthase inhibition nor hypertension had any effect on arterial longitudinal growth.

  5. Stress-induced alteration of left ventricular eccentricity: An additional marker of multivessel CAD.

    Science.gov (United States)

    Gimelli, Alessia; Liga, Riccardo; Giorgetti, Assuero; Casagranda, Mirta; Marzullo, Paolo

    2017-03-28

    Abnormal left ventricular (LV) eccentricity index (EI) is a marker of adverse cardiac remodeling. However, the interaction between stress-induced alterations of EI and major cardiac parameters has not been explored. We sought to evaluate the relationship between LV EI and coronary artery disease (CAD) burden in patients submitted to myocardial perfusion imaging (MPI). Three-hundred and forty-three patients underwent MPI and coronary angiography. LV ejection fraction (EF) and EI were computed from gated stress images as measures of stress-induced functional impairment. One-hundred and thirty-six (40%), 122 (35%), and 85 (25%) patients had normal coronary arteries, single-vessel CAD, and multivessel CAD, respectively. Post-stress EI was lower in patients with multivessel CAD than in those with normal coronary arteries and single-vessel CAD (P = 0.001). This relationship was confirmed only in patients undergoing exercise stress test, where a lower post-stress EI predicted the presence of multivessel CAD (P = 0.039). Post-stress alterations of LV EI on MPI may unmask the presence of multivessel CAD.

  6. Residual Myocardial Iron Following Intramyocardial Hemorrhage During the Convalescent Phase of Reperfused ST-Segment-Elevation Myocardial Infarction and Adverse Left Ventricular Remodeling.

    Science.gov (United States)

    Bulluck, Heerajnarain; Rosmini, Stefania; Abdel-Gadir, Amna; White, Steven K; Bhuva, Anish N; Treibel, Thomas A; Fontana, Marianna; Ramlall, Manish; Hamarneh, Ashraf; Sirker, Alex; Herrey, Anna S; Manisty, Charlotte; Yellon, Derek M; Kellman, Peter; Moon, James C; Hausenloy, Derek J

    2016-10-01

    The presence of intramyocardial hemorrhage (IMH) in ST-segment-elevation myocardial infarction patients reperfused by primary percutaneous coronary intervention has been associated with residual myocardial iron at follow-up, and its impact on adverse left ventricular (LV) remodeling is incompletely understood and is investigated here. Forty-eight ST-segment-elevation myocardial infarction patients underwent cardiovascular magnetic resonance at 4±2 days post primary percutaneous coronary intervention, of whom 40 had a follow-up scan at 5±2 months. Native T1, T2, and T2* maps were acquired. Eight out of 40 (20%) patients developed adverse LV remodeling. A subset of 28 patients had matching T2* maps, of which 15/28 patients (54%) had IMH. Eighteen of 28 (64%) patients had microvascular obstruction on the acute scan, of whom 15/18 (83%) patients had microvascular obstruction with IMH. On the follow-up scan, 13/15 patients (87%) had evidence of residual iron within the infarct zone. Patients with residual iron had higher T2 in the infarct zone surrounding the residual iron when compared with those without. In patients with adverse LV remodeling, T2 in the infarct zone surrounding the residual iron was also higher than in those without (60 [54-64] ms versus 53 [51-56] ms; P=0.025). Acute myocardial infarct size, extent of microvascular obstruction, and IMH correlated with the change in LV end-diastolic volume (Pearson's rho of 0.64, 0.59, and 0.66, respectively; P=0.18 and 0.62, respectively, for correlation coefficient comparison) and performed equally well on receiver operating characteristic curve for predicting adverse LV remodeling (area under the curve: 0.99, 0.94, and 0.95, respectively; P=0.19 for receiver operating characteristic curve comparison). The majority of ST-segment-elevation myocardial infarction patients with IMH had residual myocardial iron at follow-up. This was associated with persistently elevated T2 values in the surrounding infarct tissue and

  7. Exercise-Induced Cardiac Remodeling: Lessons from Humans, Horses, and Dogs

    Directory of Open Access Journals (Sweden)

    Rob Shave

    2017-02-01

    Full Text Available Physical activity is dependent upon the cardiovascular system adequately delivering blood to meet the metabolic and thermoregulatory demands of exercise. Animals who regularly exercise therefore require a well-adapted heart to support this delivery. The purpose of this review is to examine cardiac structure, and the potential for exercise-induced cardiac remodeling, in animals that regularly engage in strenuous activity. Specifically, we draw upon the literature that has studied the “athlete’s heart” in humans, horses, and dogs, to enable the reader to compare and contrast cardiac remodeling in these three athletic species. The available literature provides compelling evidence for exercise-induced cardiac remodeling in all three species. However, more work is required to understand the influence of species/breed specific genetics and exercise-related hemodynamics, in order to fully understand the impact of exercise on cardiac structure.

  8. A risk score to predict the absence of left ventricular reverse remodeling: Implications for the timing of ICD implantation in primary prevention.

    Science.gov (United States)

    Pérez-Rodon, Jordi; Galve, Enrique; Pérez-Bocanegra, Carmen; Soriano-Sánchez, Teresa; Recio-Iglesias, Jesús; Domingo-Baldrich, Eva; Alzola-Guevara, Mila; Ferreira-González, Ignacio; Marsal, Josep Ramon; Ribera-Solé, Aida; Gutierrez García-Moreno, Laura; Cruz-Carlos, Luz María; Rivas-Gandara, Nuria; Roca-Luque, Ivo; Francisco-Pascual, Jaume; Evangelista-Masip, Artur; Moya-Mitjans, Àngel; García-Dorado, David

    2017-11-25

    A prophylactic implantable cardioverter defibrillator (ICD) in patients with heart failure and reduced left ventricular ejection fraction (HFrEF) is only indicated when left ventricular ejection fraction (LVEF) reassessment remains ≤35% after 3-6 months on optimal pharmacological therapy. However, LVEF may not improve during this period and the patient may be exposed to an unnecessary risk of sudden cardiac death. This study aimed to determine the incidence and predictors of the absence of left ventricular reverse remodeling (LVRR) after pharmacological treatment optimization in patients with HFrEF to design a risk score of absence of LVRR. Consecutive outpatients with LVEF ≤35% were included in this observational prospective study. Up-titration of angiotensin-converting enzyme (ACE) inhibitors/angiotensin II receptor blockers (ARBs), beta-blockers, mineralocorticoid receptor antagonists (MRAs), and ivabradine was performed in our Heart Failure (HF) Unit. The absence of LVRR was defined as the persistence of an LVEF ≤35% at the 6-month follow-up. One hundred and twenty patients were included. At the 6-month follow-up, 64%, 76%, 72%, and 7% of patients were at 100% of the target dose of ACE inhibitors/ARBs, beta-blockers, MRAs, and ivabradine, respectively. LVRR was observed in 48% of the patients. Ischemic cardiomyopathy, prolonged HF duration, and larger left ventricular end-diastolic diameter index (LVEDDI) were independent predictors of the absence of LVRR. The risk score based on these predictors showed a c-statistic value of 0.81. Pharmacological treatment optimization is associated with LVRR in approximately half of cases, reducing potential ICD indications in parallel. However, ischemic cardiomyopathy, prolonged HF duration, and larger LVEDDI predict the absence of LVRR and favor ICD implantation without delay. The risk score based on the former predictors may help the clinician with the timing of ICD implantation. Copyright © 2017 Japanese College of

  9. Mid-Ventricular Variant of Dobutamine-Induced Stress Cardiomyopathy.

    Science.gov (United States)

    Chandraprakasam, Satish; Kanuri, Swapna; Hunter, Claire

    2015-05-01

    Dobutamine stress testing is a commonly used modality in detecting and estimating the prognosis in coronary artery disease (CAD). Although it is well tolerated by most patients, adverse events have been reported. Rarely, transient wall motion abnormalities can occur in the absence of obstructive CAD to suggest stress cardiomyopathy. We report a 48-year-old female with intermittent chest pain. Her physical exam, cardiac enzymes and transthoracic echocardiogram were unremarkable. She underwent dobutamine stress echocardiogram to rule out obstructive CAD. After 40 micrograms (mcg)/kg/minute and 0.5 mg atropine, she complained of intense chest pain and became hypertensive. Stress echocardiogram demonstrated mid-anterior and mid-septal hypokinesis. Emergent coronary angiogram demonstrated normal coronaries. Left ventricular angiogram in the right anterior oblique projection revealed mid-ventricular ballooning during systole with apical and basal hypercontractility. Patient demonstrated excellent recovery with expectant management. The mechanism of mid-variant of Dobutamine-induced stress cardiomyopathy remains unclear. We think that multiple mechanisms are involved and this risk should be considered in patients with comorbid psychiatric conditions and with use of centrally acting stimulants.

  10. Static stretch induces active morphological remodeling and functional impairment of alveolar epithelial cells.

    Science.gov (United States)

    Ren, Yanhong; Zhan, Qingyuan; Hu, Qinghua; Sun, Bing; Yang, Chun; Wang, Chen

    2009-01-01

    Static stretch is frequently observed in the lung. Both static stretch and cyclic stretch can induce cell death and Na(+)/K(+)-ATPase trafficking, but stretch-induced alveolar epithelial cell (AEC) functions are much less responsive to static than to cyclic stretch. AEC remodeling under static stretch may be partly explained. The aim of this study was to explore the AEC remodeling and functional changes under static stretch conditions. We used A549 cells as a model of AEC type II cells. We assessed F-actin content and cell viability by fluorescence staining at various static-stretch magnitudes and time points. Specifically, we used scanning electron microscopy to explore the possible biological mechanisms used by A549 cells to 'escape' static-stretch-induced injury. Finally, we measured choline cytidylyltransferase-alpha (CCT alpha) mRNA and protein by real-time PCR and Western blot to evaluate cellular secretory function. The results showed that the magnitude of static stretch was the primary determinant of static-stretch-induced cell death and cytoskeleton organization, but an extended duration of high static deformation/stretch (37% change in surface area) had no cumulative effects on cell death and cytoskeleton organization. AEC remodeling (expansion-contraction-reexpansion) under static stretch conditions may explain this interesting phenomenon partly. After cell remodeling, CCT alpha expression in A549 cells was influenced not only by stretch magnitude but also by stretch time. Under static stretch conditions, A549 cells undergo morphological and functional changes. They can survive stress failure from overstretching by remodeling their body to 'escape' the injury. During this complex course of remodeling, cellular function was partly damaged. (c) 2009 S. Karger AG, Basel.

  11. Early remodeling of rat cardiac muscle induced by swimming training

    Directory of Open Access Journals (Sweden)

    Verzola R.M.M.

    2006-01-01

    Full Text Available The aim of the present investigation was to study the effect of acute swimming training with an anaerobic component on matrix metallopeptidase (MMP activity and myosin heavy chain gene expression in the rat myocardium. Animals (male Wistar rats, weighing approximately 180 g were trained for 6 h/day in 3 sessions of 2 h each for 1 to 5 consecutive days (N = 5 rats per group. Rats swam in basins 47 cm in diameter and 60 cm deep filled with water at 33 to 35ºC. After the training period a significant increase (P < 0.05 was observed in the heart weight normalized to body weight by about 22 and 35% in the groups that trained for 96 and 120 h, respectively. Blood lactate levels were significantly increased (P < 0.05 in all groups after all training sessions, confirming an anaerobic component. However, lactate levels decreased (P < 0.05 with days of training, suggesting that the animals became adapted to this protocol. Myosin heavy chain-ß gene expression, analyzed by real time PCR and normalized with GAPDH gene expression, showed a significant two-fold increase (P < 0.01 after 5 days of training. Zymography analysis of myocardium extracts indicated a single ~60-kDa activity band that was significantly increased (P < 0.05 after 72, 96, and 120 h, indicating an increased expression of MMP-2 and suggesting precocious remodeling. Furthermore, the presence of MMP-2 was confirmed by Western blot analysis, but not the presence of MMP-1 and MMP-3. Taken together, our results indicate that in these training conditions, the rat heart undergoes early biochemical and functional changes required for the adaptation to the new physiological condition by tissue remodeling.

  12. Hypoxia-inducible factor-1 α/platelet derived growth factor axis in HIV-associated pulmonary vascular remodeling

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    Bartolome Sonja

    2011-08-01

    Full Text Available Abstract Background Human immunodeficiency virus (HIV infected patients are at increased risk for the development of pulmonary arterial hypertension (PAH. Recent reports have demonstrated that HIV associated viral proteins induce reactive oxygen species (ROS with resultant endothelial cell dysfunction and related vascular injury. In this study, we explored the impact of HIV protein induced oxidative stress on production of hypoxia inducible factor (HIF-1α and platelet-derived growth factor (PDGF, critical mediators implicated in the pathogenesis of HIV-PAH. Methods The lungs from 4-5 months old HIV-1 transgenic (Tg rats were assessed for the presence of pulmonary vascular remodeling and HIF-1α/PDGF-BB expression in comparison with wild type controls. Human primary pulmonary arterial endothelial cells (HPAEC were treated with HIV-associated proteins in the presence or absence of pretreatment with antioxidants, for 24 hrs followed by estimation of ROS levels and western blot analysis of HIF-1α or PDGF-BB. Results HIV-Tg rats, a model with marked viral protein induced vascular oxidative stress in the absence of active HIV-1 replication demonstrated significant medial thickening of pulmonary vessels and increased right ventricular mass compared to wild-type controls, with increased expression of HIF-1α and PDGF-BB in HIV-Tg rats. The up-regulation of both HIF-1α and PDGF-B chain mRNA in each HIV-Tg rat was directly correlated with an increase in right ventricular/left ventricular+septum ratio. Supporting our in-vivo findings, HPAECs treated with HIV-proteins: Tat and gp120, demonstrated increased ROS and parallel increase of PDGF-BB expression with the maximum induction observed on treatment with R5 type gp-120CM. Pre-treatment of endothelial cells with antioxidants or transfection of cells with HIF-1α small interfering RNA resulted in abrogation of gp-120CM mediated induction of PDGF-BB, therefore, confirming that ROS generation and

  13. Hemodialysis-Induced Regional Left Ventricular Systolic Dysfunction and Inflammation : A Cross-sectional Study

    NARCIS (Netherlands)

    Assa, Solmaz; Hummel, Yoran M.; Voors, Adriaan A.; Kuipers, Johanna; Westerhuis, Ralf; Groen, Henk; Bakker, Stephan J. L.; Muller Kobold, Anneke C.; van Oeveren, Wim; Struck, Joachim; de Jong, Paul E.; Franssen, Casper F. M.

    Background: Hemodialysis may acutely induce regional left ventricular (LV) systolic dysfunction, which is associated with increased mortality and progressive heart failure. We tested the hypothesis that hemodialysis-induced regional LV systolic dysfunction is associated with inflammation and

  14. Effect of obesity reduction on preservation of heart function and attenuation of left ventricular remodeling, oxidative stress and inflammation in obese mice.

    Science.gov (United States)

    Wang, Hui-Ting; Liu, Chu-Feng; Tsai, Tzu-Hsien; Chen, Yung-Lung; Chang, Hsueh-Wen; Tsai, Ching-Yen; Leu, Steve; Zhen, Yen-Yi; Chai, Han-Tan; Chung, Sheng-Ying; Chua, Sarah; Yen, Chia-Hung; Yip, Hon-Kan

    2012-07-11

    Obesity is an important cardiovascular risk factor. This study tested the effect of obesity reduction on preserving left ventricular ejection fraction (LVEF) and attenuating inflammation, oxidative stress and LV remodeling in obese mice. Eight-week-old C57BL/6 J mice (n=24) were equally divided into control (fed a control diet for 22 weeks), obesity (high-fat diet, 22 weeks), and obese reduction (OR) (high-fat diet, 14 weeks; then control diet, 8 weeks). Animals were sacrificed at post 22-week high-fat diet and the LV myocardium collected. Heart weight, body weight, abdominal-fat weight, total cholesterol level and fasting blood glucose were higher in obesity than in control and OR (all pobesity than in control and OR (all pobesity as compared with control and OR (all pobesity than in control and OR (all pobesity.

  15. Fibroblast cytoskeletal remodeling induced by tissue stretch involves ATP signaling.

    Science.gov (United States)

    Langevin, Helene M; Fujita, Takumi; Bouffard, Nicole A; Takano, Takahiro; Koptiuch, Cathryn; Badger, Gary J; Nedergaard, Maiken

    2013-09-01

    Fibroblasts in whole areolar connective tissue respond to static stretching of the tissue by expanding and remodeling their cytoskeleton within minutes both ex vivo and in vivo. This study tested the hypothesis that the mechanism of fibroblast expansion in response to tissue stretch involves extracellular ATP signaling. In response to tissue stretch ex vivo, ATP levels in the bath solution increased significantly, and this increase was sustained for 20 min, returning to baseline at 60 min. No increase in ATP was observed in tissue incubated without stretch or tissue stretched in the presence of the Rho kinase inhibitor Y27632. The increase in fibroblast cross sectional area in response to tissue stretch was blocked by both suramin (a purinergic receptor blocker) and apyrase (an enzyme that selectively degrades extracellular ATP). Furthermore, connexin channel blockers (octanol and carbenoxolone), but not VRAC (fluoxetine) or pannexin (probenecid) channel blockers, inhibited fibroblast expansion. Together, these results support a mechanism in which extracellular ATP signaling via connexin hemichannels mediate the active change in fibroblast shape that occurs in response to a static increase in tissue length. Copyright © 2013 Wiley Periodicals, Inc.

  16. Flecainide Therapy Reduces Exercise-Induced Ventricular Arrhythmias in Patients With Catecholaminergic Polymorphic Ventricular Tachycardia

    NARCIS (Netherlands)

    van der Werf, Christian; Kannankeril, Prince J.; Sacher, Frederic; Krahn, Andrew D.; Viskin, Sami; Leenhardt, Antoine; Shimizu, Wataru; Sumitomo, Naokata; Fish, Frank A.; Bhuiyan, Zahurul A.; Willems, Albert R.; van der Veen, Maurits J.; Watanabe, Hiroshi; Laborderie, Julien; Haïssaguerre, Michel; Knollmann, Björn C.; Wilde, Arthur A. M.

    2011-01-01

    Objectives This study evaluated the efficacy and safety of flecainide in addition to conventional drug therapy in patients with catecholaminergic polymorphic ventricular tachycardia (CPVT). Background CPVT is an inherited arrhythmia syndrome caused by gene mutations that destabilize cardiac

  17. 31P NMR 2D Mapping of Creatine Kinase Forward Flux Rate in Hearts with Postinfarction Left Ventricular Remodeling in Response to Cell Therapy.

    Directory of Open Access Journals (Sweden)

    Ling Gao

    Full Text Available Utilizing a fast 31P magnetic resonance spectroscopy (MRS 2-dimensional chemical shift imaging (2D-CSI method, this study examined the heterogeneity of creatine kinase (CK forward flux rate of hearts with postinfarction left ventricular (LV remodeling. Immunosuppressed Yorkshire pigs were assigned to 4 groups: 1 A sham-operated normal group (SHAM, n = 6; 2 A 60 minutes distal left anterior descending coronary artery ligation and reperfusion (MI, n = 6; 3 Open patch group; ligation injury plus open fibrin patch over the site of injury (Patch, n = 6; and 4 Cell group, hiPSCs-cardiomyocytes, -endothelial cells, and -smooth muscle cells (2 million, each were injected into the injured myocardium pass through a fibrin patch (Cell+Patch, n = 5. At 4 weeks, the creatine phosphate (PCr/ATP ratio, CK forward flux rate (Flux PCr→ATP, and k constant of CK forward flux rate (kPCr→ATP were severely decreased at border zone myocardium (BZ adjacent to MI. Cell treatment results in significantly increase of PCr/ATP ratio and improve the value of kPCr→ATP and Flux PCr→ATP in BZ myocardium. Moreover, the BZ myocardial CK total activity and protein expression of CK mitochondria isozyme and CK myocardial isozyme were significantly reduced, but recovered in response to cell treatment. Thus, cell therapy results in improvement of BZ bioenergetic abnormality in hearts with postinfarction LV remodeling, which is accompanied by significantly improvements in BZ CK activity and CK isozyme expression. The fast 2D 31P MR CSI mapping can reliably measure the heterogeneity of bioenergetics in hearts with post infarction LV remodeling.

  18. Long-Term Left Ventricular Remodelling in Rat Model of Nonreperfused Myocardial Infarction: Sequential MR Imaging Using a 3T Clinical Scanner

    Directory of Open Access Journals (Sweden)

    Muhammad G. Saleh

    2012-01-01

    Full Text Available Purpose. To evaluate whether 3T clinical MRI with a small-animal coil and gradient-echo (GE sequence could be used to characterize long-term left ventricular remodelling (LVR following nonreperfused myocardial infarction (MI using semi-automatic segmentation software (SASS in a rat model. Materials and Methods. 5 healthy rats were used to validate left ventricular mass (LVM measured by MRI with postmortem values. 5 sham and 7 infarcted rats were scanned at 2 and 4 weeks after surgery to allow for functional and structural analysis of the heart. Measurements included ejection fraction (EF, end-diastolic volume (EDV, end-systolic volume (ESV, and LVM. Changes in different regions of the heart were quantified using wall thickness analyses. Results. LVM validation in healthy rats demonstrated high correlation between MR and postmortem values. Functional assessment at 4 weeks after MI revealed considerable reduction in EF, increases in ESV, EDV, and LVM, and contractile dysfunction in infarcted and noninfarcted regions. Conclusion. Clinical 3T MRI with a small animal coil and GE sequence generated images in a rat heart with adequate signal-to-noise ratio (SNR for successful semiautomatic segmentation to accurately and rapidly evaluate long-term LVR after MI.

  19. Perivascular delivery of Notch 1 siRNA inhibits injury-induced arterial remodeling.

    Directory of Open Access Journals (Sweden)

    Eileen M Redmond

    Full Text Available To determine the efficacy of perivascular delivery of Notch 1 siRNA in preventing injury-induced arterial remodeling.Carotid artery ligation was performed to induce arterial remodeling. After 14 days, morphometric analysis confirmed increased vSMC growth and subsequent media thickening and neointimal formation. Laser capture microdissection, quantitative qRT-PCR and immunoblot analysis of medial tissue revealed a significant increase in Notch1 receptor and notch target gene, Hrt 1 and 2 expression in the injured vessels. Perivascular delivery of Notch 1 siRNA by pluronic gel inhibited the injury-induced increase in Notch 1 receptor and target gene expression when compared to scrambled siRNA controls while concomitantly reducing media thickening and neointimal formation to pre-injury, sham-operated levels. Selective Notch 1 knockdown also reversed the injury-induced inhibition of pro-apoptotic Bax expression while decreasing injury-induced anti-apoptotic Bcl-XL expression to sham-operated control levels. In parallel experiments, proliferative cyclin levels, as measured by PCNA expression, were reversed to sham-operated control levels following selective Notch 1 knockdown.These results suggest that injury-induced arterial remodeling can be successfully inhibited by localized perivascular delivery of Notch 1 siRNA.

  20. Influence of stentless versus stented valves on ventricular remodeling assessed at 6 months by magnetic resonance imaging and long-term follow-up.

    Science.gov (United States)

    Fouquet, Olivier; Baufreton, Christophe; Tassin, Aude; Pinaud, Frédéric; Binuani, Jean-Patrice; DangVan, Simon; Prunier, Fabrice; Rouleau, Frédéric; Willoteaux, Serge; De Brux, Jean-Louis; Furber, Alain

    2017-01-01

    To compare the effect of stented versus stentless bioprostheses on left ventricular remodeling and assess their impact on long-term survival. From January 2002 to December 2009, 62 severe aortic stenosis patients without coronary artery disease were randomized for bioprosthetic aortic valve replacement. After randomization, a cross-over was possible based on intraoperative data. Ventricular remodeling was studied by cardiovascular magnetic resonance imaging six months after surgery. Long-term survival was assessed by telephone survey. Thirty-five patients received a porcine Mosaïc(®) Medtronic bioprosthesis (Stented Group; Medtronic, Minneapolis, MN, USA) inserted using the usual supra-annular technique and 27 received a porcine Freestyle(®) Medtronic bioprosthesis (Stentless Group) inserted in the subcoronary position. Mean age was 75±3 and 73±4 years in the stentless and stented group, respectively. Nine patients who should have been implanted with a stentless bioprosthesis received a stented bioprosthesis for anatomical reasons. At 6 months, the left ventricular mass (LVM) decreased significantly in both groups (Stentless Group: 214.6±56.1g and 156.3±23g and Stented Group: 237±75.7g and 181±53.3g, respectively after surgery and at 6 months), this decrease was significantly greater in the stentless group (p=0.026). Reserve and coronary flow were increased in both groups at 6 months. Mean follow-up duration was 6.6±3.0 years and 7.2±4.0 years in the stentless and stented group, respectively. The 5-year actuarial survival was 87.5±11.7% and 82.5±17.1% for the stentless and stented group, respectively (p=0.81). Porcine stentless prosthesis results in a better LVM regression than a stented valve at 6 months without changing the long-term survival. Copyright © 2016 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.

  1. Overexpression of Cardiomyocyte Alpha1A-Adrenergic Receptors Attenuates Post-Infarct Remodeling by Inducing Angiogenesis Through Heterocellular Signaling

    Science.gov (United States)

    Zhao, Xin; Balaji, Poornima; Pachon, Ronald; Beniamen, Daniella M.; Vatner, Dorothy E.; Graham, Robert M.; Vatner, Stephen F.

    2015-01-01

    Objective We tested the hypothesis that simulation of cardiac α1A-adrenergic receptors (α1A-AR) protects against the development of heart failure through induction of angiogenesis. Approach and Results 4–6 weeks after permanent coronary artery occlusion (CAO), transgenic (TG) rats with cardiomyocyte-specific α1A-AR overexpression had less remodeling than their non-transgenic littermates (NTLs), with less fibrosis, hypertrophy and lung wt, and preserved left ventricular ejection fraction and wall stress, all p<0.05. Coronary blood flow, measured with microspheres, increased in the infarct zone in TG compared to NTLs (1.4±0.2 vs. 0.5±0.08ml/min/g) (p<0.05), which is consistent with angiogenesis, as reflected by a 20% increase in capillary density in the zone adjacent to the infarct. The question arose, how does TG overexpression of a gene in cardiomyocytes induce angiogenesis? We identified a paracrine mechanism, whereby VEGF-A mRNA and protein were increased in isolated TG cardiomyocytes, and also by NTL cardiomyocytes treated with an α1A-agonist, resulting in angiogenesis. Conditioned medium from cultured TG cardiomyocytes enhanced human umbilical vein endothelial cell (HUVEC) tubule formation, which was blocked by an anti-VEGF-A antibody. Moreover, improved cardiac function, blood flow and increased capillary density after chronic CAO in TG rats were blocked by either a MEK or a VEGF-A inhibitor. Conclusions Cardiomyocyte-specific overexpression of the α1A-AR resulted in enhanced MEK-dependent cardiomyocyte VEGF-A expression, which stimulates angiogenesis via a paracrine mechanism involving heterocellular cardiomyocyte/endothelial cell signalling, protecting against remodeling and heart failure following chronic CAO. PMID:26338300

  2. Serial Echocardiographic Assessment of Left Ventricular Filling Pressure and Remodeling among ST-Segment Elevation Myocardial Infarction Patients Treated by Primary Percutaneous Intervention.

    Science.gov (United States)

    Shacham, Yacov; Khoury, Shafik; Flint, Nir; Steinvil, Arie; Sadeh, Ben; Arbel, Yaron; Topilsky, Yan; Keren, Gad

    2016-08-01

    Acute myocardial infarction and remodeling of the left ventricle is associated with significant changes in systolic and diastolic echocardiographic derived indices. The investigators have tried to determine whether persistence of increased ratio of transmitral flow velocity (E) to early mitral annulus velocity (e'), signifying increased cardiac filling pressure, is associated with left ventricular (LV) remodeling and increased chamber size among patients presenting with ST-segment elevation myocardial infarction, who underwent successful reperfusion with primary percutaneous coronary intervention. Fifty-two patients (76% men; mean age, 61 ± 10 years) with first ST-segment elevation myocardial infarctions who underwent primary percutaneous coronary intervention were retrospectively studied. Echocardiography was performed at baseline (days 1-3) and after 178 ± 62 days. Patients were stratified according to E/septal e' ratio >15 and ≤15 in both examinations. All patients received optimal medical therapy according to guidelines and local practice. Patients with maintained or worsened E/septal e' ratios to >15 demonstrated on the second examination worse LV ejection fractions (mean, 45 ± 12% vs 52 ± 8%; P = .03) and higher indexed LV end-diastolic volumes (mean, 81.3 ± 22.9 vs 69.2 ± 13.4 mL/m(2); P = .01) and end-systolic volumes (mean, 33.0 ± 12.2 vs 23.7 ± 13.4 mL/m(2); P = .02) compared with the first examination, representing LV remodeling. Patients with E/septal e' ratios > 15 on the second examination demonstrated a positive correlation between the change in E/septal e' ratio and the change in indexed LV end-diastolic volume (linear R(2) = 0.344, P = .03). Among patients with ST-segment elevation myocardial infarctions undergoing primary percutaneous coronary intervention, early and persistent elevation of the E/septal e' ratio may be associated with LV remodeling. Copyright © 2016 American Society of Echocardiography

  3. Myocardial extracellular volume fraction quantified by cardiovascular magnetic resonance is increased in hypertension and associated with left ventricular remodeling.

    Science.gov (United States)

    Wang, Shuli; Hu, Hongjie; Lu, Minjie; Sirajuddin, Arlene; Li, Jinghui; An, Jing; Chen, Xiuyu; Yin, Gang; Lan, Tian; Dai, Linlin; Zhang, Yan; Yin, Xiaorong; Song, Lei; Dang, Aimin; Kellman, Peter; Arai, Andrew E; Zhao, Shihua

    2017-04-24

    To determine whether extracellular volume fraction (ECV) quantification by cardiac magnetic resonance (CMR) can demonstrate left ventricle (LV) abnormalities and relationship between ECV and LV remodeling in hypertension (HTN) patients METHODS: ECV quantification was prospectively performed in 134 consecutive HTN patients and 97 healthy subjects. Individual and regional ECV were compared to the regions on late gadolinium enhancement (LGE) images. Statistical analysis of the relationship between LV global functional parameters and ECV was carried out using Pearson's correlation, Student's t test and multiple regressions. In the HTN group, 70.1% (94/134) were LGE negative and 29.9% (40/134) LGE positive. The mean ECV after adjusting for age, sex, BMI, diabetes, smoking and dyslipidaemia in healthy controls and LGE-negative patients were 26.9 ± 2.67% and 28.5 ± 2.9% (p ECV reached statistical significance among the regions of LGE, LGE-Peri, LGE remote and the normal area between the control and LGE-positive subgroup (all p ECV significantly correlated with LVEF (r = -0.466, p ECV can identify LV abnormalities at an early stage in HTN patients without LGE. These abnormalities may reflect an increase in diffuse myocardial fibrosis and are associated with LV remodeling. • Diffuse myocardial fibrosis may develop in hypertensive cardiomyopathy before conventional MRI detectable LGE. • ECV can identify myocardial fibrosis at an early stage in hypertensive patients. • Elevated ECV is associated with decreased LV global function and LV remodeling in hypertension.

  4. Biophysics of α-synuclein induced membrane remodelling

    OpenAIRE

    Shi, Zheng; Sachs, Jonathan; Rhoades, Elizabeth; Baumgart, Tobias

    2015-01-01

    α-synuclein is an intrinsically disordered protein whose aggregation is a hallmark of Parkinson’s disease. In neurons, α-synuclein is thought to play important roles in mediating both endo- and exocytosis of synaptic vesicles through interactions with either the lipid bilayer or other proteins. Upon membrane binding, the N-terminus of α-synuclein forms a helical structure and inserts into the hydrophobic region of the outer membrane leaflet. However, membrane structural changes induced by α-s...

  5. Myocardial extracellular volume fraction quantified by cardiovascular magnetic resonance is increased in hypertension and associated with left ventricular remodeling

    Energy Technology Data Exchange (ETDEWEB)

    Wang, Shuli; Li, Jinghui; Chen, Xiuyu; Yin, Gang; Lan, Tian; Dai, Linlin; Zhang, Yan; Yin, Xiaorong; Zhao, Shihua [Chinese Academy of Medical Sciences and Peking Union Medical College, Department of Magnetic Resonance Imaging, Cardiovascular Imaging and Intervention Center, State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Beijing (China); Hu, Hongjie [Zhejiang University, Department of Radiology, Sir Run Run Shaw Hospital, School of Medicine, Hangzhou (China); Lu, Minjie [Chinese Academy of Medical Sciences and Peking Union Medical College, Department of Magnetic Resonance Imaging, Cardiovascular Imaging and Intervention Center, State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Beijing (China); Laboratory for Advanced Cardiovascular Imaging, National Heart, Lung, and Blood Institute (NHLBI), National Institutes of Health (NIH), Department of Health and Human Services, Bethesda, MD (United States); Sirajuddin, Arlene; Arai, Andrew E. [Laboratory for Advanced Cardiovascular Imaging, National Heart, Lung, and Blood Institute (NHLBI), National Institutes of Health (NIH), Department of Health and Human Services, Bethesda, MD (United States); An, Jing [Siemens Shenzhen Magnetic Resonance Ltd., Siemens MRI Center, Shenzhen, Guangdong (China); Song, Lei; Dang, Aimin [Chinese Academy of Medical Sciences and Peking Union Medical College, Department of Cardiology, State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Beijing (China); Kellman, Peter [National Heart, Lung and Blood Institute (NHLBI), National Institutes of Health (NIH), US Department of Health and Human Services, Cardiovascular and Pulmonary Branch, Bethesda, MD (United States)

    2017-11-15

    To determine whether extracellular volume fraction (ECV) quantification by cardiac magnetic resonance (CMR) can demonstrate left ventricle (LV) abnormalities and relationship between ECV and LV remodeling in hypertension (HTN) patients ECV quantification was prospectively performed in 134 consecutive HTN patients and 97 healthy subjects. Individual and regional ECV were compared to the regions on late gadolinium enhancement (LGE) images. Statistical analysis of the relationship between LV global functional parameters and ECV was carried out using Pearson's correlation, Student's t test and multiple regressions. In the HTN group, 70.1% (94/134) were LGE negative and 29.9% (40/134) LGE positive. The mean ECV after adjusting for age, sex, BMI, diabetes, smoking and dyslipidaemia in healthy controls and LGE-negative patients were 26.9 ± 2.67% and 28.5 ± 2.9% (p < 0.001), respectively. The differences in ECV reached statistical significance among the regions of LGE, LGE-Peri, LGE remote and the normal area between the control and LGE-positive subgroup (all p < 0.05). Global ECV significantly correlated with LVEF (r = -0.466, p < 0.001) and LV hypertrophy (r = 0.667, p < 0.001). ECV can identify LV abnormalities at an early stage in HTN patients without LGE. These abnormalities may reflect an increase in diffuse myocardial fibrosis and are associated with LV remodeling. (orig.)

  6. [Effects of long-term exercise training on left ventricular function and remodeling in patients with anterior wall myocardial infarction].

    Science.gov (United States)

    Rivas-Estany, Eduardo; Sixto-Fernández, Sherien; Barrera-Sarduy, José; Hernández-García, Susana; González-Guerra, Roberto; Stusser-Beltranena, Rodolfo

    2013-01-01

    To assess the effects of long-term exercise training on the function and remodeling of the left ventricle after myocardial infarction. We studied 90 patients with a first acute anterior-wall myocardial infarction, all received conventional medical treatment. Symptom-limited maximal exercise stress tests, echocardiograms and effort-rest isotopic ventriculographies at 2, 6 and 12 months after myocardial infarction were performed; the follow-up time averaged 36.3±17 months. All patients joined a cardiac rehabilitation program with moderate or intense exercise training lasting at least a year. Of all patients, 41.1% suffered severe left ventricle dysfunction. Ergometric parameters that expressed functional capacity increased significantly (Pcardiovascular cause. Long-term exercise training showed no deleterious effects on left ventricle function or remodeling and beneficial functional and clinical effects were obtained in these rehabilitated postinfarction patients. Copyright © 2012 Instituto Nacional de Cardiología Ignacio Chávez. Published by Masson Doyma México S.A. All rights reserved.

  7. Ventricular fibrillation induced by coagulating mode bipolar electrocautery during pacemaker implantation in Myotonic Dystrophy type 1 patient

    OpenAIRE

    Russo, Vincenzo; Rago, Anna; Di Meo, Federica; CIOPPA, NADIA DELLA; PAPA, ANDREA ANTONIO; Russo, Maria Giovanna; Nigro, Gerardo

    2014-01-01

    The occurrence of ventricular fibrillation, induced by bipolar electrocautery during elective dual chamber pacemaker implantation, is reported in a patient affected by Myotonic Distrophy type 1 with normal left ventricular ejection fraction

  8. Ventricular fibrillation induced by coagulating mode bipolar electrocautery during pacemaker implantation in Myotonic Dystrophy type 1 patient.

    Science.gov (United States)

    Russo, Vincenzo; Rago, Anna; DI Meo, Federica; Cioppa, Nadia Della; Papa, Andrea Antonio; Russo, Maria Giovanna; Nigro, Gerardo

    2014-12-01

    The occurrence of ventricular fibrillation, induced by bipolar electrocautery during elective dual chamber pacemaker implantation, is reported in a patient affected by Myotonic Distrophy type 1 with normal left ventricular ejection fraction.

  9. Biomechanical and morphological remodelings of gastrointestinal tract in STZ-induced diabetic rats

    DEFF Research Database (Denmark)

    Sha, Hong; Zhao, Jingbo; Liu, Gui-Fang

    2012-01-01

    AIM: The aim of the study was to investigate the biomechanical and morphometrical remodeling of gastrointestinal (GI) tract in streptozotocin (STZ) induced diabetic rats. METERIALS AND METHODS: Eighteen SD male rats of diabetic group(DM, a single tail vein injection 40mg/kg of STZ, 9 rats......) and normal group (CON, 9 rats) were used in the study. Blood glucose and body weight was regularly measured. After 60 days of experiment, morphometric properties and residual strains were studied in esophageal, duodenal, jejunal, ileal, colonic and rectal segments. Stress-strain of the wall was also studied......, jejunal, colonic wall in circumferential direction and the esophageal, colonic wall in longitudinal direction increased in DM group compared those with CON group (Pdiabetes induces morphometric and biomechanical remodeling in the gastrointestinal tract which is likely...

  10. The complex regulation of tanshinone IIA in rats with hypertension-induced left ventricular hypertrophy.

    Directory of Open Access Journals (Sweden)

    Hui Pang

    Full Text Available Tanshinone IIA has definite protective effects on various cardiovascular diseases. However, in hypertension-induced left ventricular hypertrophy (H-LVH, the signaling pathways of tanshinone IIA in inhibition of remodeling and cardiac dysfunction remain unclear. Two-kidney, one-clip induced hypertensive rats (n = 32 were randomized to receive tanshinone IIA (5, 10, 15 mg/kg per day or 5% glucose injection (GS. Sham-operated rats (n = 8 received 5%GS as control. Cardiac function and dimensions were assessed by using an echocardiography system. Histological determination of the fibrosis and apoptosis was performed using hematoxylin eosin, Masson's trichrome and TUNEL staining. Matrix metalloproteinase 2 (MMP2 and tissue inhibitor of matrix metalloproteinases type 2 (TIMP2 protein expressions in rat myocardial tissues were detected by immunohistochemistry. Rat cardiomyocytes were isolated by a Langendorff perfusion method. After 48 h culture, the supernatant and cardiomyocytes were collected to determine the potential related proteins impact on cardiac fibrosis and apoptosis. Compared with the sham rats, the heart tissues of H-LVH (5%GS group suffered severely from the oxidative damage, apoptosis of cardiomyocytes and extracellular matrix (ECM deposition. In the H-LVH group, tanshinone IIA treated decreased malondialdehyde (MDA content and increased superoxide dismutase (SOD activity. Tanshinone IIA inhibited cardiomyocytes apoptosis as confirmed by the reduction of TUNEL positive cardiomyocytes and the down-regulation of Caspase-3 activity and Bax/Bcl-2 ratio. Meanwhile, plasma apelin level increased with down-regulation of APJ receptor. Tanshinone IIA suppressed cardiac fibrosis through regulating the paracrine factors released by cardiomyocytes and the TGF-β/Smads signaling pathway activity. In conclusion, our in vivo study showed that tanshinone IIA could improve heart function by enhancing myocardial contractility, inhibiting ECM

  11. Biophysics of α-synuclein induced membrane remodelling.

    Science.gov (United States)

    Shi, Zheng; Sachs, Jonathan N; Rhoades, Elizabeth; Baumgart, Tobias

    2015-06-28

    α-Synuclein is an intrinsically disordered protein whose aggregation is a hallmark of Parkinson's disease. In neurons, α-synuclein is thought to play important roles in mediating both endo- and exocytosis of synaptic vesicles through interactions with either the lipid bilayer or other proteins. Upon membrane binding, the N-terminus of α-synuclein forms a helical structure and inserts into the hydrophobic region of the outer membrane leaflet. However, membrane structural changes induced by α-synuclein are still largely unclear. Here we report a substantial membrane area expansion induced by the binding of α-synuclein monomers. This measurement is accomplished by observing the increase of membrane area during the binding of α-synuclein to pipette-aspirated giant vesicles. The extent of membrane area expansion correlates linearly with the density of α-synuclein on the membrane, revealing a constant area increase induced by the binding per α-synuclein molecule. The area expansion per synuclein is found to exhibit a strong dependence on lipid composition, but is independent of membrane tension and vesicle size. Fragmentation or tubulation of the membrane follows the membrane expansion process. However, contrary to BAR domain proteins, no distinct tubulation-transition density can apparently be identified for α-synuclein, suggesting a more complex membrane curvature generation mechanism. Consideration of α-synuclein's membrane binding free energy and biophysical properties of the lipid bilayer leads us to conclude that membrane expansion by α-synuclein results in thinning of the bilayer. These membrane thinning and tubulation effects may underlie α-synuclein's role in mediating cell trafficking processes such as endo- and exocytosis.

  12. Role of chymase in cigarette smoke-induced pulmonary artery remodeling and pulmonary hypertension in hamsters

    OpenAIRE

    Yang Ting; Xu Dan; An Jin; He Guang-Ming; Chen Ya-Juan; Chen Lei; Ning Yun-Ye; Zhang Shang-Fu; Han Su-Xia; Wang Tao; Zhang Xiao-Hong; Wen Fu-Qiang

    2010-01-01

    Abstract Background Cigarette smoking is an important risk factor for pulmonary arterial hypertension (PAH) in chronic obstructive pulmonary disease (COPD). Chymase has been shown to function in the enzymatic production of angiotensin II (AngII) and the activation of transforming growth factor (TGF)-β1 in the cardiovascular system. The aim of this study was to determine the potential role of chymase in cigarette smoke-induced pulmonary artery remodeling and PAH. Methods Hamsters were exposed ...

  13. Vagus nerve stimulation reverses ventricular electrophysiological changes induced by hypersympathetic nerve activity.

    Science.gov (United States)

    Huang, Jie; Qian, Jin; Yao, Wei; Wang, Neng; Zhang, Zhenjian; Cao, Chuanbin; Song, Bo; Zhang, Zhuo

    2015-03-01

    What is the central question of this study? Previous studies have shown that hypersympathetic nerve activity results in ventricular electrophysiological changes and facilitates the occurrence of ventricular arrhythmias. Vagus nerve stimulation has shown therapeutic potential for myocardial infarction-induced ventricular arrhythmias. However, the actions of vagus nerve stimulation on hypersympathetic nerve activity-induced ventricular electrophysiological changes are still unknown. What is the main finding and its importance? We show that vagus nerve stimulation is able to reverse hypersympathetic nerve activity-induced ventricular electrophysiological changes and suppress the occurrence of ventricular fibrillation. These findings further suggest that vagus nerve stimulation may be an effective treatment option for ventricular arrhythmias, especially in patients with myocardial infarction or heart failure. Vagus nerve stimulation (VNS) has shown therapeutic potential for myocardial infarction-induced ventricular arrhythmias. This study aimed to investigate the effects of VNS on ventricular electrophysiological changes induced by hypersympathetic nerve activity. Seventeen open-chest dogs were subjected to left stellate ganglion stimulation (LSGS) for 4 h to simulate hypersympathetic tone. All animals were randomly assigned to the VNS group (n = 9) or the control group (n = 8). In the VNS group, VNS was performed at the voltage causing a 10% decrease in heart rate for hours 3-4 during 4 h of LSGS. During the first 2 h of LSGS, the ventricular effective refractory period (ERP) and action potential duration (APD) were both progressively and significantly decreased; the spatial dispersion of ERP, maximal slope of the restitution curve and pacing cycle length of APD alternans were all increased. With LSGS + VNS during the next 2 h, there was a significant return of all the altered electrophysiological parameters towards baseline levels. In the eight control

  14. INFLUENCE OF COMBINED ANTIHYPERTENSIVE AND ANTIDEPRESSANT THERAPY ON LEFT VENTRICULAR REMODELING IN PATIENTS WITH ARTERIAL HYPERTENSION, ANXIETY AND DEPRESSION

    Directory of Open Access Journals (Sweden)

    Y. A. Vasyuk

    2008-01-01

    Full Text Available Aim. To assess influence of combined antihypertensive (captopril or metoprolol and antidepressant (thianeptin or sertralin therapy on clinical status, blood pressure (BP and myocardial function in patients with arterial hypertension (HT and affective disorders (AD.Material and methods. 106 patients with HT were involved in the study. 64 patients (60,4% had concomitant AD. All patients were divided into 3 groups. 46 patients with HT and AD were included in the 1-st group. They received metoprolol or captopril in combination with tianeptine or sertaline. The 2-nd group included 18 patients with HT and AD who received only antihypertensive therapy. The 3-rd group consisted of 42 patients with HT without AD. They also received only antihypertensive therapy.Results. After 6 month therapy patients of the 1-st and the 3-rd groups had more significant clinical improvement and BP reduction (according to 24- hour BP monitoring as well as more farourable structural and functional changes of left ventricular in comparison with patients of the 2-nd group.Conclusion. In patients with HT and concomitant AD combined antihypertensive and antidepressant therapy result in favourable clinical changes, effectively reduce BP, improve left ventricular structure and function.

  15. Impact on Left Ventricular Function and Remodeling and on 1-Year Outcome in Patients With Left Bundle Branch Block After Transcatheter Aortic Valve Implantation.

    Science.gov (United States)

    Carrabba, Nazario; Valenti, Renato; Migliorini, Angela; Marrani, Marco; Cantini, Giulia; Parodi, Guido; Dovellini, Emilio Vincenzo; Antoniucci, David

    2015-07-01

    Conflicting results have been reported about the prognostic impact of left bundle branch block (LBBB) after transcatheter aortic valve implantation (TAVI). The aim of this study was to evaluate the impact of LBBB after TAVI on left ventricular (LV) function and remodeling and on 1-year outcomes. Of 101 TAVI patients, 9 were excluded. All complications were evaluated according to the Valve Academic Research Consortium 2 definition. Of 92 patients, 34 developed LBBB without more advanced myocardial damage or inflammation biomarkers in comparison with patients without LBBB. The only predictor of new LBBB was larger baseline LV end-diastolic volume. LBBB plus advanced atrioventricular block was strongly correlated with permanent pacemaker implantation (p <0.0001). Patients with LBBB had a higher rate of permanent pacemaker implantation at 30 days (59% vs 19%, p <0.0001) and less recovery of LV systolic function and a trend toward a lower rate of LV reverse remodeling at 1 year. The development of acute kidney injury and the logistic European System for Cardiac Operative Risk Evaluation score were associated with poor outcomes (all-cause mortality and heart failure) (hazard ratio 6.86, 95% confidence interval 2.51 to 18.74, p <0.0001, and hazard ratio 1.04, 95% confidence interval 1.01 to 1.08, p = 0.021, respectively), but not LBBB. In conclusion, after TAVI, 37% of patients developed new LBBB without more advanced myocardial damage or inflammation biomarkers. LBBB was associated with a higher rate of permanent pacemaker implantation, which negatively affected the recovery of LV systolic function. The development of acute kidney injury, rather than LBBB, increases the 1-year risk for mortality and hospitalization for heart failure. Copyright © 2015 Elsevier Inc. All rights reserved.

  16. Relationship between myocardial extracellular space expansion estimated with post-contrast T1 mapping MRI and left ventricular remodeling and neurohormonal activation in patients with dilated cardiomyopathy

    Energy Technology Data Exchange (ETDEWEB)

    Yoon, Ji Hyun; Son, Jung Woo; Chung, Hye Moon [Cardiology Division, Dept. of Internal Medicine, Yonsei University College of Medicine, Seoul (Korea, Republic of); and others

    2015-10-15

    Post-contrast T1 values are closely related to the degree of myocardial extracellular space expansion. We determined the relationship between post-contrast T1 values and left ventricular (LV) diastolic function, LV remodeling, and neurohormonal activation in patients with dilated cardiomyopathy (DCM). Fifty-nine patients with DCM (mean age, 55 ± 15 years; 41 males and 18 females) who underwent both 1.5T magnetic resonance imaging and echocardiography were enrolled. The post-contrast 10-minute T1 value was generated from inversion time scout images obtained using the Look-Locker inversion recovery sequence and a curve-fitting algorithm. The T1 sample volume was obtained from three interventricular septal points, and the mean T1 value was used for analysis. The N-Terminal pro-B-type natriuretic peptide (NT-proBNP) level was measured in 40 patients. The mean LV ejection fraction was 24 ± 9% and the post-T1 value was 254.5 ± 46.4 ms. The post-contrast T1 value was significantly correlated with systolic longitudinal septal velocity (s'), peak late diastolic velocity of the mitral annulus (a'), the diastolic elastance index (Ed, [E/e']/stroke volume), LV mass/volume ratio, LV end-diastolic wall stress, and LV end-systolic wall stress. In a multivariate analysis without NT-proBNP, T1 values were independently correlated with Ed (β = -0.351, p = 0.016) and the LV mass/volume ratio (β = 0.495, p = 0.001). When NT-proBNP was used in the analysis, NT-proBNP was independently correlated with the T1 values (β = -0.339, p = 0.017). Post-contrast T1 is closely related to LV remodeling, diastolic function, and neurohormonal activation in patients with DCM.

  17. Autologous bone marrow cell implantation attenuates left ventricular remodeling and improves heart function in porcine myocardial infarction: an echocardiographic, six-month angiographic, and molecular-cellular study.

    Science.gov (United States)

    Leu, Steve; Sun, Cheuk-Kwan; Sheu, Jiunn-Jye; Chang, Li-Teh; Yuen, Chun-Man; Yen, Chia-Hung; Chiang, Chiang-Hua; Ko, Sheung-Fat; Pei, Sung-Nan; Chua, Sarah; Youssef, Ali A; Wu, Chiung-Jen; Yip, Hon-Kan

    2011-07-15

    We investigated the potential benefits and the underlying mechanisms of autologous bone marrow-derived mononuclear cell (BMDMNC) implantation in a porcine model of acute anterior wall myocardial infarction (AAWMI) by studying 6-month left ventricular (LV) function and LV remodeling. After being aspirated from the iliac crest and cultured for 1 week, BMDMNCs were implanted immediately after AAWMI induction through the left anterior descending artery ligation. Thirty male mini-pigs (16-18 kg) were equally divided into group 1 [AAWMI plus saline injection into infarct-ischemia area (IA)], group 2 (AAWMI plus 3.0 × 10⁷ BMDMNC transplantation into non-IA), group 3 (AAWMI plus 3.0 × 10⁷ BMDMNC transplantation into IA), group 4 (sham control plus 3.0 × 10⁷ BMDMNC transplantation into LV myocardium), and group 5 (normal control). By day 90, echocardiography demonstrated an increased LV end-diastolic and end-systolic dimensions but reduced LV ejection fraction (LVEF) in groups 1 and 2 than in other groups (all p infarct area, the number of small vessels and mRNA expressions of endothelial nitric oxide synthase, Bcl-2, interleukin (IL)-10, and peroxisome proliferator-activated receptor-γ coactivator-1α were lower, whereas the number of apoptotic nuclei, caspase-3, Bax, endothelin-1, IL-8, and matrix metalloproteinase was higher in groups 1 and 2 than in other groups (all p < 0.01). Autologous BMDMNC transplantation into IA rather non-IA improves LV function and reduces LV remodeling via eliciting a broad-spectrum of molecular-cellular defensive mechanisms. Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.

  18. Adenosine induced ventricular arrhythmias in the emergency room

    NARCIS (Netherlands)

    Tan, H. L.; Spekhorst, H. H.; Peters, R. J.; Wilde, A. A.

    2001-01-01

    While adenosine effectively terminates most supraventricular tachycardias (SVT), rare case reports have demonstrated its proarrhythmic potential, including induction of ventricular tachycardia (VT). The aim of this study was to define the proarrhythmic effects of adenosine in a large, unselected

  19. Abnormal Left Ventricular Mechanics of Ventricular Ectopic Beats: Insights into Origin and Coupling Interval in Premature Ventricular Contraction-Induced Cardiomyopathy

    Science.gov (United States)

    Potfay, Jonathan; Kaszala, Karoly; Tan, Alex Y.; Sima, Adam P.; Gorcsan, John; Ellenbogen, Kenneth A.; Huizar, Jose F.

    2015-01-01

    Background Left ventricular (LV) dyssynchrony caused by premature ventricular contractions (PVCs) has been proposed as a mechanism of PVC-induced cardiomyopathy (CM). We sought to understand the impact of different PVC locations and coupling intervals (prematurity) on LV regional mechanics and global function of the PVC beat itself. Methods and Results Using our premature pacing algorithm, pentageminal PVCs at coupling intervals of 200–375ms were delivered from the epicardial right ventricular (RV) apex, RV outflow tract (RVOT), and LV free wall, as well as premature atrial contractions (PACs) from the left atrial (LA) appendage at a coupling interval of 200ms in seven healthy canines. LV short axis echocardiographic images, LV stroke volume (SV) and dP/dtmax were obtained during all ectopic beats and VP. LV dyssynchrony was assessed by dispersion of QRS-to-peak strain (earliest – last QRS-to-peak strain) between 6 different LV segments during each of the aforementioned beats (GE, EchoPac). LV dyssynchrony was greater during long- rather than short-coupled PVCs and PVCs at 375ms compared with rapid VP at 400ms (P<0.0001), whereas, no difference was found between PVC locations. Longer PVC coupling intervals were associated with greater SV and dP/dtmax despite more pronounced dyssynchrony (P<0.001). Conclusions PVCs with longer coupling intervals demonstrate more pronounced LV dyssynchrony, whereas PVC location has minimal impact. LV dyssynchrony cannot be attributed to prematurity or abnormal ventricular activation alone, but rather to a combination of both. This study suggests that late-coupled PVCs may cause a more severe cardiomyopathy if dyssynchrony is the leading mechanism responsible for PVC-induced CM. PMID:26297787

  20. Electrophysiological Remodeling in Heart Failure Dyssynchrony vs. Resynchronization

    Directory of Open Access Journals (Sweden)

    Takeshi Aiba, MD PhD

    2010-01-01

    In conclusion, CRT partially restores DHF-induced ion channel remodeling, abnormal Ca homeostasis, blunted β-adrenergic response and regional heterogeneity of APD, thus may suppress ventricular arrhythmias and contribute to the mortality benefit of CRT as well as improve mechanical performance of the heart.

  1. Myocardial extracellular remodeling is associated with ventricular diastolic dysfunction in children and young adults with congenital aortic stenosis.

    Science.gov (United States)

    Dusenbery, Susan M; Jerosch-Herold, Michael; Rickers, Carsten; Colan, Steven D; Geva, Tal; Newburger, Jane W; Powell, Andrew J

    2014-05-06

    This study sought to analyze cardiac magnetic resonance (CMR) measurements of myocardial extracellular volume fraction (ECV) and late gadolinium enhancement (LGE) in children and young adults with congenital aortic stenosis (AS) to determine the extent of fibrosis and examine their association with aortic valve and ventricular function. Patients with congenital AS frequently have impaired diastolic ventricular function and exercise capacity that may be related to myocardial fibrosis. A total of 35 patients with congenital AS (median age 16 years) and 27 normal control subjects (median age 16 years) were evaluated by CMR. ECV was calculated from pre- and post-gadolinium contrast T1 measurements of blood and myocardium, and the hematocrit. ECV was significantly higher in AS patients than in normal subjects (median 0.27 [range 0.22 to 0.42] vs. 0.25 [range 0.18 to 0.27], p = 0.001). LGE was present in 8 (24%) of the AS patients. A higher ECV was correlated with echocardiographic indexes of diastolic dysfunction including a higher mitral E-wave z-score (r = 0.58, p = 0.002), E/septal E' z-score (r = 0.56, p = 0.003), E/mean E' z-score (r = 0.55, p = 0.003), and indexed left atrial volume (r = 0.56, p = 0.001). Other factors associated with an elevated ECV (>0.28) included a greater number of aortic valve interventions (p = 0.004) and a greater number of aortic valve balloon valvuloplasties (p = 0.003). ECV was not significantly associated with AS gradient, left ventricular mass, mass/volume ratio, or ejection fraction. In young patients with AS, myocardial ECV is significantly elevated compared with control subjects and is associated with echocardiographic indexes of diastolic dysfunction. ECV measured by CMR may be a useful method for risk stratification and monitoring therapies targeting fibrosis. Copyright © 2014 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

  2. Exercise-induced inhibition of remodelling is focally offset with fatigue fracture in racehorses.

    Science.gov (United States)

    Whitton, R C; Mirams, M; Mackie, E J; Anderson, G A; Seeman, E

    2013-07-01

    Bone remodelling is inhibited by high repetitive loading. However, in subchondral bone of racehorses in training, eroded surface doubled in association with fatigue fracture and there was greater surrounding trabecular bone volume suggesting trabecular modelling unloads the bone focally, allowing damage repair by remodelling. Remodelling replaces damaged bone with new bone but is suppressed during high magnitude repetitive loading when damage is most likely. However, in cortical bone of racehorses, at sites of fatigue fracture, focal porosity, consistent with remodelling, is observed in proportion to the extent of surrounding callus. Focal areas of porosity are also observed at sites of fatigue damage in subchondral bone. We hypothesised that fatigued subchondral bone, like damaged cortical bone, is remodelled focally in proportion to the modelling of surrounding trabecular bone. Eroded and mineralizing surfaces and bone area were measured using backscattered scanning electron microscopy of post-mortem specimens of the distal third metacarpal bone in 11 racehorses with condylar fractures (cases) and eight racehorses in training without fractures (controls). Cases had a two-fold greater eroded surface per unit area at the fracture site than controls (0.81 ± 0.10 vs. 0.40 ± 0.12 mm(-1), P = 0.021) but not at an adjacent site (0.22 ± 0.09 vs. 0.30 ± 0.11 mm(-1), P = 0.59). Area fraction of surrounding trabecular bone was higher in cases than controls (81 ± 2 vs. 72 ± 2 %, P = 0.0020) and the eroded surface at the fracture site correlated with the surrounding trabecular area (adjusted R (2) = 0.63, P = 0.0010). In conclusion, exercise-induced inhibition of remodelling is offset at sites of fatigue fracture. Modelling of trabecular bone may contribute to unloading these regions, allowing repair by remodelling.

  3. The impact of anabolic androgenic steroids abuse and type of training on left ventricular remodeling and function in competitive athletes.

    Science.gov (United States)

    Ilić, Ivan; Djordjević, Vitomir; Stanković, Ivan; Vlahović-Stipac, Alja; Putniković, Biljana; Babić, Rade; Nesković, Aleksandar N

    2014-04-01

    Long-term intensive training is associated with distinctive cardiac adaptations which are known as athlete's heart. The aim of this study was to determine whether the use of anabolic androgenic steroids (AAS) could affect echocardiographic parameters of left ventricular (LV) morphology and function in elite strength and endurance athletes. A total of 20 elite strength athletes (10 AAS users and 10 non-users) were compared to 12 steroid-free endurance athletes. All the subjects underwent comprehensive standard echocardiography and tissue Doppler imaging. After being indexed for body surface area, both left atrium (LA) and LV end-diastolic diameter (LVEDD) were significantly higher in the endurance than strength athletes, regardless of AAS use (p steroid-free endurance athletes, showing that 75% of LA size variability depends on variability of LVEDD (p steroid-free athletes, regardless of training type (p abuse.

  4. Brain remodelling following endothelin-1 induced stroke in conscious rats.

    Directory of Open Access Journals (Sweden)

    Hima C S Abeysinghe

    Full Text Available The extent of stroke damage in patients affects the range of subsequent pathophysiological responses that influence recovery. Here we investigate the effect of lesion size on development of new blood vessels as well as inflammation and scar formation and cellular responses within the subventricular zone (SVZ following transient focal ischemia in rats (n = 34. Endothelin-1-induced stroke resulted in neurological deficits detected between 1 and 7 days (P<0.001, but significant recovery was observed beyond this time. MCID image analysis revealed varying degrees of damage in the ipsilateral cortex and striatum with infarct volumes ranging from 0.76-77 mm3 after 14 days, where larger infarct volumes correlated with greater functional deficits up to 7 days (r = 0.53, P<0.05. Point counting of blood vessels within consistent sample regions revealed that increased vessel numbers correlated significantly with larger infarct volumes 14 days post-stroke in the core cortical infarct (r = 0.81, P<0.0001, core striatal infarct (r = 0.91, P<0.005 and surrounding border zones (r = 0.66, P<0.005; and r = 0.73, P<0.05. Cell proliferation within the SVZ also increased with infarct size (P<0.01 with a greater number of Nestin/GFAP positive cells observed extending towards the border zone in rats with larger infarcts. Lesion size correlated with both increased microglia and astrocyte activation, with severely diffuse astrocyte transition, the formation of the glial scar being more pronounced in rats with larger infarcts. Thus stroke severity affects cell proliferation within the SVZ in response to injury, which may ultimately make a further contribution to glial scar formation, an important factor to consider when developing treatment strategies that promote neurogenesis.

  5. Left ventricular mechanics in humans with high aerobic fitness: adaptation independent of structural remodelling, arterial haemodynamics and heart rate

    Science.gov (United States)

    Stöhr, Eric J; McDonnell, Barry; Thompson, Jane; Stone, Keeron; Bull, Tom; Houston, Rory; Cockcroft, John; Shave, Rob

    2012-01-01

    Individuals with high aerobic fitness have lower systolic left ventricular strain, rotation and twist (‘left ventricular (LV) mechanics’) at rest, suggesting a beneficial reduction in LV myofibre stress and more efficient systolic function. However, the mechanisms responsible for this functional adaptation are not known and the influence of aerobic fitness on LV mechanics during dynamic exercise has never been studied. We assessed LV mechanics, LV wall thickness and dimensions, central augmentation index (AIx), aortic pulse wave velocity (aPWV), blood pressure and heart rate in 28 males (age: 21 ± 2 years SD) with a consistent physical activity level (no change >6 months). Individuals were examined at rest and during exercise (40% peak exercise capacity) and separated post hoc into a moderate and high aerobic fitness group (: 49 ± 5 and 63 ± 7 ml kg−1 min−1, respectively, P 0.05). However, for the same AIx, the high group had significantly lower LV apical rotation (P = 0.002) and LV twist (P = 0.003) while basal rotation and strain indices did not differ between groups (P > 0.05). We conclude that young males with high aerobic fitness have lower LV apical rotation at rest and during submaximal exercise that can occur without changes in gross LV structure, arterial haemodynamics or heart rate. The findings suggest a previously unknown type of physiological adaptation of the left ventricle that may have important implications for exercise training in older individuals and patient populations in which exercise training has previously failed to show clear benefits for LV function. PMID:22431336

  6. Basal cardiomyopathy develops in rabbits with ventricular tachyarrhythmias induced by a single injection of adrenaline.

    Science.gov (United States)

    Ashida, Terunao; Takato, Tetsuya; Matsuzaki, Gen; Seko, Yoshinori; Fujii, Jun; Kawai, Sachio

    2014-01-01

    We have recently demonstrated that basal cardiomyopathy develops in rabbits with ventricular tachyarrhythmias that have been induced by electrical stimulation of the cervical vagus. This study investigated whether similar basal cardiomyopathy would develop in rabbits with ventricular tachyarrhythmias induced by a single injection of adrenaline. Adrenaline was intravenously infused for 10-360 seconds in anesthetized rabbits. Colloidal carbon was injected after adrenaline infusion. Wall movement velocity of the left ventricular base was assessed by tissue Doppler echocardiography. Animals were killed either 1 week or 3-4 weeks later. Pathological lesions were identified by deposits of carbon particles. Animals were divided into two groups according to the infused dose of adrenaline. The small-dose group (group S, n = 15) received 1-10 μg and the large-dose group (group L, n = 23) received 15-60 μg of adrenaline. Adrenaline infusion induced premature ventricular contractions followed by monomorphic ventricular tachycardias in 22 of 23 animals in group L, but in only 1 of 15 animals in group S. Wall movement velocity of the left ventricular base decreased just after adrenaline infusion, remained low after 1 week, and recovered to near-baseline levels after 3-4 weeks in group L. Unique cardiac lesions identified by deposits of carbon particles were frequently observed on the left ventricular basal portion, almost always associated with the mitral valve and papillary muscles, but were never observed in the apical area. Lesions involving all areas of the left ventricular basal portion were observed in 22 of 23 animals in group L, but in only 2 of 15 animals in group S. Basal cardiomyopathy developed in rabbits with ventricular tachycardias induced by a single injection of adrenaline.

  7. Lymphatics in human lymphatic filariasis: in vitro models of parasite-induced lymphatic remodeling.

    Science.gov (United States)

    Bennuru, Sasisekhar; Nutman, Thomas B

    2009-12-01

    Lymphatic filariasis characterized by the dysfunction of the lymphatics can lead to severe (and often) irreversible lymphedema and elephantiasis. Decades of research in the field shows that the establishment of the adult parasites in the lymphatics triggers a cascade of events that ultimately results in tissue scarring and fibrosis. In this minireview, we focus on the studies addressing the mechanisms underlying the parasite-induced lymphatic dilatation that suggests parasite-induced lymphatic remodeling and lymphangiogenesis may be the prelude towards developing chronic and irreversible filarial pathology.

  8. ECG myocardial scar quantification predicts reverse left ventricular remodeling and survival after cardiac resynchronization therapy implantation: A retrospective pilot study.

    Science.gov (United States)

    Atwater, Brett D; Babatunde, Adefolakemi; Swan, Christopher; Wieslander, Bjorn; Andresen, Abraham; Rabineau, Dawn; Tomfohr, Jennifer; Wagner, Galen; Jackson, Kevin P; Daubert, James P

    2015-01-01

    Electrocardiographic (ECG) LV scar quantification may improve prediction of CRT response. Data were abstracted in 76 patients who underwent a first CRT implantation at 2 US centers. Selvester QRS scar quantification was performed using the LBBB modified QRS scoring method. Seven clinical variables previously associated with reverse LV remodeling (RLVR) and QRS score were included in logistic regression analysis. Survival was compared across QRS score quartiles using Kaplan-Meier curves. RLVR occurred more frequently in patients with QRS score ≤ 5 (63%) than QRS score>5 (22%), (OR=5.83, 95% CI=2.11-16.07). After adjustment for clinical variables using logistic regression, QRS score>5 predicted RLVR (Chi-square=20.3, P=0.005, AUC=0.782). Patients in the lowest quartile of QRS score (<4) had improved survival compared to patients in the other QRS score quartiles (P=0.037). ECG quantified LV scar predicts RLVR and long-term survival in patients with LBBB undergoing CRT implantation. Copyright © 2015 Elsevier Inc. All rights reserved.

  9. Development of nonfibrotic left ventricular hypertrophy in an ANG II-induced chronic ovine hypertension model

    DEFF Research Database (Denmark)

    Klatt, Niklas; Scherschel, Katharina; Schad, Claudia

    2016-01-01

    Hypertension is a major risk factor for many cardiovascular diseases and leads to subsequent concomitant pathologies such as left ventricular hypertrophy (LVH). Translational approaches using large animals get more important as they allow the use of standard clinical procedures in an experimental...... setting. Therefore, the aim of this study was to establish a minimally invasive ovine hypertension model using chronic angiotensin II (ANG II) treatment and to characterize its effects on cardiac remodeling after 8 weeks. Sheep were implanted with osmotic minipumps filled with either vehicle control (n...

  10. Double-blind, randomized, placebo-controlled study of high-dose HMG CoA reductase inhibitor therapy on ventricular remodeling, pro-inflammatory cytokines and neurohormonal parameters in patients with chronic systolic heart failure.

    Science.gov (United States)

    Krum, Henry; Ashton, Emma; Reid, Christopher; Kalff, Victor; Rogers, Jim; Amarena, John; Singh, Bhuwan; Tonkin, Andrew

    2007-02-01

    Statins decrease mortality in patients with coronary artery disease. However, chronic heart failure (CHF) patients were often excluded in such trials. Statins possess pharmacologic properties (independent of cholesterol lowering) that may be beneficial on ventricular remodeling in such patients. We conducted a 6-month randomized placebo (PBO)-controlled study of rosuvastatin (ROS) in patients with systolic (left ventricular ejection fraction [LVEF] ventriculogram. Secondary end points included change in echocardiographic parameters, neurohormonal and inflammatory markers, Packer composite score, death, and heart failure hospitalization. Patients were well matched for baseline values. Compared with PBO (n = 46), ROS patients (n = 40) had a decrease in low-density lipoprotein cholesterol (PBO +3, ROS -54%, P ventriculogram (PBO +5.3, ROS +3.2%), fractional shortening by echocardiographic (PBO +2.7, ROS +1.8%), left ventricular end-diastolic diameter (PBO -1.7, ROS +0.8 mm), left ventricular end-systolic diameter (PBO -1.9, ROS +0.1 mm). Plasma norepinephrine, endothelin-1, brain natriuretic peptide, hsCRP, tumor necrosis factor-alpha and interleukin-6, patient global assessment, Packer composite, death/heart failure hospitalization, and adverse events were similar between PBO and ROS. Despite being safe and effective at decreasing plasma cholesterol, high-dose ROS did not beneficially alter parameters of LV remodeling. Reasons for absence of benefit are uncertain, but may include patient population studied, high dose of ROS used or high use of effective background CHF medications.

  11. Exercise-Induced Ventricular Fibrillation: Seven Years Follow-Up

    Directory of Open Access Journals (Sweden)

    Gökmen Gemici

    2011-11-01

    Full Text Available We present a 7-year follow-up of a 55-year-old male who experienced ventricular fibrillation during the recovery period of exercise testing and refused implantation of an ICD. Normal left ventricular systolic function was found on echocardiographic examination, and coronary angiography revealed only a side branch disease with a vessel diameter of less than 2 millimeters. The patient was discharged on metoprolol and ASA in addition to his previous treatment with lisinopril and simvastatin. Outpatient cardiac evaluation by repeated 24-hour ECG monitorizations (Holter revealed normal findings. On follow up visits every six months for the past seven years, the patient was found to be asymptomatic.

  12. Mineralized collagen scaffolds induce hMSC osteogenesis and matrix remodeling.

    Science.gov (United States)

    Weisgerber, Daniel W; Caliari, Steven R; Harley, Brendan A C

    2015-03-01

    Biomaterials for bone tissue engineering must be able to instruct cell behavior in the presence of the complex biophysical and biomolecular environments encountered in vivo. While soluble supplementation strategies have been identified to enhance osteogenesis, they are subject to significant diffusive loss in vivo or the need for frequent re-addition in vitro. This investigation therefore explored whether biophysical and biochemical properties of a mineralized collagen-GAG scaffold were sufficient to enhance human mesenchymal stem cell (hMSC) osteogenic differentiation and matrix remodeling in the absence of supplementation. We examined hMSC metabolic health, osteogenic and matrix gene expression profiles, as well as matrix remodeling and mineral formation as a function of scaffold mineral content. We found that scaffold mineral content enhanced long term hMSC metabolic activity relative to non-mineralized scaffolds. While osteogenic supplementation or exogenous BMP-2 could enhance some markers of hMSC osteogenesis in the mineralized scaffold, we found the mineralized scaffold was itself sufficient to induce osteogenic gene expression, matrix remodeling, and mineral formation. Given significant potential for unintended consequences with the use of mixed media formulations and potential for diffusive loss in vivo, these findings will inform the design of instructive biomaterials for regenerative repair of critical-sized bone defects, as well as for applications where non-uniform responses are required, such as in biomaterials to address spatially-graded interfaces between orthopedic tissues.

  13. Right Ventricular Remodeling and Dysfunction in Obstructive Sleep Apnea: A Systematic Review of the Literature and Meta-Analysis

    Directory of Open Access Journals (Sweden)

    Abdirashit Maripov

    2017-01-01

    Full Text Available Background. Recent studies have reported that obstructive sleep apnea (OSA patients present alterations in right ventricular (RV structure and function. However, large randomized controlled trials evaluating the impact of OSA on the right ventricle are lacking. Methods. A comprehensive electronic database (PubMed, Web of Science, and Google Scholar and reference search up to October 30, 2016, was performed. A systematic review and meta-analysis were performed to assess RV structure and function in OSA patients based on conventional echocardiography and tissue Doppler imaging. Results. Twenty-five studies with 1,503 OSA patients and 796 controls were included in this study. OSA patients exhibited an increase in RV internal diameter (weighted mean difference (WMD (95% confidence intervals (CIs 2.49 (1.62 to 3.37; p=0.000 and RV wall thickness (WMD (95% CIs 0.82 (0.51 to 1.13; p=0.000. Furthermore, OSA patients had a significantly elevated RV myocardial performance index (WMD (95% CI 0.08 (0.06 to 0.10; p=0.000, decreased RV S’ (WMD (95% CI −0.95 (−1.59 to −0.32; p=0.003, tricuspid annular plane systolic excursion (WMD (95% CI −1.76 (−2.73 to −0.78; p=0.000, and RV fractional area change (WMD (95% CI −3.16 (−5.60 to −0.73; p=0.011. Conclusion. OSA patients display RV dilatation, increased wall thickening, and altered RV function.

  14. The impact of anabolic androgenic steroids abuse and type of training on left ventricular remodeling and function in competitive athletes

    Directory of Open Access Journals (Sweden)

    Ilić Ivan

    2014-01-01

    Full Text Available Background/Aim. Long-term intensive training is associated with distinctive cardiac adaptations which are known as athlete’s heart. The aim of this study was to determine whether the use of anabolic androgenic steroids (AAS could affect echocardiographic parameters of left ventricular (LV morphology and function in elite strength and endurance athletes. Methods. A total of 20 elite strength athletes (10 AAS users and 10 non-users were compared to 12 steroid-free endurance athletes. All the subjects underwent comprehensive standard echocardiography and tissue Doppler imaging. Results. After being indexed for body surface area, both left atrium (LA and LV end-diastolic diameter (LVEDD were significantly higher in the endurance than strength athletes, regardless of AAS use (p < 0.05, for both. A significant correlation was found between LA diameter and LVEDD in the steroid-free endurance athletes, showing that 75% of LA size variability depends on variability of LVEDD (p < 0.001. No significant differences in ejection fraction and cardiac output were observed among the groups, although mildly reduced LV ejection fraction was seen only in the AAS users. The AAS-using strength athletes had higher A-peak velocity when compared to steroidfree athletes, regardless of training type (p < 0.05 for both. Both AAS-using and AAS-free strength athletes had lower e’ peak velocity and higher E/e’ ratio than endurance athletes (p < 0.05, for all. Conclusions. There is no evidence that LV ejection fraction in elite athletes is altered by either type of training or AAS misuse. Long-term endurance training is associated with preferable effects on LV diastolic function compared to strength training, particularly when the latter is combined with AAS abuse.

  15. Effects of (−)-epicatechin on myocardial infarct size and left ventricular remodeling following permanent coronary occlusion

    Science.gov (United States)

    Yamazaki, Katrina Go; Taub, Pam R; Barraza-Hidalgo, Maraliz; Rivas, Maria M; Zambon, Alexander C; Ceballos, Guillermo; Villarreal, Francisco J

    2010-01-01

    Objectives We examined the effects of the flavanol (−)-epicatechin on short and long-term infarct size and left ventricular (LV) structure/function after permanent coronary occlusion (PCO) and the potential involvement of the protective AKT/ERK signaling pathways. Background (−)-Epicatechin reduces blood pressure in hypertensive patients and limits infarct size in animal models of myocardial ischemia-reperfusion injury. However, nothing is known about its effects on infarction after PCO. Methods (−)-Epicatechin (1mg/kg/day) treatment (Tx) was administered via daily oral gavage to 250 g male rats for 10 days prior to PCO and continued afterwards. PCO controls received water. Sham animals underwent thoracotomy and treatment in the absence of PCO. Immunoblots assessed AKT/ERK involvement 2 h after PCO. LV morphometry and function were measured 48 h and 3 weeks post-PCO. Results In the 48 h group, Tx reduced infarct size by 52%. There were no differences in hemodynamics amongst the different groups (heart rate, aortic and LV pressures). Western blots revealed no differences in AKT or ERK phosphorylation levels. At 3 weeks, PCO control animals demonstrated significant increases in LV end-diastolic pressure, heart weight/body weight, and LV chamber diameter vs. sham. PCO + (−)-epicatechin group values were comparable to sham + (−)-epicatechin. Tx resulted in a 33% decrease in MI size. LV pressure-volume curves demonstrated a right shift in control PCO animals, whereas (−)-epicatechin were comparable to sham. LV scar area strains were significantly improved with (−)-epicatechin. Conclusions These results demonstrate the unique capacity of (−)-epicatechin to confer cardioprotection in the setting of a severe form of myocardial ischemic injury. Protection is sustained over time and preserves LV structure/function. The cardioprotective mechanism(s) of (−)-epicatechin appear unrelated to AKT or ERK activation. (−)-Epicatechin warrants further investigation

  16. T-tubule remodelling disturbs localized β2-adrenergic signalling in rat ventricular myocytes during the progression of heart failure.

    Science.gov (United States)

    Schobesberger, Sophie; Wright, Peter; Tokar, Sergiy; Bhargava, Anamika; Mansfield, Catherine; Glukhov, Alexey V; Poulet, Claire; Buzuk, Andrey; Monszpart, Aron; Sikkel, Markus; Harding, Sian E; Nikolaev, Viacheslav O; Lyon, Alexander R; Gorelik, Julia

    2017-06-01

    Cardiomyocyte β2-adrenergic receptor (β2AR) cyclic adenosine monophosphate (cAMP) signalling is regulated by the receptors' subcellular location within transverse tubules (T-tubules), via interaction with structural and regulatory proteins, which form a signalosome. In chronic heart failure (HF), β2ARs redistribute from T-tubules to the cell surface, which disrupts functional signalosomes and leads to diffuse cAMP signalling. However, the functional consequences of structural changes upon β2AR-cAMP signalling during progression from hypertrophy to advanced HF are unknown. Rat left ventricular myocytes were isolated at 4-, 8-, and 16-week post-myocardial infarction (MI), β2ARs were stimulated either via whole-cell perfusion or locally through the nanopipette of the scanning ion conductance microscope. cAMP release was measured via a Förster Resonance Energy Transfer-based sensor Epac2-camps. Confocal imaging of di-8-ANNEPS-stained cells and immunoblotting were used to determine structural alterations. At 4-week post-MI, T-tubule regularity, density and junctophilin-2 (JPH2) expression were significantly decreased. The amplitude of local β2AR-mediated cAMP in T-tubules was reduced and cAMP diffused throughout the cytosol instead of being locally confined. This was accompanied by partial caveolin-3 (Cav-3) dissociation from the membrane. At 8-week post-MI, the β2AR-mediated cAMP response was observed at the T-tubules and the sarcolemma (crest). Finally, at 16-week post-MI, the whole cell β2AR-mediated cAMP signal was depressed due to adenylate cyclase dysfunction, while overall Cav-3 levels were significantly increased and a substantial portion of Cav-3 dissociated into the cytosol. Overexpression of JPH2 in failing cells in vitro or AAV9.SERCA2a gene therapy in vivo did not improve β2AR-mediated signal compartmentation or reduce cAMP diffusion. Although changes in T-tubule structure and β2AR-mediated cAMP signalling are significant even at 4-week post

  17. Impaired flow-induced arterial remodeling in DOCA-salt hypertensive rats

    DEFF Research Database (Denmark)

    Lemkens, Pieter; Nelissen, Jelly; Meens, Merlijn J P M T

    2012-01-01

    )-salt hypertension in rats, a model for an upregulated endothelin-1 system. Mesenteric small arteries (MrA) were exposed to low blood flow (LF) or high blood flow (HF) for 4 or 7 weeks. The bioavailability of vasoactive peptides was modified by chronic treatment of the rats with the dual neutral endopeptidase (NEP...... arteries but reduced the infiltration of monocyte/macrophages. We show for the first time that flow-induced remodeling is impaired during the development of DOCA-salt hypertension and that this can be prevented by chronic NEP/ECE inhibition....

  18. Quantitative Positron Emission Tomography Imaging Detects Early Metabolic Remodeling in a Mouse Model of Pressure Overload Left Ventricular Hypertrophy in vivo

    Science.gov (United States)

    Zhong, Min; Alonso, Clayton E.; Taegtmeyer, Heinrich; Kundu, Bijoy K.

    2013-01-01

    We proposed that metabolic remodeling in the form of increased myocardial glucose analogue 2-[18F] fluoro-2deoxy-D-glucose (FDG) uptake precedes and triggers the onset of severe contractile dysfunction in pressure overload left ventricular hypertrophy (LVH) in vivo. To test this hypothesis we used a mouse model of transverse aortic constriction (TAC) together with Positron Emission Tomography (PET) and assessed serial changes in cardiac metabolism and function over 7 days. Methods PET scans of 16 C57BL/6 male mice were performed using a microPET scanner under sevofluorane anesthesia. A 10-minute transmission scan was followed by a 60-minute dynamic FDG-PET scan with cardiac and respiratory gating. Blood glucose levels were measured before and after the emission scan. Transverse aortic constriction (TAC) and sham surgeries were performed after baseline imaging. Osmotic mini-pumps containing either propranolol (5 mg/kg/day) or vehicle alone were implanted subcutaneously at the end of surgery. Subsequent scans were taken at days 1 and 7 after surgery. A compartment model, in which the blood input function with spill-over and partial volume corrections and the metabolic rate constants in a 3-compartment model are simultaneously estimated, was used to determine the net myocardial FDG influx constant, Ki. The rate of myocardial glucose use, rMGU, was also computed. Estimations of the ejection fractions (EF) were based on the high resolution gated PET images Results Mice undergoing TAC surgery exhibited an increase in the Ki (580%) and glucose usage the day after surgery indicating early adaptive response. On day 7 the EF had decreased by 24% indicating a maladaptive response. Average Ki increases were not linearly associated with increases in rMGU. Ki exceeded rMGU by 29% in the TAC mice. TAC Mice treated with propranolol attenuated rate of FDG uptake, diminished mismatch between Ki and rMGU (9%) and rescued cardiac function. Conclusions Metabolic maladaptation precedes

  19. Structural and functional remodeling of skeletal muscle microvasculature is induced by simulated microgravity

    Science.gov (United States)

    Delp, M. D.; Colleran, P. N.; Wilkerson, M. K.; McCurdy, M. R.; Muller-Delp, J.

    2000-01-01

    Hindlimb unloading of rats results in a diminished ability of skeletal muscle arterioles to constrict in vitro and elevate vascular resistance in vivo. The purpose of the present study was to determine whether alterations in the mechanical environment (i.e., reduced fluid pressure and blood flow) of the vasculature in hindlimb skeletal muscles from 2-wk hindlimb-unloaded (HU) rats induces a structural remodeling of arterial microvessels that may account for these observations. Transverse cross sections were used to determine media cross-sectional area (CSA), wall thickness, outer perimeter, number of media nuclei, and vessel luminal diameter of feed arteries and first-order (1A) arterioles from soleus and the superficial portion of gastrocnemius muscles. Endothelium-dependent dilation (ACh) was also determined. Media CSA of resistance arteries was diminished by hindlimb unloading as a result of decreased media thickness (gastrocnemius muscle) or reduced vessel diameter (soleus muscle). ACh-induced dilation was diminished by 2 wk of hindlimb unloading in soleus 1A arterioles, but not in gastrocnemius 1A arterioles. These results indicate that structural remodeling and functional adaptations of the arterial microvasculature occur in skeletal muscles of the HU rat; the data suggest that these alterations may be induced by reductions in transmural pressure (gastrocnemius muscle) and wall shear stress (soleus muscle).

  20. Benefício da revascularização do miocárdio em pacientes com disfunção ventricular e músculo viável: remodelamento ventricular reverso e prognóstico The beneficial effect of revascularization on patients with severe left ventricular dysfunction and viable myocardium: reverse remodeling and prognosis

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    Gustavo Calado de Aguiar Ribeiro

    2005-06-01

    Full Text Available OBJETIVO: Analisar a importância da viabilidade do miocárdio e parâmetros clínicos na melhora da função ventricular, sintomas e prognóstico, como reversão do remodelamento. MÉTODO: Cento e quinze pacientes submetidos a revascularização do miocárdio com análise prévia da viabilidade do miocárdio com thallium-201. Fração de ejeção, volumes sistólicos e diastólicos do ventrículo esquerdo e classe funcional foram determinados, antes da cirurgia e a cada seis meses por 3 anos. RESULTADOS: Pacientes com > 4 segmentos viáveis demonstraram melhora da fração de ejeção de 34±6 para 44±4% (pOBJECTIVES: To evaluate the integration of both viability and clinical parameters on the improvement in systolic performance, symptoms and prognosis, with post-revascularization reverse remodeling. METHOD: One hundred and fifteen patients underwent thallium-201 imaging before myocardial revascularization. Left ventricular ejection fraction, left ventricular end-systolic volume index and left ventricular end-diastolic volume index were determined before and at each 6 months post-revascularization for 3 years. RESULTS: Patients with > 4 viable segments on thallium-201 imaging demonstrated an improvement in left ventricular ejection fraction from 34±6 to 44±4%, p<0.001, left ventricular end-systolic volume decreased from 78.3±11 to 57±17 mL/m², p<0.001; left end-diastolic volume decreased from 113±31 to 91±22 ml/m², p<0.001. Patients with < 4 viable segments failed to demonstrate an improvement of the left ventricle ejection fraction, 33.4±4 vs. 35.1±5% (p=0.19, and exhibited ongoing left ventricle end-systolic remodeling, 72±23 vs. 73±12 mL/m² (p= 0.81, and the left ventricle end-diastolic volume increased from 112±24 to 118±16 mL/m² (p=0.34, without improvement in NYHA class, and worse long-term prognosis (event; log rank test, p=0.0053. The multivariable analysis demonstrated clinical variables related to the unfavorable

  1. Semaphorin 4D induces vaginal epithelial cell apoptosis to control mouse postnatal vaginal tissue remodeling.

    Science.gov (United States)

    Ito, Takuji; Bai, Tao; Tanaka, Tetsuji; Yoshida, Kenji; Ueyama, Takashi; Miyajima, Masayasu; Negishi, Takayuki; Kawasaki, Takahiko; Takamatsu, Hyota; Kikutani, Hitoshi; Kumanogoh, Atsushi; Yukawa, Kazunori

    2015-02-01

    The opening of the mouse vaginal cavity to the skin is a postnatal tissue remodeling process that occurs at approximately five weeks of age for the completion of female genital tract maturation at puberty. The tissue remodeling process is primarily composed of a hormonally triggered apoptotic process predominantly occurring in the epithelium of the distal section of the vaginal cavity. However, the detailed mechanism underlying the apoptotic induction remains to be elucidated. In the present study, it was observed that the majority of BALB/c mice lacking the class 4 semaphorin, semaphorin 4D (Sema4D), developed imperforate vagina and hydrometrocolpos resulting in a perpetually unopened vaginal cavity regardless of a normal estrogen level comparable with that in wild‑type (WT) mice. Administration of β‑estradiol to infant Sema4D‑deficient (Sema4D‑/‑) mice did not induce precocious vaginal opening, which was observed in WT mice subjected to the same β‑estradiol administration, excluding the possibility that the closed vaginal phenotype was due to insufficient estrogen secretion at the time of vaginal opening. In order to assess the role of Sema4D in the postnatal vaginal tissue remodeling process, the expression of Sema4D and its receptor, plexin‑B1, was examined as well as the level of apoptosis in the vaginal epithelia of five‑week‑old WT and Sema4D‑/‑ mice. Immunohistochemical analyses confirmed the localization of Sema4D and plexin‑B1 in the mouse vaginal epithelia. Terminal deoxynucleotidyl transferase dUTP nick end labeling assay and immunohistochemistry detecting activated caspase‑3 revealed significantly fewer apoptotic cells in situ in the vaginal mucosa of five‑week‑old Sema4D‑/‑ mice compared with WT mice. The addition of recombinant Sema4D to Sema4D‑/‑ vaginal epithelial cells in culture significantly enhanced apoptosis of the vaginal epithelial cells, demonstrating the apoptosis‑inducing activity of Sema4D. The

  2. Optimization of left ventricular pacing site plus multipoint pacing improves remodeling and clinical response to cardiac resynchronization therapy at 1 year.

    Science.gov (United States)

    Zanon, Francesco; Marcantoni, Lina; Baracca, Enrico; Pastore, Gianni; Lanza, Daniela; Fraccaro, Chiara; Picariello, Claudio; Conte, Luca; Aggio, Silvio; Roncon, Loris; Pacetta, Domenico; Badie, Nima; Noventa, Franco; Prinzen, Frits W

    2016-08-01

    Approximately one-third of the patients with heart failure (HF) treated with cardiac resynchronization therapy (CRT) fail to respond. Positioning the left ventricular (LV) pacing lead in the area of the latest electrical delay may improve the response to CRT. Multipoint pacing (MPP) of the LV has been shown to improve the acute hemodynamic response. The purpose of this study was to test the hypothesis that patients treated with MPP in whom LV pacing location is optimized have better long-term clinical outcomes than do patients treated with conventional CRT. We evaluated the echocardiographic and clinical response of 110 patients with HF treated for nearly 1 year with either conventional CRT (standard [STD] group, n = 54, 49%), CRT with hemodynamic and electrical optimization of the LV pacing site (optimized [OPT] group, n = 36, 33%), or OPT combined with MPP (OPT + MPP group, n = 20, 18%). Responders were classified in terms of reduction in end-systolic volume index ≥15%, reduction in New York Heart Association (NYHA) class ≥1, and Packer score variation (NYHA response with no HF-related hospitalization events or death). In STD, OPT, and OPT + MPP groups, 56%, 72%, and 90% of patients, respectively, were end-systolic volume index responders (P = .004) and 67%, 78%, and 95% were NYHA class responders (P = .012); 59%, 67%, and 90% of patients exhibited a 1-year Packer score of 0 (P = .018). These trends remained significant after adjustment for confounding factors by multivariate logistic analysis. Combining MPP with optimal positioning of the LV lead on the basis of electrical delay and hemodynamics enhances reverse remodeling and improves clinical outcomes beyond the effect due to conventional CRT. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

  3. Temporal change of myocardial tissue character is associated with left ventricular reverse remodeling in patients with dilated cardiomyopathy: A cardiovascular magnetic resonance study.

    Science.gov (United States)

    Nabeta, Takeru; Inomata, Takayuki; Fujita, Teppei; Iida, Yuichiro; Ikeda, Yuki; Sato, Takanori; Ishii, Shunsuke; Maekawa, Emi; Mizutani, Tomohiro; Naruke, Takashi; Koitabashi, Toshimi; Inoue, Yusuke; Ako, Junya

    2017-08-01

    Prognostic significance of temporal change in myocardial tissue characterization by cardiovascular magnetic resonance (CMR) has not been elucidated in patients with non-ischemic dilated cardiomyopathy (DCM). Sixty-eight patients with newly-diagnosed DCM who underwent CMR including late gadolinium enhancement (LGE) both at baseline and during follow-up period were enrolled. LGE score was defined by a signal intensity of ≥5 standard deviations above the remote reference myocardium mean. Left ventricular reverse remodeling (LVRR) defined as a LV ejection fraction increase of ≥10% and a decrease in indexed LV end-diastolic diameter of ≥10% compared to those at baseline was detected in 38% of the patients. There was no significant difference in LGE score between baseline and follow-up (5.8% vs. 7.3%; p=0.38). The change in LGE area (delta-LGE) was significantly lower in patients with LVRR than those without (-0.5%±3.4% vs. 3.0±7.4%; p=0.02). On the other hand, T2 ratio during the follow-up significantly reduced (1.95±0.48 vs. 1.67±0.56; plogistic analysis indicated that baseline LGE score [odds ratio; 0.78; 95% confidence interval (CI) 0.66 to 0.90; p<0.01] together with delta-LGE (odds ratio; 0.77; 95% CI 0.61 to 0.92; p=0.01) were independently associated with subsequent LVRR (p<0.01). The temporal change of LGE-CMR score during the clinical course was significantly correlated with following LVRR. Copyright © 2016 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.

  4. Padrão de remodelação e função ventricular em ratos expostos à fumaça do cigarro Estándar de remodelación y función ventricular en ratones expuestos al humo del cigarrillo Remodeling pattern and ventricular function in rats exposed to cigarette smoke

    Directory of Open Access Journals (Sweden)

    Paula S. Azevedo

    2010-02-01

    concéntrica (índice de masa aumentado y espesor relativo aumentado y hipertrofia excéntrica (índice de masa aumentado y espesor relativo normal. RESULTADOS: Los ratos fumadores presentaron uno de los cuatro estándares de geometría: estándar normal, el 51%; hipertrofia excéntrica: el 32%; hipertrofia concéntrica, el 13% y remodelación concéntrica, el 4%. Los grupos normal e hipertrofia excéntrica presentaron menores valores de fracción de eyección y porcentaje de acortamiento que el grupo hipertrofia concéntrica. Trece animales (28% presentaron disfunción sistólica, detectada por la fracción de eyección y por el porcentaje de acortamiento. En el análisis de regresión univariado, los estándares de geometría y el índice de masa no fueron factor de predicción de disfunción ventricular (p > 0,05. Por otro lado, el aumento del espesor relativo de la pared fue factor de predicción de disfunción ventricular en el análisis univariado (p BACKGROUND: The relevance of the remodeling pattern in the model of rats exposed to cigarette smoke is not known. OBJECTIVE: Analyzing the presence of different remodeling patterns in this model and its relation with the ventricular function. METHODS: Smoking rats (n=47 have been divided according to the geometry pattern, analyzed by echocardiogram: normal (normal mass index and normal relative wall thickness, concentric remodeling (normal mass index and increased relative wall thickness, concentric hypertrophy (increased mass index and increased relative wall thickness and eccentric hypertrophy (increased mass index and normal relative wall thickness. RESULTS: Smoking rats presented one of the following geometry patterns: normal pattern, 51%; eccentric hypertrophy; 32%; concentric hypertrophy, 13% and concentric remodeling, 4%. The normal and eccentric hypertrophy groups presented smaller ejection fraction values and fractional shortening than the concentric hypertrophy group. Thirteen animals (28% presented

  5. Quantification of Coupled Stiffness and Fiber Orientation Remodeling in Hypertensive Rat Right-Ventricular Myocardium Using 3D Ultrasound Speckle Tracking with Biaxial Testing.

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    Dae Woo Park

    Full Text Available Mechanical and structural changes of right ventricular (RV in response to pulmonary hypertension (PH are inadequately understood. While current standard biaxial testing provides information on the mechanical behavior of RV tissues using surface markers, it is unable to fully assess structural and mechanical properties across the full tissue thickness. In this study, the mechanical and structural properties of normotensive and pulmonary hypertension right ventricular (PHRV myocardium through its full thickness were examined using mechanical testing combined with 3D ultrasound speckle tracking (3D-UST. RV pressure overload was induced in Sprague-Dawley rats by pulmonary artery (PA banding. The second Piola-Kirchhoff stress tensors and Green-Lagrangian strain tensors were computed in the RV myocardium using the biaxial testing combined with 3D-UST. A previously established non-linear curve-fitting algorithm was applied to fit experimental data to a Strain Energy Function (SEF for computation of myofiber orientation. The fiber orientations obtained by the biaxial testing with 3D-UST compared well with the fiber orientations computed from the histology. In addition, the re-orientation of myofiber in the right ventricular free wall (RVFW along longitudinal direction (apex-to-outflow-tract direction was noticeable in response to PH. For normotensive RVFW samples, the average fiber orientation angles obtained by 3D-UST with biaxial test spiraled from 20° at the endo-cardium to -42° at the epi-cardium (Δ = 62°. For PHRV samples, the average fiber orientation angles obtained by 3D-UST with biaxial test had much less spiral across tissue thickness: 3° at endo-cardium to -7° at epi-cardium (Δ = 10°, P<0.005 compared to normotensive.

  6. Left-Ventricular Energetics in Pulmonary Arterial Hypertension-Induced Right-Ventricular Hypertrophic Failure.

    Science.gov (United States)

    Han, June-Chiew; Guild, Sarah-Jane; Pham, Toan; Nisbet, Linley; Tran, Kenneth; Taberner, Andrew J; Loiselle, Denis S

    2017-01-01

    Pulmonary arterial hypertension (PAH) alters the geometries of both ventricles of the heart. While the right ventricle (RV) hypertrophies, the left ventricle (LV) atrophies. Multiple lines of clinical and experimental evidence lead us to hypothesize that the impaired stroke volume and systolic pressure of the LV are a direct consequence of the effect of pressure overload in the RV, and that atrophy in the LV plays only a minor role. In this study, we tested this hypothesis by examining the mechanoenergetic response of the atrophied LV to RV hypertrophy in rats treated with monocrotaline. Experiments were performed across multiple-scales: the whole-heart in vivo and ex vivo , and its trabeculae in vitro . Under the in vivo state where the RV was pressure-overloaded, we measured reduced systemic blood pressure and LV ventricular pressure. In contrast, under both ex vivo and in vitro conditions, where the effect of RV pressure overload was circumvented, we found that LV was capable of developing normal systolic pressure and stress. Nevertheless, LV atrophy played a minor role in that LV stroke volume remained lower, thereby contributing to lower LV mechanical work output. Concomitantly lower oxygen consumption and change of enthalpy were observed, and hence LV energy efficiency was unchanged. Our internally consistent findings between working-heart and trabecula experiments explain the rapid improvement of LV systolic function observed in patients with chronic pulmonary hypertension following surgical relief of RV pressure overload.

  7. Long Non-Coding RNA Malat-1 Is Dispensable during Pressure Overload-Induced Cardiac Remodeling and Failure in Mice.

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    Tim Peters

    Full Text Available Long non-coding RNAs (lncRNAs are a class of RNA molecules with diverse regulatory functions during embryonic development, normal life, and disease in higher organisms. However, research on the role of lncRNAs in cardiovascular diseases and in particular heart failure is still in its infancy. The exceptionally well conserved nuclear lncRNA Metastasis associated in lung adenocarcinoma transcript 1 (Malat-1 is a regulator of mRNA splicing and highly expressed in the heart. Malat-1 modulates hypoxia-induced vessel growth, activates ERK/MAPK signaling, and scavenges the anti-hypertrophic microRNA-133. We therefore hypothesized that Malat-1 may act as regulator of cardiac hypertrophy and failure during cardiac pressure overload induced by thoracic aortic constriction (TAC in mice.Absence of Malat-1 did not affect cardiac hypertrophy upon pressure overload: Heart weight to tibia length ratio significantly increased in WT mice (sham: 5.78±0.55, TAC 9.79±1.82 g/mm; p<0.001 but to a similar extend also in Malat-1 knockout (KO mice (sham: 6.21±1.12, TAC 8.91±1.74 g/mm; p<0.01 with no significant difference between genotypes. As expected, TAC significantly reduced left ventricular fractional shortening in WT (sham: 38.81±6.53%, TAC: 23.14±11.99%; p<0.01 but to a comparable degree also in KO mice (sham: 37.01±4.19%, TAC: 25.98±9.75%; p<0.05. Histological hallmarks of myocardial remodeling, such as cardiomyocyte hypertrophy, increased interstitial fibrosis, reduced capillary density, and immune cell infiltration, did not differ significantly between WT and KO mice after TAC. In line, the absence of Malat-1 did not significantly affect angiotensin II-induced cardiac hypertrophy, dysfunction, and overall remodeling. Above that, pressure overload by TAC significantly induced mRNA levels of the hypertrophy marker genes Nppa, Nppb and Acta1, to a similar extend in both genotypes. Alternative splicing of Ndrg2 after TAC was apparent in WT (isoform ratio

  8. Aerobic interval training reduces inducible ventricular arrhythmias in diabetic mice after myocardial infarction.

    Science.gov (United States)

    Rolim, Natale; Skårdal, Kristine; Høydal, Morten; Sousa, Mirta M L; Malmo, Vegard; Kaurstad, Guri; Ingul, Charlotte B; Hansen, Harald E M; Alves, Marcia N; Thuen, Marte; Haraldseth, Olav; Brum, Patricia C; Slupphaug, Geir; Loennechen, Jan Pål; Stølen, Tomas; Wisløff, Ulrik

    2015-01-01

    Diabetes mellitus (DM) increases the risk of heart failure after myocardial infarction (MI), and aggravates ventricular arrhythmias in heart failure patients. Although exercise training improves cardiac function in heart failure, it is still unclear how it benefits the diabetic heart after MI. To study the effects of aerobic interval training on cardiac function, susceptibility to inducible ventricular arrhythmias and cardiomyocyte calcium handling in DM mice after MI (DM-MI). Male type 2 DM mice (C57BLKS/J Lepr (db) /Lepr (db) ) underwent MI or sham surgery. One group of DM-MI mice was submitted to aerobic interval training running sessions during 6 weeks. Cardiac function and structure were assessed by echocardiography and magnetic resonance imaging, respectively. Ventricular arrhythmias were induced by high-frequency cardiac pacing in vivo. Protein expression was measured by Western blot. DM-MI mice displayed increased susceptibility for inducible ventricular arrhythmias and impaired diastolic function when compared to wild type-MI, which was associated with disruption of cardiomyocyte calcium handling and increased calcium leak from the sarcoplasmic reticulum. High-intensity exercise recovered cardiomyocyte function in vitro, reduced sarcoplasmic reticulum diastolic calcium leak and significantly reduced the incidence of inducible ventricular arrhythmias in vivo in DM-MI mice. Exercise training also normalized the expression profile of key proteins involved in cardiomyocyte calcium handling, suggesting a potential molecular mechanism for the benefits of exercise in DM-MI mice. High-intensity aerobic exercise training recovers cardiomyocyte function and reduces inducible ventricular arrhythmias in infarcted diabetic mice.

  9. Voltage dependent potassium channel remodeling in murine intestinal smooth muscle hypertrophy induced by partial obstruction.

    Directory of Open Access Journals (Sweden)

    Dong-Hai Liu

    Full Text Available Partial obstruction of the small intestine causes obvious hypertrophy of smooth muscle cells and motility disorder in the bowel proximate to the obstruction. To identify electric remodeling of hypertrophic smooth muscles in partially obstructed murine small intestine, the patch-clamp and intracellular microelectrode recording methods were used to identify the possible electric remodeling and Western blot, immunofluorescence and immunoprecipitation were utilized to examine the channel protein expression and phosphorylation level changes in this research. After 14 days of obstruction, partial obstruction caused obvious smooth muscle hypertrophy in the proximally located intestine. The slow waves of intestinal smooth muscles in the dilated region were significantly suppressed, their amplitude and frequency were reduced, whilst the resting membrane potentials were depolarized compared with normal and sham animals. The current density of voltage dependent potassium channel (KV was significantly decreased in the hypertrophic smooth muscle cells and the voltage sensitivity of KV activation was altered. The sensitivity of KV currents (IKV to TEA, a nonselective potassium channel blocker, increased significantly, but the sensitivity of IKv to 4-AP, a KV blocker, stays the same. The protein levels of KV4.3 and KV2.2 were up-regulated in the hypertrophic smooth muscle cell membrane. The serine and threonine phosphorylation levels of KV4.3 and KV2.2 were significantly increased in the hypertrophic smooth muscle cells. Thus this study represents the first identification of KV channel remodeling in murine small intestinal smooth muscle hypertrophy induced by partial obstruction. The enhanced phosphorylations of KV4.3 and KV2.2 may be involved in this process.

  10. Cadherin-11 Overexpression Induces Extracellular Matrix Remodeling and Calcification in Mature Aortic Valves.

    Science.gov (United States)

    Sung, Derek C; Bowen, Caitlin J; Vaidya, Kiran A; Zhou, Jingjing; Chapurin, Nikita; Recknagel, Andrew; Zhou, Bin; Chen, Jonathan; Kotlikoff, Michael; Butcher, Jonathan T

    2016-08-01

    Calcific aortic valve (AoV) disease is a significant clinical problem for which the regulatory mechanisms are poorly understood. Enhanced cell-cell adhesion is a common mechanism of cellular aggregation, but its role in calcific lesion formation is not known. Cadherin-11 (Cad-11) has been associated with lesion formation in vitro, but its function during adult valve homeostasis and pathogenesis is not known. This study aims to elucidate the specific functions of Cad-11 and its downstream targets, RhoA and Sox9, in extracellular matrix remodeling and AoV calcification. We conditionally overexpressed Cad-11 in murine heart valves using a novel double-transgenic Nfatc1(Cre);R26-Cad11(TglTg) mouse model. These mice developed hemodynamically significant aortic stenosis with prominent calcific lesions in the AoV leaflets. Cad-11 overexpression upregulated downstream targets, RhoA and Sox9, in the valve interstitial cells, causing calcification and extensive pathogenic extracellular matrix remodeling. AoV interstitial cells overexpressing Cad-11 in an osteogenic environment in vitro rapidly form calcific nodules analogous to in vivo lesions. Molecular analyses revealed upregulation of osteoblastic and myofibroblastic markers. Treatment with a Rho-associated protein kinase inhibitor attenuated nodule formation, further supporting that Cad-11-driven calcification acts through the small GTPase RhoA/Rho-associated protein kinase signaling pathway. This study identifies one of the underlying molecular mechanisms of heart valve calcification and demonstrates that overexpression of Cad-11 upregulates RhoA and Sox9 to induce calcification and extracellular matrix remodeling in adult AoV pathogenesis. The findings provide a potential molecular target for clinical treatment. © 2016 American Heart Association, Inc.

  11. Coenzyme Q10 prevents oxidative stress and fibrosis in isoprenaline induced cardiac remodeling in aged rats.

    Science.gov (United States)

    Ulla, Anayt; Mohamed, Mustafe Khalid; Sikder, Biswajit; Rahman, Afm Towheedur; Sumi, Farzana Akther; Hossain, Murad; Reza, Hasan Mahmud; Rahman, G M Sayedur; Alam, Md Ashraful

    2017-04-20

    The objective of the present study aimed to investigate the effect of CoQ10 treatment on isoprenaline (ISO)-induced cardiac remodeling in rats. Rats were divided into three groups namely Control group, ISO treated group and CoQ10 + ISO treated group, each consisting of 6 rats. The cardiac specific CK-MB, AST, ALT activity and other oxidative stress parameters were estimated in heart and kidneys. Additionally histological examination was also performed to visualize the inflammatory cells infiltration and fibrosis in both tissues. Administration of ISO resulted in an increase in the heart-to-body weight (HW/BW) ratio and an also increased the serum CK-MB, AST and ALT enzyme activity. Serum levels of lipid peroxidation products, and oxidative stress markers showed significant increase in ISO-treated rats. Histopathological examination of heart tissue revealed focal areas of endocardium degeneration, mononuclear cells infiltration, fibrous tissue deposition, and increased thickness of the myocardium of left ventricle. Similar degeneration was also found in kidneys. Treatment with CoQ10 (100 mg/kg) significantly improved the oxidative stresses in ISO treated rats. Moreover, CoQ10 treatment prevented inflammatory cells infiltration and reduced fibrosis in ISO administered rats. In conclusion, our study provides evidence that CoQ10 may prevent the development of cardiac remodeling, and fibrosis in ISO administered rats.

  12. Sildenafil limits monocrotaline-induced pulmonary hypertension in rats through suppression of pulmonary vascular remodeling.

    Science.gov (United States)

    Yen, Chia-Hung; Leu, Steve; Lin, Yu-Chun; Kao, Ying-Hsien; Chang, Li-Teh; Chua, Sarah; Fu, Morgan; Wu, Chiung-Jen; Sun, Cheuk-Kwan; Yip, Hon-Kan

    2010-06-01

    We hypothesize that sildenafil attenuates pulmonary hypertension through suppressing pulmonary vascular remodeling. Thirty male adult Sprague-Dawley rats were randomized to receive saline injection (Group 1), subcutaneous monocrotaline (MCT) (60 mg/kg) (Group 2), and MCT plus oral sildenafil (30 g/kg per day) (Group 3) 5 days after MCT administration. By Day 35, Western blot showed lower connexin43 and membranous protein kinase C epsilon expressions but higher oxidative stress in right ventricle in Group 2 compared with the other groups. Additionally, pulmonary Smad1/5 was lowest, whereas connexin43 and Smad3 were highest in Group 2. Pulmonary mRNA expressions of tumor necrosis factor-alpha, caspase-3, plasminogen activator inhibitor-1, and transforming growth factor-beta were higher, whereas bone morphogenetic protein Type II receptor, Bcl-2, and endothelial nitric oxide synthase were lower in Group 2 than in the other groups. Similarly, mRNA expressions of tumor necrosis factor-alpha, caspase-3, and beta-myosin heavy chain were increased, whereas Bcl-2, endothelial nitric oxide synthase, and alpha-myosin heavy chain expressions in right ventricle were reduced in Group 2 compared with the other groups. Number of lung arterioles was lowest, whereas number of arterioles with muscularization of the medial layer was highest in Group 2. Right ventricle systolic pressure and weight were elevated in Group 2 compared with the other groups. In conclusion, sildenafil effectively alleviates MCT-induced pulmonary hypertension through suppressing pulmonary vascular remodeling.

  13. Inhalation exposure to ethylene induces eosinophilic rhinitis and nasal epithelial remodeling in Fischer 344 rats.

    Science.gov (United States)

    Brandenberger, Christina; Hotchkiss, Jon A; Krieger, Shannon M; Pottenger, Lynn H; Harkema, Jack R

    2015-11-05

    This study investigated the time- and concentration-dependent effects of inhaled ethylene on eosinophilic rhinitis and nasal epithelial remodeling in Fisher 344 rats exposed to 0, 10, 50, 300, or 10,000 ppm ethylene, 6 h/day, 5 days/week for up to 4 weeks. Morphometric quantitation of eosinophilic inflammation and mucous cell metaplasia/hyperplasia (MCM) and nasal mucosal gene expression were evaluated at anatomic sites previously shown to undergo ethylene-induced epithelial remodeling. Serum levels of total IgE, IgG1 and IgG2a were measured to determine if ethylene exposure increased the expression of Th2-associated (IgE and IgG1) relative to Th1-associated (IgG2a) antibody isotypes. Rats exposed to 0 or 10,000 ppm for 1, 3, 5, 10, or 20 days were analyzed to assess the temporal pattern of ethylene-induced alterations in nasal epithelial cell proliferation, morphology and gene expression. Rats exposed to 0, 10, 50, 300, and 10,000 ppm ethylene for 20 days were analyzed to assess concentration-dependent effects on lesion development. Additional rats exposed 4 weeks to 0, 300, or 10,000 ppm ethylene were held for 13 weeks post-exposure to examine the persistence of ethylene-induced mucosal alterations. The data indicate that cell death and reparative cell proliferation were not a part of the pathogenesis of ethylene-induced nasal lesions. Enhanced gene expression of Th2 cytokines (e.g., IL-5, IL-13) and chitinase (YM1/2) in the nasal mucosa was much greater than that of Th1 cytokines (e.g., IFNγ) after ethylene exposure. A significant increase in MCM was measured after 5 days of exposure to 10,000 ppm ethylene and after 20 days of exposure 10 ppm ethylene. Ethylene-induced MCM was reversible after cessation of exposure. No increase in total serum IgE, IgG1 or IgG2a was measured in any ethylene-exposed group. These data do not support involvement of an immune-mediated allergic mechanism in the pathogenesis of ethylene-induced nasal lesions in rats. Repeated

  14. How chromatin is remodelled during DNA repair of UV-induced DNA damage in Saccharomyces cerevisiae.

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    Shirong Yu

    2011-06-01

    Full Text Available Global genome nucleotide excision repair removes DNA damage from transcriptionally silent regions of the genome. Relatively little is known about the molecular events that initiate and regulate this process in the context of chromatin. We've shown that, in response to UV radiation-induced DNA damage, increased histone H3 acetylation at lysine 9 and 14 correlates with changes in chromatin structure, and these alterations are associated with efficient global genome nucleotide excision repair in yeast. These changes depend on the presence of the Rad16 protein. Remarkably, constitutive hyperacetylation of histone H3 can suppress the requirement for Rad7 and Rad16, two components of a global genome repair complex, during repair. This reveals the connection between histone H3 acetylation and DNA repair. Here, we investigate how chromatin structure is modified following UV irradiation to facilitate DNA repair in yeast. Using a combination of chromatin immunoprecipitation to measure histone acetylation levels, histone acetylase occupancy in chromatin, MNase digestion, or restriction enzyme endonuclease accessibility assays to analyse chromatin structure, and finally nucleotide excision repair assays to examine DNA repair, we demonstrate that global genome nucleotide excision repair drives UV-induced chromatin remodelling by controlling histone H3 acetylation levels in chromatin. The concerted action of the ATPase and C3HC4 RING domains of Rad16 combine to regulate the occupancy of the histone acetyl transferase Gcn5 on chromatin in response to UV damage. We conclude that the global genome repair complex in yeast regulates UV-induced histone H3 acetylation by controlling the accessibility of the histone acetyl transferase Gcn5 in chromatin. The resultant changes in histone H3 acetylation promote chromatin remodelling necessary for efficient repair of DNA damage. Recent evidence suggests that GCN5 plays a role in NER in human cells. Our work provides

  15. How chromatin is remodelled during DNA repair of UV-induced DNA damage in Saccharomyces cerevisiae.

    Science.gov (United States)

    Yu, Shirong; Teng, Yumin; Waters, Raymond; Reed, Simon H

    2011-06-01

    Global genome nucleotide excision repair removes DNA damage from transcriptionally silent regions of the genome. Relatively little is known about the molecular events that initiate and regulate this process in the context of chromatin. We've shown that, in response to UV radiation-induced DNA damage, increased histone H3 acetylation at lysine 9 and 14 correlates with changes in chromatin structure, and these alterations are associated with efficient global genome nucleotide excision repair in yeast. These changes depend on the presence of the Rad16 protein. Remarkably, constitutive hyperacetylation of histone H3 can suppress the requirement for Rad7 and Rad16, two components of a global genome repair complex, during repair. This reveals the connection between histone H3 acetylation and DNA repair. Here, we investigate how chromatin structure is modified following UV irradiation to facilitate DNA repair in yeast. Using a combination of chromatin immunoprecipitation to measure histone acetylation levels, histone acetylase occupancy in chromatin, MNase digestion, or restriction enzyme endonuclease accessibility assays to analyse chromatin structure, and finally nucleotide excision repair assays to examine DNA repair, we demonstrate that global genome nucleotide excision repair drives UV-induced chromatin remodelling by controlling histone H3 acetylation levels in chromatin. The concerted action of the ATPase and C3HC4 RING domains of Rad16 combine to regulate the occupancy of the histone acetyl transferase Gcn5 on chromatin in response to UV damage. We conclude that the global genome repair complex in yeast regulates UV-induced histone H3 acetylation by controlling the accessibility of the histone acetyl transferase Gcn5 in chromatin. The resultant changes in histone H3 acetylation promote chromatin remodelling necessary for efficient repair of DNA damage. Recent evidence suggests that GCN5 plays a role in NER in human cells. Our work provides important insight into

  16. Exercise-Induced Skeletal Muscle Remodeling and Metabolic Adaptation: Redox Signaling and Role of Autophagy

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    Giammarioli, Anna Maria; Chiandotto, Sergio; Spoletini, Ilaria

    2014-01-01

    Abstract Significance: Skeletal muscle is a highly plastic tissue. Exercise evokes signaling pathways that strongly modify myofiber metabolism and physiological and contractile properties of skeletal muscle. Regular physical activity is beneficial for health and is highly recommended for the prevention of several chronic conditions. In this review, we have focused our attention on the pathways that are known to mediate physical training-induced plasticity. Recent Advances: An important role for redox signaling has recently been proposed in exercise-mediated muscle remodeling and peroxisome proliferator-activated receptor γ (PPARγ) coactivator-1α (PGC-1α) activation. Still more currently, autophagy has also been found to be involved in metabolic adaptation to exercise. Critical Issues: Both redox signaling and autophagy are processes with ambivalent effects; they can be detrimental and beneficial, depending on their delicate balance. As such, understanding their role in the chain of events induced by exercise and leading to skeletal muscle remodeling is a very complicated matter. Moreover, the study of the signaling induced by exercise is made even more difficult by the fact that exercise can be performed with several different modalities, with this having different repercussions on adaptation. Future Directions: Unraveling the complexity of the molecular signaling triggered by exercise on skeletal muscle is crucial in order to define the therapeutic potentiality of physical training and to identify new pharmacological compounds that are able to reproduce some beneficial effects of exercise. In evaluating the effect of new “exercise mimetics,” it will also be necessary to take into account the involvement of reactive oxygen species, reactive nitrogen species, and autophagy and their controversial effects. Antioxid. Redox Signal. 21, 154–176. PMID:24450966

  17. Effect of lysyl oxidase inhibition on angiotensin II-induced arterial hypertension, remodeling, and stiffness.

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    Lance S Eberson

    Full Text Available It is well accepted that angiotensin II (Ang II induces altered vascular stiffness through responses including both structural and material remodeling. Concurrent with remodeling is the induction of the enzyme lysyl oxidase (LOX through which ECM proteins are cross-linked. The study objective was to determine the effect of LOX mediated cross-linking on vascular mechanical properties. Three-month old mice were chronically treated with Ang II with or without the LOX blocker, β -aminopropionitrile (BAPN, for 14 days. Pulse wave velocity (PWV from Doppler measurements of the aortic flow wave was used to quantify in vivo vascular stiffness in terms of an effective Young's modulus. The increase in effective Young's modulus with Ang II administration was abolished with the addition of BAPN, suggesting that the material properties are a major controlling element in vascular stiffness. BAPN inhibited the Ang II induced collagen cross-link formation by 2-fold and PWV by 44% (P<0.05. Consistent with this observation, morphometric analysis showed that BAPN did not affect the Ang II mediated increase in medial thickness but significantly reduced the adventitial thickness. Since the hypertensive state contributes to the measured in vivo PWV stiffness, we removed the Ang II infusion pumps on Day 14 and achieved normal arterial blood pressures. With pump removal we observed a decrease of the PWV in the Ang II group to 25% above that of the control values (P=0.002, with a complete return to control values in the Ang II plus BAPN group. In conclusion, we have shown that the increase in vascular stiffness with 14 day Ang II administration results from a combination of hypertension-induced wall strain, adventitial wall thickening and Ang II mediated LOX ECM cross-linking, which is a major material source of vascular stiffening, and that the increased PWV was significantly inhibited with co-administration of BAPN.

  18. H-ras deletion protects against angiotensin II-induced arterial hypertension and cardiac remodeling through protein kinase G-Iβ pathway activation.

    Science.gov (United States)

    Martín-Sánchez, Paloma; Luengo, Alicia; Griera, Mercedes; Orea, María Jesús; López-Olañeta, Marina; Chiloeches, Antonio; Lara-Pezzi, Enrique; de Frutos, Sergio; Rodríguez-Puyol, Manuel; Calleros, Laura; Rodríguez-Puyol, Diego

    2017-10-20

    Ras proteins regulate cell survival, growth, differentiation, blood pressure, and fibrosis in some organs. We have demonstrated that H-ras gene deletion produces mice hypotension via a soluble guanylate cyclase-protein kinase G (PKG)-dependent mechanism. In this study, we analyzed the consequences of H-ras deletion on cardiac remodeling induced by continuous angiotensin II (AngII) infusion and the molecular mechanisms implied. Left ventricular posterior wall thickness and mass and cardiomyocyte cross-sectional area were similar between AngII-treated H-Ras knockout (H-ras(-/-) ) and control wild-type (H-ras(+/+) ) mice, as were extracellular matrix protein expression. Increased cardiac PKG-Iβ protein expression in H-ras(-/-) mice suggests the involvement of this protein in heart protection. Ex vivo experiments on cardiac explants could support this mechanism, as PKG blockade blunted protection against AngII-induced cardiac hypertrophy and fibrosis markers in H-ras(-/-) mice. Genetic modulation studies in cardiomyocytes and cardiac and embryonic fibroblasts revealed that the lack of H-Ras down-regulates the B-RAF/MEK/ERK pathway, which induces the glycogen synthase kinase-3β-dependent activation of the transcription factor, cAMP response element-binding protein, which is responsible for PKG-Iβ overexpression in H-ras(-/-) mouse embryonic fibroblasts. This study demonstrates that H-ras deletion protects against AngII-induced cardiac remodeling, possibly via a mechanism in which PKG-Iβ overexpression could play a partial role, and points to H-Ras and/or downstream proteins as potential therapeutic targets in cardiovascular disease.-Martín-Sánchez, P., Luengo, A., Griera, M., Orea, M. J., López-Olañeta, M., Chiloeches, A., Lara-Pezzi, E., de Frutos, S., Rodríguez-Puyol, M., Calleros, L., Rodríguez-Puyol, D. H-ras deletion protects against angiotensin II-induced arterial hypertension and cardiac remodeling through protein kinase G-Iβ pathway activation.

  19. Predictive value of electrical restitution in hypokalemia-induced ventricular arrhythmogenicity

    DEFF Research Database (Denmark)

    Osadchii, Oleg E; Larsen, Anders Peter; Olesen, Soren Peter

    2009-01-01

    the predictive value of electrical restitution in hypokalemia-induced arrhythmogenicity. We recorded monophasic APs and measured effective refractory periods (ERP) at distinct ventricular epicardial and endocardial sites and monitored volume-conducted ECG at baseline and after hypokalemic perfusion (2.5 mM K...

  20. Hemodialysis-Induced Regional Left Ventricular Systolic Dysfunction: Prevalence, Patient and Dialysis Treatment-Related Factors, and Prognostic Significance

    Science.gov (United States)

    Assa, Solmaz; Hummel, Yoran M.; Voors, Adriaan A.; Kuipers, Johanna; Westerhuis, Ralf; de Jong, Paul E.

    2012-01-01

    Summary Background and objectives The hemodialysis procedure may acutely induce regional left ventricular systolic dysfunction. This study evaluated the prevalence, time course, and associated patient- and dialysis-related factors of this entity and its association with outcome. Design, setting, participants, & measurements Hemodialysis patients (105) on a three times per week dialysis schedule were studied between March of 2009 and March of 2010. Echocardiography was performed before dialysis, at 60 and 180 minutes intradialysis, and at 30 minutes postdialysis. Hemodialysis-induced regional left ventricular systolic dysfunction was defined as an increase in wall motion score in more than or equal to two segments. Results Hemodialysis-induced regional left ventricular systolic dysfunction occurred in 29 (27%) patients; 17 patients developed regional left ventricular systolic dysfunction 60 minutes after onset of dialysis. Patients with hemodialysis-induced left ventricular systolic dysfunction were more often male, had higher left ventricular mass index, and had worse predialysis left ventricular systolic function (left ventricular ejection fraction). The course of blood volume, BP, heart rate, electrolytes, and acid–base parameters during dialysis did not differ significantly between the two groups. Patients with hemodialysis-induced regional left ventricular systolic dysfunction had a significantly higher mortality after correction for age, sex, dialysis vintage, diabetes, cardiovascular history, ultrafiltration volume, left ventricular mass index, and predialysis wall motion score index. Conclusions Hemodialysis induces regional wall motion abnormalities in a significant proportion of patients, and these changes are independently associated with increased mortality. Hemodialysis-induced regional left ventricular systolic dysfunction occurs early during hemodialysis and is not related to changes in blood volume, electrolytes, and acid–base parameters. PMID

  1. Effect of intracoronary administration of AAV1/SERCA2a on ventricular remodelling in patients with advanced systolic heart failure: results from the AGENT-HF randomized phase 2 trial.

    Science.gov (United States)

    Hulot, Jean-Sébastien; Salem, Joe-Elie; Redheuil, Alban; Collet, Jean-Philippe; Varnous, Shaida; Jourdain, Patrick; Logeart, Damien; Gandjbakhch, Estelle; Bernard, Claude; Hatem, Stéphane N; Isnard, Richard; Cluzel, Philippe; Le Feuvre, Claude; Leprince, Pascal; Hammoudi, Nadjib; Lemoine, François M; Klatzmann, David; Vicaut, Eric; Komajda, Michel; Montalescot, Gilles; Lompré, Anne-Marie; Hajjar, Roger J

    2017-11-01

    Restoration of sarco/endoplasmic reticulum Ca2+ ATPase (SERCA2a) activity through gene transfer improved cardiac function in experimental and pilot studies in humans with heart failure. The AGENT-HF (NCT01966887) trial investigated the impact of adeno-associated virus (AAV1)/SERCA2a on ventricular remodelling using multimodality non-invasive cardiac imaging. AGENT-HF was a single centre, randomized, double-blind, placebo-controlled trial in adult patients with NYHA class III-IV ischaemic or non-ischaemic heart failure and left ventricular ejection fraction ≤35%. Eligible patients were randomized to receive a single intracoronary infusion of either 1 × 1013 DNase-resistant particles of AAV1/SERCA2a or placebo. The primary endpoint was change in left ventricular end-systolic volume (LVESV), measured by cardiac computed tomography at 6 month follow-up. We planned to include 40 patients but the trial was terminated prematurely as the sponsor suspended further enrolment following neutral results of the CUPID-2 outcome trial. At the time of termination, nine patients were randomized with five patients infused with AAV1/SERCA2a and four with placebo. At 6 months, LVESV was increased in both groups compared with baseline: median (interquartile range) in AAV1/SERCA2a vs. placebo: 13 (13;14) mL vs. 3.5 (-36;36) mL, P = 0.74, with a mean difference between groups of 11.4 mL in favour of placebo. No safety issues were noted. AGENT-HF failed to demonstrate any improvement in ventricular remodelling in response to AAV1/SERCA2a at the dose studied. However, because of premature termination, the study was underpowered to demonstrate an effect of AAV1/SERCA2a and these data should be interpreted with caution. © 2017 The Authors. European Journal of Heart Failure © 2017 European Society of Cardiology.

  2. Polycomb and Hox Genes Control JNK-Induced Remodeling of the Segment Boundary during Drosophila Morphogenesis

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    Solange Roumengous

    2017-04-01

    Full Text Available In segmented tissues, anterior and posterior compartments represent independent morphogenetic domains, which are made of distinct lineages separated by boundaries. During dorsal closure of the Drosophila embryo, specific “mixer cells” (MCs are reprogrammed in a JNK-dependent manner to express the posterior determinant engrailed (en and cross the segment boundary. Here, we show that JNK signaling induces de novo expression of en in the MCs through repression of Polycomb (Pc and release of the en locus from the silencing PcG bodies. Whereas reprogramming occurs in MCs from all thoracic and abdominal segments, cell mixing is restricted to the central abdominal region. We demonstrate that this spatial control of MC remodeling depends on the antagonist activity of the Hox genes abdominal-A and Abdominal-B. Together, these results reveal an essential JNK/en/Pc/Hox gene regulatory network important in controlling both the plasticity of segment boundaries and developmental reprogramming.

  3. Cathepsin B gene disruption induced Leishmania donovani proteome remodeling implies cathepsin B role in secretome regulation.

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    Teklu Kuru Gerbaba

    Full Text Available Leishmania cysteine proteases are potential vaccine candidates and drug targets. To study the role of cathepsin B cysteine protease, we have generated and characterized cathepsin B null mutant L. donovani parasites. L. donovani cathepsin B null mutants grow normally in culture, but they show significantly attenuated virulence inside macrophages. Quantitative proteome profiling of wild type and null mutant parasites indicates cathepsin B disruption induced remodeling of L. donovani proteome. We identified 83 modulated proteins, of which 65 are decreased and 18 are increased in the null mutant parasites, and 66% (55/83 of the modulated proteins are L. donovani secreted proteins. Proteins involved in oxidation-reduction (trypanothione reductase, peroxidoxins, tryparedoxin, cytochromes and translation (ribosomal proteins are among those decreased in the null mutant parasites, and most of these proteins belong to the same complex network of proteins. Our results imply virulence role of cathepsin B via regulation of Leishmania secreted proteins.

  4. PLC-gamma1 and Rac1 coregulate EGF-induced cytoskeleton remodeling and cell migration.

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    Li, Siwei; Wang, Qian; Wang, Yi; Chen, Xinmei; Wang, Zhixiang

    2009-06-01

    It is well established that epidermal growth factor (EGF) induces the cytoskeleton reorganization and cell migration through two major signaling cascades: phospholipase C-gamma1 (PLC-gamma1) and Rho GTPases. However, little is known about the cross talk between PLC-gamma1 and Rho GTPases. Here we showed that PLC-gamma1 forms a complex with Rac1 in response to EGF. This interaction is direct and mediated by PLC-gamma1 Src homology 3 (SH3) domain and Rac1 (106)PNTP(109) motif. This interaction is critical for EGF-induced Rac1 activation in vivo, and PLC-gamma1 SH3 domain is actually a potent and specific Rac1 guanine nucleotide exchange factor in vitro. We have also demonstrated that the interaction between PLC-gamma1 SH3 domain and Rac1 play a significant role in EGF-induced F-actin formation and cell migration. We conclude that PLC-gamma1 and Rac1 coregulate EGF-induced cell cytoskeleton remodeling and cell migration by a direct functional interaction.

  5. Drinking Citrus Fruit Juice Inhibits Vascular Remodeling in Cuff-Induced Vascular Injury Mouse Model

    Science.gov (United States)

    Ohnishi, Arika; Asayama, Rie; Mogi, Masaki; Nakaoka, Hirotomo; Kan-no, Harumi; Tsukuda, Kana; Chisaka, Toshiyuki; Wang, Xiao-Li; Bai, Hui-Yu; Shan, Bao-Shuai; Kukida, Masayoshi; Iwanami, Jun; Horiuchi, Masatsugu

    2015-01-01

    Citrus fruits are thought to have inhibitory effects on oxidative stress, thereby attenuating the onset and progression of cancer and cardiovascular disease; however, there are few reports assessing their effect on vascular remodeling. Here, we investigated the effect of drinking the juice of two different citrus fruits on vascular neointima formation using a cuff-induced vascular injury mouse model. Male C57BL6 mice were divided into five groups as follows: 1) Control (water) (C), 2) 10% Citrus unshiu (CU) juice (CU10), 3) 40% CU juice (CU40), 4) 10% Citrus iyo (CI) juice (CI10), and 5) 40% CI juice (CI40). After drinking them for 2 weeks from 8 weeks of age, cuff injury was induced by polyethylene cuff placement around the femoral artery. Neointima formation was significantly attenuated in CU40, CI10 and CI40 compared with C; however, no remarkable preventive effect was observed in CU10. The increases in levels of various inflammatory markers including cytokines such as monocyte chemotactic protein-1, interleukin-6 (IL-6), IL-1β, and tumor necrosis factor-α in response to vascular injury did not differ significantly between C, CU10 and CI10. The increases in cell proliferation and superoxide anion production were markedly attenuated in CI10, but not in CU10 compared with C. The increase in phosphorylated ERK expression was markedly attenuated both in CU10 and CI10 without significant difference between CU10 and CI10. Accumulation of immune cells did not differ between CU10 and CI10. These results indicate that drinking citrus fruit juice attenuates vascular remodeling partly via a reduction of oxidative stress. Interestingly, the preventive efficacy on neointima formation was stronger in CI than in CU at least in part due to more prominent inhibitory effects on oxidative stress by CI. PMID:25692290

  6. Ezrin regulating the cytoskeleton remodelling is required for hypoxia-induced Myofibroblast proliferation and migration

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    Bin eYi

    2015-03-01

    Full Text Available Background: Hypoxia pulmonary arterial hypertension (HPAH is a disease of the small vessels characterized by sustained vasoconstriction, thickening of arterial walls, vascular remodelling, and progressive increase in pulmonary vascular resistance, thus leading to right heart failure and finally death. Recent evidence demonstrated that massive Pulmonary Artery Smooth Muscle-like Cells (PASMLCs accumulating in the intima might also be developed from the differentiation of Pulmonary Myofibroblast (PMF of tunica media. And PMF appeared the phenomenon of the cytoskeleton remodeling. So, it would be important in the clarification of the pivotal factors controlling this cytoskeleton structure change. Methods: PMFs were cultured from the normal rats and then divided into three groups and incubated by nomal or hypoxic conditions respectively. mRNA level was evaluated by real time reverse transcription polymerase chain reaction, and protein expression was detected by western blot. Cell proliferation was determined by the MTT and thymidine incorporation assay. Results: Here, we report that the hypoxia increased the expression levels of Ezrin mRNA and protein in PMFs, which might explain the expression of cytoskeletal proteins (Destrin, a1-actin, and a1-tubulin in PMFs was significantly induced by hypoxia. After inhibiting Ezrin in PMFs by siRNA transfection, we found the over-expression of cytoskeletal proteins induced by hypoixa were significantly suppressed at all time points. Additionally, we found that hypoxia or over-expression of Ezrin through Ad-Ezrin transfection significantly increases the proliferation and migration of PMFs, and which could be inverted by the transfection of siRNA. Conclusion: These findings suggest that Ezrin regulating of aberrant dysregulation of cytoskeletal proteins may be the major cause of PMFs' proliferation and migration under the condition of hypoxia and may, therefore, play a fundamental role in the accumulation of

  7. A joined role of canopy and reversal cells in bone remodeling--lessons from glucocorticoid-induced osteoporosis.

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    Jensen, Pia Rosgaard; Andersen, Thomas Levin; Hauge, Ellen-Margrethe; Bollerslev, Jens; Delaissé, Jean-Marie

    2015-04-01

    Successful bone remodeling demands that osteoblasts restitute the bone removed by osteoclasts. In human cancellous bone, a pivotal role in this restitution is played by the canopies covering the bone remodeling surfaces, since disruption of canopies in multiple myeloma, postmenopausal- and glucocorticoid-induced osteoporosis is associated with the absence of progression of the remodeling cycle to bone formation, i.e., uncoupling. An emerging concept explaining this critical role of canopies is that they represent a reservoir of osteoprogenitors to be delivered to reversal surfaces. In postmenopausal osteoporosis, this concept is supported by the coincidence between the absence of canopies and scarcity of cells on reversal surfaces together with abortion of the remodeling cycle. Here we tested whether this concept holds true in glucocorticoid-induced osteoporosis. A histomorphometric analysis of iliac crest biopsies from patients exposed to long-term glucocorticoid treatment revealed a subpopulation of reversal surfaces corresponding to the characteristics of arrest found in postmenopausal osteoporosis. Importantly, these arrested reversal surfaces were devoid of canopy coverage in almost all biopsies, and their prevalence correlated with a deficiency in bone forming surfaces. Taken together with the other recent data, the functional link between canopies, reversal surface activity, and the extent of bone formation surface in postmenopausal- and glucocorticoid-induced osteoporosis, supports a model where bone restitution during remodeling demands recruitment of osteoprogenitors from the canopy onto reversal surfaces. These data suggest that securing the presence of functional local osteoprogenitors deserves attention in the search of strategies to prevent the bone loss that occurs during bone remodeling in pathological situations. Copyright © 2014 Elsevier Inc. All rights reserved.

  8. ATP-Sensitive K+ Channel Knockout Induces Cardiac Proteome Remodeling Predictive of Heart Disease Susceptibility

    Science.gov (United States)

    Arrell, D. Kent; Zlatkovic, Jelena; Kane, Garvan C.; Yamada, Satsuki; Terzic, Andre

    2010-01-01

    Forecasting disease susceptibility requires detection of maladaptive signatures prior to onset of overt symptoms. A case-in-point are cardiac ATP-sensitive K+ (KATP) channelopathies, for which the substrate underlying disease vulnerability remains to be identified. Resolving molecular pathobiology, even for single genetic defects, mandates a systems platform to reliably diagnose disease predisposition. High-throughput proteomic analysis was here integrated with network biology to decode consequences of Kir6.2 KATP channel pore deletion. Differential two-dimensional gel electrophoresis reproducibly resolved > 800 protein species from hearts of asymptomatic wild-type and Kir6.2-knockout counterparts. KATP channel ablation remodeled the cardiac proteome, significantly altering 71 protein spots, from which 102 unique identities were assigned following hybrid linear ion trap quadrupole-Orbitrap tandem mass spectrometry. Ontological annotation stratified the KATP channel-dependent protein cohort into a predominant bioenergetic module (63 resolved identities), with additional focused sets representing signaling molecules (6), oxidoreductases (8), chaperones (6), and proteins involved in catabolism (6), cytostructure (8), and transcription and translation (5). Protein interaction mapping, in conjunction with expression level changes, localized a KATP channel-associated subproteome within a nonstochastic scale-free network. Global assessment of the KATP channel deficient environment verified the primary impact on metabolic pathways and revealed overrepresentation of markers associated with cardiovascular disease. Experimental imposition of graded stress precipitated exaggerated structural and functional myocardial defects in the Kir6.2-knockout, decreasing survivorship and validating the forecast of disease susceptibility. Proteomic cartography thus provides an integral view of molecular remodeling in the heart induced by KATP channel deletion, establishing a systems

  9. Mechanism Investigation of the Improvement of Chang Run Tong on the Colonic Remodeling in Streptozotocin-Induced Diabetic Rats

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    Hong Sha

    2016-01-01

    Full Text Available Previous study demonstrated that Chang Run Tong (CRT could partly restore the colon remodeling in streptozotocin- (STZ- induced diabetic rats. Here we investigated the mechanisms of such effects of CRT. Diabetes was induced by a single injection of 40 mg/kg of STZ. CRT was poured into the stomach by gastric lavage once daily for 60 days. The remodeling parameters were obtained from diabetic (DM, CRT treated diabetic (T1, 50 g/kg; T2, 25 g/kg, and normal (Con rats. Expressions of advanced glycation end product (AGE, AGE receptor, transforming growth factor-β1 (TGF-β1, and TGF-β1 receptor in the colon wall were immunochemically detected and quantitatively analyzed. The association between the expressions of those proteins and the remodeling parameters was analyzed. The expressions of those proteins were significantly higher in different colon layers in the DM group (P0.05. The corrective effect on the expressions of those proteins is likely to be one molecular pathway for the improvement of CRT on the diabetes-induced colon remodeling.

  10. Endothelial Mineralocorticoid Receptor Mediates Parenchymal Arteriole and Posterior Cerebral Artery Remodeling During Angiotensin II-Induced Hypertension.

    Science.gov (United States)

    Diaz-Otero, Janice M; Fisher, Courtney; Downs, Kelsey; Moss, M Elizabeth; Jaffe, Iris Z; Jackson, William F; Dorrance, Anne M

    2017-12-01

    The brain is highly susceptible to injury caused by hypertension because the increased blood pressure causes artery remodeling that can limit cerebral perfusion. Mineralocorticoid receptor (MR) antagonism prevents hypertensive cerebral artery remodeling, but the vascular cell types involved have not been defined. In the periphery, the endothelial MR mediates hypertension-induced vascular injury, but cerebral and peripheral arteries are anatomically distinct; thus, these findings cannot be extrapolated to the brain. The parenchymal arterioles determine cerebrovascular resistance. Determining the effects of hypertension and MR signaling on these arterioles could lead to a better understanding of cerebral small vessel disease. We hypothesized that endothelial MR signaling mediates inward cerebral artery remodeling and reduced cerebral perfusion during angiotensin II (AngII) hypertension. The biomechanics of the parenchymal arterioles and posterior cerebral arteries were studied in male C57Bl/6 and endothelial cell-specific MR knockout mice and their appropriate controls using pressure myography. AngII increased plasma aldosterone and decreased cerebral perfusion in C57Bl/6 and MR-intact littermates. Endothelial cell MR deletion improved cerebral perfusion in AngII-treated mice. AngII hypertension resulted in inward hypotrophic remodeling; this was prevented by MR antagonism and endothelial MR deletion. Our studies suggest that endothelial cell MR mediates hypertensive remodeling in the cerebral microcirculation and large pial arteries. AngII-induced inward remodeling of cerebral arteries and arterioles was associated with a reduction in cerebral perfusion that could worsen the outcome of stroke or contribute to vascular dementia. © 2017 American Heart Association, Inc.

  11. Functional and structural remodeling of glutamate synapses in prefrontal and frontal cortex induced by behavioral stress

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    Laura eMusazzi

    2015-04-01

    Full Text Available Increasing evidence has shown that the pathophysiology of neuropsychiatric disorders, including mood disorders, is associated with abnormal function and regulation of the glutamatergic system. Consistently, preclinical studies on stress-based animal models of pathology showed that glucocorticoids and stress exert crucial effects on neuronal excitability and function, especially in cortical and limbic areas. In prefrontal and frontal cortex, acute stress was shown to induce enhancement of glutamate release/transmission dependent on activation of corticosterone receptors. Although the mechanisms whereby stress affects glutamate transmission have not yet been fully understood, it was shown that synaptic, non-genomic action of corticosterone is required to increase the readily releasable pool of glutamate vesicles but is not sufficient to enhance transmission in prefrontal and frontal cortex. Slower, partly genomic mechanisms are probably necessary for the enhancement of glutamate transmission induced by stress.Combined evidence has suggested that the changes in glutamate release and transmission are responsible for the dendritic remodeling and morphological changes induced by stress and it has been argued that sustained alterations of glutamate transmission may play a key role in the long-term structural/functional changes associated with mood disorders in patients. Intriguingly, modifications of the glutamatergic system induced by stress in the prefrontal cortex seem to be biphasic. Indeed, while the fast response to stress suggests an enhancement in the number of excitatory synapses, synaptic transmission and working memory, long-term adaptive changes -including those consequent to chronic stress- induce opposite effects. Better knowledge of the cellular effectors involved in this biphasic effect of stress may be useful to understand the pathophysiology of stress-related disorders, and open new paths for the development of therapeutic approaches.

  12. Effect of gender on training-induced vascular remodeling in SHR

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    S.L. Amaral

    2011-09-01

    Full Text Available There is accumulating evidence that physical inactivity, associated with the modern sedentary lifestyle, is a major determinant of hypertension. It represents the most important modifiable risk factor for cardiovascular diseases, which are the leading cause of morbidity and mortality for both men and women. In addition to involving sympathetic overactivity that alters hemodynamic parameters, hypertension is accompanied by several abnormalities in the skeletal muscle circulation including vessel rarefaction and increased arteriole wall-to-lumen ratio, which contribute to increased total peripheral resistance. Low-intensity aerobic training is a promising tool for the prevention, treatment and control of high blood pressure, but its efficacy may differ between men and women and between male and female animals. This review focuses on peripheral training-induced adaptations that contribute to a blood pressure-lowering effect, with special attention to differential responses in male and female spontaneously hypertensive rats (SHR. Heart, diaphragm and skeletal muscle arterioles (but not kidney arterioles undergo eutrophic outward remodeling in trained male SHR, which contributed to a reduction of peripheral resistance and to a pressure fall. In contrast, trained female SHR showed no change in arteriole wall-to-lumen ratio and no pressure fall. On the other hand, training-induced adaptive changes in capillaries and venules (increased density were similar in male and female SHR, supporting a similar hyperemic response to exercise.

  13. Mas receptor contributes to pregnancy-induced cardiac remodeling.

    Science.gov (United States)

    Carmos-Silva, Cintia; Almeida, Jônathas Fernandes Queiroz de; Macedo, Larissa Matuda; Melo, Marcos Barrouin B; Pedrino, Gustavo Rodrigues; Santos, Fernanda Fernanda Cristina Alcantara; Biancardi, Manoel Francisco; Santos, Robson Augusto Souza Dos Augusto Souza; Carvalho, Adryano Augustto; Mendes, Elizabeth Pereira; Colugnati, Diego Basile; Mazaro-Costa, Renata; Castro, Carlos Henrique de

    2016-09-13

    Previous studies have demonstrated a protective effect of the Ang-(1-7)/Mas receptor axis on pathological cardiac hypertrophy. Also, the involvement of Mas receptor in the exercise-induced cardiac hypertrophy has been suggested. However, the role of the Ang-(1-7)/Mas receptor on pregnancy-induced cardiac remodeling remains unknown. The objective of this study was to evaluate the participation of the Mas receptor in the development of the cardiac hypertrophy and fibrosis induced by gestation. Female Wistar rats were shared in 3 groups: control , pregnant , and pregnant treated with Mas receptor antagonist A-779 . Wild type (WT) and Mas-knockout mice (KO) were distributed in non-pregnant  and pregnant  groups. Systolic blood pressure (SBP) was measured by tail-cuff plethysmography. The medial part of the left ventricle (LV) was collected for histological analysis. Echocardiographic analysis was used to evaluate the cardiac function. SBP was not changed by pregnancy or A-779 treatment in the Wistar rats. Pharmacological blockade or genetic deletion of Mas receptor attenuates the pregnancy-induced myocyte hypertrophy. The treatment with A-779 or genetic deletion of the Mas receptor increased the collagen III deposition in LV from pregnant animals without changing the fibroblast proliferation. KO mice presented a lower ejection fraction, fraction shortening, stroke volume and higher end systolic volume compared to WT. Interestingly, the pregnancy restored these parameters. In conclusion, these data show that while Mas receptor blockade or deletion decreases physiological hypertrophy of pregnancy, it is associated with more extracellular matrix deposition. These alterations are associated with improvement of the cardiac function through Mas-independent mechanism. ©2016 The Author(s).

  14. A joined role of canopy and reversal cells in bone remodeling - Lessons from glucocorticoid-induced osteoporosis

    DEFF Research Database (Denmark)

    Jensen, Pia Rosgaard; Andersen, Thomas Levin; Hauge, Ellen-Margrethe

    2015-01-01

    - and glucocorticoid-induced osteoporosis is associated with the absence of progression of the remodeling cycle to bone formation, i.e. uncoupling. An emerging concept explaining this critical role of canopies is that they represent a reservoir of osteoprogenitors to be delivered to reversal surfaces....... In postmenopausal osteoporosis, this concept is supported by the coincidence between the absence of canopies and scarcity of cells on reversal surfaces together with abortion of the remodeling cycle. Here we tested whether this concept holds true in glucocorticoid-induced osteoporosis. A histomorphometric analysis...... biopsies, and their prevalence correlated with a deficiency in bone forming surfaces. Taken together with the other recent data, the functional link between canopies, reversal surface activity, and the extent of bone formation surface in postmenopausal- and glucocorticoid-induced osteoporosis, supports...

  15. Loss of progesterone receptor-mediated actions induce preterm cellular and structural remodeling of the cervix and premature birth.

    Science.gov (United States)

    Yellon, Steven M; Dobyns, Abigail E; Beck, Hailey L; Kurtzman, James T; Garfield, Robert E; Kirby, Michael A

    2013-01-01

    A decline in serum progesterone or antagonism of progesterone receptor function results in preterm labor and birth. Whether characteristics of premature remodeling of the cervix after antiprogestins or ovariectomy are similar to that at term was the focus of the present study. Groups of pregnant rats were treated with vehicle, a progesterone receptor antagonist (onapristone or mifepristone), or ovariectomized on day 17 postbreeding. As expected, controls given vehicle delivered at term while rats delivered preterm after progesterone receptor antagonist treatment or ovariectomy. Similar to the cervix before term, the preterm cervix of progesterone receptor antagonist-treated rats was characterized by reduced cell nuclei density, decreased collagen content and structure, as well as a greater presence of macrophages per unit area. Thus, loss of nuclear progesterone receptor-mediated actions promoted structural remodeling of the cervix, increased census of resident macrophages, and preterm birth much like that found in the cervix at term. In contrast to the progesterone receptor antagonist-induced advance in characteristics associated with remodeling, ovariectomy-induced loss of systemic progesterone did not affect hypertrophy, extracellular collagen, or macrophage numbers in the cervix. Thus, the structure and macrophage census in the cervix appear sufficient for premature ripening and birth to occur well before term. With progesterone receptors predominantly localized on cells other than macrophages, the findings suggest that interactions between cells may facilitate the loss of progesterone receptor-mediated actions as part of a final common mechanism that remodels the cervix in certain etiologies of preterm and with parturition at term.

  16. Exercise training does not improve cardiac function in compensated or decompensated left ventricular hypertrophy induced by aortic stenosis.

    Science.gov (United States)

    van Deel, Elza D; de Boer, Martine; Kuster, Diederik W; Boontje, Nicky M; Holemans, Patricia; Sipido, Karin R; van der Velden, Jolanda; Duncker, Dirk J

    2011-06-01

    There is ample evidence that regular exercise exerts beneficial effects on left ventricular (LV) hypertrophy, remodeling and dysfunction produced by ischemic heart disease or systemic hypertension. In contrast, the effects of exercise on pathological LV hypertrophy and dysfunction produced by LV outflow obstruction have not been studied to date. Consequently, we evaluated the effects of 8 weeks of voluntary wheel running in mice (which mitigates post-infarct LV dysfunction) on LV hypertrophy and dysfunction produced by mild (mTAC) and severe (sTAC) transverse aortic constriction. mTAC produced ~40% LV hypertrophy and increased myocardial expression of hypertrophy marker genes but did not affect LV function, SERCA2a protein levels, apoptosis or capillary density. Exercise had no effect on global LV hypertrophy and function in mTAC but increased interstitial collagen, and ANP expression. sTAC produced ~80% LV hypertrophy and further increased ANP expression and interstitial fibrosis and, in contrast with mTAC, also produced LV dilation, systolic as well as diastolic dysfunction, pulmonary congestion, apoptosis and capillary rarefaction and decreased SERCA2a and ryanodine receptor (RyR) protein levels. LV diastolic dysfunction was likely aggravated by elevated passive isometric force and Ca(2+)-sensitivity of myofilaments. Exercise training failed to mitigate the sTAC-induced LV hypertrophy and capillary rarefaction or the decreases in SERCA2a and RyR. Exercise attenuated the sTAC-induced increase in passive isometric force but did not affect myofilament Ca(2+)-sensitivity and tended to aggravate interstitial fibrosis. In conclusion, exercise had no effect on LV function in compensated and decompensated cardiac hypertrophy produced by LV outflow obstruction, suggesting that the effect of exercise on pathologic LV hypertrophy and dysfunction depends critically on the underlying cause. Copyright © 2011 Elsevier Ltd. All rights reserved.

  17. Effects of ventricular pacing-induced tachycardia on aortic mechanics in man.

    Science.gov (United States)

    Stefanadis, C; Dernellis, J; Vavuranakis, M; Tsiamis, E; Vlachopoulos, C; Toutouzas, K; Diamandopoulos, L; Pitsavos, C; Toutouzas, P

    1998-08-01

    Effects of pacing-induced tachycardia on left ventricular function have been studied extensively. However, little attention has been focused on aortic elastic properties during heart rate increments. The aim was to determine the effects of right ventricular pacing on the aortic elastic properties. We studied 14 normal subjects (baseline blood pressure, 129/84 +/- 10/6 mmHg; aortic diameter, 23.5/21.3 +/- 2.4/1.9 mm) at rest, during rapid right ventricular pacing (at five stepwise heart rate increases of 20 bpm every 2 min) and after 5 min recovery. Shifts as well as changes in the slope and the stiffness constant of the pressure diameter (p-d) relation, derived from simultaneous tip-micromanometer aortic pressure recordings and high-fidelity ultrasonic intravascular aortic diameter recordings, were used as indices of aortic stiffness. Wave reflection was also studied. Aortic pulse pressure and strain significantly decreased after pacing-induced tachycardia (p < 0.0001 and < 0.05, respectively). During pacing, the slope of the linear p-d relation as well as the stiffness constant were decreased, followed by increases at recovery (p < 0.0001). The augmentation index and the aortoventricular coupling ratio were significantly decreased (p < 0.0001). Pacing-induced increases in pulse frequency may result in improved aortic distensibility and aortoventricular coupling.

  18. Nanofibrous clinical-grade collagen scaffolds seeded with human cardiomyocytes induces cardiac remodeling in dilated cardiomyopathy.

    Science.gov (United States)

    Joanne, Pierre; Kitsara, Maria; Boitard, Solène-Emmanuelle; Naemetalla, Hany; Vanneaux, Valérie; Pernot, Mathieu; Larghero, Jérôme; Forest, Patricia; Chen, Yong; Menasché, Philippe; Agbulut, Onnik

    2016-02-01

    Limited data are available on the effects of stem cells in non-ischemic dilated cardiomyopathy (DCM). Since the diffuse nature of the disease calls for a broad distribution of cells, this study investigated the scaffold-based delivery of human induced pluripotent stem cell-derived cardiomyocytes (hiPS-CM) in a mouse model of DCM. Nanofibrous scaffolds were produced using a clinical grade atelocollagen which was electrospun and cross-linked under different conditions. As assessed by scanning electron microscopy and shearwave elastography, the optimum crosslinking conditions for hiPS-CM colonization proved to be a 10% concentration of citric acid crosslinking agent and 150 min of post-electrospinning baking. Acellular collagen scaffolds were first implanted in both healthy mice and those with induced DCM by a cardiac-specific invalidation of serum response factor (SRF). Seven and fourteen days after implantation, the safety of the scaffold was demonstrated by echocardiography and histological assessments. The subsequent step of implantation of the scaffolds seeded with hiPS-CM in DCM induced mice, using cell-free scaffolds as controls, revealed that after fourteen days heart function decreased in controls while it remained stable in the treated mice. This pattern was associated with an increased number of endothelial cells, in line with the greater vascularity of the scaffold. Moreover, a lesser degree of fibrosis consistent with the upregulation of several genes involved in extracellular matrix remodeling was observed. These results support the interest of the proposed hiPS-CM seeded electrospun scaffold for the stabilization of the DCM outcome with potential for its clinical use in the future. Copyright © 2015 Elsevier Ltd. All rights reserved.

  19. Role of epidermal growth factor receptor and endoplasmic reticulum stress in vascular remodeling induced by angiotensin II.

    Science.gov (United States)

    Takayanagi, Takehiko; Kawai, Tatsuo; Forrester, Steven J; Obama, Takashi; Tsuji, Toshiyuki; Fukuda, Yamato; Elliott, Katherine J; Tilley, Douglas G; Davisson, Robin L; Park, Joon-Young; Eguchi, Satoru

    2015-06-01

    The mechanisms by which angiotensin II (AngII) elevates blood pressure and enhances end-organ damage seem to be distinct. However, the signal transduction cascade by which AngII specifically mediates vascular remodeling such as medial hypertrophy and perivascular fibrosis remains incomplete. We have previously shown that AngII-induced epidermal growth factor receptor (EGFR) transactivation is mediated by disintegrin and metalloproteinase domain 17 (ADAM17), and that this signaling is required for vascular smooth muscle cell hypertrophy but not for contractile signaling in response to AngII. Recent studies have implicated endoplasmic reticulum (ER) stress in hypertension. Interestingly, EGFR is capable of inducing ER stress. The aim of this study was to test the hypothesis that activation of EGFR and ER stress are critical components required for vascular remodeling but not hypertension induced by AngII. Mice were infused with AngII for 2 weeks with or without treatment of EGFR inhibitor, erlotinib, or ER chaperone, 4-phenylbutyrate. AngII infusion induced vascular medial hypertrophy in the heart, kidney and aorta, and perivascular fibrosis in heart and kidney, cardiac hypertrophy, and hypertension. Treatment with erlotinib as well as 4-phenylbutyrate attenuated vascular remodeling and cardiac hypertrophy but not hypertension. In addition, AngII infusion enhanced ADAM17 expression, EGFR activation, and ER/oxidative stress in the vasculature, which were diminished in both erlotinib-treated and 4-phenylbutyrate-treated mice. ADAM17 induction and EGFR activation by AngII in vascular cells were also prevented by inhibition of EGFR or ER stress. In conclusion, AngII induces vascular remodeling by EGFR activation and ER stress via a signaling mechanism involving ADAM17 induction independent of hypertension. © 2015 American Heart Association, Inc.

  20. Modulation of chromatin remodelling induced by the freshwater cyanotoxin cylindrospermopsin in human intestinal caco-2 cells.

    Directory of Open Access Journals (Sweden)

    Antoine Huguet

    Full Text Available Cylindrospermopsin (CYN is a cyanotoxin that has been recognised as an emerging potential public health risk. Although CYN toxicity has been demonstrated, the mechanisms involved have not been fully characterised. To identify some key pathways related to this toxicity, we studied the transcriptomic profile of human intestinal Caco-2 cells exposed to a sub-toxic concentration of CYN (1.6 µM for 24hrs using a non-targeted approach. CYN was shown to modulate different biological functions which were related to growth arrest (with down-regulation of cdkn1a and uhrf1 genes, and DNA recombination and repair (with up-regulation of aptx and pms2 genes. Our main results reported an increased expression of some histone-modifying enzymes (histone acetyl and methyltransferases MYST1, KAT5 and EHMT2 involved in chromatin remodelling, which is essential for initiating transcription. We also detected greater levels of acetylated histone H2A (Lys5 and dimethylated histone H3 (Lys4, two products of these enzymes. In conclusion, CYN overexpressed proteins involved in DNA damage repair and transcription, including modifications of nucleosomal histones. Our results highlighted some new cell processes induced by CYN.

  1. Stunning and Right Ventricular Dysfunction Is Induced by Coronary Balloon Occlusion and Rapid Pacing in Humans: Insights From Right Ventricular Conductance Catheter Studies.

    Science.gov (United States)

    Axell, Richard G; Giblett, Joel P; White, Paul A; Klein, Andrew; Hampton-Til, James; O'Sullivan, Michael; Braganza, Denise; Davies, William R; West, Nick E J; Densem, Cameron G; Hoole, Stephen P

    2017-06-06

    We sought to determine whether right ventricular stunning could be detected after supply (during coronary balloon occlusion [BO]) and supply/demand ischemia (induced by rapid pacing [RP] during transcatheter aortic valve replacement) in humans. Ten subjects with single-vessel right coronary artery disease undergoing percutaneous coronary intervention with normal ventricular function were studied in the BO group. Ten subjects undergoing transfemoral transcatheter aortic valve replacement were studied in the RP group. In both, a conductance catheter was placed into the right ventricle, and pressure volume loops were recorded at baseline and for intervals over 15 minutes after a low-pressure BO for 1 minute or a cumulative duration of RP for up to 1 minute. Ischemia-induced diastolic dysfunction was seen 1 minute after RP (end-diastolic pressure [mm Hg]: 8.1±4.2 versus 12.1±4.1, P right coronary artery balloon occlusion both cause ischemic right ventricular dysfunction with stunning observed later during the procedure. This may have intraoperative implications in patients without right ventricular functional reserve. © 2017 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley.

  2. Amiodarone-induced exudative bullous lesion and hepatotoxicity in a patient with ventricular tachycardia

    Directory of Open Access Journals (Sweden)

    Ahmet Karakurt

    2015-09-01

    Full Text Available Amiodarone is a potent, iodine rich, highly lipophilic class III antiarrhythmic drug widely used for the management of both supraventricular and ventricular arrhythmias. It tends to concentrate in tissues including fat, lung, liver cornea and skin. Several side effects have been reported in patients taking amiodarone. The mechanisms of amiodarone-induced side effects are poorly understood. Accumulation of amiodarone in tissues and organs has been suggested as a possible mechanism. The most frequent dermatologic side effects are photosensitivity, skin discoloration and erythema. This article presents the case of a patient who developed amiodarone-induced bullous skin lesions and hepatotoxicity.

  3. Cancer induces cardiomyocyte remodeling and hypoinnervation in the left ventricle of the mouse heart.

    Directory of Open Access Journals (Sweden)

    Christian Mühlfeld

    Full Text Available Cancer is often associated with cachexia, cardiovascular symptoms and autonomic dysregulation. We tested whether extracardiac cancer directly affects the innervation of left ventricular myocardium. Mice injected with Lewis lung carcinoma cells (tumor group, TG or PBS (control group, CG were analyzed after 21 days. Cardiac function (echocardiography, serum levels of TNF-α and Il-6 (ELISA, structural alterations of cardiomyocytes and their innervation (design-based stereology and levels of innervation-related mRNA (quantitative RT-PCR were analysed. The groups did not differ in various functional parameters. Serum levels of TNF-α and Il-6 were elevated in TG. The total length of axons in the left ventricle was reduced. The number of dense core vesicles per axon profile was reduced. Decreased myofibrillar volume, increased sarcoplasmic volume and increased volume of lipid droplets were indicative of metabolic alterations of TG cardiomyocytes. In the heart, the mRNA level of nerve growth factor was reduced whereas that of β1-adrenergic receptor was unchanged in TG. In the stellate ganglion of TG, mRNA levels of nerve growth factor and neuropeptide Y were decreased and that of tyrosine hydroxylase was increased. In summary, cancer induces a systemic pro-inflammatory state, a significant reduction in myocardial innervation and a catabolic phenotype of cardiomyocytes in the mouse. Reduced expression of nerve growth factor may account for the reduced myocardial innervation.

  4. Taser-induced rapid ventricular myocardial capture demonstrated by pacemaker intracardiac electrograms.

    Science.gov (United States)

    Cao, Michael; Shinbane, Jerold S; Gillberg, Jeffrey M; Saxon, Leslie A; Swerdlow, Charles D

    2007-08-01

    A Taser weapon is designed to incapacitate violent individuals by causing temporary neuromuscular paralysis due to current application. We report the first case of a Taser application in a person with a dual-chamber pacemaker demonstrating evidence of Taser-induced myocardial capture. Device interrogation was performed in a 53-year-old man with a dual-chamber pacemaker who had received a Taser shot consisting of two barbs delivered simultaneously. Assessment of pacemaker function after Taser application demonstrated normal sensing, pacing thresholds, and lead impedances. Stored event data revealed two high ventricular rate episodes corresponding to the exact time of the Taser application. This report describes the first human case of ventricular myocardial capture at a rapid rate resulting from a Taser application. This raises the issue as to whether conducted energy devices can cause primary myocardial capture or capture only in association with cardiac devices providing a preferential pathway of conduction to the myocardium.

  5. Reduced Sodium Current in the Lateral Ventricular Wall Induces Inferolateral J-Waves.

    Science.gov (United States)

    Meijborg, Veronique M F; Potse, Mark; Conrath, Chantal E; Belterman, Charly N W; De Bakker, Jacques M T; Coronel, Ruben

    2016-01-01

    J-waves in inferolateral leads are associated with a higher risk for idiopathic ventricular fibrillation. We aimed to test potential mechanisms (depolarization or repolarization dependent) responsible for inferolateral J-waves. We hypothesized that inferolateral J-waves can be caused by regional delayed activation of myocardium that is activated late during normal conditions. Computer simulations were performed to evaluate how J-point elevation is influenced by reducing sodium current conductivity (GNa), increasing transient outward current conductivity (Gto), or cellular uncoupling in three predefined ventricular regions (lateral, anterior, or septal). Two pig hearts were Langendorff-perfused with selective perfusion with a sodium channel blocker of lateral or anterior/septal regions. Volume-conducted pseudo-electrocardiograms (ECG) were recorded to detect the presence of J-waves. Epicardial unipolar electrograms were simultaneously recorded to obtain activation times (AT). Simulation data showed that conduction slowing, caused by reduced sodium current, in lateral, but not in other regions induced inferolateral J-waves. An increase in transient outward potassium current or cellular uncoupling in the lateral zone elicited slight J-point elevations which did not meet J-wave criteria. Additional conduction slowing in the entire heart attenuated J-waves and J-point elevations on the ECG, because of masking by the QRS. Experimental data confirmed that conduction slowing attributed to sodium channel blockade in the left lateral but not in the anterior/septal ventricular region induced inferolateral J-waves. J-waves coincided with the delayed activation. Reduced sodium current in the left lateral ventricular myocardium can cause inferolateral J-waves on the ECG.

  6. Reduced sodium current in the lateral ventricular wall induces inferolateral J-waves

    Directory of Open Access Journals (Sweden)

    Veronique Marlinde Frederica Meijborg

    2016-08-01

    Full Text Available Background: J-waves in inferolateral leads are associated with a higher risk for idiopathic ventricular fibrillation. We aimed to test potential mechanisms (depolarization or repolarization dependent responsible for inferolateral J-waves. We hypothesized that inferolateral J-waves can be caused by regional delayed activation of myocardium that is activated late during normal conditions. Methods: Computer simulations were performed to evaluate how J-point elevation is influenced by reducing sodium current conductivity (GNa, increasing transient outward current conductivity (Gto or cellular uncoupling in three predefined ventricular regions (lateral, anterior or septal. Two pig hearts were Langendorff-perfused with selective perfusion with a sodium channel blocker of lateral or anterior/septal regions. Volume-conducted pseudo-electrocardiograms (ECG were recorded to detect the presence of J-waves. Epicardial unipolar electrograms were simultaneously recorded to obtain activation times (AT.Results: Simulation data showed that conduction slowing, caused by reduced sodium current, in lateral, but not in other regions induced inferolateral J-waves. An increase in transient outward potassium current or cellular uncoupling in the lateral zone elicited slight J-point elevations which did not meet J-wave criteria. Additional conduction slowing in the entire heart attenuated J-waves and J-point elevations on the ECG, because of masking by the QRS. Experimental data confirmed that conduction slowing attributed to sodium channel blockade in the left lateral but not in the anterior/septal ventricular region induced inferolateral J-waves. J-waves coincided with the delayed activation.Conclusion: Reduced sodium current in the left lateral ventricular myocardium can cause inferolateral J-waves on the ECG.

  7. Does surgically induced right bundle branch block really effect ventricular function in children after ventricular septal defect closure?

    Science.gov (United States)

    Karadeniz, Cem; Atalay, Semra; Demir, Fikri; Tutar, Ercan; Ciftci, Omer; Ucar, Tayfun; Uysalel, Adnan; Eyileten, Zeynep

    2015-03-01

    In this prospective study, we aimed to assess left and right ventricular function in terms of the presence of right bundle branch block (RBBB) in the cases with repaired ventricular septal defect (VSD). Fifty-three patients who had VSD surgery at least 1-year preceding admission and 52 healthy controls were enrolled into the study. All the participants underwent electrocardiographic and echocardiographic examination. The cases with RBBB were determined. The conventional and tissue Doppler echocardiographic measurements of the patients with and without RBBB were compared with each other and healthy controls. Twenty-eight of VSD repair groups were male and 25 were female. Control group consisted of 30 males and 22 females. The mean age of the study and control groups was 7.5 ± 5.0 and 6.9 ± 4.3 years, respectively. RBBB was detected in 20 of 53 (37.7 %) operated patients. The only significant difference between the cases with and without RBBB was decreased right ventricular fractional area change (%) in the former group (33 ± 7 vs. 39 ± 5 p < 0.05). When compared to controls, operated group had statistically lower [corrected] tricuspid annular plane systolic excursion (p < 0.05), lower systolic, early diastolic, and late diastolic myocardial velocities, higher left and right ventricular myocardial performance indices, irrespective of the presence of RBBB. The ratios of mitral or tricuspid inflow to left or right ventricular myocardial in early diastolic velocities measured from lateral annular levels were increased in operated group (all p values <0.05). In conclusion, RBBB in the cases with surgical VSD repair might be associated with right ventricular dysfunction. Biventricular systolic and diastolic dysfunction may develop following VSD repair irrespective of the presence of RBBB. Tissue Doppler-derived myocardial performance indices are useful in detection of those subclinical dysfunctions.

  8. Does diabetes mellitus-induced bladder remodeling affect lower urinary tract function? ICI-RS 2011.

    Science.gov (United States)

    Kirschner-Hermanns, Ruth; Daneshgari, Firouz; Vahabi, Bahareh; Birder, Lori; Oelke, Matthias; Chacko, Samuel

    2012-03-01

    Due to an increase in aging population and changing eating habits diabetes mellitus (DM) type II is a rapidly increasing condition worldwide. Although not so detrimental as other co-morbidities, uropathy contributes to a significantly reduced quality-of-life in those affected. The purpose of this ICS-RS report is to highlight clinical and basic research data to outline directions for further research and possible treatment approaches. This report is based on a think tank presentation and discussion at the ICI-RS 2011, original research data and literature research. Clinical and experimental data confirm that detrusor overactivity, both neurogenic and myogenic, and changes in transmitter regulation leading to a hyper- excitability of the detrusor are the major findings in diabetic neuropathic bladders. These findings seem to be related to an earlier stage of DM, whereas detrusor underactivity appears to be linked to later stages of DM. Detrusor smooth muscle cells seem to be modulated directly by hyperglycemia. Data support the theory that hyperglycemia-induced oxidative stress in the detrusor smooth muscle and that micro- and macrovascular events are also responsible for urologic complications of DM. DM causes bladder remodelling leading to uropathy in a mulitfactorial way. Future research should focus on the effects of DM as a function of time and develop novel animal models looking at defined aspects as well as interaction of different aspects- such as oxidative stress in neurogenic, myogenic and urothelial components and the role of inflammation and hypoxia caused by vascular complications. Copyright © 2012 Wiley Periodicals, Inc.

  9. Impact of marked weight loss induced by bariatric surgery on bone mineral density and remodeling

    Directory of Open Access Journals (Sweden)

    F.A. Pereira

    2007-04-01

    Full Text Available Data about the impact of bariatric surgery (BS and subsequent weight loss on bone are limited. The objective of the present study was to determine bone mineral density (BMD, bone remodeling metabolites and hormones that influence bone trophism in premenopausal women submitted to BS 9.8 months, on average, before the study (OGg, N = 16. The data were compared to those obtained for women of normal weight (CG, N = 11 and for obese women (OG, N = 12. Eight patients in each group were monitored for one year, with the determination of BMD, of serum calcium, phosphorus, magnesium, parathyroid hormone, 25-hydroxyvitamin D, insulin-like growth factor-I (IGF-I and osteocalcin, and of urinary calcium and deoxypyridinoline. The biochemical determinations were repeated every three months in the longitudinal study and BMD was measured at the end of the study. Parathyroid hormone levels were similar in the three groups. IGF-I levels (CG = 332 ± 62 vs OG = 230 ± 37 vs OGg = 128 ± 19 ng/mL were significantly lower in the operated patients compared to the non-operated obese women. Only OGg patients presented a significant fall in BMD of 6.2% at L1-L4, of 10.2% in the femoral neck, and of 5.1% in the forearm. These results suggest that the weight loss induced by BS is associated with a significant loss of bone mass even at sites that are not influenced by weight overload, with hormonal factors such as IGF-I being associated with this process.

  10. Recurrent left atrial and left ventricular thrombosis due to heparin-induced thrombocytopenia: case report and short review.

    Science.gov (United States)

    Kuhl, Thomas; Wendt, Stefanie; Langebartels, Georg; Kröner, Axel; Wahlers, Thorsten

    2013-09-01

    The combination of heparin-induced thrombocytopenia (HIT) II, left ventricular failure with extracorporeal membrane oxygenation (ECMO) therapy, and recurrent left ventricular thrombosis is rare and predicts a poor outcome. In this case, HIT II occurred after an ischemic cardiogenic shock. We initiated ECMO and intra-aortic balloon pump therapy during coronary artery bypass grafting and ventricular thrombectomy. Despite continued therapeutic therapy with heparin and later argatroban, the patient developed solid and recurrent thrombotic masses in the left atrium and left ventricle. Georg Thieme Verlag KG Stuttgart · New York.

  11. Fluid loading and norepinephrine infusion mask the left ventricular preload decrease induced by pleural effusion.

    Science.gov (United States)

    Wemmelund, Kristian Borup; Ringgård, Viktor Kromann; Vistisen, Simon Tilma; Hyldebrandt, Janus Adler; Sloth, Erik; Juhl-Olsen, Peter

    2017-09-11

    Pleural effusion (PLE) may lead to low blood pressure and reduced cardiac output. Low blood pressure and reduced cardiac output are often treated with fluid loading and vasopressors. This study aimed to determine the impact of fluid loading and norepinephrine infusion on physiologic determinants of cardiac function obtained by ultrasonography during PLE. In this randomised, blinded, controlled laboratory study, 30 piglets (21.9 ± 1.3 kg) had bilateral PLE (75 mL/kg) induced. Subsequently, the piglets were randomised to intervention as follows: fluid loading (80 mL/kg/h for 1.5 h, n = 12), norepinephrine infusion (0.01, 0.03, 0.05, 0.1, 0.2 and 0.3 μg/kg/min (15 min each, n = 12)) or control (n = 6). Main outcome was left ventricular preload measured as left ventricular end-diastolic area. Secondary endpoints included contractility and afterload as well as global measures of circulation. All endpoints were assessed with echocardiography and invasive pressure-flow measurements. PLE decreased left ventricular end-diastolic area, mean arterial pressure and cardiac output (p values  0.05) to baseline. Left ventricular contractility increased with norepinephrine infusion (p = 0.002), but was not affected by fluid loading (p = 0.903). Afterload increased in both active groups (p values > 0.001). Overall, inferior vena cava distensibility remained unchanged during intervention (p values ≥ 0.085). Evacuation of PLE caused numerical increases in left ventricular end-diastolic area, but only significantly so in controls (p = 0.006). PLE significantly reduced left ventricular preload. Both fluid and norepinephrine treatment reverted this effect and normalised global haemodynamic parameters. Inferior vena cava distensibility remained unchanged. The haemodynamic significance of PLE may be underestimated during fluid or norepinephrine administration, potentially masking the presence of PLE.

  12. Identifying and Managing Premature Ventricular Contraction-Induced Cardiomyopathy: What, Why, and How?

    Science.gov (United States)

    Alqarawi, Wael A; Ramirez, F Daniel; Nery, Pablo B; Redpath, Calum J; Sadek, Mouhannad M; Green, Martin S; Birnie, David H; Nair, Girish M

    2017-02-01

    Premature ventricular contraction (PVC)-induced cardiomyopathy is increasingly being recognized as a reversible cause of left ventricular (LV) systolic dysfunction (LVSD). The diagnosis of PVC-induced cardiomyopathy is considered in subjects with high PVC burdens (> 10,000 per 24 hours) after excluding other known causes of LVSD. PVC suppression is the mainstay of the management of PVC-induced cardiomyopathy, in addition to proven evidence-based medical therapy recommended for subjects with LVSD. Management strategies for PVC-induced cardiomyopathy include medical therapy and/or catheter ablation, with an increasing role for catheter ablation as a first-line therapy in view of the potential for permanent suppression of PVCs. Recovery of LVSD is typically a gradual process over months after effective suppression of PVCs. Last, asymptomatic patients with high PVC burdens and preserved LV systolic function appear to be at low risk over the intermediate term for developing LVSD. However, it is prudent to monitor LV function periodically because of the potential for deterioration of LV function observed during long-term follow-up in some subjects. Copyright © 2016 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.

  13. Effects of L-carnitine administration on left ventricular remodeling after acute anterior myocardial infarction: The L-carnitine Ecocardiografia Digitalizzata Infarto Miocardico (CEDIM) trial

    NARCIS (Netherlands)

    S. Iliceto (Sabino); D. Scrutinio (Domenico); P. Bruzzi (P.); G. D'Ambrosio (Gaetano); A. Boni (Alejandro); M. Di Biase (Matteo); G. Biasco (Giuseppina); P.G. Hugenholtz (Paul); P. Rizzon (Paolo)

    1995-01-01

    textabstractObjectives. This study was performed to evaluate the effects of l-carnitine administration on long-term left ventricular dilation in patients with acute anterior myocardial infarction. Background. Carnitine is a physiologic compound that performs an essential role in myocardial energy

  14. Effects of a timely therapy with doxycycline on the left ventricular remodeling according to the pre-procedural TIMI flow grade in patients with ST-elevation acute myocardial infarction.

    Science.gov (United States)

    Cerisano, Giampaolo; Buonamici, Piergiovanni; Valenti, Renato; Moschi, Guia; Taddeucci, Enrico; Giurlani, Letizia; Migliorini, Angela; Vergara, Ruben; Parodi, Guido; Sciagrà, Roberto; Romito, Roberta; Colonna, Paolo; Antoniucci, David

    2014-07-01

    Doxycycline has been demonstrated to reduced left ventricular (LV) remodeling, but its effect in patients with ST-elevation myocardial infarction (STEMI) and a baseline occluded [thrombolysis in myocardial infarction (TIMI) flow grade ≤1] infarct-related artery (IRA) is unknown. According to the baseline TIMI flow grade, 110 patients with a first STEMI were divided into 2 groups. Group 1: 77 patients with TIMI flow ≤1 (40 patients treated with doxycycline and 37 with standard therapy, respectively), and a Group 2: 33 patients with TIMI flow 2-3 (15 patients treated with doxycycline and 18 with standard therapy, respectively). The two randomized groups were well matched in baseline characteristics. A 2D-Echo was performed at baseline and at 6 months, together with a coronary angiography, for the remodeling and IRA patency assessment, respectively. The LV end-diastolic volume index (LVEDVi) decreased in Group 2 [-3 mL/m(2) (IQR: -12 to 4 mL/m(2))], and increased in Group 1 [6 mL/m(2) (IQR: -2 to 14 mL/m(2))], (p = 0.001). In Group 2, LVEDVi reduction was similar regardless of drug therapy, while in Group 1 the LVEDVi was smaller in patients treated with doxycycline as compared to control [3 mL/m(2) (IQR: -3 to 8 mL/m(2)) vs. 10 mL/m(2) (IQR: 1-27 mL/m(2)), p = 0.006]. A similar pattern was observed also for LV end-systolic volume and ejection fraction. In STEMI patients at higher risk, as those with a baseline TIMI flow grade ≤1, doxycycline reduces LV remodeling.

  15. Heart Rate Reduction With Ivabradine Protects Against Left Ventricular Remodeling by Attenuating Infarct Expansion and Preserving Remote-Zone Contractile Function and Synchrony in a Mouse Model of Reperfused Myocardial Infarction.

    Science.gov (United States)

    O'Connor, Daniel M; Smith, Robert S; Piras, Bryan A; Beyers, Ronald J; Lin, Dan; Hossack, John A; French, Brent A

    2016-04-22

    Ivabradine selectively inhibits the pacemaker current of the sinoatrial node, slowing heart rate. Few studies have examined the effects of ivabradine on the mechanical properties of the heart after reperfused myocardial infarction (MI). Advances in ultrasound speckle-tracking allow strain analyses to be performed in small-animal models, enabling the assessment of regional mechanical function. After 1 hour of coronary occlusion followed by reperfusion, mice received 10 mg/kg per day of ivabradine dissolved in drinking water (n=10), or were treated as infarcted controls (n=9). Three-dimensional high-frequency echocardiography was performed at baseline and at days 2, 7, 14, and 28 post-MI. Speckle-tracking software was used to calculate intramural longitudinal myocardial strain (Ell) and strain rate. Standard deviation time to peak radial strain (SD Tpeak Err) and temporal uniformity of strain were calculated from short-axis cines acquired in the left ventricular remote zone. Ivabradine reduced heart rate by 8% to 16% over the course of 28 days compared to controls (Pleft ventricular remodeling and dyssynchrony, as well as improved mechanical performance in remote myocardium after heart rate reduction with ivabradine. © 2016 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell.

  16. Loss of progesterone receptor-mediated actions induce preterm cellular and structural remodeling of the cervix and premature birth.

    Directory of Open Access Journals (Sweden)

    Steven M Yellon

    Full Text Available A decline in serum progesterone or antagonism of progesterone receptor function results in preterm labor and birth. Whether characteristics of premature remodeling of the cervix after antiprogestins or ovariectomy are similar to that at term was the focus of the present study. Groups of pregnant rats were treated with vehicle, a progesterone receptor antagonist (onapristone or mifepristone, or ovariectomized on day 17 postbreeding. As expected, controls given vehicle delivered at term while rats delivered preterm after progesterone receptor antagonist treatment or ovariectomy. Similar to the cervix before term, the preterm cervix of progesterone receptor antagonist-treated rats was characterized by reduced cell nuclei density, decreased collagen content and structure, as well as a greater presence of macrophages per unit area. Thus, loss of nuclear progesterone receptor-mediated actions promoted structural remodeling of the cervix, increased census of resident macrophages, and preterm birth much like that found in the cervix at term. In contrast to the progesterone receptor antagonist-induced advance in characteristics associated with remodeling, ovariectomy-induced loss of systemic progesterone did not affect hypertrophy, extracellular collagen, or macrophage numbers in the cervix. Thus, the structure and macrophage census in the cervix appear sufficient for premature ripening and birth to occur well before term. With progesterone receptors predominantly localized on cells other than macrophages, the findings suggest that interactions between cells may facilitate the loss of progesterone receptor-mediated actions as part of a final common mechanism that remodels the cervix in certain etiologies of preterm and with parturition at term.

  17. Effects of L-carnitine administration on left ventricular remodeling after acute anterior myocardial infarction: the L-Carnitine Ecocardiografia Digitalizzata Infarto Miocardico (CEDIM) Trial.

    Science.gov (United States)

    Iliceto, S; Scrutinio, D; Bruzzi, P; D'Ambrosio, G; Boni, L; Di Biase, M; Biasco, G; Hugenholtz, P G; Rizzon, P

    1995-08-01

    This study was performed to evaluate the effects of L-carnitine administration on long-term left ventricular dilation in patients with acute anterior myocardial infarction. Carnitine is a physiologic compound that performs an essential role in myocardial energy production at the mitochondrial level. Myocardial carnitine deprivation occurs during ischemia, acute myocardial infarction and cardiac failure. Experimental studies have suggested that exogenous carnitine administration during these events has a beneficial effect on function. The L-Carnitine Ecocardiografia Digitalizzata Infarto Miocardico (CEDIM) trial was a randomized, double-blind, placebo-controlled, multicenter trial in which 472 patients with a first acute myocardial infarction and high quality two-dimensional echocardiograms received either placebo (239 patients) or L-carnitine (233 patients) within 24 h of onset of chest pain. Placebo or L-carnitine was given at a dose of 9 g/day intravenously for the first 5 days and then 6 g/day orally for the next 12 months. Left ventricular volumes and ejection fraction were evaluated on admission, at discharge from hospital and at 3, 6 and 12 months after acute myocardial infarction. A significant attenuation of left ventricular dilation in the first year after acute myocardial infarction was observed in patients treated with L-carnitine compared with those receiving placebo. The percent increase in both end-diastolic and end-systolic volumes from admission to 3-, 6- and 12-month evaluation was significantly reduced in the L-carnitine group. No significant differences were observed in left ventricular ejection fraction changes over time in the two groups. Although not designed to demonstrate differences in clinical end points, the combined incidence of death and congestive heart failure after discharge was 14 (6%) in the L-carnitine treatment group versus 23 (9.6%) in the placebo group (p = NS). Incidence of ischemic events during follow-up was similar in the

  18. Mesoscale computational studies of membrane bilayer remodeling by curvature-inducing proteins

    Energy Technology Data Exchange (ETDEWEB)

    Ramakrishnan, N., E-mail: ramn@seas.upenn.edu [Department of Chemical and Biomolecular Engineering, University of Pennsylvania, Philadelphia, PA-19104 (United States); Department of Bioengineering, University of Pennsylvania, Philadelphia, PA-19104 (United States); Department of Biochemistry and Biophysics, University of Pennsylvania, Philadelphia, PA-19104 (United States); Sunil Kumar, P.B., E-mail: sunil@physics.iitm.ac.in [Department of Physics, Indian Institute of Technology Madras, Chennai, 600036 (India); Radhakrishnan, Ravi, E-mail: rradhak@seas.upenn.edu [Department of Chemical and Biomolecular Engineering, University of Pennsylvania, Philadelphia, PA-19104 (United States); Department of Bioengineering, University of Pennsylvania, Philadelphia, PA-19104 (United States); Department of Biochemistry and Biophysics, University of Pennsylvania, Philadelphia, PA-19104 (United States)

    2014-10-01

    Biological membranes constitute boundaries of cells and cell organelles. These membranes are soft fluid interfaces whose thermodynamic states are dictated by bending moduli, induced curvature fields, and thermal fluctuations. Recently, there has been a flood of experimental evidence highlighting active roles for these structures in many cellular processes ranging from trafficking of cargo to cell motility. It is believed that the local membrane curvature, which is continuously altered due to its interactions with myriad proteins and other macromolecules attached to its surface, holds the key to the emergent functionality in these cellular processes. Mechanisms at the atomic scale are dictated by protein–lipid interaction strength, lipid composition, lipid distribution in the vicinity of the protein, shape and amino acid composition of the protein, and its amino acid contents. The specificity of molecular interactions together with the cooperativity of multiple proteins induce and stabilize complex membrane shapes at the mesoscale. These shapes span a wide spectrum ranging from the spherical plasma membrane to the complex cisternae of the Golgi apparatus. Mapping the relation between the protein-induced deformations at the molecular scale and the resulting mesoscale morphologies is key to bridging cellular experiments across various length scales. In this review, we focus on the theoretical and computational methods used to understand the phenomenology underlying protein-driven membrane remodeling. Interactions at the molecular scale can be computationally probed by all atom and coarse grained molecular dynamics (MD, CGMD), as well as dissipative particle dynamics (DPD) simulations, which we only describe in passing. We choose to focus on several continuum approaches extending the Canham–Helfrich elastic energy model for membranes to include the effect of curvature-inducing proteins and explore the conformational phase space of such systems. In this description

  19. Arginase inhibition prevents bleomycin-induced pulmonary hypertension, vascular remodeling, and collagen deposition in neonatal rat lungs.

    Science.gov (United States)

    Grasemann, Hartmut; Dhaliwal, Rupinder; Ivanovska, Julijana; Kantores, Crystal; McNamara, Patrick J; Scott, Jeremy A; Belik, Jaques; Jankov, Robert P

    2015-03-15

    Arginase is an enzyme that limits substrate L-arginine bioavailability for the production of nitric oxide by the nitric oxide synthases and produces L-ornithine, which is a precursor for collagen formation and tissue remodeling. We studied the pulmonary vascular effects of arginase inhibition in an established model of repeated systemic bleomycin sulfate administration in neonatal rats that results in pulmonary hypertension and lung injury mimicking the characteristics typical of bronchopulmonary dysplasia. We report that arginase expression is increased in the lungs of bleomycin-exposed neonatal rats and that treatment with the arginase inhibitor amino-2-borono-6-hexanoic acid prevented the bleomycin-induced development of pulmonary hypertension and deposition of collagen. Arginase inhibition resulted in increased L-arginine and L-arginine bioavailability and increased pulmonary nitric oxide production. Arginase inhibition also normalized the expression of inducible nitric oxide synthase, and reduced bleomycin-induced nitrative stress while having no effect on bleomycin-induced inflammation. Our data suggest that arginase is a promising target for therapeutic interventions in neonates aimed at preventing lung vascular remodeling and pulmonary hypertension. Copyright © 2015 the American Physiological Society.

  20. Rhinovirus infection induces expression of airway remodelling factors in vitro and in vivo

    NARCIS (Netherlands)

    Kuo, Curtis; Lim, Sam; King, Nicholas J C; Bartlett, Nathan W; Walton, Ross P; Zhu, Jie; Glanville, Nicholas; Aniscenko, Julia; Johnston, Sebastian L; Burgess, Janette K; Black, Judith L; Oliver, Brian G

    BACKGROUND AND OBJECTIVE: A hallmark of asthma is airway remodelling, which includes increased deposition of extracellular matrix (ECM) protein. Viral infections may promote the development of asthma and are the most common causes of asthma exacerbations. We evaluated whether rhinovirus (RV)

  1. Correlations of Serum Cyclophilin A and Melatonin Concentrations with Hypertension-induced Left Ventricular Hypertrophy.

    Science.gov (United States)

    Su, Hongyan; Chen, Tongshuai; Li, Jingyuan; Xiao, Jie; Wang, Shujian; Guo, Xiaobin; Bu, Peili

    2017-12-14

    Cyclophilin A (CyPA) is an abundantly expressed pro-inflammatory cytokine and a major secreted oxidative stress-induced factor (SOXF). Melatonin is an important chronobiological regulatory molecule that is mainly released from the pineal gland and exerts antioxidant effects by acting as a radical scavenger. Based on accumulating evidence, both CyPA and melatonin play important roles in cardiovascular diseases. However, further investigations are required to determine whether CyPA and melatonin are associated with hypertension-induced left ventricular hypertrophy (LVH). A total of 135 patients with essential hypertension were divided into an LVH (+) group and an LVH (-) group according to Doppler echocardiography results. Clinical data of the two groups were evaluated. High CyPA levels and low melatonin levels are independent risk factors for LVH (p = 0.000). In addition, body mass index (BMI) and systolic blood pressure (SBP) are correlated with the risk of LVH (p = 0.000). However, other factors did not display statistically significant associations (p >0.05). The Pearson correlation and linear regression analyses show that BMI, SBP, and CyPA levels were positively correlated with left ventricular mass (LVM) and the left ventricular mass index (LVMI) (p <0.05), whereas melatonin levels were negatively correlated with LVM and the LVMI (p = 0.000). Furthermore, according to the results of the Pearson correlation analysis, CyPA levels were negatively correlated with melatonin levels (p <0.01) in subjects with LVH. Based on these results, both CyPA and melatonin are closely related to the pathogenesis of LVH. As CyPA was negatively correlated with melatonin in patients with LVH, additional studies are required to determine whether melatonin may partially protect the myocardium by decreasing CyPA levels. Copyright © 2017 IMSS. Published by Elsevier Inc. All rights reserved.

  2. Role of Cytokine Hemoadsorption in Cardiopulmonary Bypass-Induced Ventricular Dysfunction in a Porcine Model

    Science.gov (United States)

    Vocelka, Craig R.; Jones, Krystal M.; Mikhova, Krasimira M.; Ebisu, Ryan M.; Shar, Ashley; Kellum, John A.; Verrier, Edward D.; Rabkin, David G.

    2013-01-01

    Abstract: Little is known about the effect of cardiopulmonary bypass alone on cardiac function; in an attempt to illuminate this relationship and test a possible mechanism, we used Cytosorb™, a device capable of removing virtually all types of circulating cytokines to test the hypothesis that hemoadsorption of cytokines during bypass attenuates bypass-induced acute organ dysfunction. Twelve Yorkshire pigs (50–65 kg) were instrumented with a left ventricular conductance catheter. Baseline mechanics and cytokine expression (tumor necrosis factor [TNF], interleukin-6 [IL-6], and interleukin-10) were measured before and hourly after 1 hour of normothermic cardiopulmonary bypass. Animals underwent bypass without (cardiopulmonary bypass [CPB], n = 6) or with (CPB+HA, n = 6) the Cytosorb™ device. Data were compared with “historical” controls (n = 6) that were similarly instrumented but underwent observation instead of bypass. Five hours after separation from bypass (or observation), animals were euthanized. Myocardial water content was determined postmortem. Neither TNF nor IL-6 was significantly elevated in either experimental group versus controls at any time point. Preload recruitable stroke work and dP/dtmax were significantly depressed immediately after separation from bypass in both CPB+HA and CPB and remained depressed for the duration of the experiment. Although Tau remained unchanged, dP/dTmin was significantly diminished in both bypass groups at all time points after separation from bypass. Cytokine hemoadsorption had no effect on any measurable index of function. Differences in postmortem data were not evident between groups. One hour of normothermic CPB results in a significant and sustained decline in left ventricular function that appears unrelated to changes in cytokine expression. Because we did not appreciate a significant change in cytokine concentrations postbypass, the capacity of cytokine hemoadsorption to attenuate CPB-induced ventricular

  3. The Impact of Distal Stent Graft-Induced New Entry on Aortic Remodeling of Chronic Type B Dissection.

    Science.gov (United States)

    Huang, Chun-Yang; Hsu, Hung-Lung; Chen, Po-Lin; Chen, I-Ming; Hsu, Chiao-Po; Shih, Chun-Che

    2017-12-01

    In chronic type B aortic dissection, late distal stent graft-induced new entry (SINE) has a possible negative role in long-term aortic remodeling. This study aimed to investigate the impact of SINE occurrence on survival by evaluating true and false lumen remodeling in thoracic and abdominal segments at midterm surveillance. This study enrolled 65 patients with chronic type B aortic dissection (DeBakey type IIIb), who had received hybrid thoracic endovascular aortic repair (TEVAR) and had completed surveillance for at least 3 years. The 3-year survival rate was 84.7%. The patients were classified into non-SINE (n = 47) and SINE (n = 18) groups. Serial computed tomography scans were used to analyze volumetric change, true and false lumens, and thrombus volume from arch to aortic bifurcation level. The SINE event occurred at a median of 22.5 months. In the SINE group, there was a significant interruption of the abdominal true lumen expansion in the second year (median 0.01 [interquartile range (IQR), -0.03 to 0.12] in the non-SINE group versus median -0.04 [IQR, -0.12 to 0.04] in the SINE group; p = 0.014). There was a significantly worse thoracic false lumen remodeling in the SINE group compared with the non-SINE group in the third year after the SINE event occurred (median 0 [IQR, -0.09 to 0.05] in the non-SINE group versus median 0.06 [IQR, 0 to 0.13] in the SINE group; p = 0.038). For chronic aortic dissection, late occurrence of distal SINE could influence abdominal true lumen expansion and thoracic false lumen shrinkage. Early reintervention for distal SINE could improve aortic remodeling in chronic aortic dissection. Copyright © 2017 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.

  4. Recovery of cardiomyopathy induced by ventricular premature beats of paraHisian origin after successful radiofrequency catheter ablation.

    Science.gov (United States)

    Aksan, Gökhan; Elitok, Ali; Tezcan, Mehmet; Bilge, Ahmet Kaya; Adalet, Kamil

    2017-12-01

    A 51-year-old male patient presented with frequent and symptomatic premature ventricular complexes (PVCs) that had induced cardiomyopathy. Radiofrequency (RF) catheter ablation of the origin of the PVCs was planned and the patient underwent electrophysiological study. During activation mapping, the earliest ventricular activation was identified at the His bundle region. Small His bundle electrogram recording by the distal ablation electrode during sinus rhythm revealed that the earliest ventricular activation during PVC preceded the QRS onset by 58 milliseconds. The PVCs were successfully eliminated without occurrence of atrioventricular block using incremental application of RF energy to the para-Hisian region. At the conclusion of a 5-month follow-up period, the patient remained asymptomatic and transthoracic echocardiography demonstrated an improvement in left ventricular ejection fraction.

  5. Left atrial remodelling in patients with myocardial infarction complicated by heart failure, left ventricular dysfunction, or both: the VALIANT Echo study

    DEFF Research Database (Denmark)

    Meris, Alessandra; Amigoni, Maria; Uno, Hajime

    2009-01-01

    (LV) dysfunction, heart failure (HF), or both following MI. We assessed LA volume indexed to body surface area (LAVi) at baseline, 1 month, and 20 months after MI. Baseline LAVi was an independent predictor of all-cause death or HF hospitalization (P = 0.004). In patients who survived to 20 months......, LAVi increased a mean of 3.00 +/- 7.08 mL/m(2) from baseline. Hypertension, lower estimated glomerular filtration rate, and LV mass were the only baseline independent predictors of LA remodelling. Changes in LA size were related to worsening in MR and increasing in LV volumes. LA enlargement during...

  6. Alterations in left ventricular diastolic function in conscious dogs with pacing-induced heart failure

    Science.gov (United States)

    Komamura, K.; Shannon, R. P.; Pasipoularides, A.; Ihara, T.; Lader, A. S.; Patrick, T. A.; Bishop, S. P.; Vatner, S. F.

    1992-01-01

    We investigated in conscious dogs (a) the effects of heart failure induced by chronic rapid ventricular pacing on the sequence of development of left ventricular (LV) diastolic versus systolic dysfunction and (b) whether the changes were load dependent or secondary to alterations in structure. LV systolic and diastolic dysfunction were evident within 24 h after initiation of pacing and occurred in parallel over 3 wk. LV systolic function was reduced at 3 wk, i.e., peak LV dP/dt fell by -1,327 +/- 105 mmHg/s and ejection fraction by -22 +/- 2%. LV diastolic dysfunction also progressed over 3 wk of pacing, i.e., tau increased by +14.0 +/- 2.8 ms and the myocardial stiffness constant by +6.5 +/- 1.4, whereas LV chamber stiffness did not change. These alterations were associated with increases in LV end-systolic (+28.6 +/- 5.7 g/cm2) and LV end-diastolic stresses (+40.4 +/- 5.3 g/cm2). When stresses and heart rate were matched at the same levels in the control and failure states, the increases in tau and myocardial stiffness were no longer observed, whereas LV systolic function remained depressed. There were no increases in connective tissue content in heart failure. Thus, pacing-induced heart failure in conscious dogs is characterized by major alterations in diastolic function which are reversible with normalization of increased loading condition.

  7. Uni- or bi-ventricular hypertrophy and susceptibility to drug-induced torsades de pointes.

    Science.gov (United States)

    Panyasing, Yaowalak; Kijtawornrat, Anusak; Del Rio, Carlos; Carnes, Cynthia; Hamlin, Robert L

    2010-01-01

    Cardiac hypertrophy is an independent risk factor for torsades de pointes (TdP), a polymorphic ventricular tachycardia that is often drug-induced, that may evolve into ventricular fibrillation and sudden death. Therefore this study was designed to determine if right (RVH), left (LVH), or biventricular (BVH) hypertrophy increases susceptibility to drug-induced TdP. Rabbits were separated into 4 groups: control or RVH, LVH, BVH (studied 8weeks after banding of one or both great arteries). ECGs were recorded continuously under anesthesia after baseline and after rabbits received escalating doses of torsadogens (dofetilide, clofilium and terfenadine) or non-torsadogens (cilobradine, diltiazem and vehicle). The following parameters were measured [RR, PQ, QRS and QT] or calculated [QTc (F), short term variability of QT interval]. Generally, torsadogenicity for the compounds tested was dofetilide>clofilium>terfenadine, and there was no TdP following cilobradine, diltiazem or vehicle. In general the susceptibility to TdP was RVH>BVH>LVH>control. Rabbits with RVH developed TdP much more prevalently than for those with either LVH or BVH (p<0.05). At the low dose of dofetilide, LVH was actually protective. Rabbits with any form of hypertrophy develop prolongation of QT, QTc and increased QT instability. Rabbits with any form of hypertrophy are more prone to arrhythmia than normals in response to known torsadogens. 2010 Elsevier Inc. All rights reserved.

  8. Proteomic analysis reveals that proteasome subunit beta 6 is involved in hypoxia-induced pulmonary vascular remodeling in rats.

    Directory of Open Access Journals (Sweden)

    Jian Wang

    Full Text Available Chronic hypoxia (CH is known to be one of the major causes of pulmonary hypertension (PH, which is characterized by sustained elevation of pulmonary vascular resistance resulting from vascular remodeling. In this study, we investigated whether the ubiquitin proteasome system (UPS was involved in the mechanism of hypoxia-induced pulmonary vascular remodeling. We isolated the distal pulmonary artery (PA from a previously defined chronic hypoxic pulmonary hypertension (CHPH rat model, performed proteomic analyses in search of differentially expressed proteins belonging to the UPS, and subsequently identified their roles in arterial remodeling.Twenty-two proteins were differently expressed between the CH and normoxic group. Among them, the expression of proteasome subunit beta (PSMB 1 and PSMB6 increased after CH exposure. Given that PSMB1 is a well-known structural subunit and PSMB6 is a functional subunit, we sought to assess whether PSMB6 could be related to the multiple functional changes during the CHPH process. We confirmed the proteomic results by real-time PCR and Western blot. With the increase in quantity of the active subunit, proteasome activity in both cultured pulmonary artery smooth muscle cells (PASMCs and isolated PA from the hypoxic group increased. An MTT assay revealed that the proteasome inhibitor MG132 was able to attenuate the hypoxia-induced proliferation of PASMC in a dose-dependent manner. Knockdown of PSMB6 using siRNA also prevented hypoxia-induced proliferation.The present study revealed the association between increased PSMB6 and CHPH. CH up-regulated proteasome activity and the proliferation of PASMCs, which may have been related to increased PSMB6 expression and the subsequently enhanced functional catalytic sites of the proteasome. These results suggested an essential role of the proteasome during CHPH development, a novel finding requiring further study.

  9. Inducibility of ventricular fibrillation during mild therapeutic hypothermia: electrophysiological study in a swine model.

    Science.gov (United States)

    Kudlicka, Jaroslav; Mlcek, Mikulas; Belohlavek, Jan; Hala, Pavel; Lacko, Stanislav; Janak, David; Havranek, Stepan; Malik, Jan; Janota, Tomas; Ostadal, Petr; Neuzil, Petr; Kittnar, Otomar

    2015-02-22

    Mild therapeutic hypothermia (MTH) is being used after cardiac arrest for its expected improvement in neurological outcome. Safety of MTH concerning inducibility of malignant arrhythmias has not been satisfactorily demonstrated. This study compares inducibility of ventricular fibrillation (VF) before and after induction of MTH in a whole body swine model and evaluates possible interaction with changing potassium plasma levels. The extracorporeal cooling was introduced in fully anesthetized swine (n = 6) to provide MTH. Inducibility of VF was studied by programmed ventricular stimulation three times in each animal under the following: during normothermia (NT), after reaching the core temperature of 32°C (HT) and after another 60 minutes of stable hypothermia (HT60). Inducibility of VF, effective refractory period of the ventricles (ERP), QTc interval and potassium plasma levels were measured. Starting at normothermia of 38.7 (IQR 38.2; 39.8)°C, HT was achieved within 54 (39; 59) minutes and the core temperature was further maintained constant. Overall, the inducibility of VF was 100% (18/18 attempts) at NT, 83% (15/18) after reaching HT (P = 0.23) and 39% (7/18) at HT60 (P = 0.0001) using the same protocol. Similarly, ERP prolonged from 140 (130; 150) ms at NT to 206 (190; 220) ms when reaching HT (P < 0.001) and remained 206 (193; 220) ms at HT60. QTc interval was inversely proportional to the core temperature and extended from 376 (362; 395) at NT to 570 (545; 599) ms at HT. Potassium plasma level changed spontaneously: decreased during cooling from 4.1 (3.9; 4.8) to 3.7 (3.4; 4.1) mmol/L at HT (P < 0.01), then began to increase and returned to baseline level at HT60 (4.6 (4.4; 5.0) mmol/L, P = NS). According to our swine model, MTH does not increase the risk of VF induction by ventricular pacing in healthy hearts. Moreover, when combined with normokalemia, MTH exerts an antiarrhythmic effect despite prolonged QTc interval.

  10. Lung tissue remodelling in MCT-induced pulmonary hypertension: a proposal for a novel scoring system and changes in extracellular matrix and fibrosis associated gene expression

    Science.gov (United States)

    Franz, Marcus; Grün, Katja; Betge, Stefan; Rohm, Ilonka; Ndongson-Dongmo, Bernadin; Bauer, Reinhard; Schulze, P. Christian; Lichtenauer, Michael; Petersen, Iver; Neri, Dario; Berndt, Alexander; Jung, Christian

    2016-01-01

    Pulmonary hypertension (PH) is associated with vasoconstriction and remodelling. We studied lung tissue remodelling in a rat model of PH with special focus on histology and extracellular matrix (ECM) remodelling. After induction of PH by monocrotaline, lung tissue was analysed histologically, by gene expression analysis and immunofluorescence labelling of ED-A domain containing fibronectin (ED-A+ Fn), B domain containing tenascin-C (B+ Tn-C) as well as alpha-smooth muscle actin (α-SMA). Serum concentrations of ED-A+ Fn were determined by ELISA. Systolic right ventricular pressure (RVPsys) values were significantly elevated in PH (n = 18; 75 ± 26.4 mmHg) compared to controls (n = 10; 29 ± 19.3 mmHg; p = 0.015). The histological sum-score was significantly increased in PH (8.0 ± 2.2) compared to controls (2.5 ± 1.6; p < 0.001). Gene expression analysis revealed relevant induction of several key genes of extracellular matrix remodelling. Increased protein deposition of ED-A+ Fn but not of B+ Tn-C and α-SMA in lung tissue was found in PH (2.88 ± 3.19 area%) compared to controls (1.32 ± 0.16 area%; p = 0.030). Serum levels of ED-A+ Fn were significantly higher in PH (p = 0.007) positively correlating with RVPsys (r = 0.618, p = 0.019). We here present a novel histological scoring system to assess lung tissue remodelling in PH. Gene expression analysis revealed induction of candidate genes involved in collagen matrix turnover, fibrosis and vascular remodelling. The stable increased tissue deposition of ED-A+ Fn in PH as well as its dynamics in serum suggests a role as a promising novel biomarker and potential therapeutic target. PMID:27835899

  11. Kinetics of gene expression and bone remodelling in the clinical phase of collagen induced arthritis

    DEFF Research Database (Denmark)

    Denninger, Katja Caroline Marie; Litman, Thomas; Marstrand, Troels

    2015-01-01

    -wide association studies (GWAS) revealed differential expression of several genes associated with human arthritis. Conclusions: In the CIA model, bone formation in the joint starts shortly after onset of clinical symptoms, which results in bony fusion within one to two weeks. This makes it a candidate model...... of clinical manifestations. The objective of this study was to use this model to characterise the histological and molecular changes in bone remodelling, and relate these to the clinical disease development. Methods: A histological and gene expression profiling time-course study on bone remodelling in CIA...... was linked to onset of clinical symptoms. Global gene expression was studied with a gene chip array system. Results: The main histopathological changes in bone structure and inflammation occurred during the first two weeks following the onset of clinical symptoms in the joint. Hereafter, the inflammation...

  12. Ginsenoside Re prevents angiotensin II-induced gap-junction remodeling by activation of PPARγ in isolated beating rat atria.

    Science.gov (United States)

    Zhang, Bo; Cui, Xun; Jin, Hong-Hua; Hong, Lan; Liu, Xia; Li, Xiang; Zhang, Qing-Gao; Liu, Li-Ping

    2017-12-01

    Ginsenoside Re (G-Re), a major ginsenoside in ginseng, has many beneficial pharmacological effects on negative cardiac contractility, electromechanical alternans, antiarrhythmia, angiogenic regeneration and cardiac electrophysiological function. However, effects of G-Re on gap-junction remodeling are unclear. Therefore, this study aimed to investigate the effect of G-Re on angiotensin II (Ang II)-induced downregulation of connexin-40 (CX40) and -43 (CX43) in beating rat left atria. In this study, the isolated perfused beating rat atrial model was used and atrial gap-junction remodeling was induced by Ang II. In vivo hemodynamic experiments were analyzed with a biological recorder. Changes in protein expression were analyzed by western blot. G-Re attenuated Ang II-induced abnormal changes in heart rate, MAP, LVESP, LVEDP, +dp/dt max, -dp/dt min, P wave amplitude, P-R interval and P wave length. This indicated a dose-dependent preventive role against Ang II-induced hyper hemodynamics in rats. Atrial activities of p38 mitogen-activated protein kinase (MAPK), nuclear factor kappa-B (NF-κB) and activator protein 1 (AP-1) were significantly increased by Ang II, as was expression of atrial collagen I and matrix metalloproteinase 2 (MMP2). Atrial CX40 and CX43 expression was downregulated by Ang II. These Ang II-induced atrial effects were blocked by G-Re, as well as rosiglitazone, an agonist of peroxisome proliferator-activated receptor γ (PPARγ), in a dose-dependent manner. However, this inhibition was abolished by the PPARγ inhibitor GW9662. G-Re may suppress Ang II-induced downregulation of CX40 and CX43, by activating PPARγ signaling, in isolated perfused beating rat atria. Copyright © 2017. Published by Elsevier Inc.

  13. Noradrenergic Activation of the Basolateral Amygdala Enhances Object Recognition Memory and Induces Chromatin Remodeling in the Insular Cortex

    Directory of Open Access Journals (Sweden)

    Hassiba eBeldjoud

    2015-04-01

    Full Text Available It is well established that arousal-induced memory enhancement requires noradrenergic activation of the basolateral complex of the amygdala (BLA and modulatory influences on information storage processes in its many target regions. While this concept is well accepted, the molecular basis of such BLA effects on neural plasticity changes within other brain regions remains to be elucidated. The present study investigated whether noradrenergic activation of the BLA after object recognition training induces chromatin remodeling through histone post-translational modifications in the insular cortex (IC, a brain region that is importantly involved in object recognition memory. Male Sprague–Dawley rats were trained on an object recognition task, followed immediately by bilateral microinfusions of norepinephrine (1.0 µg or saline administered into the BLA. Saline-treated control rats exhibited poor 24-h retention, whereas norepinephrine treatment induced robust 24-h object recognition memory. Most importantly, this memory-enhancing dose of norepinephrine induced a global reduction in the acetylation levels of histone H3 at lysine 14, H2B and H4 in the IC 1 h later, whereas it had no effect on the phosphorylation of histone H3 at serine 10 or tri-methylation of histone H3 at lysine 27. Norepinephrine administered into the BLA of non-trained control rats did not induce any changes in the histone marks investigated in this study. These findings indicate that noradrenergic activation of the BLA induces training-specific effects on chromatin remodeling mechanisms, and presumably gene transcription, in its target regions, which may contribute to the understanding of the molecular mechanisms of stress and emotional arousal effects on memory consolidation.

  14. Nitrite-induced cross-linking alters remodeling and mechanical properties of collagenous engineered tissues.

    Science.gov (United States)

    Paik, David C; Saito, Lynne Y; Sugirtharaj, Dorcas D; Holmes, Jeffrey W

    2006-01-01

    Cumulative damage to long-lived connective tissue proteins play a key role in the development of age-related human diseases such as cardiovascular stiffening and age-related macular degeneration. The processes that result in the accumulation of increasingly insoluble, undigestible damaged collagen are only partially known. Nonenzymatic glycation (NEG) is one such process and has been linked to the development of diabetic-related complications and aging. An additional novel mechanism particularly relevant to smoking- and inflammation-related diseases involves the nonenzymatic nitrite (NEN) modification of connective tissue proteins. The present study was undertaken to examine the effects of NEN of fibrillar type I collagen on cell-mediated remodeling and mechanical properties of collagenous tissues. Using a modification of an in vitro fibroblast-populated collagen gel model system developed in our laboratory, we tested two hypotheses: NEN reduces the ability of primary adult cardiac fibroblasts to remodel type I collagen gels; NEN reduces the deformability of type I collagen gels subjected to mechanical testing. The results show that NEN impairs both cell-mediated remodeling and mechanical deformability in collagenous engineered tissues. Furthermore, these mechanical changes correlate with the degree of cross-linking as determined by SDS-PAGE. Thus, we concluded that NEN reactions may contribute to alterations in the biomechanical properties of collagen-containing tissues consistent with the age-related functional decline observed in human disease.

  15. Epigenetics of amphetamine-induced sensitization: HDAC5 expression and microRNA in neural remodeling.

    Science.gov (United States)

    Liu, Philip K; Liu, Christina H

    2016-12-08

    Histone deacetylase (HDAC) activities modify chromatin structure and play a role in learning and memory during developmental processes. Studies of adult mice suggest HDACs are involved in neural network remodeling in brain repair, but its function in drug addiction is less understood. We aimed to examine in vivo HDAC5 expression in a preclinical model of amphetamine-induced sensitization (AIS) of behavior. We generated specific contrast agents to measure HDAC5 levels by in vivo molecular contrast-enhanced (MCE) magnetic resonance imaging (MRI) in amphetamine-naïve mice as well as in mice with AIS. To validate the MRI results we used ex vivo methods including in situ hybridization, RT-PCR, immunohistochemistry, and transmision electron microscopy. We compared the expression of HDAC5 mRNA in an acute exposure paradigm (in which animals experienced a single drug exposure [A1]) and in a chronic-abstinence-challenge paradigm (in which animals were exposed to the drug once every other day for seven doses, then underwent 2 weeks of abstinence followed by a challenge dose [A7WA]). Control groups for each of these exposure paradigms were given saline. To delineate how HDAC5 expression was related to AIS, we compared the expression of HDAC5 mRNA at sequences where no known microRNA (miR) binds (hdac5AS2) and at sequences where miR-2861 is known to bind (miD2861). We synthesized and labeled phosphorothioated oligonucleic acids (sODN) of hdac5AS2 or miD2861 linked to superparamagentic iron oxide nanoparticles (SPION), and generated HDAC5-specific contrast agents (30 ± 20 nm, diameter) for MCE MRI; the same sequences were used for primers for TaqMan® analysis (RT-qPCR) in ex vivo validation. In addition, we used subtraction R2* maps to identify regional HDAC5 expression. Naïve C57black6 mice that experience acute exposure to amphetamine (4 mg/kg, by injection intraperitoneally) show expression of both total and phosphorylated (S259) HDAC5 antigens in GFAP+ and GFAP

  16. Protective and Therapeutic Effects of Chinese Medicine Formula Jiajian Yunvjian on Experimental Cardiac Remodeling after Myocardial Infarction Induced by Coronary Artery Ligation.

    Science.gov (United States)

    Du, Jun; Gu, Wei-Liang; Chen, Chang-Xun; Wang, Ying; Lv, Jian

    2015-01-01

    Introduction. This study was designed to explore the effect and mechanism of a classic Chinese medicine formula Jiajian Yunvjian (JJYNJ) on cardiac remodeling. Cardiac remodeling after myocardial infarction (MI) model was achieved by coronary artery ligation (CAL). Methodology. When dosed orally once daily, the effects of JJYNJ on hemodynamics, left ventricular weight index (LVWI), heart weight index (HWI), concentration, and gene expression of neuroendocrine factors as well as the histomorphological observation were determined. Results. After 4 weeks, mild cardiac remodeling in CAL group was characterized compared with sham group, but after 4 weeks of treatment of JJYNJ, hemodynamics improved, HWI reduced, and circulating angiotensin II (Ang II), endothelin-1 (ET-1), tumor necrosis factor-α (TNF-α), and hydroxyproline (Hyp) concentrations as well as Ang II receptor type 1 (AT1R) mRNA, transforming growth factor β 1 (TGF-β 1) mRNA, and TNF-α mRNA levels in myocardium were lower than in CAL group. Decreased plasma aldosterone (ALD) concentration, cross-sectional area of cardiomyocyte, collagen volume fraction (CVF), collagen types I and III, perivascular collagen area (PVCA), and upregulated nitric oxide (NO) levels were observed at the same time. Conclusions. These findings suggest that JJYNJ may have a protective and therapeutic function on cardiac remodeling related to MI.

  17. Idiopathic ventricular arrhythmias detected by an implantable loop recorder in a child with exercise-induced syncope.

    Science.gov (United States)

    Akdeniz, Celal; Ozyilmaz, Isa; Saygi, Murat; Ergul, Yakup; Tuzcu, Volkan

    2013-01-01

    Syncope is common in the general population. Despite extensive evaluation, including tilt-table testing and electrophysiologic studies, approximately 30% of cases of recurrent syncope remain unexplained. An implantable loop recorder can be used for diagnosis when recurrent syncope has an idiopathic cause. We present the case of a 9-year-old boy who had a history of recurrent, exercise-induced syncope. Results of physical examination and noninvasive diagnostic testing were inconclusive, and an electrophysiologic study revealed no inducible supraventricular or ventricular arrhythmias. Sixteen months after an implantable loop recorder was placed, the patient had a syncopal episode while swimming in a pool. Cardiopulmonary resuscitation was performed, and data from the loop recorder revealed polymorphic ventricular tachycardia and ventricular fibrillation. A cardioverter-defibrillator was subsequently implanted. Implantable loop recorders can play an important role in the diagnosis of life-threatening arrhythmias in children whose syncope is otherwise unexplained.

  18. Ectopic automaticity induced in ventricular myocytes by transgenic overexpression of HCN2.

    Science.gov (United States)

    Oshita, Kensuke; Itoh, Masayuki; Hirashima, Shingo; Kuwabara, Yoshihiro; Ishihara, Keiko; Kuwahara, Koichiro; Nakao, Kazuwa; Kimura, Takeshi; Nakamura, Kei-Ichiro; Ushijima, Kazuo; Takano, Makoto

    2015-03-01

    Hyperpolarization-activated cyclic nucleotide-gated channels (HCNs) are expressed in the ventricles of fetal hearts but are normally down-regulated as development progresses. In the hypertrophied heart, however, these channels are re-expressed and generate a hyperpolarization-activated, nonselective cation current (Ih), which evidence suggests may increase susceptibility to arrhythmia. To test this hypothesis, we generated and analyzed transgenic mice overexpressing HCN2 specifically in their hearts (HCN2-Tg). Under physiological conditions, HCN2-Tg mice exhibited no discernible abnormalities. After the application of isoproterenol (ISO), however, ECG recordings from HCN2-Tg mice showed intermittent atrioventricular dissociation followed by idioventricular rhythm. Consistent with this observation, 0.3 μmol/L ISO-induced spontaneous action potentials (SAPs) in 76% of HCN2-Tg ventricular myocytes. In the remaining 24%, ISO significantly depolarized the resting membrane potential (RMP), and the late repolarization phase of evoked action potentials (APs) was significantly longer than in WT myocytes. Analysis of membrane currents revealed that these differences are attributable to the Ih tail current. These findings suggest HCN2 channel activity reduces the repolarization reserve of the ventricular action potential and increases ectopic automaticity under pathological conditions such as excessive β-adrenergic stimulation. Copyright © 2015. Published by Elsevier Ltd.

  19. Streptozotocin-induced diabetes prolongs twitch duration without affecting the energetics of isolated ventricular trabeculae.

    Science.gov (United States)

    Han, June-Chiew; Tran, Kenneth; Nielsen, Poul M F; Taberner, Andrew J; Loiselle, Denis S

    2014-04-15

    Diabetes induces numerous electrical, ionic and biochemical defects in the heart. A general feature of diabetic myocardium is its low rate of activity, commonly characterised by prolonged twitch duration. This diabetes-induced mechanical change, however, seems to have no effect on contractile performance (i.e., force production) at the tissue level. Hence, we hypothesise that diabetes has no effect on either myocardial work output or heat production and, consequently, the dependence of myocardial efficiency on afterload of diabetic tissue is the same as that of healthy tissue. We used isolated left ventricular trabeculae (streptozotocin-induced diabetes versus control) as our experimental tissue preparations. We measured a number of indices of mechanical (stress production, twitch duration, extent of shortening, shortening velocity, shortening power, stiffness, and work output) and energetic (heat production, change of enthalpy, and efficiency) performance. We calculated efficiency as the ratio of work output to change of enthalpy (the sum of work and heat). Consistent with literature results, we showed that peak twitch stress of diabetic tissue was normal despite suffering prolonged duration. We report, for the first time, the effect of diabetes on mechanoenergetic performance. We found that the indices of performance listed above were unaffected by diabetes. Hence, since neither work output nor change of enthalpy was affected, the efficiency-afterload relation of diabetic tissue was unaffected, as hypothesised. Diabetes prolongs twitch duration without having an effect on work output or heat production, and hence efficiency, of isolated ventricular trabeculae. Collectively, our results, arising from isolated trabeculae, reconcile the discrepancy between the mechanical performance of the whole heart and its tissues.

  20. Does Down-Sized Ring Annuloplasty Induce Papillary Muscle Relocation in Ischemic Mitral Regurgitation?

    DEFF Research Database (Denmark)

    Jensen, Henrik; Jensen, Morten O; Smerup, Morten H

    2010-01-01

    Down-sized ring annuloplasty has been shown to induce left ventricular remodeling in patients with functional ischemic mitral regurgitation (FIMR). To determine if this remodeling comprised papillary muscle (PM) relocation, a chronic FIMR porcine model was used to assess the impact on three...

  1. A novel fluoroscopic method of measuring right-to-left interlead distance as a predictor of reverse left ventricular remodeling after cardiac resynchronization therapy.

    Science.gov (United States)

    Covino, Gregorio; Volpicelli, Mario; Belli, Pietro; Ratti, Gennaro; Tammaro, Paolo; Provvisiero, Ciro; Ciardiello, Carmine; Auricchio, Luca; Fiorentino, Ciro; Capogrosso, Paolo

    2014-03-01

    In spite of technological breakthroughs, the choice of a suitable location for the coronary sinus (CS) lead in biventricular implants is still mostly empiric. The aim of this study was to investigate the utility of a radiological index-the distance between the right ventricular (RV) and CS lead tips on fluoroscopic recordings, measured by means of a new method-as a tool for selecting the most profitable left ventricular (LV) lead position. Forty-nine consecutive patients (36 male, 13female; mean age 63 ± 19 year), in whom the LV electrode was implanted in a lateral/postero-lateral position in the CS, were evaluated immediately after implantation. The fluoroscopic distances between the RV and LV lead tips were calculated off-line in antero-posterior (2DAP) and latero-lateral (2DLL) projections by means of integrated software. On 1-year follow-up evaluation, 53 % patients were classed as responders (R) (>15 % reduction in LV end-systolic volume) and 47 % as non-responders (NR). On receiver-operating curve analysis, 2DAP and 2DLL showed cut-off values of 81 mm and 51 mm, respectively. In discriminating between R and NR, 2DAP >81 mm displayed 95 % specificity and 74 % sensitivity, while 2DLL >51 mm displayed 74 % specificity and 92 % sensitivity. On multivariate analysis, the cut-off values of 2DAP and 2DLL were significantly predictive of R to CRT. In our single-center prospective experience, RV-LV interlead distance measured by means of a novel method on fluorographic recordings correlated with CRT response. The use of this method as an intra-operative guide to identifying suitable lead placement in the CS needs evaluating on-line and on a large scale.

  2. Remodelamento cardíaco: análise seriada e índices de detecção precoce de disfunção ventricular Remodelación cardiaca: análisis seriado e índices de detección precoz de disfunción ventricular Cardiac remodeling: serial analysis and indexes for early detection of ventricular dysfunction

    Directory of Open Access Journals (Sweden)

    Olga de Castro Mendes

    2010-01-01

    comportamiento del RC desde la fase inicial, ni los mejores parámetros para la identificación de la disfunción ventricular. OBJETIVO: 1 Caracterizar, precoz y evolutivamente, las modificaciones morfofuncionales durante el RC en ratones con EAo, y 2 identificar el índice más sensible para detección del momento de la aparición de la disfunción diastólica y sistólica del ventrículo izquierdo (VI. MÉTODOS: Ratones Wistar se dividieron en dos grupos - control (GC, n=13 y EAo (GEAo, n=24 - y estudiados en las 3ª, 6ª, 12ª y 18ª semanas post cirugía. Los corazones se analizaron por medio de ecocardiograma (ECO. RESULTADOS: Al final del experimento, las relaciones del VI, del ventrículo derecho y de los atrios con el peso corporal final fueron aumentadas en el GEAo. El ECO mostró que el atrio izquierdo sufrió una remodelación significativa a partir de la 6ª semana. En el GEAo, el porcentaje de acortamiento endocárdico presentó disminución significativa a partir de la 12ª semana y el porcentaje de acortamiento mesocárdico, en la 18ª semana. La relación onda E y onda A (E/A fue superior en el GC en comparación al GEAo en todos los momentos analizados. CONCLUSIÓN: El ventrículo izquierdo de los ratones con EAo, durante el proceso de remodelación, presentó hipertrofia concéntrica, disfunción diastólica precoz y mejora de la función sistólica, con posterior deterioro del desempeño. Además de ello, se constató que los índices ecocardiográficos más sensibles para la detección de la disfunción diastólica y sistólica son, respectivamente, la relación E/A y el porcentaje de acortamiento endocárdico.BACKGROUND: Supravalvar aortic stenosis (SVAS is used to study overload-induced cardiac remodeling (CR. In this model, neither CR behavior since beginning stage nor the best parameters to identify ventricular dysfunction are clearly stated. Objective: 1 Characterizing, early and evolutively, morphological and functional modifications during CR in rats

  3. Natriuretic peptides in the monitoring of anthracycline induced reduction in left ventricular ejection fraction

    DEFF Research Database (Denmark)

    Daugaard, Gedske; Lassen, Ulrik; Bie, Peter

    2005-01-01

    peptide (N-ANP) and brain natriuretic peptide (BNP)) for monitoring and predicting anthracycline induced cardiotoxicity using radionuclide left ventricular ejection fraction (EF) measurements as reference. METHODS AND RESULTS: A total of 107 consecutive patients receiving anthracycline as part...... of their chemotherapy for malignant disease were studied. Plasma concentrations of the peptides were measured by radioimmunoassay and EF by radionuclide cardiography. For reduced EF values, i.e. below 0.50 a fairly strong correlation was found between N-ANP or BNP and EF. Of 48 patients with serial EF and peptide...... measurements, 19% showed a significant EF decrease (>0.10) and ended with a final EF value below 0.50. Baseline EF was no predictor of a change in EF during treatment. Neither baseline levels of N-ANP or BNP nor a change in the same variables during therapy were predictive of a change in EF. CONCLUSIONS...

  4. Clarithromycine-Induced Ventricular Tachycardia in a Geriatric Patient Using Multiple Drugs

    Directory of Open Access Journals (Sweden)

    Gulsah Karaoren

    2016-07-01

    Full Text Available Long QT syndrome is a cardiac repolarization disorder, which can be either idiopathic or congenital, and cause sudden cardiac death. The iatrogenic form is generally associated with drugs or electrolyte imbalance. Although prolonged QT interval is frequently seen due to antiarrhythmic agents, it can also be seen with antibiotics or anti-epileptics. Adverse drug interaction can manifest in several clinicopathological forms in elder individuals. In such cases, potential adverse effects of drugs used should be taken into consideration before prescribing additional drugs. Here, we present a case of clarithromycine-induced ventricular arrhythmia accompanied by QT prolongation on the third day of therapy, and the subsequent therapeutic approach, in a 91-year-old man. The patient was taking multiple drugs due to comorbid conditions and was prescribed clarithromycine therapy in the intensive care unit.

  5. Prevalence of exercise-induced left ventricular outflow tract obstruction in symptomatic patients with non-obstructive hypertrophic cardiomyopathy.

    LENUS (Irish Health Repository)

    Shah, J S

    2008-10-01

    Resting left ventricular outflow tract obstruction (LVOTO) occurs in 25% of patients with hypertrophic cardiomyopathy (HCM) and is an important cause of symptoms and disease progression. The prevalence and clinical significance of exercise induced LVOTO in patients with symptomatic non-obstructive HCM is uncertain.

  6. LATE POTENTIALS IN A PORCINE MODEL OF ANTERIOR WALL MYOCARDIAL-INFARCTION AND THEIR RELATION TO INDUCIBLE VENTRICULAR-TACHYCARDIA

    NARCIS (Netherlands)

    TOBE, TJM; DELANGEN, CDJ; MOOK, PH; TIO, RA; BEL, KJ; DEGRAEFF, PA; VANGILST, WH; WESSELING, H

    1992-01-01

    In this study, normal values for signal averaged electrocardiographic parameters were assessed in healthy pigs (n = 100) and the development of late potentials after myocardial infarction (n = 41) in relation to inducible ventricular tachycardia was investigated. Normal values are: filtered QRS

  7. Anatomy and Physiology of Left Ventricular Suction Induced by Rotary Blood Pumps.

    Science.gov (United States)

    Salamonsen, Robert Francis; Lim, Einly; Moloney, John; Lovell, Nigel Hamilton; Rosenfeldt, Franklin L

    2015-08-01

    This study in five large greyhound dogs implanted with a VentrAssist left ventricular assist device focused on identification of the precise site and physiological changes induced by or underlying the complication of left ventricular suction. Pressure sensors were placed in left and right atria, proximal and distal left ventricle, and proximal aorta while dual perivascular and tubing ultrasonic flow meters measured blood flow in the aortic root and pump outlet cannula. When suction occurred, end-systolic pressure gradients between proximal and distal regions of the left ventricle on the order of 40-160 mm Hg indicated an occlusive process of variable intensity in the distal ventricle. A variable negative flow difference between end systole and end diastole (0.5-3.4 L/min) was observed. This was presumably mediated by variable apposition of the free and septal walls of the ventricle at the pump inlet cannula orifice which lasted approximately 100 ms. This apposition, by inducing an end-systolic flow deficit, terminated the suction process by relieving the imbalance between pump requirement and delivery from the right ventricle. Immediately preceding this event, however, unnaturally low end-systolic pressures occurred in the left atrium and proximal left ventricle which in four dogs lasted for 80-120 ms. In one dog, however, this collapse progressed to a new level and remained at approximately -5 mm Hg across four heart beats at which point suction was relieved by manual reduction in pump speed. Because these pressures were associated with a pulmonary capillary wedge pressure of -5 mm Hg as well, they indicate total collapse of the entire pulmonary venous system, left atrium, and left ventricle which persisted until pump flow requirement was relieved by reducing pump speed. We suggest that this collapse caused the whole vascular region from pulmonary capillaries to distal left ventricle to behave as a Starling resistance which further reduced right

  8. Fibrose miocárdica e remodelamento ventricular na insuficiência aórtica crônica importante Fibrosis miocárdica y remodelación ventricular en la insuficiencia aórtica crónica severa Myocardial fibrosis and ventricular remodeling in severe chronic aortic regurgitation

    Directory of Open Access Journals (Sweden)

    Nelson Elias

    2009-01-01

    miociotos y remodelación de la matriz extracelular. Se desconoce la relevancia de la concentración de fibrosis intersticial en los pacientes acometidos. Analizamos el grado de fibrosis en el ventrículo izquierdo (VI en pacientes sintomáticos con IAo crónica severa sometidos a tratamiento quirúrgico y su relación con características funcionales y anatómicas. OBJETIVO: Evaluar la fibrosis miocárdica en la insuficiencia aórtica crónica severa. MÉTODOS: Se seleccionaron a 28 pacientes con IAo crónica severa (16 con función VI normal y 12 con disfunción del VI, los que se analizaron en el pre y el postoperatorio por ecocardiografía Doppler. Se midió la capacidad funcional por la prueba de esfuerzo cardiopulmonar. Para comparación de los resultados histopatológicos, se constituyó a un Grupo Control de 9 pacientes. RESULTADOS: El promedio de edad fue de 39±12 años, el 75% del sexo masculino con el 84% de etiología reumática. El total de 25 pacientes permanecieron en clases funcionales I e II al fin del estudio y presentaron reducción significativa de los diámetros del VI entre los momentos pre y postoperatorios. Hubo tres óbitos no relacionados a la disfunción VI. Los parámetros de la prueba cardiopulmonar no se modificaron entre el pre y el postoperatorio. El volumen de fibrosis intersticial en pacientes con IAo crónica severa fue significativo cuando mayor, comparado al Grupo control (3,47 ± 1,9% vs. 0,82 ±0,96%, respectivamente, p = 0,001. No hubo correlación entre el grado de fibrosis del VI, parámetros ecocardiográficos y funcionales. CONCLUSIÓN: En pacientes con IAo crónica severa, la presencia de fibrosis miocárdica no se asoció a las alteraciones clínicas, ecocardiográficas o funcionales.BACKGROUND: Significant symptomatic chronic aortic regurgitation (AR leads to considerable left ventricular remodeling at the expense of myocyte hypertrophy and extracellular matrix remodeling. The relevance of interstitial fibrosis concentration

  9. Cardiac remodeling in a new pig model of chronic heart failure: Assessment of left ventricular functional, metabolic, and structural changes using PET, CT, and echocardiography.

    Science.gov (United States)

    Tarkia, Miikka; Stark, Christoffer; Haavisto, Matti; Kentala, Rasmus; Vähäsilta, Tommi; Savunen, Timo; Strandberg, Marjatta; Hynninen, Ville-Veikko; Saunavaara, Virva; Tolvanen, Tuula; Teräs, Mika; Rokka, Johanna; Pietilä, Mikko; Saukko, Pekka; Roivainen, Anne; Saraste, Antti; Knuuti, Juhani

    2015-08-01

    Large animal models are needed to study disease mechanisms in heart failure (HF). In the present study we characterized the functional, metabolic, and structural changes of myocardium in a novel pig model of chronic myocardial infarction (MI) by using multimodality imaging and histology. Male farm pigs underwent a two-step occlusion of the left anterior descending coronary artery with concurrent distal ligation and implantation of a proximal ameroid constrictor (HF group), or sham operation (control group). Three months after the operation, cardiac output and wall stress were measured by echocardiography. Left ventricle (LV) volumes and mass were measured by computed tomography (CT). Myocardial perfusion was evaluated by [(15)O]water and oxygen consumption using [(11)C]acetate positron emission tomography, and the efficiency of myocardial work was calculated. Histological examinations were conducted to detect MI, hypertrophy, and fibrosis. Animals in the HF group had a large anterior MI scar. CT showed larger LV diastolic volume and lower ejection fraction in HF pigs than in controls. Perfusion and oxygen consumption in the remote non-infarcted myocardium were preserved in HF pigs as compared to controls. Global LV work and efficiency were significantly lower in HF than control pigs and was associated with increased wall stress. Histology showed myocyte hypertrophy but not increased interstitial fibrosis in the remote segments in HF pigs. The chronic post-infarction model of HF is suitable for studies aimed to evaluate LV remodeling and changes in oxidative metabolism and can be useful for testing new therapies for HF.

  10. Cadmium-induced proteome remodeling regulated by Spc1/Sty1 and Zip1 in fission yeast.

    Science.gov (United States)

    Guo, Lan; Ghassemian, Majid; Komives, Elizabeth A; Russell, Paul

    2012-09-01

    Stress-activated protein kinases and transcription factors are crucial for surviving exposure to cadmium and other environmental toxicants, but their effects on the proteome remain largely unexplored. In this study, isobaric tag for relative and absolute quantitation reveals that cadmium stress triggers rapid proteome remodeling in the fission yeast Schizosaccharomyces pombe. Spc1/Sty1, a mitogen/stress-activated protein kinase homologous to human p38 and Saccharomyces cerevisiae Hog1, controls many of these changes, including enzymes of the oxidative phase of the pentose phosphate pathway and trehalose metabolism. Genetic studies indicate that control of carbohydrate metabolism by Spc1 is required for cadmium tolerance. The bZIP transcription factor Zip1, which is functionally related to human Nrf2 and S. cerevisiae Met4, has a smaller effect on cadmium-induced proteome remodeling, but it is required for production of key proteins involved in sulfur metabolism, which are essential for cadmium resistance. These studies reveal how Spc1 and Zip1 independently reshape the proteome to modulate cellular defense mechanisms against the toxic effects of cadmium.

  11. Bone Marrow Transplantation Transfers Age-Related Susceptibility to Neovascular Remodeling in Murine Laser-Induced Choroidal Neovascularization

    Science.gov (United States)

    Espinosa-Heidmann, Diego G.; Malek, Goldis; Mettu, Priyatham S.; Caicedo, Alejandro; Saloupis, Peter; Gach, Sarah; Dunnon, Askia K.; Hu, Peng; Spiga, Maria-Grazia; Cousins, Scott W.

    2013-01-01

    Purpose. Neovascular remodeling (NVR), the progression of small capillaries into large-caliber arterioles with perivascular fibrosis, represents a major therapeutic challenge in neovascular age-related macular degeneration (AMD). Neovascular remodeling occurs after laser-induced choroidal neovascularization (CNV) in aged but not young mice. Additionally, bone marrow–derived cells, including macrophages, endothelial precursor cells, and mesenchymal precursor cells, contribute to CNV severity. In this study, we investigated the impact of aged bone marrow transplantation (BMT) on the degree of fibrosis, size, and vascular morphology of CNV lesions in a mouse model of laser-induced CNV. Methods. Young (2 months) and old (16 months) mice were transplanted with green fluorescent protein (GFP)-labeled bone marrow isolated from either young or old donors. Laser CNV was induced 1 month following transplant, and eyes were analyzed via choroidal flat mounts and immunohistochemistry 1 month postlaser. The identity of cells infiltrating CNV lesions was determined using specific markers for the labeled transplanted cells (GFP+), macrophages (F4/80+), perivascular mesenchymal-derived cells (smooth muscle actin, SMA+), and endothelial cells (CD31+). Results. Bone marrow transplantation from aged mice transferred susceptibility to NVR into young recipients. Inversely, transplantation of young marrow into old mice prevented NVR, preserving small size and minimal fibrosis. Mice with NVR demonstrated a greater relative contribution of marrow-derived SMA+ perivascular mesenchymal cells as compared to other cells. Conclusions. Our findings indicate that the status of bone marrow is an important determining factor of neovascular severity. Furthermore, we find that perivascular mesenchymal cells, rather than endothelial cells, derived from aged bone marrow may contribute to increased CNV severity in this murine model of experimental neovascularization. PMID:24135751

  12. Modeling Catecholaminergic Polymorphic Ventricular Tachycardia using Induced Pluripotent Stem Cell-derived Cardiomyocytes

    Directory of Open Access Journals (Sweden)

    Atara Novak

    2012-07-01

    Full Text Available Catecholaminergic polymorphic ventricular tachycardia (CPVT is an inherited arrhythmogenic cardiac disorder characterized by life-threatening arrhythmias induced by physical or emotional stress, in the absence structural heart abnormalities. The arrhythmias may cause syncope or degenerate into cardiac arrest and sudden death which usually occurs during childhood. Recent studies have shown that CPVT is caused by mutations in the cardiac ryanodine receptor type 2 (RyR2 or calsequestrin 2 (CASQ2 genes. Both proteins are key contributors to the intracellular Ca2+ handling process and play a pivotal role in Ca2+ release from the sarcoplasmic reticulum to the cytosol during systole. Although the molecular pathogenesis of CPVT is not entirely clear, it was suggested that the CPVT mutations promote excessive sarcoplasmic reticulum Ca2+ leak, which initiates delayed afterdepolarizations (DADs and triggered arrhythmias in cardiac myocytes. The recent breakthrough discovery of induced pluripotent stem cells (iPSC generated from somatic cells (e.g. fibroblasts, keratinocytes now enables researches to investigate mutated cardiomyocytes generated from the patient’s iPSC. To this end, in the present article we review recent studies on CPVT iPSC-derived cardiomyocytes, thus demonstrating in the mutated cells catecholamine-induced DADs and triggered arrhythmias.

  13. Increased oxidative stress and severe arterial remodeling induced by permanent high-flow challenge in experimental pulmonary hypertension

    Directory of Open Access Journals (Sweden)

    Fadel Elie

    2011-09-01

    Full Text Available Abstract Background Involvement of inflammation in pulmonary hypertension (PH has previously been demonstrated and recently, immune-modulating dendritic cells (DCs infiltrating arterial lesions in patients suffering from idiopathic pulmonary arterial hypertension (IPAH and in experimental monocrotaline-induced PH have been reported. Occurrence of perivascular inflammatory cells could be linked to local increase of oxidative stress (OS, as it has been shown for systemic atherosclerosis. The impact of OS on vascular remodeling in PH is still to be determined. We hypothesized, that augmented blood-flow could increase OS and might thereby contribute to DC/inflammatory cell-recruitment and smooth-muscle-cell-proliferation. Methods We applied a monocrotaline-induced PH-model and combined it with permanent flow-challenge. Thirty Sprague-Dawley rats were assigned to following groups: control, monocrotaline-exposure (MCT, monocrotaline-exposure/pneumonectomy (MCT/PE. Results Hemodynamic exploration demonstrated most severe effects in MCT/PE, corresponding in histology to exuberant medial and adventitial remodeling of pulmonary muscular arteries, and intimal remodeling of smaller arterioles; lung-tissue PCR evidenced increased expression of DCs-specific fascin, CD68, proinflammatory cytokines (IL-6, RANTES, fractalkine in MCT/PE and to a lesser extent in MCT. Major OS enzyme NOX-4 was maximal in MCT/PE. Antioxidative stress enzymes Mn-SOD and glutathion-peroxidase-1 were significantly elevated, while HO-1 showed maximal expression in MCT with significant decrease in MCT/PE. Catalase was decreased in MCT and MCT/PE. Expression of NOX-4, but also of MN-SOD in MCT/PE was mainly attributed to a highly increased number of interstitial and perivascular CXCR4/SDF1 pathway-recruited mast-cells. Stress markers malonedialdehyde and nitrotyrosine were produced in endothelial cells, medial smooth muscle and perivascular leucocytes of hypertensive vasculature

  14. Increased oxidative stress and severe arterial remodeling induced by permanent high-flow challenge in experimental pulmonary hypertension.

    Science.gov (United States)

    Dorfmüller, Peter; Chaumais, Marie-Camille; Giannakouli, Maria; Durand-Gasselin, Ingrid; Raymond, Nicolas; Fadel, Elie; Mercier, Olaf; Charlotte, Frédéric; Montani, David; Simonneau, Gérald; Humbert, Marc; Perros, Frédéric

    2011-09-09

    Involvement of inflammation in pulmonary hypertension (PH) has previously been demonstrated and recently, immune-modulating dendritic cells (DCs) infiltrating arterial lesions in patients suffering from idiopathic pulmonary arterial hypertension (IPAH) and in experimental monocrotaline-induced PH have been reported. Occurrence of perivascular inflammatory cells could be linked to local increase of oxidative stress (OS), as it has been shown for systemic atherosclerosis. The impact of OS on vascular remodeling in PH is still to be determined. We hypothesized, that augmented blood-flow could increase OS and might thereby contribute to DC/inflammatory cell-recruitment and smooth-muscle-cell-proliferation. We applied a monocrotaline-induced PH-model and combined it with permanent flow-challenge. Thirty Sprague-Dawley rats were assigned to following groups: control, monocrotaline-exposure (MCT), monocrotaline-exposure/pneumonectomy (MCT/PE). Hemodynamic exploration demonstrated most severe effects in MCT/PE, corresponding in histology to exuberant medial and adventitial remodeling of pulmonary muscular arteries, and intimal remodeling of smaller arterioles; lung-tissue PCR evidenced increased expression of DCs-specific fascin, CD68, proinflammatory cytokines (IL-6, RANTES, fractalkine) in MCT/PE and to a lesser extent in MCT. Major OS enzyme NOX-4 was maximal in MCT/PE. Antioxidative stress enzymes Mn-SOD and glutathion-peroxidase-1 were significantly elevated, while HO-1 showed maximal expression in MCT with significant decrease in MCT/PE. Catalase was decreased in MCT and MCT/PE. Expression of NOX-4, but also of MN-SOD in MCT/PE was mainly attributed to a highly increased number of interstitial and perivascular CXCR4/SDF1 pathway-recruited mast-cells. Stress markers malonedialdehyde and nitrotyrosine were produced in endothelial cells, medial smooth muscle and perivascular leucocytes of hypertensive vasculature. Immunolabeling for OX62, CD68 and actin revealed

  15. Impairment of cardiac function and remodeling induced by myocardial infarction in rats are attenuated by the nonpeptide angiotensin-(1-7) analog AVE 0991.

    Science.gov (United States)

    Zeng, Wu-tao; Chen, Wei-yan; Leng, Xiu-yu; Tang, Li-long; Sun, Xiu-ting; Li, Cui-ling; Dai, Gang

    2012-06-01

    We evaluated effects of the nonpeptide angiotensin (ANG)-(1-7) analog AVE 0991 (AVE) on cardiac function and remodeling as well as transforming growth factor-beta1 (TGF-β1)/tumor necrosis factor-alpha (TNF-α) expression in myocardial infarction rat models. Sprague-Dawley rats underwent either sham surgery or coronary ligation. They were divided into four groups: sham, control, AVE, and AVE+A-779 [[D-Ala(7) ]-ANG-(1-7), a selective antagonist for the ANG-(1-7)] group. After 4 weeks of treatment, the AVE group displayed a significant elevation in left ventricular fractional shorting (LVFS) (25.5 ± 7.3% vs. 18.4 ± 3.3%, P AVE group when compared to the control group. There were no differences in LVFS, LVEF, myocyte diameter, and infarct size between the control and AVE+A-779 groups. AVE also markedly attenuated the increased mRNA expression of collagen I (P AVE could improve cardiac function and attenuate ventricular remodeling in MI rat models. It may involve the inhibition of inflammatory factors TGF-β1/TNF-α overexpression and the action on the specific receptor Mas of ANG-(1-7). © 2010 Blackwell Publishing Ltd.

  16. Preservation of diastolic function in monocrotaline-induced right ventricular hypertrophy in rats.

    Science.gov (United States)

    Lamberts, Regis R; Caldenhoven, Eric; Lansink, Mirian; Witte, Gerrit; Vaessen, Rob J; St Cyr, John A; Stienen, Ger J M

    2007-09-01

    During ischemic heart diseases and when heart failure progresses depletion of myocardial energy stores occurs. D-Ribose (R) has been shown to improve cardiac function and energy status after ischemia. Folic acid (FA) is an essential cofactor in the formation of adenine nucleotides. Therefore, we assessed whether chronic R-FA administration during the development of hypertrophy resulted in an improved cardiac function and energy status. In Wistar rats (n = 40) compensatory right ventricular (RV) hypertrophy was induced by monocrotaline (30 mg/kg; MCT), whereas saline served as control. Both groups received a daily oral dose of either 150 mg.kg(-1).day(-1) dextrose (placebo) or R-FA (150 and 40 mg.kg(-1).day(-1), respectively). In Langendorff-perfused hearts, RV and left ventricular (LV) pressure development and collagen content as well as total RV adenine nucleotides (TAN), creatine content, and RV and LV collagen content were determined. In the control group R-FA had no effect. In the MCT-placebo group, TAN and creatine content were reduced, RV and LV diastolic pressure-volume relations were steeper, RV systolic pressures were elevated, RV and LV collagen content was increased, and RV-LV diastolic interaction was altered compared with controls. In the MCT-R-FA group, TAN, RV and LV diastolic stiffness, RV and LV collagen content, and RV-LV diastolic interaction were normalized to the values in the control group while creatine content remained depressed and RV systolic function remained elevated. In conclusion, the depression of energy status in compensated hypertrophic myocardium observed was partly prevented by chronic R-FA administration and accompanied by a preservation of diastolic function and collagen deposition.

  17. Longer Paced QRS Duration is Associated With Increased Prevalence of Right Ventricular Pacing-Induced Cardiomyopathy.

    Science.gov (United States)

    Khurshid, Shaan; Liang, Jackson J; Owens, Anjali; Lin, David; Schaller, Robert; Epstein, Andrew E; Marchlinski, Francis E; Frankel, David S

    2016-10-01

    Pacing-induced cardiomyopathy (PICM) is an important cause of heart failure in patients exposed to frequent right ventricular (RV) pacing. While echocardiography is diagnostic, the optimal surveillance strategy remains unknown. We sought to identify clinical and electrocardiographic factors associated with the presence of PICM to guide further testing. We retrospectively studied 1,750 consecutive patients undergoing pacemaker implantation 2003-2012. Patients were included if baseline LVEF was normal, single chamber ventricular or dual chamber pacemaker (but not ICD or cardiac resynchronization therapy device) was implanted, frequent (≥20%) RV pacing was present and repeat echocardiogram was available following implantation. PICM was defined as ≥10% decrease in LVEF, resulting in LVEF cardiomyopathy were excluded. Clinical and electrocardiographic indicators of PICM were identified using multivariate logistic regression. Of 184 patients meeting study criteria, 42 (22.8%) developed PICM, with decrease in mean LVEF from 62.1% to 35.3% over mean follow-up 2.5 years. Longer follow-up paced QRS duration was associated with the presence of PICM (multivariate odds ratio 1.34 per 10 millisecond increase, 95% CI 1.06-1.63, p = 0.01). Paced QRS duration ≥150 milliseconds was 95% sensitive for PICM. Only half of patients with PICM had heart failure signs or symptoms at the time of echocardiographic diagnosis. Patients with frequent RV pacing and paced QRS duration ≥150 milliseconds should be screened by echocardiogram to assess for PICM. Patients with paced QRS duration <150 milliseconds likely do not require screening, in the absence of heart failure signs or symptoms. © 2016 Wiley Periodicals, Inc.

  18. Intestinal Mechanomorphological Remodeling Induced by Long-Term Low-Fiber Diet in Rabbits

    DEFF Research Database (Denmark)

    Liu, Yue; Zhao, Jingbo; Liao, Donghua

    2017-01-01

    , respectively. The wall thickness, wall area, mucosa and muscle layer thickness decreased whereas the submucosa layer thickness increased in the IG (p intestine and decreased......Short-term feeding with low-fiber diet remodels the mechanomorphological properties in the rabbit small intestine. The aims were to study the effect of feeding low-fiber diet for 5 months on mechanomorphological properties including the collagen fraction in the rabbit intestines. Fifteen rabbits...... were divided into an Intervention group (IG, n = 10) fed a low-fiber diet and a Control group (CG, n = 5) fed a normal diet for 5 months. Five months later, four 10-cm-long segments obtained from the duodenum, jejunum, ileum and large intestine were used for histological and mechanical analysis...

  19. Research into the effect Of SGLT2 inhibition on left ventricular remodelling in patients with heart failure and diabetes mellitus (REFORM) trial rationale and design.

    Science.gov (United States)

    Singh, Jagdeep S S; Fathi, Amir; Vickneson, Keeran; Mordi, Ify; Mohan, Mohapradeep; Houston, J Graeme; Pearson, Ewan R; Struthers, Allan D; Lang, Chim C

    2016-07-15

    Heart failure (HF) and diabetes (DM) are a lethal combination. The current armamentarium of anti-diabetic agents has been shown to be less efficacious and sometimes even harmful in diabetic patients with concomitant cardiovascular disease, especially HF. Sodium glucose linked co-transporter type 2 (SGLT2) inhibitors are a new class of anti-diabetic agent that has shown potentially beneficial cardiovascular effects such as pre-load and after load reduction through osmotic diuresis, blood pressure reduction, reduced arterial stiffness and weight loss. This has been supported by the recently published EMPA-REG trial which showed a striking 38 and 35 % reduction in cardiovascular death and HF hospitalisation respectively. The REFORM trial is a novel, phase IV randomised, double blind, placebo controlled clinical trial that has been ongoing since March 2015. It is designed specifically to test the safety and efficacy of the SLGT2 inhibitor, dapagliflozin, on diabetic patients with known HF. We utilise cardiac-MRI, cardio-pulmonary exercise testing, body composition analysis and other tests to quantify the cardiovascular and systemic effects of dapagliflozin 10 mg once daily against standard of care over a 1 year observation period. The primary outcome is to detect the change in left ventricular (LV) end systolic and LV end diastolic volumes. The secondary outcome measures include LV ejection fraction, LV mass index, exercise tolerance, fluid status, quality of life measures and others. This trial will be able to determine if SGLT2 inhibitor therapy produces potentially beneficial effects in patients with DM and HF, thereby replacing current medications as the drug of choice when treating patients with both DM and HF. Trial registration Clinical Trials.gov: NCT02397421. Registered 12th March 2015.

  20. Nurse-coordinated collaborative disease management improves the quality of guideline-recommended heart failure therapy, patient-reported outcomes, and left ventricular remodelling.

    Science.gov (United States)

    Güder, Gülmisal; Störk, Stefan; Gelbrich, Goetz; Brenner, Susanne; Deubner, Nikolas; Morbach, Caroline; Wallenborn, Julia; Berliner, Dominik; Ertl, Georg; Angermann, Christiane E

    2015-04-01

    Heart failure (HF) pharmacotherapy is often not prescribed according to guidelines. This longitudinal study investigated prescription rates and dosages of angiotensin-converting enzyme inhibitors/angiotensin receptor blockers (ACEi/ARB), beta-blockers, and mineralocorticoid receptor antagonists (MRA), and concomitant changes of symptoms, echocardiographic parameters of left ventricular (LV) function and morphology and results of the Short Form-36 (SF-36) Health Survey in participants of the Interdisciplinary Network Heart Failure (INH) programme. The INH study evaluated a nurse-coordinated management, HeartNetCare-HF(TM) (HNC), against Usual Care (UC) in patients hospitalized for decompensated HF [LV ejection fraction (LVEF) ≤40% before discharge). A total of 706 subjects surviving >18 months (363 UC, 343 HNC) were examined 6-monthly. At baseline, 92% received ACEi/ARB, (HNC/UC 91/93%, P = 0.28), 86% received beta-blockers (86/86%, P = 0.83), and 44% received MRA (42/47%, P = 0.07). After 18 months, beta-blocker use had increased only in HNC (+7.6%, P change +17/+14%, P = 0.010), LV end-diastolic diameter (59 ± 9 vs. 61 ± 9.6 mm, P = 0.024, change -2.3/-1.4 mm, P = 0.13), New York Heart Association class (1.9 ± 0.7 vs. 2.1 ± 0.7, P = 0.001, change -0.44/-0.25, P = 0.002) and SF-36 physical component summary score (41.6 ± 11.2 vs. 38.5 ± 11.8, P = 0.004, change +3.3 vs. +1.1 score points, P changes after 18 months. © 2015 The Authors. European Journal of Heart Failure © 2015 European Society of Cardiology.

  1. Rationale and design of the Multidisciplinary Approach to Novel Therapies in Cardiology Oncology Research Trial (MANTICORE 101 - Breast: a randomized, placebo-controlled trial to determine if conventional heart failure pharmacotherapy can prevent trastuzumab-mediated left ventricular remodeling among patients with HER2+ early breast cancer using cardiac MRI

    Directory of Open Access Journals (Sweden)

    Ezekowitz Justin

    2011-07-01

    Full Text Available Abstract Background MANTICORE 101 - Breast (Multidisciplinary Approach to Novel Therapies in Cardiology Oncology Research is a randomized trial to determine if conventional heart failure pharmacotherapy (angiotensin converting enzyme inhibitor or beta-blocker can prevent trastuzumab-mediated left ventricular remodeling, measured with cardiac MRI, among patients with HER2+ early breast cancer. Methods/Design One hundred and fifty-nine patients with histologically confirmed HER2+ breast cancer will be enrolled in a parallel 3-arm, randomized, placebo controlled, double-blind design. After baseline assessments, participants will be randomized in a 1:1:1 ratio to an angiotensin-converting enzyme inhibitor (perindopril, beta-blocker (bisoprolol, or placebo. Participants will receive drug or placebo for 1 year beginning 7 days before trastuzumab therapy. Dosages for all groups will be systematically up-titrated, as tolerated, at 1 week intervals for a total of 3 weeks. The primary objective of this randomized clinical trial is to determine if conventional heart failure pharmacotherapy can prevent trastuzumab-mediated left ventricular remodeling among patients with HER2+ early breast cancer, as measured by 12 month change in left ventricular end-diastolic volume using cardiac MRI. Secondary objectives include 1 determine the evolution of left ventricular remodeling on cardiac MRI in patients with HER2+ early breast cancer, 2 understand the mechanism of trastuzumab mediated cardiac toxicity by assessing for the presence of myocardial injury and apoptosis on serum biomarkers and cardiac MRI, and 3 correlate cardiac biomarkers of myocyte injury and extra-cellular matrix remodeling with left ventricular remodeling on cardiac MRI in patients with HER2+ early breast cancer. Discussion Cardiac toxicity as a result of cancer therapies is now recognized as a significant health problem of increasing prevalence. To our knowledge, MANTICORE will be the first

  2. Training-induced right ventricular remodelling in pre-adolescent endurance athletes: The athlete's heart in children.

    Science.gov (United States)

    D'Ascenzi, Flavio; Pelliccia, Antonio; Valentini, Francesca; Malandrino, Angela; Natali, Benedetta Maria; Barbati, Riccardo; Focardi, Marta; Bonifazi, Marco; Mondillo, Sergio

    2017-06-01

    Little is known about the adaptation of the right ventricle (RV) to endurance exercise in children. The aim of this study was to assess the effects of 5months of intensive training on RV morphology and function in preadolescent endurance athletes. Ninety-four children were evaluated in this study. Fifty-seven male competitive swimmers (aged 10.8±0.2years) were evaluated before (baseline) and after 5months of the training (peak-training), and compared to 37 age- and sex-matched non-athlete children evaluated at baseline and after 5months of natural growth. All subjects were asymptomatic, with negative family history for cardiomyopathies. At baseline no differences were found between athletes and controls for indexed RV outflow tract (RVOT) (18.5±2.7 vs. 16.8±5.0mm/m2, p=0.18) and RV basal end-diastolic diameter (EDD) (24.9±4.1 vs. 23.6±3.0mm/m2, p=0.15). After 5months, indexed RVOT and RV basal EDD significantly increased in athletes (20.2±2.9mm/m2 and 25.4±3.3mm/m2, pchildren engaged in endurance sports the increase in RV size associated with normal RV function represents a physiological expression of the athlete's heart and should not be misinterpreted as an expression of incipient RV cardiomyopathy. Copyright © 2017 Elsevier B.V. All rights reserved.

  3. Altered Liver Proteoglycan/Glycosaminoglycan Structure as a Manifestation of Extracellular Matrix Remodeling upon BCG-induced Granulomatosis in Mice.

    Science.gov (United States)

    Kim, L B; Shkurupy, V A; Putyatina, A N

    2017-01-01

    Experimental BCG-induced granulomatosis in mice was used to study changes in the dynamics of individual liver proteoglycan components reflecting phasic extracellular matrix remodeling, determined by the host-parasite interaction and associated with granuloma development. In the early BCG-granulomatosis period, the increase in individual proteoglycan components promotes granuloma formation, providing conditions for mycobacteria adhesion to host cells, migration of phagocytic cells from circulation, and cell-cell interaction leading to granuloma development and fibrosis. Later, reduced reserve capacity of the extracellular matrix, development of interstitial fibrosis and granuloma fibrosis can lead to trophic shortage for cells within the granulomas, migration of macrophages out of them, and development of spontaneous necrosis and apoptosis typical of tuberculosis.

  4. Time-dependent evolution of functional vs. remodeling signaling in induced pluripotent stem cell-derived cardiomyocytes and induced maturation with biomechanical stimulation.

    Science.gov (United States)

    Jung, Gwanghyun; Fajardo, Giovanni; Ribeiro, Alexandre J S; Kooiker, Kristina Bezold; Coronado, Michael; Zhao, Mingming; Hu, Dong-Qing; Reddy, Sushma; Kodo, Kazuki; Sriram, Krishna; Insel, Paul A; Wu, Joseph C; Pruitt, Beth L; Bernstein, Daniel

    2016-04-01

    Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) are a powerful platform for uncovering disease mechanisms and assessing drugs for efficacy/toxicity. However, the accuracy with which hiPSC-CMs recapitulate the contractile and remodeling signaling of adult cardiomyocytes is not fully known. We used β-adrenergic receptor (β-AR) signaling as a prototype to determine the evolution of signaling component expression and function during hiPSC-CM maturation. In "early" hiPSC-CMs (less than or equal to d 30), β2-ARs are a primary source of cAMP/PKA signaling. With longer culture, β1-AR signaling increases: from 0% of cAMP generation at d 30 to 56.8 ± 6.6% by d 60. PKA signaling shows a similar increase: 15.7 ± 5.2% (d 30), 49.8 ± 0.5% (d 60), and 71.0 ± 6.1% (d 90). cAMP generation increases 9-fold from d 30 to 60, with enhanced coupling to remodeling pathways (e.g., Akt and Ca(2+)/calmodulin-dependent protein kinase type II) and development of caveolin-mediated signaling compartmentalization. By contrast, cardiotoxicity induced by chronic β-AR stimulation, a major component of heart failure, develops much later: 5% cell death at d 30vs 55% at d 90. Moreover, β-AR maturation can be accelerated by biomechanical stimulation. The differential maturation of β-AR functionalvs remodeling signaling in hiPSC-CMs has important implications for their use in disease modeling and drug testing. We propose that assessment of signaling be added to the indices of phenotypic maturation of hiPSC-CMs.-Jung, G., Fajardo, G., Ribeiro, A. J. S., Kooiker, K. B., Coronado, M., Zhao, M., Hu, D.-Q., Reddy, S., Kodo, K., Sriram, K., Insel, P. A., Wu, J. C., Pruitt, B. L., Bernstein, D. Time-dependent evolution of functionalvs remodeling signaling in induced pluripotent stem cell-derived cardiomyocytes and induced maturation with biomechanical stimulation. © FASEB.

  5. Fluoxetine induces input-specific hippocampal dendritic spine remodeling along the septo-temporal axis in adulthood and middle age

    Science.gov (United States)

    McAvoy, Kathleen; Russo, Craig; Kim, Shannen; Rankin, Genelle; Sahay, Amar

    2015-01-01

    Fluoxetine, a selective serotonin-reuptake inhibitor (SSRI), is known to induce structural rearrangements and changes in synaptic transmission in hippocampal circuitry. In the adult hippocampus, structural changes include neurogenesis, dendritic and axonal plasticity of pyramidal and dentate granule neurons, and dedifferentiation of dentate granule neurons. However, much less is known about how chronic fluoxetine affects these processes along the septo-temporal axis and during the aging process. Importantly, studies documenting the effects of fluoxetine on density and distribution of spines along different dendritic segments of dentate granule neurons and CA1 pyramidal neurons along the septo-temporal axis of hippocampus in adulthood and during aging are conspicuously absent. Here, we use a transgenic mouse line in which mature dentate granule neurons and CA1 pyramidal neurons are genetically labeled with green fluorescent protein (GFP) to investigate the effects of chronic fluoxetine treatment (18mg/kg/day) on input-specific spine remodeling and mossy fiber structural plasticity in the dorsal and ventral hippocampus in adulthood and middle age. In addition, we examine levels of adult hippocampal neurogenesis, maturation state of dentate granule neurons, neuronal activity and glutamic acid decarboxylase-67 expression in response to chronic fluoxetine in adulthood and middle age. Our studies reveal that while chronic fluoxetine fails to augment adult hippocampal neurogenesis in middle age, the middle-aged hippocampus retains high sensitivity to changes in the dentate gyrus (DG) such as dematuration, hypoactivation, and increased glutamic acid decarboxylase 67 (GAD67) expression. Interestingly, the middle-aged hippocampus shows greater sensitivity to fluoxetine-induced input-specific synaptic remodeling than the hippocampus in adulthood with the stratum-oriens of CA1 exhibiting heightened structural plasticity. The input-specific changes and circuit

  6. Fluoxetine induces input-specific hippocampal dendritic spine remodeling along the septotemporal axis in adulthood and middle age.

    Science.gov (United States)

    McAvoy, Kathleen; Russo, Craig; Kim, Shannen; Rankin, Genelle; Sahay, Amar

    2015-11-01

    Fluoxetine, a selective serotonin-reuptake inhibitor (SSRI), is known to induce structural rearrangements and changes in synaptic transmission in hippocampal circuitry. In the adult hippocampus, structural changes include neurogenesis, dendritic, and axonal plasticity of pyramidal and dentate granule neurons, and dedifferentiation of dentate granule neurons. However, much less is known about how chronic fluoxetine affects these processes along the septotemporal axis and during the aging process. Importantly, studies documenting the effects of fluoxetine on density and distribution of spines along different dendritic segments of dentate granule neurons and CA1 pyramidal neurons along the septotemporal axis of hippocampus in adulthood and during aging are conspicuously absent. Here, we use a transgenic mouse line in which mature dentate granule neurons and CA1 pyramidal neurons are genetically labeled with green fluorescent protein (GFP) to investigate the effects of chronic fluoxetine treatment (18 mg/kg/day) on input-specific spine remodeling and mossy fiber structural plasticity in the dorsal and ventral hippocampus in adulthood and middle age. In addition, we examine levels of adult hippocampal neurogenesis, maturation state of dentate granule neurons, neuronal activity, and glutamic acid decarboxylase-67 expression in response to chronic fluoxetine in adulthood and middle age. Our studies reveal that while chronic fluoxetine fails to augment adult hippocampal neurogenesis in middle age, the middle-aged hippocampus retains high sensitivity to changes in the dentate gyrus (DG) such as dematuration, hypoactivation, and increased glutamic acid decarboxylase 67 (GAD67) expression. Interestingly, the middle-aged hippocampus shows greater sensitivity to fluoxetine-induced input-specific synaptic remodeling than the hippocampus in adulthood with the stratum-oriens of CA1 exhibiting heightened structural plasticity. The input-specific changes and circuit

  7. Impact of leucine supplementation on exercise training induced anti-cardiac remodeling effect in heart failure mice.

    Science.gov (United States)

    de Moraes, Wilson Max Almeida Monteiro; Melara, Thaís Plasti; de Souza, Pamella Ramona Moraes; Guimarães, Fabiana de Salvi; Bozi, Luiz Henrique Marchesi; Brum, Patricia Chakur; Medeiros, Alessandra

    2015-05-15

    Leucine supplementation potentiates the effects of aerobic exercise training (AET) on skeletal muscle; however, its potential effects associated with AET on cardiac muscle have not been clarified yet. We tested whether leucine supplementation would potentiate the anti-cardiac remodeling effect of AET in a genetic model of sympathetic hyperactivity-induced heart failure in mice (α2A/α2CARKO). Mice were assigned to five groups: wild type mice treated with placebo and sedentary (WT, n = 11), α2A/α2CARKO treated with placebo and sedentary (KO, n = 9), α2A/α2CARKO treated with leucine and sedentary (KOL, n = 11), α2A/α2CARKO treated with placebo and AET (KOT, n = 12) or α2A/α2CARKO treated with leucine and AET (KOLT, n = 12). AET consisted of four weeks on a treadmill with 60 min sessions (six days/week, 60% of maximal speed) and administration by gavage of leucine (1.35 g/kg/day) or placebo (distilled water). The AET significantly improved exercise capacity, fractional shortening and re-established cardiomyocytes' diameter and collagen fraction in KOT. Additionally, AET significantly prevented the proteasome hyperactivity, increased misfolded proteins and HSP27 expression. Isolated leucine supplementation displayed no effect on cardiac function and structure (KOL), however, when associated with AET (KOLT), it increased exercise tolerance to a higher degree than isolated AET (KOT) despite no additional effects on AET induced anti-cardiac remodeling. Our results provide evidence for the modest impact of leucine supplementation on cardiac structure and function in exercised heart failure mice. Leucine supplementation potentiated AET effects on exercise tolerance, which might be related to its recognized impact on skeletal muscle.

  8. Left ventricular SERCA2a gene down-regulation does not parallel ANP gene up-regulation during post-MI remodelling in rats.

    Science.gov (United States)

    Prunier, Fabrice; Chen, Ying; Gellen, Barnabas; Heimburger, Michèle; Choqueux, Christine; Escoubet, Brigitte; Michel, Jean-Baptiste; Mercadier, Jean-Jacques

    2005-08-01

    In most animal models of chronic hemodynamic overload of the left ventricle (LV) as well as in human end stage heart failure, the sarcoplasmic reticulum (SR) Ca2+-ATPase (SERCA2a) mRNA levels are decreased in parallel with increased atrial natriuretic peptide (ANP) mRNA levels. The situation in the remote myocardium following myocardial infarction (MI) is unclear. (1) To examine SERCA2a mRNA levels in the non-infarcted LV myocardium of rats at the chronic stage of experimental MI and (2) To examine whether a negative linear correlation exists between SERCA2a and ANP mRNA levels in this model. Anesthetized adult male Wistar rats underwent left coronary artery ligation or sham operation. Three months later, the rats were divided into three groups: sham-operated rats (sham, n=21), HF-free rats with MI (non-failing (NF)-MI, n=29) and rats with both MI and HF (congestive heart failure (CHF)-MI, n=14). LV remodelling and function were assessed by echocardiography and hemodynamic measurements. SERCA2a and ANP mRNA levels were determined by Northern and dot blot analysis with specific cDNA probes. LV SERCA2a mRNA levels varied markedly in sham-operated rats (0.9-1.8). Mean ANP mRNA level increased markedly and mean SERCA2a mRNA level decreased moderately in the remote myocardium. In some NF-MI rats, SERCA2a mRNA levels were higher than those in some sham controls. Whereas ANP mRNA levels correlated well with MI severity (r2=0.79, p<0.001), this was not the case for SERCA2a mRNA levels (r2=0.42, p<0.01). We found no negative correlation between ANP and SERCA2a mRNA levels. SERCA2a gene down-regulation in the non-infarcted myocardium of rats with MI does not correlate with ANP gene up-regulation, suggesting that the two genes are not antithetically regulated.

  9. Whole-thorax irradiation induces hypoxic respiratory failure, pleural effusions and cardiac remodeling.

    Science.gov (United States)

    Medhora, Meetha; Gao, Feng; Glisch, Chad; Narayanan, Jayashree; Sharma, Ashish; Harmann, Leanne M; Lawlor, Michael W; Snyder, Laura A; Fish, Brian L; Down, Julian D; Moulder, John E; Strande, Jennifer L; Jacobs, Elizabeth R

    2015-03-01

    To study the mechanisms of death following a single lethal dose of thoracic radiation, WAG/RijCmcr (Wistar) rats were treated with 15 Gy to the whole thorax and followed until they were morbid or sacrificed for invasive assays at 6 weeks. Lung function was assessed by breathing rate and arterial oxygen saturation. Lung structure was evaluated histologically. Cardiac structure and function were examined by echocardiography. The frequency and characteristics of pleural effusions were determined. Morbidity from 15 Gy radiation occurred in all rats 5 to 8 weeks after exposure, coincident with histological pneumonitis. Increases in breathing frequencies peaked at 6 weeks, when profound arterial hypoxia was also recorded. Echocardiography analysis at 6 weeks showed pulmonary hypertension and severe right ventricular enlargement with impaired left ventricular function and cardiac output. Histologic sections of the heart revealed only rare foci of lymphocytic infiltration. Total lung weight more than doubled. Pleural effusions were present in the majority of the irradiated rats and contained elevated protein, but low lactate dehydrogenase, when compared with serum from the same animal. Pleural effusions had a higher percentage of macrophages and large monocytes than neutrophils and contained mast cells that are rarely present in other pathological states. Lethal irradiation to rat lungs leads to hypoxia with infiltration of immune cells, edema and pleural effusion. These changes may contribute to pulmonary vascular and parenchymal injury that result in secondary changes in heart structure and function. We report that conditions resembling congestive heart failure contribute to death during radiation pneumonitis, which indicates new targets for therapy. © The Author 2014. Published by Oxford University Press on behalf of The Japan Radiation Research Society and Japanese Society for Radiation Oncology.

  10. Unusual cause of exercise-induced ventricular fibrillation in a well-trained adult endurance athlete: a case report

    Directory of Open Access Journals (Sweden)

    Vogt Stefan

    2008-04-01

    Full Text Available Abstract Introduction The diseases responsible for sudden deaths in athletes differ considerably with regard to age. In young athletes, congenital malformations of the heart and/or vascular system cause the majority of deaths and can only be detected noninvasively by complex diagnostics. In contrast, in older athletes who die suddenly, atherosclerotic disease of the coronary arteries is mostly found. Reports of congenital coronary anomalies as a cause of sudden death in older athletes are rare. Case presentation A 48-year-old man who was a well-trained, long-distance runner collapsed at the finish of a half marathon because of a myocardial infarction with ventricular fibrillation. Coronary angiography showed an anomalous origin of the right coronary artery from the left sinus of Valsalva with minimal wall alterations. Multislice computed tomography of the coronary arteries confirmed these findings. Cardiomagnetic resonance imaging demonstrated a mild hypokinesia of the basal right- and left-ventricular posterior wall. An electrophysiological study showed an inducible temporary polymorphic ventricular tachycardia and an inducible ventricular fibrillation. The athlete was subsequently treated by acetylsalicylic acid 100 mg (0-1-0, bisoprolol 2.5 mg (1-0-0 and atorvastatin 10 mg (0-0-1 and was instructed to keep his training intensity under the 'individual anaerobic threshold'. Intense and long-lasting exercise under extreme environmental conditions, particularly heat, should also be avoided. Conclusion This case report presents a coronary anomaly as the most likely reason for an exercise-induced myocardial infarction with ventricular fibrillation in a well-trained 48-year-old endurance athlete. Therefore, coronary anomalies have also to be considered as a possible cause of cardiac problems in older athletes.

  11. Static Stretch Induces Active Morphological Remodeling and Functional Impairment of Alveolar Epithelial Cells

    National Research Council Canada - National Science Library

    Ren, Yanhong; Zhan, Qingyuan; Hu, Qinghua; Sun, Bing; Yang, Chun; Wang, Chen

    2009-01-01

    Background: Static stretch is frequently observed in the lung. Both static stretch and cyclic stretch can induce cell death and Na /K -ATPase trafficking, but stretch-induced alveolar epithelial cell (AEC...

  12. β3-Adrenoceptor Mediates Metabolic Protein Remodeling in a Rabbit Model of Tachypacing-Induced Atrial Fibrillation

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    Yixi Liu

    2013-12-01

    Full Text Available Background: The beta 3-adrenoceptor (β3-AR is closely associated with energy metabolism. This study aimed to explore the role of β3-AR in energy remodeling in a rabbit model of pacing-induced atrial fibrillation (AF. Methods: Rabbits with a sham-operation or pacing-induced AF were used for this study, and the latter group was further divided into three subgroups: 1 the pacing group, 2 the β3-AR agonist (BRL37344-treated group, and 3 the β3-AR antagonist (SR59230A-treated group. Atrial electrogram morphology and surface ECG were used to monitor the induction of AF and atrial effective refractory period (AERP. RT-PCR and western blot (WB were used to show alterations in β3-AR and metabolic-related protein. Results: RT-PCR and WB results showed that β3-AR was significantly upregulated in the pacing group, and that it corresponded with high AF inducibility and significantly decreased AERP200 and ATP production in this group. Inhibition of β3-AR decreased the AF induction rate, reversed AERP200 reduction, and restored ATP levels in the AF rabbits. Further activation of β3-AR using agonist BRL37344 exacerbated AF-induced metabolic disruption. Periodic acid Schiff (PAS and Oil Red O staining showed β3-AR-dependent glycogen and lipid droplet accumulation in cardiac myocytes with AF. Glucose transporter-4 (GLUT-4 and CD36, key transporters of glucose and fatty acids, were downregulated in the pacing group. Expression of carnitine-palmitoyltransferase I (CPT-1, a key regulator in fatty acid metabolism, was also significantly downregulated in the pacing group. Reduced glucose transportation and fatty acid oxidation could be restored by inhibition of β3-AR. Furthermore, key regulators of metabolism, peroxisome proliferator-activated receptor-α (PPARα and PPAR co-activator (PGC-1α can be regulated by pharmacological intervention of the β3-AR. Conclusions: β3-AR is involved in metabolic protein remodeling in AF. PPARα/PGC-1α signaling pathway

  13. Trimetazidine attenuates pressure overload-induced early cardiac energy dysfunction via regulation of neuropeptide Y system in a rat model of abdominal aortic constriction

    OpenAIRE

    Chen, Ailan; Li, Wanglin; Chen, Xinyu; Shen, Yuechun; Dai, Wenjun; Dong, Qi; Li, Xinchun; Ou, Caiwen; Chen, Minsheng

    2016-01-01

    Background Metabolism remodeling has been recognized as an early event following cardiac pressure overload. However, its temporal association with ventricular hypertrophy has not been confirmed. Moreover, whether trimetazidine could favorably affect this process also needs to be determined. The aim of the study was to explore the temporal changes of myocardial metabolism remodeling following pressure-overload induced ventricular hypertrophy and the potential favorable effect of trimetazidine ...

  14. S-diclofenac protects against doxorubicin-induced cardiomyopathy in mice via ameliorating cardiac gap junction remodeling.

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    Huili Zhang

    Full Text Available Hydrogen sulfide (H(2S, as a novel gaseous mediator, plays important roles in mammalian cardiovascular tissues. In the present study, we investigated the cardioprotective effect of S-diclofenac (2-[(2,6-dichlorophenylamino] benzeneacetic acid 4-(3H-1,2,dithiol-3-thione-5-ylphenyl ester, a novel H(2S-releasing derivative of diclofenac, in a murine model of doxorubicin-induced cardiomyopathy. After a single dose injection of doxorubicin (15 mg/kg, i.p., male C57BL/6J mice were given daily treatment of S-diclofenac (25 and 50 µmol/kg, i.p., diclofenac (25 and 50 µmol/kg, i.p., NaHS (50 µmol/kg, i.p., or same volume of vehicle. The cardioprotective effect of S-diclofenac was observed after 14 days. It showed that S-diclofenac, but not diclofenac, dose-dependently inhibited the doxorubicin-induced downregulation of cardiac gap junction proteins (connexin 43 and connexin 45 and thus reversed the remodeling of gap junctions in hearts. It also dose-dependently suppressed doxorubicin-induced activation of JNK in hearts. Furthermore, S-diclofenac produced a dose-dependent anti-inflammatory and anti-oxidative effect in this model. As a result, S-diclofenac significantly attenuated doxorubicin-related cardiac injury and cardiac dysfunction, and improved the survival rate of mice with doxorubicin-induced cardiomyopathy. These effects of S-diclofenac were mimicked in large part by NaHS. Therefore, we propose that H(2S released from S-diclofenac in vivo contributes to the protective effect in doxorubicin-induced cardiomyopathy. These data also provide evidence for a critical role of H(2S in the pathogenesis of doxorubicin-induced cardiomyopathy.

  15. Iron oxide nanoparticles induce human microvascular endothelial cell permeability through reactive oxygen species production and microtubule remodeling

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    Shi Xianglin

    2009-01-01

    Full Text Available Abstract Background Engineered iron nanoparticles are being explored for the development of biomedical applications and many other industry purposes. However, to date little is known concerning the precise mechanisms of translocation of iron nanoparticles into targeted tissues and organs from blood circulation, as well as the underlying implications of potential harmful health effects in human. Results The confocal microscopy imaging analysis demonstrates that exposure to engineered iron nanoparticles induces an increase in cell permeability in human microvascular endothelial cells. Our studies further reveal iron nanoparticles enhance the permeability through the production of reactive oxygen species (ROS and the stabilization of microtubules. We also showed Akt/GSK-3β signaling pathways are involved in iron nanoparticle-induced cell permeability. The inhibition of ROS demonstrate ROS play a major role in regulating Akt/GSK-3β – mediated cell permeability upon iron nanoparticle exposure. These results provide new insights into the bioreactivity of engineered iron nanoparticles which can inform potential applications in medical imaging or drug delivery. Conclusion Our results indicate that exposure to iron nanoparticles induces an increase in endothelial cell permeability through ROS oxidative stress-modulated microtubule remodeling. The findings from this study provide new understandings on the effects of nanoparticles on vascular transport of macromolecules and drugs.

  16. The effect of cannabidiol on ischemia/reperfusion-induced ventricular arrhythmias: the role of adenosine A1 receptors.

    Science.gov (United States)

    Gonca, Ersöz; Darıcı, Faruk

    2015-01-01

    Cannabidiol (CBD) is a nonpsychoactive phytocannabinoid with anti-inflammatory activity mediated by enhancing adenosine signaling. As the adenosine A1 receptor activation confers protection against ischemia/reperfusion (I/R)-induced ventricular arrhythmias, we hypothesized that CBD may have antiarrhythmic effect through the activation of adenosine A1 receptor. Cannabidiol has recently been shown to suppress ischemia-induced ventricular arrhythmias. We aimed to research the effect of CBD on the incidence and the duration of I/R-induced ventricular arrhythmias and to investigate the role of adenosine A1 receptor activation in the possible antiarrhythmic effect of CBD. Myocardial ischemia and reperfusion was induced in anesthetized male rats by ligating the left anterior descending coronary artery for 6 minutes and by loosening the bond at the coronary artery, respectively. Cannabidiol alone was given in a dose of 50 µg/kg, 10 minutes prior to coronary artery occlusion and coadministrated with adenosine A1 receptor antagonist 8-cyclopentyl-1,3-dipropylxanthine (DPCPX) in a dose of 100 µg/kg, 15 minutes prior to coronary artery occlusion to investigate whether the antiarrhythmic effect of CBD is modified by the activation of adenosine A1 receptors. The experimental groups were as follows: (1) vehicle control (n = 10), (2) CBD (n = 9), (3) DPCPX (n = 7), and (4) CBD + DPCPX group (n = 7). Cannabidiol treatment significantly decreased the incidence and the duration of ventricular tachycardia, total length of arrhythmias, and the arrhythmia scores compared to control during the reperfusion period. The DPCPX treatment alone did not affect the incidence and the duration of any type of arrhythmias. However, DPCPX aborted the antiarrhythmic effect of CBD when it was combined with it. The present results demonstrated that CBD has an antiarrhythmic effect against I/R-induced arrhythmias, and the antiarrhythmic effect of CBD may be mediated through the activation of adenosine

  17. The role of chemokine ligand 16 in high salt induced myocardial remodeling in salt sensitive hypertensive rats

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    Mei-li LIU

    2015-11-01

    Full Text Available Objective To investigate the effects of chemokine ligand 16 (CXCL16 in high salt induced myocardial remodeling in salt sensitive hypertensive rats. Methods Sixty-four Dahl salt sensitive (Dahl-SS rats were randomly divided into normal salt (NS, 0.3% NaCl and high salt (HS, 8.0% NaCl group, 32 rats for each group. Blood pressure was measured by tail-cuff method every week. Hearts were harvested and the expression of CXCL16 in heart tissues was detected by Western blotting at the 2nd, 4th, 6th and 8th week after NS or HS feeding. Immunofluorescence double staining was used to detect the colocalization of CXCL16 with both cardiomyocytes and cardiac fibroblasts. Immunofluorescence and immunohistochemical staining were used to detect the expression of CXCL16 and the biomarker of macrophage in the myocardial tissue after 6 week and 8 week of NS or HS feeding. Myocardial fibrosis was evaluated by HE and Masson trichrome staining. Results Compared with that in NS group, the systolic pressure and diastolic pressure in HS group increased significantly after 1 week of HS feeding (147.10±3.67mmHg vs128.57±6.32mmHg, P<0.01 and 110.86±4.24mmHg vs90.69±4.51mmHg, P<0.01, respectively. HS feeding significantly increased the myocardial CXCL16 expression in rats of HS group at the 6th week (1.18±0.05 vs0.58±0.02, P<0.05, and the expression of CXCL16 was further up-regulated at the 8th week (1.43±0.06 vs0.67±0.03, P<0.05. At the 8th week, obvious fibrosis remodeling and macrophage infiltration appeared in the myocardial tissue of the rats in HS group. Conclusion High salt intervention could up-regulate the expression of CXCL16 in salt sensitive hypertensive myocardial remodeling, which may promote macrophage infiltration and participate in the pathological process of myocardial fibrosis accordingly. DOI: 10.11855/j.issn.0577-7402.2015.11.04

  18. An overproduction of astellolides induced by genetic disruption of chromatin-remodeling factors in Aspergillus oryzae.

    Science.gov (United States)

    Shinohara, Yasutomo; Kawatani, Makoto; Futamura, Yushi; Osada, Hiroyuki; Koyama, Yasuji

    2016-01-01

    The filamentous fungus Aspergillus oryzae is an important industrial mold. Recent genomic analysis indicated that A. oryzae has a large number of biosynthetic genes for secondary metabolites (SMs), but many of the SMs they produce have not been identified. For better understanding of SMs production by A. oryzae, we screened a gene-disruption library of transcription factors including chromatin-remodeling factors and found two gene disruptions that show similarly altered SM production profiles. One is a homolog of Aspergillus nidulans cclA, a component of the histone 3 lysine 4 (H3K4) methyltransferase complex of proteins associated with Set1 complex, and the other, sppA, is an ortholog of Saccharomyces cerevisiae SPP1, another component of a complex of proteins associated with Set1 complex. The cclA and sppA disruptions in A. oryzae are deficient in trimethylation of H3K4. Furthermore, one of the SMs that increased in the cclA disruptant was identified as astellolide F (14-deacetyl astellolide B). These data indicate that both cclA and sppA affect production of SMs including astellolides by affecting the methylation status of H3K4 in A. oryzae.

  19. Endovascular photodynamic therapy with aminolaevulinic acid prevents balloon induced intimal hyperplasia and constrictive remodelling.

    Science.gov (United States)

    Gabeler, E E E; van Hillegersberg, R; Statius van Eps, R G; Sluiter, W; Mulder, P; van Urk, H

    2002-10-01

    intimal hyperplasia (IH) and constrictive remodelling are important causes of restenosis following endovascular interventions, such as percutaneous transluminal angioplasty. Photodynamic therapy (PDT) with 5-aminolaevulinic (ALA) may prevent restenosis by cellular depletion and the elimination of cholinergic innervation. rats (n=90) were subdivided into 4 main groups. In the experimental group (n=36: 3 replications x 4 doses x 3 examination time-points), ALA was administered (200mg/kg i.v.) 2-3h before balloon injury (BI) of the common iliac artery followed by endovascular illumination with 633nm at either 12.5, 25, 50 or 100J/cm diffuser length (dl BI+PDT group). As control groups served the BI+Light only (LO) group (n=36) that received no ALA, the BI only group (n=9) (BI), and a group (n=9) that received a Sham procedure (Sham group). planimetric analysis showed IH of 0.28+/-0.12mm(2) (BI), 0.27+/-0.12mm(2) (BI+LO at 100J/cmdl) in contrast to 0.02+/-0.02mm(2) after BI+PDT at 100J/cmdl at 16 weeks (pcmdl.

  20. The Role of the Rho/ROCK Pathway in Ang II and TGF-β1-Induced Atrial Remodeling.

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    Li-Juan Liu

    Full Text Available To study the role of the Rho/ROCK pathway in Ang II and TGF-β1-induced atrial remodeling.A canine atrial fibrillation (AF model was established by rapid atrial pacing (RAP of the left atrium. The roles of TGF-β1, the RhoA/ROCK signaling pathway and connective tissue growth factor (CTGF in atrial remodeling were studied via both in vitro and in vivo experiments. Each of the dogs that received RAP developed persistent AF within 4 weeks. The mRNA expression levels of TGF-β1 (1.32±0.38, Collagen-I(1.33±0.91, CTGF(5.83±3.71, RhoA(1.23±0.57 and ROCK-1 (1.02±0.27 in the left atrium were significantly increased following 4 weeks of RAP. Angiotensin II (Ang II induced the proliferation of atrial fibroblasts and up-regulated the expression of both CTGF and ROCK-1 in a dose-dependent manner. Simvastatin and Y27632 reversed Ang II-induced CFs proliferation, as well as ROCK-1(0.89±0.05 and 1.27±0.03, respectively and CTGF (0.87±0.04 and 0.91±0.02, respectively expression. The expression mRNA of ROCK-1(1.74±0.13 and CTGF (2.28±0.11 can upregulated by TGF-β1, and down-regulated by Simvastatin (1.22±0.03 vs 2.27±0.11, Y27632 (1.01±0.04 vs 1.64±0.03, Los (1.04±0.11 vs 1.26±0.05, respectively. Losartan and Simvastatin attenuated the effects of TGF-β1, inhibited RhoA activity as opposed to RhoA protein expression. Y27632 had no effect on either the expression or the activity of RhoA.The increased expression of profibrotic factors (CTGF, ROCK1 and Smad2/3 played an important role in our RAP-induced AF model. Increased atrial profibrotic factors involve the activation of either the TGF-β1/RhoA/ROCK-1 or the TGF-β1/Smad2/3 signaling pathway.

  1. The Role of the Rho/ROCK Pathway in Ang II and TGF-β1-Induced Atrial Remodeling.

    Science.gov (United States)

    Liu, Li-Juan; Yao, Feng-Juan; Lu, Gui-Hua; Xu, Cheng-Gui; Xu, Zhe; Tang, Kai; Cheng, Yun-Jiu; Gao, Xiu-Ren; Wu, Su-Hua

    2016-01-01

    To study the role of the Rho/ROCK pathway in Ang II and TGF-β1-induced atrial remodeling. A canine atrial fibrillation (AF) model was established by rapid atrial pacing (RAP) of the left atrium. The roles of TGF-β1, the RhoA/ROCK signaling pathway and connective tissue growth factor (CTGF) in atrial remodeling were studied via both in vitro and in vivo experiments. Each of the dogs that received RAP developed persistent AF within 4 weeks. The mRNA expression levels of TGF-β1 (1.32±0.38), Collagen-I(1.33±0.91), CTGF(5.83±3.71), RhoA(1.23±0.57) and ROCK-1 (1.02±0.27) in the left atrium were significantly increased following 4 weeks of RAP. Angiotensin II (Ang II) induced the proliferation of atrial fibroblasts and up-regulated the expression of both CTGF and ROCK-1 in a dose-dependent manner. Simvastatin and Y27632 reversed Ang II-induced CFs proliferation, as well as ROCK-1(0.89±0.05 and 1.27±0.03, respectively) and CTGF (0.87±0.04 and 0.91±0.02, respectively) expression. The expression mRNA of ROCK-1(1.74±0.13) and CTGF (2.28±0.11) can upregulated by TGF-β1, and down-regulated by Simvastatin (1.22±0.03 vs 2.27±0.11), Y27632 (1.01±0.04 vs 1.64±0.03), Los (1.04±0.11 vs 1.26±0.05), respectively. Losartan and Simvastatin attenuated the effects of TGF-β1, inhibited RhoA activity as opposed to RhoA protein expression. Y27632 had no effect on either the expression or the activity of RhoA. The increased expression of profibrotic factors (CTGF, ROCK1 and Smad2/3) played an important role in our RAP-induced AF model. Increased atrial profibrotic factors involve the activation of either the TGF-β1/RhoA/ROCK-1 or the TGF-β1/Smad2/3 signaling pathway.

  2. Adipose tissue remodeling in late-lactation dairy cows during feed-restriction-induced negative energy balance.

    Science.gov (United States)

    Contreras, G Andres; Thelen, Kyan; Schmidt, Sarah E; Strieder-Barboza, Clarissa; Preseault, Courtney L; Raphael, William; Kiupel, Matti; Caron, John; Lock, Adam L

    2016-12-01

    Excessive rates of demand lipolysis in the adipose tissue (AT) during periods of negative energy balance (NEB) are associated with increased susceptibility to disease and limited lactation performance. Lipolysis induces a remodeling process within AT that is characterized by an inflammatory response, cellular proliferation, and changes in the extracellular matrix (ECMT). The adipose tissue macrophage (ATM) is a key component of the inflammatory response. Infiltration of ATM-forming cellular aggregates was demonstrated in transition cows, suggesting that ATM trafficking and phenotype changes may be associated with disease. However, it is currently unknown if ATM infiltration occurs in dairy cows only during NEB states related to the transition period or also during NEB-induced lipolysis at other stages of lactation. The objective of this study was to evaluate changes in ATM trafficking and inflammatory phenotypes, and the expression of genetic markers of AT remodeling in healthy late-lactation cows during feed restriction-induced NEB. After a 14-d (d -14 to d -1) preliminary period, Holstein cows were randomly assigned to 1 of 2 feeding protocols, ad libitum (AL) or feed restriction (FR), for 4 d (d 1-4). Caloric intake was reduced in FR to achieve a targeted energy balance of -15 Mcal/d of net energy for lactation. Omental and subcutaneous AT samples were collected laparoscopically to harvest stromal vascular fraction (SVF) cells on d -3 and 4. The FR induced a NEB of -14.1±0.62 Mcal/d of net energy for lactation, whereas AL cows remained in positive energy balance (3.2±0.66 Mcal/d of NEL). The FR triggered a lipolytic response reflected in increased plasma nonesterified fatty acids (0.65±0.05 mEq/L on d 4), enhanced phosphorylation of hormone sensitive lipase, and reduced adipocyte diameter. Flow cytometry and immunohistochemistry analysis revealed that on d 4, FR cows had increased numbers of CD172a+, an ATM (M1 and M2) surface marker, cells in SVF that were

  3. Combined therapy with shock wave and autologous bone marrow-derived mesenchymal stem cells alleviates left ventricular dysfunction and remodeling through inhibiting inflammatory stimuli, oxidative stress & enhancing angiogenesis in a swine myocardial infarction model.

    Science.gov (United States)

    Sheu, Jiunn-Jye; Lee, Fan-Yen; Yuen, Chun-Man; Chen, Yi-Ling; Huang, Tien-Hung; Chua, Sarah; Chen, Yung-Lung; Chen, Chih-Hung; Chai, Han-Tan; Sung, Pei-Hsun; Chang, Hsueh-Wen; Sun, Cheuk-Kwan; Yip, Hon-Kan

    2015-08-15

    We hypothesized that combined therapy with shock wave (SW) and autologous bone marrow-derived mesenchymal stem cells (BMDMSCs) is superior to either therapy alone for alleviating left ventricular (LV) dysfunction. Male mini-pigs (n=30) equally divided into group 1 (sham control), group 2 [acute myocardial infarction (AMI) by left coronary artery ligation], group 3 (AMI-SW), group 4 (AMI-BMDMSC), and group 5 (AMI-SW-BMDMSC) were sacrificed by day 60 and the hearts were collected for studies. Baseline LV injection fraction [LVEF (%)] and LV chamber size did not differ among the five groups (p>0.5). By day 60, LVEF was highest in group 1 and lowest in group 2, significantly higher in group 5 than that in groups 3 and 4, and significantly higher in group 4 than that in group 3 (p<0.001). Cellular and protein levels of VEGF, CXCR4, and SDF-1α were significantly increased progressively from groups 1 to 5 (all p<0.05). Small vessel number and protein expressions of CD31 and eNOS were highest in groups 1 and 5, lowest in group 2, and significantly higher in group 4 than those in group 3 (p<0.001). Protein (MMP-9, TNF-1α and NF-κB) and cellular (CD14+, CD40+) levels of inflammatory biomarkers, protein expressions of oxidative stress (oxidized protein, NOX-1, NOX-2), apoptosis (Bax, caspase-3, PARP), infarct size, and LV dimensions showed a pattern opposite to that of LVEF among all groups (all p<0.001). Combined SW-BMDMSC therapy is superior to either therapy alone for improving LVEF, reducing infarct size, and inhibiting LV remodeling. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

  4. Spice up the hypertension diet - curcumin and piperine prevent remodeling of aorta in experimental L-NAME induced hypertension

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    Janega Pavol

    2011-10-01

    Full Text Available Abstract Background Increase of blood pressure is accompanied by functional and morphological changes in the vascular wall. The presented study explored the effects of curcuma and black pepper compounds on increased blood pressure and remodeling of aorta in the rat model of experimental NO-deficient hypertension. Methods Wistar rats were administered for 6 weeks clear water or L-NAME (40 mg/kg/day dissolved in water, piperine (20 mg/kg/day, curcumin (100 mg/kg/day or their combination in corn oil by oral gavage. The systolic blood pressure was measured weekly. Histological slices of thoracic aorta were stained with hematoxylin and eosin, Mallory's phosphotungstic acid hematoxylin (PTAH, orcein, picrosirius red and van Gieson staining and with antibodies against smooth muscle cells actin. Microscopic pictures were digitally processed and morphometrically evaluated. Results The increase of blood pressure caused by L-NAME was partially prevented by piperine and curcumin, but the effect of their combination was less significant. Animals with hypertension had increased wall thickness and cross-sectional area of the aorta, accompanied by relative increase of PTAH positive myofibrils and decrease of elastin, collagen and actin content. Piperine was able to decrease the content of myofibrils and slightly increase actin, while curcumin also prevented elastin decrease. The combination of spices had similar effects on aortic morphology as curcumin itself. Conclusions Administration of piperine or curcumin, less their combination, is able to partially prevent the increase of blood pressure caused by chronic L-NAME administration. The spices modify the remodeling of the wall of the aorta induced by hypertension. Our results show that independent administration of curcumin is more effective in preventing negative changes in blood vessel morphology accompanying hypertensive disease.

  5. Sigma-1 receptor mediates cocaine-induced transcriptional regulation by recruiting chromatin-remodeling factors at the nuclear envelope.

    Science.gov (United States)

    Tsai, Shang-Yi A; Chuang, Jian-Ying; Tsai, Meng-Shan; Wang, Xiao-Fei; Xi, Zheng-Xiong; Hung, Jan-Jong; Chang, Wen-Chang; Bonci, Antonello; Su, Tsung-Ping

    2015-11-24

    The sigma-1 receptor (Sig-1R) chaperone at the endoplasmic reticulum (ER) plays important roles in cellular regulation. Here we found a new function of Sig-1R, in that it translocates from the ER to the nuclear envelope (NE) to recruit chromatin-remodeling molecules and regulate the gene transcription thereof. Sig-1Rs mainly reside at the ER-mitochondrion interface. However, on stimulation by agonists such as cocaine, Sig-1Rs translocate from ER to the NE, where Sig-1Rs bind NE protein emerin and recruit chromatin-remodeling molecules, including lamin A/C, barrier-to-autointegration factor (BAF), and histone deacetylase (HDAC), to form a complex with the gene repressor specific protein 3 (Sp3). Knockdown of Sig-1Rs attenuates the complex formation. Cocaine was found to suppress the gene expression of monoamine oxidase B (MAOB) in the brain of wild-type but not Sig-1R knockout mouse. A single dose of cocaine (20 mg/kg) in rats suppresses the level of MAOB at nuclear accumbens without affecting the level of dopamine transporter. Daily injections of cocaine in rats caused behavioral sensitization. Withdrawal from cocaine in cocaine-sensitized rats induced an apparent time-dependent rebound of the MAOB protein level to about 200% over control on day 14 after withdrawal. Treatment of cocaine-withdrawn rats with the MAOB inhibitor deprenyl completely alleviated the behavioral sensitization to cocaine. Our results demonstrate a role of Sig-1R in transcriptional regulation and suggest cocaine may work through this newly discovered genomic action to achieve its addictive action. Results also suggest the MAOB inhibitor deprenyl as a therapeutic agent to block certain actions of cocaine during withdrawal.

  6. Tissue remodeling: a mating-induced differentiation program for the Drosophila oviduct

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    Hoy Ronald R

    2008-12-01

    Full Text Available Abstract Background In both vertebrates and invertebrates, the oviduct is an epithelial tube surrounded by visceral muscles that serves as a conduit for gamete transport between the ovary and uterus. While Drosophila is a model system for tubular organ development, few studies have addressed the development of the fly's oviduct. Recent studies in Drosophila have identified mating-responsive genes and proteins whose levels in the oviduct are altered by mating. Since many of these molecules (e.g. Muscle LIM protein 84B, Coracle, Neuroglian have known roles in the differentiation of muscle and epithelia of other organs, mating may trigger similar differentiation events in the oviduct. This led us to hypothesize that mating mediates the last stages of oviduct differentiation in which organ-specific specializations arise. Results Using electron- and confocal-microscopy we identified tissue-wide post-mating changes in the oviduct including differentiation of cellular junctions, remodeling of extracellular matrix, increased myofibril formation, and increased innervation. Analysis of once- and twice-mated females reveals that some mating-responsive proteins respond only to the first mating, while others respond to both matings. Conclusion We uncovered ultrastructural changes in the mated oviduct that are consistent with the roles that mating-responsive proteins play in muscle and epithelial differentiation elsewhere. This suggests that mating triggers the late differentiation of the oviduct. Furthermore, we suggest that mating-responsive proteins that respond only to the first mating are involved in the final maturation of the oviduct while proteins that remain responsive to later matings are also involved in maintenance and ongoing function of the oviduct. Taken together, our results establish the oviduct as an attractive system to address mechanisms that regulate the late stages of differentiation and maintenance of a tubular organ.

  7. Tissue remodeling: a mating-induced differentiation program for the Drosophila oviduct

    Science.gov (United States)

    Kapelnikov, Anat; Rivlin, Patricia K; Hoy, Ronald R; Heifetz, Yael

    2008-01-01

    Background In both vertebrates and invertebrates, the oviduct is an epithelial tube surrounded by visceral muscles that serves as a conduit for gamete transport between the ovary and uterus. While Drosophila is a model system for tubular organ development, few studies have addressed the development of the fly's oviduct. Recent studies in Drosophila have identified mating-responsive genes and proteins whose levels in the oviduct are altered by mating. Since many of these molecules (e.g. Muscle LIM protein 84B, Coracle, Neuroglian) have known roles in the differentiation of muscle and epithelia of other organs, mating may trigger similar differentiation events in the oviduct. This led us to hypothesize that mating mediates the last stages of oviduct differentiation in which organ-specific specializations arise. Results Using electron- and confocal-microscopy we identified tissue-wide post-mating changes in the oviduct including differentiation of cellular junctions, remodeling of extracellular matrix, increased myofibril formation, and increased innervation. Analysis of once- and twice-mated females reveals that some mating-responsive proteins respond only to the first mating, while others respond to both matings. Conclusion We uncovered ultrastructural changes in the mated oviduct that are consistent with the roles that mating-responsive proteins play in muscle and epithelial differentiation elsewhere. This suggests that mating triggers the late differentiation of the oviduct. Furthermore, we suggest that mating-responsive proteins that respond only to the first mating are involved in the final maturation of the oviduct while proteins that remain responsive to later matings are also involved in maintenance and ongoing function of the oviduct. Taken together, our results establish the oviduct as an attractive system to address mechanisms that regulate the late stages of differentiation and maintenance of a tubular organ. PMID:19063748

  8. Tissue remodeling: a mating-induced differentiation program for the Drosophila oviduct.

    Science.gov (United States)

    Kapelnikov, Anat; Rivlin, Patricia K; Hoy, Ronald R; Heifetz, Yael

    2008-12-08

    In both vertebrates and invertebrates, the oviduct is an epithelial tube surrounded by visceral muscles that serves as a conduit for gamete transport between the ovary and uterus. While Drosophila is a model system for tubular organ development, few studies have addressed the development of the fly's oviduct. Recent studies in Drosophila have identified mating-responsive genes and proteins whose levels in the oviduct are altered by mating. Since many of these molecules (e.g. Muscle LIM protein 84B, Coracle, Neuroglian) have known roles in the differentiation of muscle and epithelia of other organs, mating may trigger similar differentiation events in the oviduct. This led us to hypothesize that mating mediates the last stages of oviduct differentiation in which organ-specific specializations arise. Using electron- and confocal-microscopy we identified tissue-wide post-mating changes in the oviduct including differentiation of cellular junctions, remodeling of extracellular matrix, increased myofibril formation, and increased innervation. Analysis of once- and twice-mated females reveals that some mating-responsive proteins respond only to the first mating, while others respond to both matings. We uncovered ultrastructural changes in the mated oviduct that are consistent with the roles that mating-responsive proteins play in muscle and epithelial differentiation elsewhere. This suggests that mating triggers the late differentiation of the oviduct. Furthermore, we suggest that mating-responsive proteins that respond only to the first mating are involved in the final maturation of the oviduct while proteins that remain responsive to later matings are also involved in maintenance and ongoing function of the oviduct. Taken together, our results establish the oviduct as an attractive system to address mechanisms that regulate the late stages of differentiation and maintenance of a tubular organ.

  9. A exposição crônica à fumaça do cigarro resulta em remodelação cardíaca e prejuízo da função ventricular em ratos Chronic cigarette smoke exposure results in cardiac remodeling and impaired ventricular function in rats

    Directory of Open Access Journals (Sweden)

    Édson Castardeli

    2005-04-01

    Full Text Available OBJETIVO: Determinar as alterações cardíacas estruturais e funcionais causadas pela exposição à fumaça do cigarro em ratos. MÉTODOS: Os animais foram aleatoriamente distribuídos em dois grupos: fumante (F, composto por 10 animais, expostos à fumaça do cigarro, na taxa de 40 cigarros/dia e controle (C, constituído por 10 animais não submetidos à exposição. Após 4 meses, os animais foram submetidos a estudo morfológico e funcional por meio do ecocardiograma. As variáveis estudadas foram analisadas pelo teste t ou pelo teste de Mann-Whitney. RESULTADOS: Os ratos fumantes apresentaram maior átrio esquerdo (F=4,2± 0,7mm; C=3,5±0,6mm; pOBJECTIVE: To determine the cardiac structural and functional alterations caused by cigarette smoke exposure in rats. METHODS: The animals were randomly distributed into the following 2 groups: 1 smokers (S, comprising 10 animals exposed to cigarette smoke at a rate of 40 cigarettes/day; and 2 control (C, comprising 10 animals not exposed to cigarette smoke. After 4 months, the animals underwent morphological and functional study with echocardiography. The variables studied were analyzed by use of the t test or the Mann-Whitney test. RESULTS: The smoking rats had a greater left atrium (S=4.2±0.7mm; C=3.5±0.6mm; P<0.05, and greater left ventricular diastolic (S=7.9±0.7mm; C=7.2±0.5mm; P<0.05 and systolic (S=4.1±0.5; C=3.4±0.5; P<0.05 diameters. The left ventricular mass index was greater in the smoking animals (S=1.5mg/kg±0.2; C=1.3mg/kg±0.2; P<0.05, and the ejection fraction (S=0.85±0.03; C=0.89±0.03; P<0.05 and the shortening fraction (S=47.8%±3.7; C=52.7%±4.6; P<0.05 were greater in the control group. No differences were observed in the diastolic transmitral flow variables (E wave, A wave, and E/A ratio. CONCLUSION: Chronic cigarette smoke exposure results in cardiac remodeling with a decrease in ventricular functional capacity.

  10. Adaptation of Candida albicans to environmental pH induces cell wall remodelling and enhances innate immune recognition.

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    Sarah L Sherrington

    2017-05-01

    Full Text Available Candida albicans is able to proliferate in environments that vary dramatically in ambient pH, a trait required for colonising niches such as the stomach, vaginal mucosal and the GI tract. Here we show that growth in acidic environments involves cell wall remodelling which results in enhanced chitin and β-glucan exposure at the cell wall periphery. Unmasking of the underlying immuno-stimulatory β-glucan in acidic environments enhanced innate immune recognition of C. albicans by macrophages and neutrophils, and induced a stronger proinflammatory cytokine response, driven through the C-type lectin-like receptor, Dectin-1. This enhanced inflammatory response resulted in significant recruitment of neutrophils in an intraperitoneal model of infection, a hallmark of symptomatic vaginal colonisation. Enhanced chitin exposure resulted from reduced expression of the cell wall chitinase Cht2, via a Bcr1-Rim101 dependent signalling cascade, while increased β-glucan exposure was regulated via a non-canonical signalling pathway. We propose that this "unmasking" of the cell wall may induce non-protective hyper activation of the immune system during growth in acidic niches, and may attribute to symptomatic vaginal infection.

  11. The TRPM4 channel is functionally important for the beneficial cardiac remodeling induced by endurance training.

    Science.gov (United States)

    Gueffier, Mélanie; Zintz, Justin; Lambert, Karen; Finan, Amanda; Aimond, Franck; Chakouri, Nourdine; Hédon, Christophe; Granier, Mathieu; Launay, Pierre; Thireau, Jérôme; Richard, Sylvain; Demion, Marie

    2017-02-01

    Cardiac hypertrophy (CH) is an adaptive process that exists in two distinct forms and allows the heart to adequately respond to an organism's needs. The first form of CH is physiological, adaptive and reversible. The second is pathological, irreversible and associated with fibrosis and cardiomyocyte death. CH involves multiple molecular mechanisms that are still not completely defined but it is now accepted that physiological CH is associated more with the PI3-K/Akt pathway while the main signaling cascade activated in pathological CH involves the Calcineurin-NFAT pathway. It was recently demonstrated that the TRPM4 channel may act as a negative regulator of pathological CH by regulating calcium entry and thus the Cn-NFAT pathway. In this study, we examined if the TRPM4 channel is involved in the physiological CH process. We evaluated the effects of 4 weeks endurance training on the hearts of Trpm4 +/+ and Trpm4 -/- mice. We identified an elevated functional expression of the TRPM4 channel in cardiomyocytes after endurance training suggesting a potential role for the channel in physiological CH. We then observed that Trpm4 +/+ mice displayed left ventricular hypertrophy after endurance training associated with enhanced cardiac function. By contrast, Trpm4 -/- mice did not develop these adaptions. While Trpm4 -/- mice did not develop gross cardiac hypertrophy, the cardiomyocyte surface area was larger and associated with an increase of Tunel positive cells. Endurance training in Trpm4 +/+ mice did not increase DNA fragmentation in the heart. Endurance training in Trpm4 +/+ mice was associated with activation of the classical physiological CH Akt pathway while Trpm4 -/- favored the Calcineurin pathway. Calcium studies demonstrated that TRPM4 channel negatively regulates calcium entry providing support for activation of the Cn-NFAT pathway in Trpm4 -/- mice. In conclusion, we provide evidence for the functional expression of TRPM4 channel in response to endurance

  12. Lymphatics in Human Lymphatic Filariasis: In Vitro Models of Parasite-Induced Lymphatic Remodeling

    OpenAIRE

    Bennuru, Sasisekhar; Thomas B Nutman

    2009-01-01

    Lymphatic filariasis characterized by the dysfunction of the lymphatics can lead to severe (and often) irreversible lymphedema and elephantiasis. Decades of research in the field shows that the establishment of the adult parasites in the lymphatics triggers a cascade of events that ultimately results in tissue scarring and fibrosis. In this minireview, we focus on the studies addressing the mechanisms underlying the parasite-induced lymphatic dilatation that suggests parasite-induced lymphati...

  13. Calpain inhibition prevents pacing-induced cellular remodeling in a HL-1 myocyte model for atrial fibrillation

    NARCIS (Netherlands)

    Brundel, BJJM; Kampinga, HH; Henning, RH

    2004-01-01

    Objective: Atrial fibrillation (AF) is a progressive disease. Previously, clinical and animal experimental studies in AF revealed a variety of myocyte remodeling processes including L-type Ca(2+) channel reduction and structural changes, which finally result in electrical remodeling and contractile

  14. Regadenoson induces comparable left ventricular perfusion defects as adenosine: a quantitative analysis from the ADVANCE MPI 2 trial.

    Science.gov (United States)

    Mahmarian, John J; Cerqueira, Manuel D; Iskandrian, Ami E; Bateman, Timothy M; Thomas, Gregory S; Hendel, Robert C; Moye, Lemuel A; Olmsted, Ann W

    2009-08-01

    This study sought to determine whether regadenoson induces left ventricular perfusion defects of similar size and severity as seen with adenosine stress. Total and ischemic left ventricular perfusion defect size predict patient outcome. Therefore, it is important to show that newer stressor agents induce similar perfusion abnormalities as observed with currently available ones. The ADVANCE MPI 2 (Adenosine versus Regadenoson Comparative Evaluation for Myocardial Perfusion Imaging) study was a prospective, double-blind, randomized trial comparing image results in patients undergoing standard gated adenosine single-photon emission computed tomography (SPECT) myocardial perfusion imaging who were then randomized in a 2:1 ratio to either regadenoson (N = 495) or a second adenosine SPECT (N = 260). Quantitative SPECT analysis was used to determine total left ventricular perfusion defect size and the extent of ischemia. Quantification was performed by a single observer who was blinded to randomization and image sequence. Baseline gated perfusion results were similar in patients randomized to adenosine or regadenoson. No significant differences in total (11.5 +/- 15.7 vs. 11.4 +/- 15.8, p = 0.88) or ischemic (4.8 +/- 9.2 vs. 4.6 +/- 8.9, p = 0.43) perfusion defect sizes were observed between the regadenoson and adenosine groups, respectively. Linear regression showed a close correlation between adenosine and regadenoson for total (r = 0.97, p regadenoson versus adenosine, respectively. The good correlation between serial adenosine and regadenoson studies regarding total (0.41 +/- 5.43 vs. 0.21 +/- 5.23, p = 0.76) and ischemic (0.17 +/- 5.31 vs. 0.23 +/- 6.08, p = 0.94) perfusion defects persisted in the subgroup of 308 patients with an abnormal baseline SPECT. Applying quantitative analysis, regadenoson induces virtually identical scintigraphic results as adenosine regarding the size and severity of left ventricular perfusion defects and the extent of scintigraphic

  15. Ondansetron-induced ventricular tachycardia in a patient of caesarian section

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    Arpita Saxena

    2012-01-01

    Full Text Available We report a rare adverse effect of ondansetron in a 24-year-old female undergoing caesarian section, presenting as ventricular tachycardia and ectopics. Patient was treated with cardioversion and intravenous Amiodarone 150 mg.

  16. Candesartan ameliorates arsenic-induced hypertensive vascular remodeling by regularizing angiotensin II and TGF-beta signaling in rats.

    Science.gov (United States)

    Khuman, Maibam Wanta; Harikumar, Sankaran Kutty; Sadam, Abdul; Kesavan, Manickam; Susanth, Vattaparambil Sukumaran; Parida, Subhashree; Singh, Karam Pal; Sarkar, Souvendra Nath

    2016-12-30

    Arsenic exposure can cause several cardiovascular diseases, including hypertension, atherosclerosis and microvascular disease. Earlier, we reported that arsenic-mediated enhancement of angiotensin II (AngII) signaling can impair vascular physiology. Here, we investigated whether the AT1 receptor (AT1R) blocker candesartan can ameliorate the arsenic-induced hypertensive vascular remodeling in rats and whether the amelioration could relate to attenuation in vascular AngII and TGF-β signaling. Rats were exposed to sodium arsenite (50ppm) through drinking water for 90 consecutive days. Candesartan (1mg/kg bw, orally) was administered once daily during the last 30days of arsenic exposure. Non-invasive blood pressure was recorded weekly in conscious rats, while AngII-induced change in mean arterial pressure in anaesthetized rats was measured by invasive method on the 91st day. On this day, blood was collected from other animals for measuring AngII level. Western blot of AT1, AT2 and TβRII receptors; ELISA of PTK, RasGAP, ERK-1/2, TGF-β and CTGF; immunohistochemistry of phosphorylated Smad3, Smad4 and collagen III, hydroxyproline/total collagen estimation, collagen deposition by Masson's trichrome staining and histomorphometry were carried out in thoracic aorta. Arsenic increased non-invasive systolic, diastolic and mean arterial pressure. Further, AngII caused concentration-dependent incremental change in mean arterial pressure in the arsenic-exposed rats. Arsenic upregulated AT1 and TβRII receptor proteins; elevated the levels of PTK, ERK-1/2, TGF-β and CTGF, decreased RasGAP level and augmented the immunoreactivities of Smad3, Smad4 and collagen III. Arsenic also increased hydroxyproline/total collagen level, proliferation of collagen fibres and thickness of aortic wall and collagenous adventitia. Candesartan normalized blood pressure, regularized receptor expressions, MAP kinase and TGF-β signaling, restored collagen deposition and regressed aortic thickness

  17. A exposição à fumaça de cigarro intensifica a remodelação ventricular após o infarto agudo do miocárdio Cigarette smoke exposure intensifies ventricular remodeling process following myocardial infarction

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    Leonardo A. M. Zornoff

    2006-04-01

    Full Text Available OBJETIVO: Analisar os efeitos da exposição à fumaça de cigarro (EFC na remodelação ventricular após o infarto agudo do miocárdio (IAM. MÉTODOS: Ratos foram infartados e distribuídos em dois grupos: C (controle, n = 31 e F (EFC: 40 cigarros/dia, n = 22. Após seis meses, foi realizado ecocardiograma, estudo funcional com coração isolado e morfometria. Para comparação, foi utilizado o teste t (com média ± desvio padrão ou teste de Mann-Whitney (com mediana e percentis 25 e 75. RESULTADOS: Os animais EFC apresentaram tendência a maiores áreas ventriculares diastólicas (C = 1,5 ± 0,4 mm², F = 1,9 ± 0,4 mm²; p = 0,08 e sistólicas (C = 1,05 ± 0,3 mm², F = 1,32 ± 0,4 mm²; p = 0,08 do VE. A função sistólica do VE, avaliada pela fração de variação de área, tendeu a ser menor nos animais EFC (C = 31,9 ± 9,3 %, F = 25,5 ± 7,6 %; p = 0,08. Os valores da - dp/dt dos animais EFC foram estatisticamente inferiores (C = 1474 ± 397 mmHg, F = 916 ± 261 mmHg; p = 0,02 aos animais-controle. Os animais EFC apresentaram maior peso do VD, ajustado ao peso corporal (C = 0,8 ± 0,3 mg/g, F = 1,3 ± 0,4 mg/g; p = 0,01, maior teor de água nos pulmões (C = 4,8 (4,3-4,8%, F = 5,4 (5,1-5,5; p = 0,03 e maior área seccional do miócito do VE (C = 239,8 ± 5,8 µm², F = 253,9 ± 7,9 µm²; p = 0,01. CONCLUSÃO: A exposição à fumaça de cigarro intensifica a remodelação ventricular após IAM.OBJECTIVE: To evaluate the role of cigarette smoke exposure (CSE on ventricular remodeling following acute myocardial infarction (AMI. METHODS: Rats were submitted to myocardial infarction and divided into two groups: C (control, n = 31 and F (CSE: 40 cigarettes/day, n = 22. After 6 months, the survivors were submitted to echocardiogram, functional study with isolated heart, and morphometric analysis. For comparison purposes, we used the t test (mean ± standard deviation or the Mann-Whitney test (with median and 25th and 75th percentiles

  18. Reactivation of Endogenous Genes and Epigenetic Remodeling Are Barriers for Generating Transgene-Free Induced Pluripotent Stem Cells in Pig.

    Science.gov (United States)

    Choi, Kwang-Hwan; Park, Jin-Kyu; Son, Dongchan; Hwang, Jae Yeon; Lee, Dong-Kyung; Ka, Hakhyun; Park, Joonghoon; Lee, Chang-Kyu

    2016-01-01

    Cellular reprogramming of committed cells into a pluripotent state can be induced by ectopic expression of genes such as OCT4, SOX2, KLF4, and MYC. Reprogrammed cells can be maintained by activating endogenous pluripotent networks without transgene expression. Although various research groups have attempted to generate pig induced pluripotent stem cells (iPSCs), authentic iPSCs have not be obtained, instead showing dependence on transgene expression. In this study, iPSCs were derived from porcine fetal fibroblasts via drug-inducible vectors carrying human transcription factors (OCT4, SOX2, KLF4, and MYC). Therefore, this study investigated characteristics of iPSCs and reprogramming mechanisms in pig. The iPSCs were stably maintained over an extended period with potential in vitro differentiation into three germ layers. In addition, the pluripotent state of iPSCs was regulated by modulating culture conditions. They showed naive- or primed-like pluripotent states in LIF or bFGF supplemented culture conditions, respectively. However, iPSCs could not be maintained without ectopic expression of transgenes. The cultured iPSCs expressed endogenous transcription factors such as OCT4 and SOX2, but not NANOG (a known gateway to complete reprogramming). Endogenous genes related to mesenchymal-to-epithelial transition (DPPA2, CDH1, EPCAM, and OCLN) were not sufficiently reactivated, as measured by qPCR. DNA methylation analysis for promoters of OCT4, NANOG, and XIST showed that epigenetic reprogramming did not occur in female iPSCs. Based on our results, expression of exogenous genes could not sufficiently activate the essential endogenous genes and remodel the epigenetic milieu to achieve faithful pluripotency in pig. Accordingly, investigating iPSCs could help us improve and develop reprogramming methods by understanding reprogramming mechanisms in pig.

  19. Reactivation of Endogenous Genes and Epigenetic Remodeling Are Barriers for Generating Transgene-Free Induced Pluripotent Stem Cells in Pig.

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    Kwang-Hwan Choi

    Full Text Available Cellular reprogramming of committed cells into a pluripotent state can be induced by ectopic expression of genes such as OCT4, SOX2, KLF4, and MYC. Reprogrammed cells can be maintained by activating endogenous pluripotent networks without transgene expression. Although various research groups have attempted to generate pig induced pluripotent stem cells (iPSCs, authentic iPSCs have not be obtained, instead showing dependence on transgene expression. In this study, iPSCs were derived from porcine fetal fibroblasts via drug-inducible vectors carrying human transcription factors (OCT4, SOX2, KLF4, and MYC. Therefore, this study investigated characteristics of iPSCs and reprogramming mechanisms in pig. The iPSCs were stably maintained over an extended period with potential in vitro differentiation into three germ layers. In addition, the pluripotent state of iPSCs was regulated by modulating culture conditions. They showed naive- or primed-like pluripotent states in LIF or bFGF supplemented culture conditions, respectively. However, iPSCs could not be maintained without ectopic expression of transgenes. The cultured iPSCs expressed endogenous transcription factors such as OCT4 and SOX2, but not NANOG (a known gateway to complete reprogramming. Endogenous genes related to mesenchymal-to-epithelial transition (DPPA2, CDH1, EPCAM, and OCLN were not sufficiently reactivated, as measured by qPCR. DNA methylation analysis for promoters of OCT4, NANOG, and XIST showed that epigenetic reprogramming did not occur in female iPSCs. Based on our results, expression of exogenous genes could not sufficiently activate the essential endogenous genes and remodel the epigenetic milieu to achieve faithful pluripotency in pig. Accordingly, investigating iPSCs could help us improve and develop reprogramming methods by understanding reprogramming mechanisms in pig.

  20. Lymphangiogenesis and lymphatic remodeling induced by filarial parasites: implications for pathogenesis.

    Science.gov (United States)

    Bennuru, Sasisekhar; Nutman, Thomas B

    2009-12-01

    Even in the absence of an adaptive immune system in murine models, lymphatic dilatation and dysfunction occur in filarial infections, although severe irreversible lymphedema and elephantiasis appears to require an intact adaptive immune response in human infections. To address how filarial parasites and their antigens influence the lymphatics directly, human lymphatic endothelial cells were exposed to filarial antigens, live parasites, or infected patient serum. Live filarial parasites or filarial antigens induced both significant LEC proliferation and differentiation into tube-like structures in vitro. Moreover, serum from patently infected (microfilaria positive) patients and those with longstanding chronic lymphatic obstruction induced significantly increased LEC proliferation compared to sera from uninfected individuals. Differentiation of LEC into tube-like networks was found to be associated with significantly increased levels of matrix metalloproteases and inhibition of their TIMP inhibitors (Tissue inhibitors of matrix metalloproteases). Comparison of global gene expression induced by live parasites in LEC to parasite-unexposed LEC demonstrated that filarial parasites altered the expression of those genes involved in cellular organization and development as well as those associated with junction adherence pathways that in turn decreased trans-endothelial transport as assessed by FITC-Dextran. The data suggest that filarial parasites directly induce lymphangiogenesis and lymphatic differentiation and provide insight into the mechanisms underlying the pathology seen in lymphatic filariasis.

  1. Lymphangiogenesis and lymphatic remodeling induced by filarial parasites: implications for pathogenesis.

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    Sasisekhar Bennuru

    2009-12-01

    Full Text Available Even in the absence of an adaptive immune system in murine models, lymphatic dilatation and dysfunction occur in filarial infections, although severe irreversible lymphedema and elephantiasis appears to require an intact adaptive immune response in human infections. To address how filarial parasites and their antigens influence the lymphatics directly, human lymphatic endothelial cells were exposed to filarial antigens, live parasites, or infected patient serum. Live filarial parasites or filarial antigens induced both significant LEC proliferation and differentiation into tube-like structures in vitro. Moreover, serum from patently infected (microfilaria positive patients and those with longstanding chronic lymphatic obstruction induced significantly increased LEC proliferation compared to sera from uninfected individuals. Differentiation of LEC into tube-like networks was found to be associated with significantly increased levels of matrix metalloproteases and inhibition of their TIMP inhibitors (Tissue inhibitors of matrix metalloproteases. Comparison of global gene expression induced by live parasites in LEC to parasite-unexposed LEC demonstrated that filarial parasites altered the expression of those genes involved in cellular organization and development as well as those associated with junction adherence pathways that in turn decreased trans-endothelial transport as assessed by FITC-Dextran. The data suggest that filarial parasites directly induce lymphangiogenesis and lymphatic differentiation and provide insight into the mechanisms underlying the pathology seen in lymphatic filariasis.

  2. Prevention of airway hyperresponsiveness induced by left ventricular dysfunction in rats

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    Petak Ferenc

    2012-12-01

    Full Text Available Abstract Background The effectiveness of strategies for treatment of the altered static lung volume and against the development of bronchial hyperreactivity (BHR following a left ventricular dysfunction (LVD induced by myocardial ischaemia was investigated in a rat model of sustained postcapillary pulmonary hypertension. Methods Airway resistance (Raw was identified from the respiratory system input impedance (Zrs in four groups of rats. End-expiratory lung volume (EELV was determined plethysmographically, and Zrs was measured under baseline conditions and following iv infusions of 2, 6 or 18 μg/kg/min methacholine. Sham surgery was performed in the rats in Group C, while the left interventricular coronary artery was ligated and Zrs and its changes following identical methacholine challenges were reassessed in the same rats 8 weeks later, during which no treatment was applied (Group I, or the animals were treated daily with a combination of an angiotensin enzyme converter inhibitor and a diuretic (enalapril and furosemide, Group IE, or a calcium channel blocker (diltiazem, Group ID. The equivalent dose of methacholine causing a 100% increase in Raw (ED50 was determined in each group. Diastolic pulmonary arterial pressure (PapD was assessed by introducing a catheter into the pulmonary artery. Results The sustained presence of a LVD increased PapD in all groups of rats, with variable but significant elevations in Groups I (p = 0.004, ID (p = 0.013 and IE (p = 0.006. A LVD for 8 weeks induced no changes in baseline Raw but elevated the EELV independently of the treatments. In Group I, BHR consistently developed following the LVD, with a significant decrease in ED50 from 10.0 ± 2.5 to 6.9 ± 2.5 μg/kg/min (p = 0.006. The BHR was completely abolished in both Groups ID and IE, with no changes in ED50 (9.5 ± 3.6 vs. 10.7 ± 4.7, p = 0.33 and 10.6 ± 2.1 vs. 9.8 ± 3.5 μg/kg/min p = 0.56, respectively

  3. Adiponectin attenuates angiotensin II-induced vascular smooth muscle cell remodeling through nitric oxide and the RhoA/ROCK pathway.

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    Wared eNour-Eldine

    2016-04-01

    Full Text Available INTRODUCTION: Adiponectin (APN, an adipocytokine, exerts protective effects on cardiac remodeling, while angiotensin II (Ang II induces hypertension and vascular remodeling. The potential protective role of APN on the vasculature during hypertension has not been fully elucidated yet. Here, we evaluate the molecular mechanisms of the protective role of APN in the physiological response of the vascular wall to Ang II.METHODS AND RESULTS: Rat aortic tissues were used to investigate the effect of APN on Ang II-induced vascular remodeling and hypertrophy. We investigated whether nitric oxide (NO, the RhoA/ROCK pathway, actin cytoskeleton remodeling, and reactive oxygen species (ROS mediate the anti-hypertrophic effect of APN. Ang II-induced protein synthesis was attenuated by pre-treatment with APN, NO donor (SNAP, or cGMP. The hypertrophic response to Ang II was associated with a significant increase in RhoA activation and vascular force production, which were prevented by APN and SNAP. NO was also associated with inhibition of Ang II-induced phosphorylation of cofilin. In addition, immunohistochemistry revealed that 24 hr Ang II treatment increased the F- to G-actin ratio, an effect that was inhibited by SNAP. Ang II-induced ROS formation and upregulation of p22phox mRNA expression were inhibited by APN and NO. Both compounds failed to inhibit Nox1 and p47phox expression. CONCLUSIONS: Our results suggest that the anti-hypertrophic effects of APN are due, in part, to NO-dependent inhibition of the RhoA/ROCK pathway and ROS formation.

  4. Total thyroidectomy in patients with amiodarone-induced thyrotoxicosis and severe left ventricular systolic dysfunction.

    Science.gov (United States)

    Tomisti, Luca; Materazzi, Gabriele; Bartalena, Luigi; Rossi, Giuseppe; Marchello, Angelica; Moretti, Manuela; De Napoli, Luigi; Mariotti, Rita; Miccoli, Paolo; Martino, Enio; Bogazzi, Fausto

    2012-10-01

    Patients with amiodarone-induced thyrotoxicosis (AIT) and left ventricular (LV) systolic dysfunction have a high mortality rate. Usually, medical therapy is the first choice for AIT patients, whereas the role of the thyroidectomy is unsettled. The objective of the study was to evaluate the effect of a total thyroidectomy on cardiac function and survival of AIT patients with severe LV systolic dysfunction. This was a retrospective cohort study. The study was conducted at a tertiary university center. All AIT patients (n=24; nine patients with type 1 AIT, 15 patients with type 2 AIT) referred to the Department of Endocrinology and submitted to a total thyroidectomy at the Department of Surgery, both at the University of Pisa, during the years 1997-2010. The intervention was a total thyroidectomy. LV ejection fraction (EF) after the thyroidectomy and survival in December 2011 were measured. All enrolled patients had previously undergone to medical treatment for AIT, as appropriate, without achieving euthyroidism. Patients with moderate to severe LV systolic dysfunction (EF50%, group 3, n=10). Two months after thyroidectomy, under levothyroxine replacement therapy, LVEF improved in patients with LV systolic dysfunction, particularly in those of group 1, in whom it increased from 28.2±7.2 to 38.3±6% (P=0.007). On the contrary, LVEF did not significantly change in group 3 (from 57.1±3.0 to 59.8±6.6%, P=0.242). The mean follow-up was 67±42 months. No death occurred during and 2 months after surgery. One death occurred in one patient of group 1, 30 months after the thyroidectomy, due to acute myocardial infarction. No patient had relevant complications of thyroidectomy. Total thyroidectomy, by rapidly restoring euthyroidism, may improve cardiac function and reduce the risk of mortality in AIT patients with severe LV dysfunction.

  5. Unconventional Human T Cells Accumulate at the Site of Infection in Response to Microbial Ligands and Induce Local Tissue Remodeling.

    Science.gov (United States)

    Liuzzi, Anna Rita; Kift-Morgan, Ann; Lopez-Anton, Melisa; Friberg, Ida M; Zhang, Jingjing; Brook, Amy C; Roberts, Gareth W; Donovan, Kieron L; Colmont, Chantal S; Toleman, Mark A; Bowen, Timothy; Johnson, David W; Topley, Nicholas; Moser, Bernhard; Fraser, Donald J; Eberl, Matthias

    2016-09-15

    The antimicrobial responsiveness and function of unconventional human T cells are poorly understood, with only limited access to relevant specimens from sites of infection. Peritonitis is a common and serious complication in individuals with end-stage kidney disease receiving peritoneal dialysis. By analyzing local and systemic immune responses in peritoneal dialysis patients presenting with acute bacterial peritonitis and monitoring individuals before and during defined infectious episodes, our data show that Vγ9/Vδ2(+) γδ T cells and mucosal-associated invariant T cells accumulate at the site of infection with organisms producing (E)-4-hydroxy-3-methyl-but-2-enyl pyrophosphate and vitamin B2, respectively. Such unconventional human T cells are major producers of IFN-γ and TNF-α in response to these ligands that are shared by many microbial pathogens and affect the cells lining the peritoneal cavity by triggering local inflammation and inducing tissue remodeling with consequences for peritoneal membrane integrity. Our data uncover a crucial role for Vγ9/Vδ2 T cells and mucosal-associated invariant T cells in bacterial infection and suggest that they represent a useful predictive marker for important clinical outcomes, which may inform future stratification and patient management. These findings are likely to be applicable to other acute infections where local activation of unconventional T cells contributes to the antimicrobial inflammatory response. Copyright © 2016 The Authors.

  6. Troglitazone Induces Extracellular Matrix and Cytoskeleton Remodeling in Mouse Collecting Duct Cells

    OpenAIRE

    Jaime Corinaldi; Rania Nasrallah; Jordan Clark; Geneviève Paris; Pedro Miura; Bernard J. Jasmin; Hébert, Richard L.

    2012-01-01

    Peroxisome proliferator-activated receptor (PPAR γ ) has been shown to have a protective role in the nephron through its ability to inhibit a transforming growth factor- (TGF- β ) mediated fibrotic response. In contrast, PPAR γ was also shown to induce a mesenchymal transformation in epithelial intestinal cells. A fibrotic response in the collecting duct has only recently been established; however, the entire collecting duct has not been fully examined. Inner medullary collecting duct cells (...

  7. PDGFRβ Regulates Adipose Tissue Expansion and Glucose Metabolism via Vascular Remodeling in Diet-Induced Obesity.

    Science.gov (United States)

    Onogi, Yasuhiro; Wada, Tsutomu; Kamiya, Chie; Inata, Kento; Matsuzawa, Takatoshi; Inaba, Yuka; Kimura, Kumi; Inoue, Hiroshi; Yamamoto, Seiji; Ishii, Yoko; Koya, Daisuke; Tsuneki, Hiroshi; Sasahara, Masakiyo; Sasaoka, Toshiyasu

    2017-04-01

    Platelet-derived growth factor (PDGF) is a key factor in angiogenesis; however, its role in adult obesity remains unclear. In order to clarify its pathophysiological role, we investigated the significance of PDGF receptor β (PDGFRβ) in adipose tissue expansion and glucose metabolism. Mature vessels in the epididymal white adipose tissue (eWAT) were tightly wrapped with pericytes in normal mice. Pericyte desorption from vessels and the subsequent proliferation of endothelial cells were markedly increased in the eWAT of diet-induced obese mice. Analyses with flow cytometry and adipose tissue cultures indicated that PDGF-B caused the detachment of pericytes from vessels in a concentration-dependent manner. M1-macrophages were a major type of cells expressing PDGF-B in obese adipose tissue. In contrast, pericyte detachment was attenuated and vascularity within eWAT was reduced in tamoxifen-inducible conditional Pdgfrb-knockout mice with decreases in adipocyte size and chronic inflammation. Furthermore, Pdgfrb-knockout mice showed enhanced energy expenditure. Consequently, diet-induced obesity and the associated deterioration of glucose metabolism in wild-type mice were absent in Pdgfrb-knockout mice. Therefore, PDGF-B-PDGFRβ signaling plays a significant role in the development of adipose tissue neovascularization and appears to be a fundamental target for the prevention of obesity and type 2 diabetes. © 2017 by the American Diabetes Association.

  8. Interleukin-2/Anti-Interleukin-2 Immune Complex Attenuates Cardiac Remodeling after Myocardial Infarction through Expansion of Regulatory T Cells

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    Zhipeng Zeng

    2016-01-01

    Full Text Available CD4+CD25+Foxp3+ regulatory T cells (Treg cells have protective effects in wound healing and adverse ventricular remodeling after myocardial infarction (MI. We hypothesize that the interleukin- (IL- 2 complex comprising the recombinant mouse IL-2/anti-IL-2 mAb (JES6-1 attenuates cardiac remodeling after MI through the expansion of Treg. Mice were subjected to surgical left anterior descending coronary artery ligation and treated with either PBS or IL-2 complex. The IL-2 complex significantly attenuates ventricular remodeling, as demonstrated by reduced infarct size, improved left ventricular (LV function, and attenuated cardiomyocyte apoptosis. The IL-2 complex increased the percentage of CD4+CD25+Foxp3+ Treg cells, which may be recruited to the infarcted heart, and decreased the frequencies of IFN-γ- and IL-17-producing CD4+ T helper (Th cells among the CD4+Foxp3− T cells in the spleen. Furthermore, the IL-2 complex inhibited the gene expression of proinflammatory cytokines as well as macrophage infiltrates in the infarcted myocardium and induced the differentiation of macrophages from M1 to M2 phenotype in border zone of infarcted myocardium. Our studies indicate that the IL-2 complex may serve as a promising therapeutic approach to attenuate adverse remodeling after MI through expanding Treg cells specifically.

  9. Exercise-induced changes in left ventricular global longitudinal strain in asymptomatic severe aortic stenosis.

    Science.gov (United States)

    Lech, Agnieszka K; Dobrowolski, Piotr P; Klisiewicz, Anna; Hoffman, Piotr

    2017-01-01

    The management of patients with asymptomatic severe aortic stenosis (ASAS) is still under discussion. Therefore, it is advisable to search for the parameters of early damage to left ventricular (LV) function. The aim of the study was to assess exercise-induced changes in LV global longitudinal strain (GLS) in ASAS. The ASAS group consisted of 50 patients (26 women and 24 men, aged 38.4 ± 18.1 years) meeting the echocardiographic criteria of severe aortic stenosis (AVA 4 m/s, mean aortic gradient > 40 mm Hg), with normal LV ejection fraction (LVEF ≥ 55%) and sinus rhythm on electrocardiogram, and without significant concomitant valvular heart diseases. The control group consisted of 21 people matched for age and sex. Echocardiographic examinations and echocardiographic stress tests with the assessment of GLS using the speckle tracking imaging were performed. The ASAS group was characterised by statistically significantly higher LV mass index (LVMI) and higher LVEF. GLS values at rest in both groups were within normal limits but were significantly higher in the control group (-18.9 ± 2.4% vs. -20.7 ± 1.7%, p = 0.006). An increase in GLS at peak exercise in both groups was observed, lower in the ASAS group (the difference was not statistically significant: -0.8 ± 3.0% vs. -2.2 ± 3.1%, p = 0.086). Changes in GLS during exercise (ΔGLS) did not correlate with the parameters of the severity of aortic stenosis. In the multivariate model, LVMI proved to be a factor associated with GLS at rest and during exercise. In patients with ASAS, GLS is a non-invasive marker of an early stage of LV myocardial damage associated with myocardial hypertrophy. An increase in GLS during exercise in the ASAS group, smaller than in the control group, indicates a preserved functional reserve of the LV myocardium but smaller than in healthy individuals. The assessment of the clinical usefulness of exercise-induced changes in GLS requires further research.

  10. IL-33 promotes growth and liver metastasis of colorectal cancer in mice by remodeling the tumor microenvironment and inducing angiogenesis.

    Science.gov (United States)

    Zhang, Yu; Davis, Celestia; Shah, Sapana; Hughes, Daniel; Ryan, James C; Altomare, Diego; Peña, Maria Marjorette O

    2017-01-01

    Liver metastasis is the major cause of death from colorectal cancer (CRC). Understanding its mechanisms is necessary for timely diagnosis and development of effective therapies. Interleukin-33 (IL-33) is an IL-1 cytokine family member that uniquely functions as a cytokine and nuclear factor. It is released by necrotic epithelial cells and activated innate immune cells, functioning as an alarmin or an early danger signal. Its role in invoking type 2 immune response has been established; however, it has contrasting roles in tumor development and metastasis. We identified IL-33 as a potently upregulated cytokine in a highly metastatic murine CRC cell line and examined its role in tumor growth and metastasis to the liver. IL-33 was transgenically expressed in murine and human adenocarcinoma and carcinoma cell lines and their growth and spontaneous metastasis to the liver were assessed in orthotopic models of CRC in wild-type C57Bl/6 and Il33 knockout mice. The results showed that increased expression of IL-33 in CRC cells enhanced their tumor take, growth, and liver metastasis. Tumor- rather than host-derived IL-33 induced the enhanced recruitment of CD11b+ GR1+ and CD11b+ F4/80+ myeloid cells to remodel the tumor microenvironment by increased expression of mobilizing cytokines, and tumor angiogenesis by activating endothelial cells. IL-33 expression was elevated in patient tumor tissues, induced early in adenoma development, and activated by pro-inflammatory cytokines derived from the tumor microenvironment. The data suggest that tumor-derived IL-33 modulates the tumor microenvironment to potently promote colon carcinogenesis and liver metastasis, underscoring its potential as a therapeutic target. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

  11. Modeling hypothermia induced effects for the heterogeneous ventricular tissue from cellular level to the impact on the ECG.

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    Roland Kienast

    Full Text Available Hypothermia has a profound impact on the electrophysiological mechanisms of the heart. Experimental investigations provide a better understanding of electrophysiological alterations associated with cooling. However, there is a lack of computer models suitable for simulating the effects of hypothermia in cardio-electrophysiology. In this work, we propose a model that describes the cooling-induced electrophysiological alterations in ventricular tissue in a temperature range from 27°C to 37°C. To model the electrophysiological conditions in a 3D left ventricular tissue block it was essential to consider the following anatomical and physiological parameters in the model: the different cell types (endocardial, M, epicardial, the heterogeneous conductivities in longitudinal, transversal and transmural direction depending on the prevailing temperature, the distinct fiber orientations and the transmural repolarization sequences. Cooling-induced alterations on the morphology of the action potential (AP of single myocardial cells thereby are described by an extension of the selected Bueno-Orovio model for human ventricular tissue using Q10 temperature coefficients. To evaluate alterations on tissue level, the corresponding pseudo electrocardiogram (pECG was calculated. Simulations show that cooling-induced AP and pECG-related parameters, i.e. AP duration, morphology of the notch of epicardial AP, maximum AP upstroke velocity, AP rise time, QT interval, QRS duration and J wave formation are in good accordance with literature and our experimental data. The proposed model enables us to further enhance our knowledge of cooling-induced electrophysiological alterations from cellular to tissue level in the heart and may help to better understand electrophysiological mechanisms, e.g. in arrhythmias, during hypothermia.

  12. Modeling hypothermia induced effects for the heterogeneous ventricular tissue from cellular level to the impact on the ECG.

    Science.gov (United States)

    Kienast, Roland; Handler, Michael; Stöger, Markus; Baumgarten, Daniel; Hanser, Friedrich; Baumgartner, Christian

    2017-01-01

    Hypothermia has a profound impact on the electrophysiological mechanisms of the heart. Experimental investigations provide a better understanding of electrophysiological alterations associated with cooling. However, there is a lack of computer models suitable for simulating the effects of hypothermia in cardio-electrophysiology. In this work, we propose a model that describes the cooling-induced electrophysiological alterations in ventricular tissue in a temperature range from 27°C to 37°C. To model the electrophysiological conditions in a 3D left ventricular tissue block it was essential to consider the following anatomical and physiological parameters in the model: the different cell types (endocardial, M, epicardial), the heterogeneous conductivities in longitudinal, transversal and transmural direction depending on the prevailing temperature, the distinct fiber orientations and the transmural repolarization sequences. Cooling-induced alterations on the morphology of the action potential (AP) of single myocardial cells thereby are described by an extension of the selected Bueno-Orovio model for human ventricular tissue using Q10 temperature coefficients. To evaluate alterations on tissue level, the corresponding pseudo electrocardiogram (pECG) was calculated. Simulations show that cooling-induced AP and pECG-related parameters, i.e. AP duration, morphology of the notch of epicardial AP, maximum AP upstroke velocity, AP rise time, QT interval, QRS duration and J wave formation are in good accordance with literature and our experimental data. The proposed model enables us to further enhance our knowledge of cooling-induced electrophysiological alterations from cellular to tissue level in the heart and may help to better understand electrophysiological mechanisms, e.g. in arrhythmias, during hypothermia.

  13. Protective effects of salidroside on epirubicin-induced early left ventricular regional systolic dysfunction in patients with breast cancer.

    Science.gov (United States)

    Zhang, Hua; Shen, Wei-sheng; Gao, Chun-heng; Deng, Li-chun; Shen, Dong

    2012-06-01

    Salidroside [2-(4-hydroxyphenyl)ethyl-β-D-glucopyranoside], one of the most potent ingredients extracted from the plant Rhodiola rosea L., has been shown to have a cardiovascular protective effect as an antioxidant, and early treatment of epirubicin-induced cardiotoxicity has been the focus of clinical chemotherapy in patients with breast cancer. However, the cardioprotective effects of salidroside on epirubicin-induced cardiotoxicity, especially early left ventricular regional systolic dysfunction, have to date been sparsely investigated. The aim of this study was to investigate the protective effects of salidroside in preventing early left ventricular regional systolic dysfunction induced by epirubicin. Sixty patients with histologically confirmed breast cancer were enrolled. Eligible patients were randomized to receive salidroside (600 mg/day; n = 30) or placebo (n = 30) starting 1 week before chemotherapy. Patients were investigated by means of echocardiography and strain rate (SR) imaging. We also measured plasma concentrations of reactive oxygen species (ROS). All parameters were assessed at baseline and 7 days