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Sample records for cardiac development remodeling

  1. Cardiac remodeling in the mouse model of Marfan syndrome develops into two distinctive phenotypes.

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    Tae, Hyun-Jin; Petrashevskaya, Natalia; Marshall, Shannon; Krawczyk, Melissa; Talan, Mark

    2016-01-15

    Marfan syndrome (MFS) is a systemic disorder of connective tissue caused by mutations in fibrillin-1. Cardiac dysfunction in MFS has not been characterized halting the development of therapies of cardiac complication in MFS. We aimed to study the age-dependent cardiac remodeling in the mouse model of MFS FbnC1039G+/- mouse [Marfan heterozygous (HT) mouse] and its association with valvular regurgitation. Marfan HT mice of 2-4 mo demonstrated a mild hypertrophic cardiac remodeling with predominant decline of diastolic function and increased transforming growth factor-β canonical (p-SMAD2/3) and noncanonical (p-ERK1/2 and p-p38 MAPK) signaling and upregulation of hypertrophic markers natriuretic peptides atrium natriuretic peptide and brain natriuretic peptide. Among older HT mice (6-14 mo), cardiac remodeling was associated with two distinct phenotypes, manifesting either dilated or constricted left ventricular chamber. Dilatation of left ventricular chamber was accompanied by biochemical evidence of greater mechanical stress, including elevated ERK1/2 and p38 MAPK phosphorylation and higher brain natriuretic peptide expression. The aortic valve regurgitation was registered in 20% of the constricted group and 60% of the dilated group, whereas mitral insufficiency was observed in 40% of the constricted group and 100% of the dilated group. Cardiac dysfunction was not associated with the increase of interstitial fibrosis and nonmyocyte proliferation. In the mouse model fibrillin-1, haploinsufficiency results in the early onset of nonfibrotic hypertrophic cardiac remodeling and dysfunction, independently from valvular abnormalities. MFS heart is vulnerable to stress-induced cardiac dilatation in the face of valvular regurgitation, and stress-activated MAPK signals represent a potential target for cardiac management in MFS.

  2. Molecular Aspects of Exercise-induced Cardiac Remodeling.

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    Bernardo, Bianca C; McMullen, Julie R

    2016-11-01

    Exercise-induced cardiac remodeling is typically an adaptive response associated with cardiac myocyte hypertrophy and renewal, increased cardiac myocyte contractility, sarcomeric remodeling, cell survival, metabolic and mitochondrial adaptations, electrical remodeling, and angiogenesis. Initiating stimuli/triggers of cardiac remodeling include increased hemodynamic load, increased sympathetic activity, and the release of hormones and growth factors. Prolonged and strenuous exercise may lead to maladaptive exercise-induced cardiac remodeling including cardiac dysfunction and arrhythmia. In addition, this article describes novel therapeutic approaches for the treatment of heart failure that target mechanisms responsible for adaptive exercise-induced cardiac remodeling, which are being developed and tested in preclinical models.

  3. Exercise-induced cardiac remodeling.

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    Weiner, Rory B; Baggish, Aaron L

    2012-01-01

    Early investigations in the late 1890s and early 1900s documented cardiac enlargement in athletes with above-normal exercise capacity and no evidence of cardiovascular disease. Such findings have been reported for more than a century and continue to intrigue scientists and clinicians. It is well recognized that repetitive participation in vigorous physical exercise results in significant changes in myocardial structure and function. This process, termed exercise-induced cardiac remodeling (EICR), is characterized by structural cardiac changes including left ventricular hypertrophy with sport-specific geometry (eccentric vs concentric). Associated alterations in both systolic and diastolic functions are emerging as recognized components of EICR. The increasing popularity of recreational exercise and competitive athletics has led to a growing number of individuals exhibiting these findings in routine clinical practice. This review will provide an overview of EICR in athletes.

  4. N-acetylcysteine attenuates the development of cardiac fibrosis and remodeling in a mouse model of heart failure.

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    Giam, Beverly; Chu, Po-Yin; Kuruppu, Sanjaya; Smith, A Ian; Horlock, Duncan; Kiriazis, Helen; Du, Xiao-Jun; Kaye, David M; Rajapakse, Niwanthi W

    2016-04-01

    Oxidative stress plays a central role in the pathogenesis of heart failure. We aimed to determine whether the antioxidantN-acetylcysteine can attenuate cardiac fibrosis and remodeling in a mouse model of heart failure. Minipumps were implanted subcutaneously in wild-type mice (n = 20) and mice with cardiomyopathy secondary to cardiac specific overexpression of mammalian sterile 20-like kinase 1 (MST-1;n = 18) to administerN-acetylcysteine (40 mg/kg per day) or saline for a period of 8 weeks. At the end of this period, cardiac remodeling and function was assessed via echocardiography. Fibrosis, oxidative stress, and expression of collagen types I andIIIwere quantified in heart tissues. Cardiac perivascular and interstitial fibrosis were greater by 114% and 209%, respectively, inMST-1 compared to wild type (P ≤ 0.001). InMST-1 mice administeredN-acetylcysteine, perivascular and interstitial fibrosis were 40% and 57% less, respectively, compared to those treated with saline (P ≤ 0. 03). Cardiac oxidative stress was 119% greater inMST-1 than in wild type (P cardiac fibrosis and related remodeling in the setting of heart failure potentially by reducing oxidative stress. This study provides the basis to investigate the role ofN-acetylcysteine in chronic heart failure.

  5. Hypothyroidism and its rapid correction alter cardiac remodeling.

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    Georges Hajje

    Full Text Available The cardiovascular effects of mild and overt thyroid disease include a vast array of pathological changes. As well, thyroid replacement therapy has been suggested for preserving cardiac function. However, the influence of thyroid hormones on cardiac remodeling has not been thoroughly investigated at the molecular and cellular levels. The purpose of this paper is to study the effect of hypothyroidism and thyroid replacement therapy on cardiac alterations. Thirty Wistar rats were divided into 2 groups: a control (n = 10 group and a group treated with 6-propyl-2-thiouracil (PTU (n = 20 to induce hypothyroidism. Ten of the 20 rats in the PTU group were then treated with L-thyroxine to quickly re-establish euthyroidism. The serum levels of inflammatory markers, such as C-reactive protein (CRP, tumor necrosis factor alpha (TNF-α, interleukin 6 (IL6 and pro-fibrotic transforming growth factor beta 1 (TGF-β1, were significantly increased in hypothyroid rats; elevations in cardiac stress markers, brain natriuretic peptide (BNP and cardiac troponin T (cTnT were also noted. The expressions of cardiac remodeling genes were induced in hypothyroid rats in parallel with the development of fibrosis, and a decline in cardiac function with chamber dilation was measured by echocardiography. Rapidly reversing the hypothyroidism and restoring the euthyroid state improved cardiac function with a decrease in the levels of cardiac remodeling markers. However, this change further increased the levels of inflammatory and fibrotic markers in the plasma and heart and led to myocardial cellular infiltration. In conclusion, we showed that hypothyroidism is related to cardiac function decline, fibrosis and inflammation; most importantly, the rapid correction of hypothyroidism led to cardiac injuries. Our results might offer new insights for the management of hypothyroidism-induced heart disease.

  6. Elevated sensitivity to cardiac ischemia in proteinuric rats is independent of adverse cardiac remodeling

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    Szymanski, Mariusz K.; Hillege, Hans L.; Danser, A. H. Jan; Garrelds, Ingrid M.; Schoemaker, Regien G.

    2013-01-01

    Objectives: Chronic renal dysfunction severely increases cardiovascular risk. Adverse cardiac remodeling is suggested to play a major role as predisposition for increased cardiac ischemic vulnerability. The aim of the present study was to examine the role of adverse cardiac remodeling in cardiac sen

  7. Intradialytic Hypotension and Cardiac Remodeling: A Vicious Cycle

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    Chia-Ter Chao

    2015-01-01

    Full Text Available Hemodynamic instability during hemodialysis is a common but often underestimated issue in the nephrologist practice. Intradialytic hypotension, namely, a decrease of systolic or mean blood pressure to a certain level, prohibits the safe and smooth achievement of ultrafiltration and solute removal goal in chronic dialysis patients. Studies have elucidated the potential mechanisms involved in the development of Intradialytic hypotension, including excessive ultrafiltration and loss of compensatory mechanisms for blood pressure maintenance. Cardiac remodeling could also be one important piece of the puzzle. In this review, we intend to discuss the role of cardiac remodeling, including left ventricular hypertrophy, in the development of Intradialytic hypotension. In addition, we will also provide evidence that a bidirectional relationship might exist between Intradialytic hypotension and left ventricular hypertrophy in chronic dialysis patients. A more complete understanding of the complex interactions in between could assist the readers in formulating potential solutions for the reduction of both phenomena.

  8. Chromatin remodeling in cardiovascular development and physiology.

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    Han, Pei; Hang, Calvin T; Yang, Jin; Chang, Ching-Pin

    2011-02-04

    Chromatin regulation provides an important means for controlling cardiac gene expression under different physiological and pathological conditions. Processes that direct the development of normal embryonic hearts and pathology of stressed adult hearts may share general mechanisms that govern cardiac gene expression by chromatin-regulating factors. These common mechanisms may provide a framework for us to investigate the interactions among diverse chromatin remodelers/modifiers and various transcription factors in the fine regulation of gene expression, essential for all aspects of cardiovascular biology. Aberrant cardiac gene expression, triggered by a variety of pathological insults, can cause heart diseases in both animals and humans. The severity of cardiomyopathy and heart failure correlates strongly with abnormal cardiac gene expression. Therefore, controlling cardiac gene expression presents a promising approach to the treatment of human cardiomyopathy. This review focuses on the roles of ATP-dependent chromatin-remodeling factors and chromatin-modifying enzymes in the control of gene expression during cardiovascular development and disease.

  9. Chromatin remodeling in cardiovascular development and physiology

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    Han, Pei; Hang, Calvin T.; Yang, Jin; Chang, Ching-Pin

    2011-01-01

    Chromatin regulation provides an important means of controlling cardiac gene expression under different physiological and pathological conditions. Processes that direct the development of normal embryonic hearts and pathology of stressed adult hearts may share general mechanisms that govern cardiac gene expression by chromatin-regulating factors. These common mechanisms may provide a framework for us to investigate the interactions among diverse chromatin remodelers/modifiers and various tran...

  10. The Cardiac TBX5 Interactome Reveals a Chromatin Remodeling Network Essential for Cardiac Septation.

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    Waldron, Lauren; Steimle, Jeffrey D; Greco, Todd M; Gomez, Nicholas C; Dorr, Kerry M; Kweon, Junghun; Temple, Brenda; Yang, Xinan Holly; Wilczewski, Caralynn M; Davis, Ian J; Cristea, Ileana M; Moskowitz, Ivan P; Conlon, Frank L

    2016-02-08

    Human mutations in the cardiac transcription factor gene TBX5 cause congenital heart disease (CHD), although the underlying mechanism is unknown. We report characterization of the endogenous TBX5 cardiac interactome and demonstrate that TBX5, long considered a transcriptional activator, interacts biochemically and genetically with the nucleosome remodeling and deacetylase (NuRD) repressor complex. Incompatible gene programs are repressed by TBX5 in the developing heart. CHD mis-sense mutations that disrupt the TBX5-NuRD interaction cause depression of a subset of repressed genes. Furthermore, the TBX5-NuRD interaction is required for heart development. Phylogenetic analysis showed that the TBX5-NuRD interaction domain evolved during early diversification of vertebrates, simultaneous with the evolution of cardiac septation. Collectively, this work defines a TBX5-NuRD interaction essential to cardiac development and the evolution of the mammalian heart, and when altered may contribute to human CHD.

  11. Galectin-3 and post-myocardial infarction cardiac remodeling

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    Meijers, Wouter C.; van der Velde, A. Rogier; Pascual-Figal, Domingo A.; de Boer, Rudolf A.

    2015-01-01

    This review summarizes the current literature regarding the involvement and the putative role(s) of galectin-3 in post-myocardial infarction cardiac remodeling. Post-myocardial infarction remodeling is characterized by acute loss of myocardium, which leads to structural and biomechanical changes in

  12. Defective branched chain amino acid catabolism contributes to cardiac dysfunction and remodeling following myocardial infarction.

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    Wang, Wei; Zhang, Fuyang; Xia, Yunlong; Zhao, Shihao; Yan, Wenjun; Wang, Helin; Lee, Yan; Li, Congye; Zhang, Ling; Lian, Kun; Gao, Erhe; Cheng, Hexiang; Tao, Ling

    2016-11-01

    Cardiac metabolic remodeling is a central event during heart failure (HF) development following myocardial infarction (MI). It is well known that myocardial glucose and fatty acid dysmetabolism contribute to post-MI cardiac dysfunction and remodeling. However, the role of amino acid metabolism in post-MI HF remains elusive. Branched chain amino acids (BCAAs) are an important group of essential amino acids and function as crucial nutrient signaling in mammalian animals. The present study aimed to determine the role of cardiac BCAA metabolism in post-MI HF progression. Utilizing coronary artery ligation-induced murine MI models, we found that myocardial BCAA catabolism was significantly impaired in response to permanent MI, therefore leading to an obvious elevation of myocardial BCAA abundance. In MI-operated mice, oral BCAA administration further increased cardiac BCAA levels, activated the mammalian target of rapamycin (mTOR) signaling, and exacerbated cardiac dysfunction and remodeling. These data demonstrate that BCAAs act as a direct contributor to post-MI cardiac pathologies. Furthermore, these BCAA-mediated deleterious effects were improved by rapamycin cotreatment, revealing an indispensable role of mTOR in BCAA-mediated adverse effects on cardiac function/structure post-MI. Of note, pharmacological inhibition of branched chain ketoacid dehydrogenase kinase (BDK), a negative regulator of myocardial BCAA catabolism, significantly improved cardiac BCAA catabolic disorders, reduced myocardial BCAA levels, and ameliorated post-MI cardiac dysfunction and remodeling. In conclusion, our data provide the evidence that impaired cardiac BCAA catabolism directly contributes to post-MI cardiac dysfunction and remodeling. Moreover, improving cardiac BCAA catabolic defects may be a promising therapeutic strategy against post-MI HF.

  13. Ouabain induces cardiac remodeling in rats independent of blood pressure

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    Xing JIANG; Yan-ping REN; Zhuo-ren L(U)

    2007-01-01

    Aim: To investigate the ouabain's effects on cardiac remodeling in rats. Methods:Male Sprague-Dawley rats were treated with ouabain. Systolic blood pressure(SBP) was recorded weekly. After 4 and 6 weeks, echocardiography were performed,hemodynamic parameters were measured by invasive cardiac catheterization,changes in cardiac ultrastructure were analyzed using transmission electron microscopy, the collagen fraction of the left ventricle was assessed with Picrosirius red stain, and RT-PCR was applied to evaluate the mRNA level of myosin heavy chain-α and-β in the left ventricle. Results: Having been treated with ouabain for 4 weeks, there was no significant difference in the mean SBP of the two groups.However, left ventricular hypertrophy, myocardial ultrastructure deterioration,and extracellular matrix remodeling were induced by ouabain treatment; meanwhile,cardiac systolic and diastolic performance were both worsened. Moreover, the cardiac MHC-β mRNA was upregulated by ouabain treatment, whereas MHC-αmRNA was downregulated. After 4 weeks, the mean SBP in the ouabain group began to increase and was significantly higher than that in control group after 6 weeks (P<0.01); the rats' cardiac structure and function were worsened.Conclusion: These results suggested that ouabain induces alterations in cardiac structure and function, and the effects happened before the increase of blood pressure. The results indicated that ouabain induced cardiac remodeling in rats independent of blood pressure.

  14. Pentoxifylline Attenuates Cardiac Remodeling Induced by Tobacco Smoke Exposure

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    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.

  15. Calcitriol attenuates cardiac remodeling and dysfunction in a murine model of polycystic ovary syndrome.

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    Gao, Ling; Cao, Jia-Tian; Liang, Yan; Zhao, Yi-Chao; Lin, Xian-Hua; Li, Xiao-Cui; Tan, Ya-Jing; Li, Jing-Yi; Zhou, Cheng-Liang; Xu, Hai-Yan; Sheng, Jian-Zhong; Huang, He-Feng

    2016-05-01

    Polycystic ovary syndrome (PCOS) is a complex reproductive and metabolic disorder affecting 10 % of reproductive-aged women, and is well associated with an increased prevalence of cardiovascular risk factors. However, there are few data concerning the direct association of PCOS with cardiac pathologies. The present study aims to investigate the changes in cardiac structure, function, and cardiomyocyte survival in a PCOS model, and explore the possible effect of calcitriol administration on these changes. PCOS was induced in C57BL/6J female mice by chronic dihydrotestosterone administration, as evidenced by irregular estrous cycles, obesity and dyslipidemia. PCOS mice progressively developed cardiac abnormalities including cardiac hypertrophy, interstitial fibrosis, myocardial apoptosis, and cardiac dysfunction. Conversely, concomitant administration of calcitriol significantly attenuated cardiac remodeling and cardiomyocyte apoptosis, and improved cardiac function. Molecular analysis revealed that the beneficial effect of calcitriol was associated with normalized autophagy function by increasing phosphorylation levels of AMP-activated protein kinase and inhibiting phosphorylation levels of mammalian target of rapamycin complex. Our findings provide the first evidence for the presence of cardiac remodeling in a PCOS model, and vitamin D supplementation may be a potential therapeutic strategy for the prevention and treatment of PCOS-related cardiac remodeling.

  16. Quantitative proteomic changes during post myocardial infarction remodeling reveals altered cardiac metabolism and Desmin aggregation in the infarct region.

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    Datta, Kaberi; Basak, Trayambak; Varshney, Swati; Sengupta, Shantanu; Sarkar, Sagartirtha

    2017-01-30

    Myocardial infarction is one of the leading causes of cardiac dysfunction, failure and sudden death. Post infarction cardiac remodeling presents a poor prognosis, with 30%-45% of patients developing heart failure, in a period of 5-25years. Oxidative stress has been labelled as the primary causative factor for cardiac damage during infarction, however, the impact it may have during the process of post infarction remodeling has not been well probed. In this study, we have implemented iTRAQ proteomics to catalogue proteins and functional processes, participating both temporally (early and late phases) and spatially (infarct and remote zones), during post myocardial infarction remodeling of the heart as functions of the differential oxidative stress manifest during the remodeling process. Cardiac metabolism was the dominant network to be affected during infarction and the remodeling time points considered in this study. A distinctive expression pattern of cytoskeletal proteins was also observed with increased remodeling time points. Further, it was found that the cytoskeletal protein Desmin, aggregated in the infarct zone during the remodeling process, mediated by the protease Calpain1. Taken together, all of these data in conjunction may lay the foundation to understand the effects of oxidative stress on the remodeling process and elaborate the mechanism behind the compromised cardiac function observed during post myocardial infarction remodeling.

  17. Contrary microRNA Expression Pattern Between Fetal and Adult Cardiac Remodeling: Therapeutic Value for Heart Failure.

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    Yan, Hualin; Li, Yifei; Wang, Chuan; Zhang, Yi; Liu, Cong; Zhou, Kaiyu; Hua, Yimin

    2016-08-10

    microRNAs (miRNAs) belong to a class of non-coding RNAs that regulate post-transcriptional gene expression during development and disease. Growing evidence indicates abundant miRNA expression changes and their important role in cardiac hypertrophy and failure. However, the role of miRNAs in fetal cardiac remodeling is little known. Here, we investigated the altered expression of fifteen miRNAs in rat fetal cardiac remodeling compared with adult cardiac remodeling. Among fifteen tested miRNAs, eleven and five miRNAs (miR-199a-5p, miR-214-3p, miR-155-3p, miR-155-5p and miR-499-5p) are significantly differentially expressed in fetal and adult cardiac remodeling, respectively. After comparison of miRNA expression in fetal and adult cardiac remodeling, we find that miRNA expression returns to the fetal level in adult cardiac failure and is activated in advance of the adult level in fetal failure. The current study highlights the contrary expression pattern between fetal and adult cardiac remodeling and that supports a novel potential therapeutic approach to treating heart failure.

  18. RSK3 – A Regulator of Pathological Cardiac Remodeling

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    Martinez, Eliana C.; Passariello, Catherine L.; Li, Jinliang; Matheson, Christopher J.; Dodge-Kafka, Kimberly; Reigan, Philip; Kapiloff, Michael S.

    2015-01-01

    Summary The family of p90 ribosomal S6 kinases (RSK) are pleiotropic effectors for extracellular signal-regulated kinase (ERK) signaling pathways. Recently, RSK3 was shown to be important for pathological remodeling of the heart. While cardiac myocyte hypertrophy can be compensatory for increased wall stress, in chronic heart diseases this non-mitotic cell growth is usually associated with interstitial fibrosis, increased cell death, and decreased cardiac function. Although RSK3 is less abundant in the cardiac myocyte than other RSK family members, RSK3 appears to serve a unique role in cardiac myocyte stress responses. A potential mechanism conferring RSK3’s unique function in the heart is anchoring by the scaffold protein muscle A-kinase Anchoring Protein β (mAKAPβ). Recent findings suggest that RSK3 should be considered as a therapeutic target for the prevention of heart failure, a clinical syndrome of major public health significance. PMID:25988524

  19. mAKAP – A Master Scaffold for Cardiac Remodeling

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    Passariello, Catherine L.; Li, Jinliang; Dodge-Kafka, Kimberly; Kapiloff, Michael S.

    2014-01-01

    Cardiac remodeling is regulated by an extensive intracellular signal transduction network. Each of the many signaling pathways in this network contributes uniquely to the control of cellular adaptation. In the last few years, it has become apparent that multimolecular signaling complexes or ‘signalosomes’ are important for fidelity in intracellular signaling and for mediating crosstalk between the different signaling pathways. These complexes integrate upstream signals and control downstream effectors. In the cardiac myocyte, the protein mAKAPβ serves as a scaffold for a large signalosome that is responsive to cAMP, calcium, hypoxia, and mitogen-activated protein kinase signaling. The main function of mAKAPβ signalosomes is to modulate stress-related gene expression regulated by the transcription factors NFATc, MEF2 and HIF-1α and type II histone deacetylases that control pathological cardiac hypertrophy. PMID:25551320

  20. Cardiac remodeling and myocardial dysfunction in obese spontaneously hypertensive rats

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    Linz Dominik

    2012-09-01

    Full Text Available Abstract Background The additive effects of obesity and metabolic syndrome on left ventricular (LV maladaptive remodeling and function in hypertension are not characterized. Methods We compared an obese spontaneously hypertensive rat model (SHR-ob with lean spontaneously hypertensive rats (SHR-lean and normotensive controls (Ctr. LV-function was investigated by cardiac magnetic resonance imaging and invasive LV-pressure measurements. LV-interstitial fibrosis was quantified and protein levels of phospholamban (PLB, Serca2a and glucose transporters (GLUT1 and GLUT4 were determined by immunohistochemistry. Results Systolic blood pressure was similar in SHR-lean and SHR-ob (252 ± 7 vs. 242 ± 7 mmHg, p = 0.398 but was higher when compared to Ctr (155 ± 2 mmHg, p  Conclusion In addition to hypertension alone, metabolic syndrome and obesity adds to the myocardial phenotype by aggravating diastolic dysfunction and a progression towards systolic dysfunction. SHR-ob may be a useful model to develop new interventional and pharmacological treatment strategies for hypertensive heart disease and metabolic disorders.

  1. Cardiac remodeling and physical training post myocardial infarction

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    Michael; A; Garza; Emily; A; Wason; John; Q; Zhang

    2015-01-01

    After myocardial infarction(MI), the heart undergoes extensive myocardial remodeling through the accumulation of fibrous tissue in both the infarcted and noninfarcted myocardium, which distorts tissue structure, increases tissue stiffness, and accounts for ventricular dysfunction. There is growing clinical consensus that exercise training may beneficially alter the course of post-MI myocardial remodeling and improve cardiac function. This review summarizes the present state of knowledge regarding the effect of post-MI exercise training on infarcted hearts. Due to the degree of difficulty to study a viable human heart at both protein and molecular levels, most of the detailed studies have been performed by using animal models. Although there are some negative reports indicating that post-MI exercise may further cause deterioration of the wounded hearts, a growing body of research from both human and animal experiments demonstrates that post-MI exercise may beneficially alter the course of wound healing and improve cardiac function. Furthermore, the improved function is likely due to exercise training-induced mitigation of reninangiotensin-aldosterone system, improved balance between matrix metalloproteinase-1 and tissue inhibitor of matrix metalloproteinase-1, favorable myosin heavy chain isoform switch, diminished oxidative stress, enhanced antioxidant capacity, improved mitochondrial calcium handling, and boosted myocardial angiogenesis. Additionally, meta-analyses revealed that exercise-based cardiac rehabilitation has proven to be effective, and remains one of the least expensive therapies for both the prevention and treatment of cardiovascular disease, and prevents re-infarction.

  2. Alteration of RhoA Prenylation Ameliorates Cardiac and Vascular Remodeling in Spontaneously Hypertensive Rats

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    Jian Yang

    2016-06-01

    Full Text Available Background: In our previous study, farnesyl pyrophosphate synthase (FPPS was shown to be increased in spontaneously hypertensive rats (SHR and in mice with angiotensin-II induced cardiac hypertrophy. Overexpression of FPPS induced cardiac hypertrophy and fibrosis in mice, accompanied by an increase in the synthesis of farnesyl pyrophosphate (FPP and geranylgeranyl pyrophosphate (GGPP. In the present study, we investigated the mechanisms of reversing cardiovascular remodeling in SHR by inhibiting FPPS. Methods and Results: Six-week-old rats were given vehicle or an FPPS inhibitor (alendronate, 100 ug/kg/d daily for twelve weeks by osmotic mini-pump. The results demonstrated that FPPS inhibition attenuated cardiac hypertrophy and fibrosis in SHR as shown by the heart weight to body weight ratio, echocardiographic parameters, and histological examination. In addition, FPPS inhibition attenuated aortic remodeling as shown by reduced media thickness, media cross-sectional area and collagen of the aorta as well as SBP, DBP, MBP. Furthermore, 12 weeks of alendronate treatment significantly decreased FPP and GGPP levels, RhoA activation and geranylgeranylation in the heart and aorta, all of which were significantly upregulated in SHR compared with normotensive Wistar-Kyoto rats. Conclusion: Taken together, these results indicate that chronic treatment with alendronate decreases the development of cardiac and aortic remodeling, by a pathway which involves inhibition of the geranylgeranylation and activation of RhoA.

  3. The Role of Nrf2-Mediated Pathway in Cardiac Remodeling and Heart Failure

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    Shanshan Zhou

    2014-01-01

    Full Text Available Heart failure (HF is frequently the consequence of sustained, abnormal neurohormonal, and mechanical stress and remains a leading cause of death worldwide. The key pathophysiological process leading to HF is cardiac remodeling, a term referring to maladaptation to cardiac stress at the molecular, cellular, tissue, and organ levels. HF and many of the conditions that predispose one to HF are associated with oxidative stress. Increased generation of reactive oxygen species (ROS in the heart can directly lead to increased necrosis and apoptosis of cardiomyocytes which subsequently induce cardiac remodeling and dysfunction. Nuclear factor-erythroid-2- (NF-E2- related factor 2 (Nrf2 is a transcription factor that controls the basal and inducible expression of a battery of antioxidant genes and other cytoprotective phase II detoxifying enzymes that are ubiquitously expressed in the cardiovascular system. Emerging evidence has revealed that Nrf2 and its target genes are critical regulators of cardiovascular homeostasis via the suppression of oxidative stress, which is the key player in the development and progression of HF. The purpose of this review is to summarize evidence that activation of Nrf2 enhances endogenous antioxidant defenses and counteracts oxidative stress-associated cardiac remodeling and HF.

  4. Aggravated Cardiac Remodeling post Aortocaval Fistula in Unilateral Nephrectomized Rats.

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    Jie Wu

    Full Text Available Aortocaval fistula (AV in rat is a unique model of volume-overload congestive heart failure and cardiac hypertrophy. Living donor kidney transplantation is regarded as beneficial to allograft recipients and not particularly detrimental to the donors. Impact of AV on animals with mild renal dysfunction is not fully understood. In this study, we explored the effects of AV in unilateral nephrectomized (UNX rats.Adult male Sprague-Dawley (SD rats were divided into Sham (n = 10, UNX (right kidney remove, n = 10, AV (AV established between the levels of renal arteries and iliac bifurcation, n = 18 and UNX+AV (AV at one week after UNX, n = 22, respectively. Renal outcome was measured by glomerular filtration rate, effective renal plasma flow, fractional excretion of sodium, albuminuria, plasma creatinine, and cystatin C. Focal glomerulosclerosis (FGS incidence was evaluated by renal histology. Cardiac function was measured by echocardiography and hemodynamic measurements.UNX alone induced compensatory left kidney enlargement, increased plasma creatinine and cystatin C levels, and slightly reduced glomerular filtration rate and increased FGS. AV induced significant cardiac enlargement and hypertrophy and reduced cardiac function and increased FGS, these changes were aggravated in UNX+AV rats.Although UNX only induces minor renal dysfunction, additional chronic volume overload placement during the adaptation phase of the remaining kidney is associated with aggravated cardiac dysfunction and remodeling in UNX rats, suggesting special medical care is required for UNX or congenital monokidney subjects in case of chronic volume overload as in the case of pregnancy and hyperthyroidism to prevent further adverse cardiorenal events in these individuals.

  5. Impact of family hypertension history on exercise-induced cardiac remodeling.

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    Baggish, Aaron L; Weiner, Rory B; Yared, Kibar; Wang, Francis; Kupperman, Eli; Hutter, Adolph M; Picard, Michael H; Wood, Malissa J

    2009-07-01

    Left ventricular (LV) hypertrophy is a well-established, but highly variable, finding among exercise-trained persons. The causes for the variability in LV remodeling in response to exercise training remain incompletely understood. The present study sought to determine whether a family history of hypertension is a determinant of the cardiac response to exercise training. The cardiac parameters in 60 collegiate rowers (30 men/30 women; age 19.8 +/- 1.1 years) with (family history positive [FH+], n = 22) and without (family history negative [FH-], n = 38) a FH of hypertension were studied with echocardiography before and after 90 days of rowing training. The LV mass increased significantly in both groups. However, the LV mass increased significantly more in FH- persons (Delta 17 +/- 5 g/m(2)) than in FH+ persons (Delta 9 +/- 6 g/m(2), p hypertrophy between the 2 groups. FH- athletes experienced eccentric LV hypertrophy (relative wall thickness index 0.39 +/- 0.4) characterized by LV dilation. In contrast, FH+ athletes developed concentric LV hypertrophy (relative wall thickness index 0.44 +/- 0.3; p eccentric LV remodeling in FH- athletes was associated with a more robust enhancement of LV diastolic function than the concentric LV remodeling that occurred in FH+ athletes. In conclusion, these findings suggest that patterns of exercise-induced LV remodeling are strongly associated with FH history status.

  6. Targeted inhibition of Focal Adhesion Kinase Attenuates Cardiac Fibrosis and Preserves Heart Function in Adverse Cardiac Remodeling

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    Zhang, Jie; Fan, Guangpu; Zhao, Hui; Wang, Zhiwei; Li, Fei; Zhang, Peide; Zhang, Jing; Wang, Xu; Wang, Wei

    2017-01-01

    Cardiac fibrosis in post-myocardial infarction (MI), seen in both infarcted and non-infarcted myocardium, is beneficial to the recovery of heart function. But progressively pathological fibrosis impairs ventricular function and leads to poor prognosis. FAK has recently received attention as a potential mediator of fibrosis, our previous study reported that pharmacological inhibition of FAK can attenuate cardiac fibrosis in post MI models. However, the long-term effects on cardiac function and adverse cardiac remodelling were not clearly investigated. In this study, we tried to determine the preliminary mechanisms in regulating CF transformation to myofibroblasts and ECM synthesis relevant to the development of adverse cardiac remolding in vivo and in vitro. Our study provides even more evidence that FAK is directly related to the activation of CF in hypoxia condition in a dose-dependent and time-dependent manner. Pharmacological inhibition of FAK significantly reduces myofibroblast differentiation; our in vivo data demonstrated that a FAK inhibitor significantly decreases fibrotic score, and preserves partial left ventricular function. Both PI3K/AKT signalling and ERK1/2 are necessary for hypoxia-induced CF differentiation and ECM synthesis; this process also involves lysyl oxidase (LOX). These findings suggest that pharmacological inhibition of FAK may become an effective therapeutic strategy against adverse fibrosis. PMID:28225063

  7. Gender-related differences in β-adrenergic receptor-mediated cardiac remodeling.

    Science.gov (United States)

    Zhu, Baoling; Liu, Kai; Yang, Chengzhi; Qiao, Yuhui; Li, Zijian

    2016-12-01

    Cardiac remodeling is the pathological basis of various cardiovascular diseases. In this study, we found gender-related differences in β-adrenergic receptor (AR)-mediated pathological cardiac remodeling. Cardiac remodeling model was established by subcutaneous injection of isoprenaline (ISO) for 14 days. Heart rate (HR), mean arterial pressure (MAP), and echocardiography were obtained on 7th and 14th days during ISO administration. Myocardial cross-sectional area and the ratio of heart mass to tibia length (HM/TL) were detected to assess cardiac hypertrophy. Picro-Sirius red staining (picric acid + Sirius red F3B) was used to evaluate cardiac fibrosis. Myocardial capillary density was assessed by immunohistochemistry for von Willebrand factor. Further, real-time PCR was used to measure the expression of β1-AR and β2-AR. Results showed that ISO induced cardiac remodeling, the extent of which was different between female and male mice. The extent of increase in cardiac wall thickness, myocardial cross-sectional area, and collagen deposition in females was less than that in males. However, no gender-related difference was observed in HR, MAP, cardiac function, and myocardial capillary density. The distinctive decrease of β2-AR expression, rather than a decrease of β1-AR expression, seemed to result in gender-related differences in cardiac remodeling.

  8. Childhood obesity and cardiac remodeling: from cardiac structure to myocardial mechanics.

    Science.gov (United States)

    Tadic, Marijana; Cuspidi, Cesare

    2015-08-01

    Epidemic of obesity, especially morbid obesity, among children and adolescents, is a key factor associated with the dramatic increase in prevalence of type 2 diabetes mellitus, arterial hypertension, and metabolic syndrome in this population. Furthermore, childhood obesity represents a very important predictor of obesity in adulthood that is related to cardiovascular and cerebrovascular diseases. Overweight and obesity in children and adolescents are associated with impairment of cardiac structure and function. The majority of studies investigated the influence of obesity on left ventricular remodeling. However, the impact of obesity on the right ventricle, both the atria, and myocardial mechanics has been insufficiently studied. The aim of this review article is to summarize all data about heart remodeling in childhood, from cardiac size, throughout systolic and diastolic function, to myocardial mechanics, using a wide range of mainly echocardiographic techniques and parameters. Additionally, we sought to present current knowledge about the influence of weight loss, achieved by various therapeutic approaches, on the improvement of cardiac geometry, structure, and function in obese children and adolescents.

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

    Directory of Open Access Journals (Sweden)

    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.

  10. Stress-dependent cardiac remodeling occurs in the absence of microRNA-21 in mice

    DEFF Research Database (Denmark)

    Patrick, David M; Montgomery, Rusty L; Qi, Xiaoxia

    2010-01-01

    contractility comparable to wild. type littermates. Similarly, inhibition of miR-21 through intravenous delivery of a locked nucleic acid-modified (LNA-modified) antimiR oligonucleotide also failed to block the remodeling response of the heart to stress. We therefore conclude that miR-21 is not essential...... for pathological cardiac remodeling....

  11. 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.

  12. Roles of HDAC2 and HDAC8 in Cardiac Remodeling in Renovascular Hypertensive Rats and the Effects of Valproic Acid Sodium.

    Science.gov (United States)

    Li, Rui-Fang; Cao, Shan-Shan; Fang, Wei-Jin; Song, Ying; Luo, Xue-Ting; Wang, Hong-Yun; Wang, Jian-Gang

    2017-01-01

    Recent studies indicate that histone deacetylases (HDACs) activity is associated with the development and progression of cardiac hypertrophy. In this study, we investigated the effects of a HDACs inhibitor, valproic acid sodium (VPA), on cardiac remodeling and the differential expression of HDACs in left ventricles (LVs) of renovascular hypertensive rats. Renovascular hypertension was induced in rats by the two-kidney two-clip (2K2C) method. Cardiac remodeling, heart function and the differential expression of HDACs were examined at different weeks after 2K2C operation. The effects of VPA on cardiac remodeling, the expressions of HDACs, transforming growth factor-beta 1 (TGF-β1) and connective tissue growth factor (CTGF) in LV were investigated. The expressions of atrial natriuretic factor, β-myosin heavy chain, HDAC2 and HDAC8 increased in LV of 2K2C rats at 4, 8, 12 weeks after operation. Cardiac dysfunction, cardiac hypertrophy and fibrosis were markedly attenuated by VPA treatment in 2K2C rats. Further studies revealed that VPA inhibited the expressions of HDAC2, HDAC8, TGF-β1 and CTGF in LV of 2K2C rats. In summary, these data indicate that HDAC2 and HDAC8 play a key role in cardiac remodeling in renovascular hypertensive rats and that VPA attenuates hypertension and cardiac remodeling. The effect of VPA is possibly exerted via decreasing HDAC2, HDAC8, TGF-β1 and CTGF expressions in LV of 2K2C rats.

  13. Angiotensin II dependent cardiac remodeling in the eel Anguilla anguilla involves the NOS/NO system

    DEFF Research Database (Denmark)

    Filice, Mariacristina; Amelio, Daniela; Garofalo, Filippo

    2017-01-01

    Angiotensin II (AngII), the principal effector of the Renin-Angiotensin System (RAS), plays an important role in controlling mammalian cardiac morpho-functional remodelling. In the eel Anguilla anguilla, one month administration of AngII improves cardiac performance and influences the expression...

  14. Enhancing cardiac repair : targeting I/R injury and adverse remodeling

    NARCIS (Netherlands)

    Arslan, F.

    2011-01-01

    In this thesis, we have investigated novel therapeutic targets to enhance cardiac repair and improve cardiac function after myocardial infarction. We have tried to approach this objective by targeting 3 major determinants of post-infarct adverse remodeling and subsequent heart function deterioration

  15. Air pollution and adverse cardiac remodeling: clinical effects and basic mechanisms

    Directory of Open Access Journals (Sweden)

    Yonggang eLiu

    2015-05-01

    Full Text Available EExposure to air pollution has long been known to trigger cardiovascular events, primarily through activation of local and systemic inflammatory pathways that affect the vasculature. Detrimental effects of air pollution exposure on heart failure and cardiac remodeling have also been described in human populations. Recent studies in both human subjects and animal models have provided insights into the basic physiological, cellular and molecular mechanisms that play a role in adverse cardiac remodeling. This review will give a brief overview of the relationship between air pollution and cardiovascular disease, describe the clinical effects of air pollution exposure on cardiac remodeling, describe the basic mechanisms that affect remodeling as described in human and animal systems and will discuss future areas of investigation.

  16. Air pollution and adverse cardiac remodeling: clinical effects and basic mechanisms.

    Science.gov (United States)

    Liu, Yonggang; Goodson, Jamie M; Zhang, Bo; Chin, Michael T

    2015-01-01

    Exposure to air pollution has long been known to trigger cardiovascular events, primarily through activation of local and systemic inflammatory pathways that affect the vasculature. Detrimental effects of air pollution exposure on heart failure and cardiac remodeling have also been described in human populations. Recent studies in both human subjects and animal models have provided insights into the basic physiological, cellular and molecular mechanisms that play a role in adverse cardiac remodeling. This review will give a brief overview of the relationship between air pollution and cardiovascular disease, describe the clinical effects of air pollution exposure on cardiac remodeling, describe the basic mechanisms that affect remodeling as described in human and animal systems and will discuss future areas of investigation.

  17. Lasting alterations of the sodium current by short-term hyperlipidemia as a mechanism for initiation of cardiac remodeling.

    Science.gov (United States)

    Biet, M; Morin, N; Benrezzak, O; Naimi, F; Bellanger, S; Baillargeon, J P; Chouinard, L; Gallo-Payet, N; Carpentier, A C; Dumaine, R

    2014-01-15

    Clinical and animal studies indicate that increased fatty acid delivery to lean tissues induces cardiac electrical remodeling and alterations of cellular calcium homeostasis. Since this may represent a mechanism initiating cardiac dysfunction during establishment of insulin resistance and diabetes or anaerobic cardiac metabolism (ischemia), we sought to determine if short-term exposure to high plasma concentration of fatty acid in vivo was sufficient to alter the cardiac sodium current (INa) in dog ventricular myocytes. Our results show that delivery of triglycerides and nonesterified fatty acids by infusion of Intralipid + heparin (IH) for 8 h increased the amplitude of INa by 43% and shifted its activation threshold by -5 mV, closer to the resting membrane potential. Steady-state inactivation (availability) of the channels was reduced by IH with no changes in recovery from inactivation. As a consequence, INa "window" current, a strong determinant of intracellular Na+ and Ca2+ concentrations, was significantly increased. The results indicate that increased circulating fatty acids alter INa gating in manners consistent with an increased cardiac excitability and augmentation of intracellular calcium. Moreover, these changes could still be measured after the dogs were left to recover for 12 h after IH perfusion, suggesting lasting changes in INa. Our results indicate that fatty acids rapidly induce cardiac remodeling and suggest that this process may be involved in the development of cardiac dysfunctions associated to insulin resistance and diabetes.

  18. Chromatin Modification and Remodeling in Heart Development

    Directory of Open Access Journals (Sweden)

    Paul Delgado-Olguín

    2006-01-01

    Full Text Available In organogenesis, cell types are specified from determined precursors as morphogenetic patterning takes place. These events are largely controlled by tissue-specific transcription factors. These transcription factors must function within the context of chromatin to activate or repress target genes. Recent evidence suggests that chromatin-remodeling and -modifying factors may have tissue-specific function. Here we review the potential roles for chromatin-remodeling and -modifying proteins in the development of the mammalian heart.

  19. Ischemia-reperfusion injury leads to distinct temporal cardiac remodeling in normal versus diabetic mice.

    Directory of Open Access Journals (Sweden)

    Megumi Eguchi

    Full Text Available Diabetes is associated with higher incidence of myocardial infarction (MI and increased propensity for subsequent events post-MI. Here we conducted a temporal analysis of the influence of diabetes on cardiac dysfunction and remodeling after ischemia reperfusion (IR injury in mice. Diabetes was induced using streptozotocin and IR performed by ligating the left anterior descending coronary artery for 30 min followed by reperfusion for up to 42 days. We first evaluated changes in cardiac function using echocardiography after 24 hours reperfusion and observed IR injury significantly decreased the systolic function, such as ejection fraction, fractional shortening and end systolic left ventricular volume (LVESV in both control and diabetic mice. The longitudinal systolic and diastolic strain rate were altered after IR, but there were no significant differences between diabetic mice and controls. However, a reduced ability to metabolize glucose was observed in the diabetic animals as determined by PET-CT scanning using 2-deoxy-2-((18Ffluoro-D-glucose. Interestingly, after 24 hours reperfusion diabetic mice showed a reduced infarct size and less apoptosis indicated by TUNEL analysis in heart sections. This may be explained by increased levels of autophagy detected in diabetic mice hearts. Similar increases in IR-induced macrophage infiltration detected by CD68 staining indicated no change in inflammation between control and diabetic mice. Over time, control mice subjected to IR developed mild left ventricular dilation whereas diabetic mice exhibited a decrease in both end diastolic left ventricular volume and LVESV with a decreased intraventricular space and thicker left ventricular wall, indicating concentric hypertrophy. This was associated with marked increases in fibrosis, indicted by Masson trichrome staining, of heart sections in diabetic IR group. In summary, we demonstrate that diabetes principally influences distinct IR-induced chronic changes

  20. Role of TGF-β on cardiac structural and electrical remodeling

    Directory of Open Access Journals (Sweden)

    Roberto Ramos-Mondragón

    2008-12-01

    Full Text Available Roberto Ramos-Mondragón, Carlos A Galindo, Guillermo AvilaDepartamento de Bioquímica, Cinvestav-IPN, MéxicoAbstract: The type β transforming growth factors (TGF-βs are involved in a number of human diseases, including heart failure and myocardial arrhythmias. In fact, during the last 20 years numerous studies have demonstrated that TGF-β affects the architecture of the heart under both normal and pathological conditions. Moreover, TGF-β signaling is currently under investigation, with the aim of discovering potential therapeutic roles in human disease. In contrast, only few studies have investigated whether TGF-β affects electrophysiological properties of the heart. This fact is surprising since electrical remodeling represents an important substrate for cardiac disease. This review discusses the potential role of TGF-β on cardiac excitation-contraction (EC coupling, action potentials, and ion channels. We also discuss the effects of TGF-β on cardiac development and disease from structural and electrophysiological points of view.Keywords: transforming growth factor, ion channel, cardiac electrophysiology

  1. Epigenetic mechanisms in cardiac development and disease

    Institute of Scientific and Technical Information of China (English)

    Marcus Vallaster; Caroline Dacwag Vallaster; Sean M. Wu

    2012-01-01

    During mammalian development,cardiac specification and ultimately lineage commitment to a specific cardiac cell type is accomplished by the action of specific transcription factors (TFs) and their meticulous control on an epigenetic level.In this review,we detail how cardiacspecific TFs function in concert with nucleosome remodeling and histone-modifying enzymes to regulate a diverse network of genes required for processes such as cell growth and proliferation,or epithelial to mesenchymal transition (EMT),for instance.We provide examples of how several cardiac TFs,such as Nkx2.5,WHSC1,Tbx5,and Tbx1,which are associated with developmental and congenital heart defects,are required for the recruitment of histone modifiers,such as Jarid2,p300,and Ash21,and components of ATP-dependent remodeling enzymes like Brg1,Baf60c,and Baf180.Binding of these TFs to their respective sites at cardiac genes coincides with a distinct pattern of histone marks,indicating that the precise regulation of cardiac gene networks is orchestrated by interactions between TFs and epigenetic modifiers.Furthermore,we speculate that an epigenetic signature,comprised of TF occupancy,histone modifications,and overall chromatin organization,is an underlying mechanism that governs cardiac morphogenesis and disease.

  2. Pioglitazone alleviates cardiac and vascular remodelling and improves survival in monocrotaline induced pulmonary arterial hypertension.

    Science.gov (United States)

    Behringer, Arnica; Trappiel, Manuela; Berghausen, Eva Maria; Ten Freyhaus, Henrik; Wellnhofer, Ernst; Odenthal, Margarete; Blaschke, Florian; Er, Fikret; Gassanov, Natig; Rosenkranz, Stephan; Baldus, Stephan; Kappert, Kai; Caglayan, Evren

    2016-04-01

    Pulmonary arterial hypertension (PAH) is a fatal disease with limited therapeutic options. Pathophysiological changes comprise obliterative vascular remodelling of small pulmonary arteries, elevated mean pulmonary arterial systolic pressure (PASP) due to elevated resistance of pulmonary vasculature, adverse right ventricular remodelling, and heart failure. Recent findings also indicate a role of increased inflammation and insulin resistance underlying the development of PAH. We hypothesized that treatment of this condition with the peroxisome proliferator-activated receptor-γ (PPARγ) activator pioglitazone, known to regulate the expression of different genes addressing insulin resistance, inflammatory changes, and vascular remodelling, could be a beneficial approach. PAH was induced in adult rats by a single subcutaneous injection of monocrotaline (MCT). Pioglitazone was administered for 2 weeks starting 3 weeks after MCT-injection. At day 35, hemodynamics, organ weights, and -indices were measured. We performed morphological and molecular characterization of the pulmonary vasculature, including analysis of the degree of muscularization, proliferation rates, and medial wall thickness of the small pulmonary arteries. Furthermore, markers of cardiac injury, collagen content, and cardiomyocyte size were analyzed. Survival rates were monitored throughout the experimental period. Pioglitazone treatment improved survival, reduced PASP, muscularization of small pulmonary arteries, and medial wall thickness. Further, MCT-induced right ventricular hypertrophy and fibrosis were attenuated. This was accompanied with reduced cardiac expression of brain natriuretic peptide, as well as decreased cardiomyocyte size. Finally, pulmonary macrophage content and osteopontin gene expression were attenuated. Based on the beneficial impact of pioglitazone, activation of PPARγ might be a promising treatment option in PAH.

  3. Interplay between cardiac function and heart development.

    Science.gov (United States)

    Andrés-Delgado, Laura; Mercader, Nadia

    2016-07-01

    Mechanotransduction refers to the conversion of mechanical forces into biochemical or electrical signals that initiate structural and functional remodeling in cells and tissues. The heart is a kinetic organ whose form changes considerably during development and disease. This requires cardiomyocytes to be mechanically durable and able to mount coordinated responses to a variety of environmental signals on different time scales, including cardiac pressure loading and electrical and hemodynamic forces. During physiological growth, myocytes, endocardial and epicardial cells have to adaptively remodel to these mechanical forces. Here we review some of the recent advances in the understanding of how mechanical forces influence cardiac development, with a focus on fluid flow forces. This article is part of a Special Issue entitled: Cardiomyocyte Biology: Integration of Developmental and Environmental Cues in the Heart edited by Marcus Schaub and Hughes Abriel.

  4. Role of matricellular proteins in cardiac tissue remodeling after myocardial infarction

    Institute of Scientific and Technical Information of China (English)

    Yutaka; Matsui; Junko; Morimoto; Toshimitsu; Uede

    2010-01-01

    After onset of myocardial infarction(MI),the left ventricle(LV) undergoes a continuum of molecular,cellular,and extracellular responses that result in LV wall thinning,dilatation,and dysfunction.These dynamic changes in LV shape,size,and function are termed cardiac remodeling.If the cardiac healing after MI does not proceed properly,it could lead to cardiac rupture or maladaptive cardiac remodeling,such as further LV dilatation and dysfunction,and ultimately death.Although the precise molecular mechanisms in this cardiac healing process have not been fully elucidated,this process is strictly coordinated by the interaction of cells with their surrounding extracellular matrix(ECM) proteins.The components of ECM include basic structural proteins such as collagen,elastin and specialized proteins such as fibronectin,proteoglycans and matricellular proteins.Matricellular proteins are a class of non-structural and secreted proteins that probably exert regulatory functions through direct binding to cell surface receptors,other matrix proteins,and soluble extracellular factors such as growth factors and cytokines.This small group of proteins,which includesosteopontin,thrombospondin-1/2,tenascin,periostin,and secreted protein,acidic and rich in cysteine,shows a low level of expression in normal adult tissue,but is markedly upregulated during wound healing and tissue remodeling,including MI.In this review,we focus on the regulatory functions of matricellular proteins during cardiac tissue healing and remodeling after MI.

  5. Ongoing controversies surrounding cardiac remodeling: is it black and white-or rather fifty shades of gray?

    Science.gov (United States)

    Spaich, Sebastian; Katus, Hugo A; Backs, Johannes

    2015-01-01

    Cardiac remodeling describes the heart's multimodal response to a myriad of external or intrinsic stimuli and stressors most of which are probably only incompletely elucidated to date. Over many years the signaling molecules involved in these remodeling processes have been dichotomized according to a classic antagonistic view of black and white, i.e., attributed either a solely maladaptive or entirely beneficial character. By dissecting controversies, recent developments and shifts in perspective surrounding the three major cardiac signaling molecules calcineurin (Cn), protein kinase A (PKA) and calcium/calmodulin-dependent kinase II (CaMKII), this review challenges this dualistic view and advocates the nature and dignity of each of these key mediators of cardiac remodeling as a multilayered, highly context-sensitive and sophisticated continuum that can be markedly swayed and influenced by a multitude of environmental factors and crosstalk mechanisms. Furthermore this review delineates the importance and essential contributions of degradation and proteolysis to cardiac plasticity and homeostasis and finally aims to integrate the various aspects of protein synthesis and turnover into a comprehensive picture.

  6. Ongoing controversies surrounding cardiac remodeling: is it black and white – or rather fifty shades of grey?

    Directory of Open Access Journals (Sweden)

    Sebastian eSpaich

    2015-07-01

    Full Text Available Cardiac remodeling describes the heart’s multimodal response to a myriad of external or intrinsic stimuli and stressors most of which are probably only incompletely elucidated to date. Over many years the signaling molecules involved in these remodeling processes have been dichotomized according to a classic antagonistic view of black and white, i.e. attributed either a solely maladaptive or entirely beneficial character. By dissecting controversies, recent developments and shifts in perspective surrounding the 3 major cardiac signaling molecules calcineurin (Cn, protein kinase A (PKA and calcium/calmodulin-dependent kinase II (CaMKII, this review challenges this dualistic view and advocates the nature and dignity of each of these key mediators of cardiac remodeling as a multilayered, highly context-sensitive and sophisticated continuum that can be markedly swayed and influenced by a multitude of environmental factors and crosstalk mechanisms.Furthermore this review delineates the importance and essential contributions of degradation and proteolysis to cardiac plasticity and homeostasis and finally aims to integrate the various aspects of protein synthesis and turnover into a comprehensive picture.

  7. Effects of Long-term Right Ventricular Apical Pacing on Left Ventricular Remodeling and Cardiac Function

    Institute of Scientific and Technical Information of China (English)

    2009-01-01

    Objective: To investigate the impacts of long-term right ventricular apical pacing on the ventricular remodeling and cardiac functions of patients with high-grade and third-degree atrioventricular blockage with normal heart structures and cardiac functions. In addition, we provide many evidences for choosing an optimal electrode implantation site.Methods: Study participants included patients who were admitted for pacemaker replacements and revisited for examinations of implanted pacemakers at outpatient. Pa...

  8. Maternal hypoxia alters matrix metalloproteinase expression patterns and causes cardiac remodeling in fetal and neonatal rats.

    Science.gov (United States)

    Tong, Wenni; Xue, Qin; Li, Yong; Zhang, Lubo

    2011-11-01

    Fetal hypoxia leads to progressive cardiac remodeling in rat offspring. The present study tested the hypothesis that maternal hypoxia results in reprogramming of matrix metalloproteinase (MMP) expression patterns and fibrillar collagen matrix in the developing heart. Pregnant rats were treated with normoxia or hypoxia (10.5% O(2)) from day 15 to 21 of gestation. Hearts were isolated from 21-day fetuses (E21) and postnatal day 7 pups (PD7). Maternal hypoxia caused a decrease in the body weight of both E21 and PD7. The heart-to-body weight ratio was increased in E21 but not in PD7. Left ventricular myocardium wall thickness and cardiomyocyte proliferation were significantly decreased in both fetal and neonatal hearts. Hypoxia had no effect on fibrillar collagen content in the fetal heart, but significantly increased the collagen content in the neonatal heart. Western blotting revealed that maternal hypoxia significantly increased collagen I, but not collagen III, levels in the neonatal heart. Maternal hypoxia decreased MMP-1 but increased MMP-13 and membrane type (MT)1-MMP in the fetal heart. In the neonatal heart, MMP-1 and MMP-13 were significantly increased. Active MMP-2 and MMP-9 levels and activities were not altered in either fetal or neonatal hearts. Hypoxia significantly increased tissue inhibitors of metalloproteinase (TIMP)-3 and TIMP-4 in both fetal and neonatal hearts. In contrast, TIMP-1 and TIMP-2 were not affected. The results demonstrate that in utero hypoxia reprograms the expression patterns of MMPs and TIMPs and causes cardiac tissue remodeling with the increased collagen deposition in the developing heart.

  9. Relationship Between Reverse Remodeling and Cardiopulmonary Exercise Capacity in Heart Failure Patients Undergoing Cardiac Resynchronization Therapy

    NARCIS (Netherlands)

    Mastenbroek, Mirjam H; van t Sant, Jetske; Versteeg, Henneke; Cramer, MJ; Doevendans, Pieter A; Pedersen, Susanne S; Meine, Mathias

    2016-01-01

    BACKGROUND: Studies on the relationship between left ventricular reverse remodeling and cardiopulmonary exercise capacity in heart failure patients undergoing cardiac resynchronization therapy (CRT) are scarce and inconclusive. METHODS AND RESULTS: Eighty-four patients with a 1st-time CRT-defibrilla

  10. Autoantibodies against α1 adrenergic receptor related with cardiac remodeling in hypertensive patients by clinical observation

    Institute of Scientific and Technical Information of China (English)

    李正在

    2006-01-01

    Objective To investigate the effects of autoantibodies against a adrenergic receptor on cardiac remodeling in patients with hypertension. Methods Five hundred and fifty three patients with hypertension in our hospital were selected. The autoantibodies againstα1 adrenergic receptor in sera of donor were detected by ELISA, and the Results of echocardiography were recorded. By

  11. Effect of phentolamine on myocardial extracellular matrix of cardiac remodeling in rats

    Institute of Scientific and Technical Information of China (English)

    Yi-Gang Yin; Ru-Zhu Wang; Zhong-Bao Ruan; Li Zhu

    2014-01-01

    Objective:To study the effects of phentolamine on myocardial extracellular matrix of cardiac remodeling induced by norepinephrine in rats.Methods:24SD rats were divided into3 groups randomly: control groups, norepinephrine groups(model groups), norepinephrine+phentolamine groups(treatment groups).Echocardiography was used to detect changes in cardiac structure and function, the level of collagen volume fraction(CVF) and hydroxyproline as well as collagen content were determined in myocardial tissue, matrix metalloproteinases-2 and collagen Ⅰ in myocardial tissue were localized by immunohistochemitry.Results:Compared with control groups, left ventricular hypertrophy in the model group rats, the hydroxyproline content and CVF was significantly higher(P<0.01), and matrix metalloproteinase-2 and collagen Ⅰ protein expression was significantly increased(P<0.01).Phentolamine significantly improved cardiac hypertrophy in treatment group rats, reduced hydroxyproline,CVF, matrix metalloproteinase2 and collagen Ⅰprotein expression(P<0.05).Conclusions:Phentolamine can effectively reduce the incidence of myocardial hypertrophy and myocardial extracellular matrix remodeling inSD rats, and it can ease myocardial extracellular matrix of cardiac remodeling.It may be associated with reduced expression of matrix metalloproteinase2 and collagen Ⅰ in myocardial tissue remodeling.

  12. Postnatal ablation of Foxm1 from cardiomyocytes causes late onset cardiac hypertrophy and fibrosis without exacerbating pressure overload-induced cardiac remodeling.

    Science.gov (United States)

    Bolte, Craig; Zhang, Yufang; York, Allen; Kalin, Tanya V; Schultz, Jo El J; Molkentin, Jeffery D; Kalinichenko, Vladimir V

    2012-01-01

    Heart disease remains a leading cause of morbidity and mortality in the industrialized world. Hypertrophic cardiomyopathy is the most common genetic cardiovascular disorder and the most common cause of sudden cardiac death. Foxm1 transcription factor (also known as HFH-11B, Trident, Win or MPP2) plays an important role in the pathogenesis of various cancers and is a critical mediator of post-injury repair in multiple organs. Foxm1 has been previously shown to be essential for heart development and proliferation of embryonic cardiomyocytes. However, the role of Foxm1 in postnatal heart development and in cardiac injury has not been evaluated. To delete Foxm1 in postnatal cardiomyocytes, αMHC-Cre/Foxm1(fl/fl) mice were generated. Surprisingly, αMHC-Cre/Foxm1(fl/fl) mice exhibited normal cardiomyocyte proliferation at postnatal day seven and had no defects in cardiac structure or function but developed cardiac hypertrophy and fibrosis late in life. The development of cardiomyocyte hypertrophy and cardiac fibrosis in aged Foxm1-deficient mice was associated with reduced expression of Hey2, an important regulator of cardiac homeostasis, and increased expression of genes critical for cardiac remodeling, including MMP9, αSMA, fibronectin and vimentin. We also found that following aortic constriction Foxm1 mRNA and protein were induced in cardiomyocytes. However, Foxm1 deletion did not exacerbate cardiac hypertrophy or fibrosis following chronic pressure overload. Our results demonstrate that Foxm1 regulates genes critical for age-induced cardiomyocyte hypertrophy and cardiac fibrosis.

  13. Adenoviral short hairpin RNA targeting phosphodiesterase 5 attenuates cardiac remodeling and cardiac dysfunction following myocardial infarction in mice

    Institute of Scientific and Technical Information of China (English)

    张健

    2014-01-01

    Objective To observe the impact of PDE5shRNA on cardiac remodeling and heart function following myocardial infarction in mice.Methods Myocardial infarction(MI)was induced in mice by left coronary artery ligation.Mice were randomly assigned to sham operation group(n=6),PDE5shRNA group(n=12),common adenovirus group(n=15)and DMEM group(n=8).Four weeks post-MI,the survival rate was evaluated.

  14. Zebrafish in the Study of Early Cardiac Development

    OpenAIRE

    Liu, Jiandong; Stainier, Didier Y.R.

    2012-01-01

    Heart development is a complex process that involves cell specification and differentiation, as well as elaborate tissue morphogenesis and remodeling, to generate a functional organ. The zebrafish has emerged as a powerful model system to unravel the basic genetic, molecular and cellular mechanisms of cardiac development and function. Here we summarize and discuss recent discoveries on early cardiac specification and the identification of the second heart field in zebrafish. In addition to th...

  15. Aggravated myocardial infarction-induced cardiac remodeling and heart failure in histamine-deficient mice

    Science.gov (United States)

    Chen, Jinmiao; Hong, Tao; Ding, Suling; Deng, Long; Abudupataer, Mieradilijiang; Zhang, Weiwei; Tong, Minghong; Jia, Jianguo; Gong, Hui; Zou, Yunzeng; Wang, Timothy C.; Ge, Junbo; Yang, Xiangdong

    2017-01-01

    Histamine has pleiotropic pathophysiological effects, but its role in myocardial infarction (MI)-induced cardiac remodeling remains unclear. Histidine decarboxylase (HDC) is the main enzyme involved in histamine production. Here, we clarified the roles of HDC-expressing cells and histamine in heart failure post-MI using HDC-EGFP transgenic mice and HDC-knockout (HDC−/−) mice. HDC+CD11b+ myeloid cell numbers markedly increased in the injured hearts, and histamine levels were up-regulated in the circulation post-MI. HDC−/− mice exhibited more adverse cardiac remodeling, poorer left ventricular function and higher mortality by increasing cardiac fibrogenesis post-MI. In vitro assays further confirmed that histamine inhibited heart fibroblast proliferation. Furthermore, histamine enhanced the signal transducer and activator of transcription (STAT)-6 phosphorylation level in murine heart fibroblasts, and the inhibitive effects of histamine on fibroblast proliferation could be blocked by JAK3/STAT6 signaling selective antagonist. STAT6-knockout (STAT6−/−) mice had a phenotype similar to that of HDC−/− mice post-MI; however, in contrast to HDC−/− mice, the beneficial effects of exogenous histamine injections were abrogated in STAT6−/− mice. These data suggest that histamine exerts protective effects by modulating cardiac fibrosis and remodeling post-MI, in part through the STAT6-dependent signaling pathway. PMID:28272448

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

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    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.

  17. Small interfering RNA therapy against carbohydrate sulfotransferase 15 inhibits cardiac remodeling in rats with dilated cardiomyopathy.

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    Watanabe, Kenichi; Arumugam, Somasundaram; Sreedhar, Remya; Thandavarayan, Rajarajan A; Nakamura, Takashi; Nakamura, Masahiko; Harima, Meilei; Yoneyama, Hiroyuki; Suzuki, Kenji

    2015-07-01

    Carbohydrate sulfotransferase 15 (CHST15) is a sulfotransferase responsible for biosynthesis of chondroitin sulfate E (CS-E), which plays important roles in numerous biological events such as biosynthesis of proinflammatory cytokines. However, the effects of CHST15 siRNA in rats with chronic heart failure (CHF) after experimental autoimmune myocarditis (EAM) have not yet been investigated. CHF was elicited in Lewis rats by immunization with cardiac myosin, and after immunization, the rats were divided into two groups and treated with either CHST15 siRNA (2μg/week) or vehicle. Age matched normal rats without immunizations were also included in this study. After 7weeks of treatment, we investigated the effects of CHST15 siRNA on cardiac function, proinflammatory cytokines, and cardiac remodeling in EAM rats. Myocardial functional parameters measured by hemodynamic and echocardiographic studies were significantly improved by CHST15 siRNA treatment in rats with CHF compared with that of vehicle-treated CHF rats. CHST15 siRNA significantly reduced cardiac fibrosis, and hypertrophy and its marker molecules (left ventricular (LV) mRNA expressions of transforming growth factor beta1, collagens I and III, and atrial natriuretic peptide) compared with vehicle-treated CHF rats. CHF-induced increased myocardial mRNA expressions of proinflammatory cytokines [interleukin (IL)-6, IL-1β], monocyte chemoattractant protein-1, and matrix metalloproteinases (MMP-2 and -9), and CHST15 were also suppressed by the treatment with CHST15 siRNA. Western blotting study has confirmed the results obtained from mRNA analysis as CHST15 siRNA treated rats expressed reduced levels of inflammatory and cardiac remodeling marker proteins. Our results demonstrate for the first time, that CHST15 siRNA treatment significantly improved LV function and ameliorated the progression of cardiac remodeling in rats with CHF after EAM.

  18. Periostin as a modulator of chronic cardiac remodeling after myocardial infarction

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    Marcos F. Minicucci

    2013-10-01

    Full Text Available OBJECTIVE: After acute myocardial infarction, during the cardiac repair phase, periostin is released into the infarct and activates signaling pathways that are essential for the reparative process. However, the role of periostin in chronic cardiac remodeling after myocardial infarction remains to be elucidated. Therefore, the objective of this study was to investigate the relationship between tissue periostin and cardiac variables in the chronic cardiac remodeling induced by myocardial infarction. METHODS: Male Wistar rats were assigned to 2 groups: a simulated surgery group (SHAM; n = 8 and a myocardial infarction group (myocardial infarction; n = 13. After 3 months, morphological, functional and biochemical analyses were performed. The data are expressed as means±SD or medians (including the lower and upper quartiles. RESULTS: Myocardial infarctions induced increased left ventricular diastolic and systolic areas associated with a decreased fractional area change and a posterior wall shortening velocity. With regard to the extracellular matrix variables, the myocardial infarction group presented with higher values of periostin and types I and III collagen and higher interstitial collagen volume fractions and myocardial hydroxyproline concentrations. In addition, periostin was positively correlated with type III collagen levels (r = 0.673, p = 0.029 and diastolic (r = 0.678, p = 0.036 and systolic (r = 0.795, p = 0.006 left ventricular areas. Considering the relationship between periostin and the cardiac function variables, periostin was inversely correlated with both the fractional area change (r = -0.783, p = 0.008 and the posterior wall shortening velocity (r = -0.767, p = 0.012. CONCLUSIONS: Periostin might be a modulator of deleterious cardiac remodeling in the chronic phase after myocardial infarction in rats.

  19. Bcl10 mediates angiotensin II-induced cardiac damage and electrical remodeling.

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    Markó, Lajos; Henke, Norbert; Park, Joon-Keun; Spallek, Bastian; Qadri, Fatimunnisa; Balogh, András; Apel, Ingrid J; Oravecz-Wilson, Katherine I; Choi, Mira; Przybyl, Lukasz; Binger, Katrina J; Haase, Nadine; Wilck, Nicola; Heuser, Arnd; Fokuhl, Verena; Ruland, Jürgen; Lucas, Peter C; McAllister-Lucas, Linda M; Luft, Friedrich C; Dechend, Ralf; Müller, Dominik N

    2014-11-01

    Angiotensin (Ang) II is a potent mediator of both hypertension and cardiac damage; however, the mechanisms by which this occur remain unclear. B-cell lymphoma/leukemia 10 (Bcl10) is a member of the CBM signalosome, which links Ang II and nuclear factor-κB signaling. We hypothesized that Bcl10 is pivotal in the pathogenesis of Ang II-induced cardiac damage. Ang II infusion in mice lacking Bcl10 resulted in reduced cardiac fibrosis, less cellular infiltration, and improved arrhythmogenic electric remodeling, despite a similar degree of hypertension or cardiac hypertrophy. Adoptive transfer of bone marrow (BM), whereby Bcl10 knockout or wildtype BM was transferred to their opposite genotype recipients, revealed the dual importance of Bcl10 within both cardiac and immune cells. Loss of Bcl10 in cardiac cells resulted in reduced expression of genes important for the adhesion and recruitment of immune cells. In vitro experiments demonstrated that adhesion of monocytes to Ang II-treated endothelial cells also required Bcl10. Additionally, Bcl10 deficiency in macrophages reduced their intrinsic migratory ability. To address the role of BM-derived fibroblasts in the formation of cardiac fibrosis, we explored whether Bcl10 is also important for the infiltration of BM-derived (myo)fibroblasts into the heart. The transfer of green fluorescent protein positive wildtype BM into Bcl10 knockout recipient mice revealed a reduced number of noncardiac (myo)fibroblasts compared with those wildtype recipients. Our results demonstrate the significant role of Bcl10 in multiple cell types important for the generation of Ang II-induced cardiac damage and electric remodeling and may provide a new avenue for therapeutic intervention.

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

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    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.

  1. MT1-MMP-dependent remodeling of cardiac extracellular matrix structure and function following myocardial infarction.

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    Koenig, Gerald C; Rowe, R Grant; Day, Sharlene M; Sabeh, Farideh; Atkinson, Jeffrey J; Cooke, Kenneth R; Weiss, Stephen J

    2012-05-01

    The myocardial extracellular matrix (ECM), an interwoven meshwork of proteins, glycoproteins, proteoglycans, and glycosaminoglycans that is dominated by polymeric fibrils of type I collagen, serves as the mechanical scaffold on which myocytes are arrayed for coordinated and synergistic force transduction. Following ischemic injury, cardiac ECM remodeling is initiated via localized proteolysis, the bulk of which has been assigned to matrix metalloproteinase (MMP) family members. Nevertheless, the key effector(s) of myocardial type I collagenolysis both in vitro and in vivo have remained unidentified. In this study, using cardiac explants from mice deficient in each of the major type I collagenolytic MMPs, including MMP-13, MMP-8, MMP-2, MMP-9, or MT1-MMP, we identify the membrane-anchored MMP, MT1-MMP, as the dominant collagenase that is operative within myocardial tissues in vitro. Extending these observations to an in vivo setting, mice heterozygous for an MT1-MMP-null allele display a distinct survival advantage and retain myocardial function relative to wild-type littermates in an experimental model of myocardial infarction, effects associated with preservation of the myocardial type I collagen network as a consequence of the decreased collagenolytic potential of cardiac fibroblasts. This study identifies MT1-MMP as a key MMP responsible for effecting postinfarction cardiac ECM remodeling and cardiac dysfunction.

  2. Monocytes increase human cardiac myofibroblast-mediated extracellular matrix remodeling through TGF-β1.

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    Mewhort, Holly E M; Lipon, Brodie D; Svystonyuk, Daniyil A; Teng, Guoqi; Guzzardi, David G; Silva, Claudia; Yong, V Wee; Fedak, Paul W M

    2016-03-15

    Following myocardial infarction (MI), cardiac myofibroblasts remodel the extracellular matrix (ECM), preventing mechanical complications. However, prolonged myofibroblast activity leads to dysregulation of the ECM, maladaptive remodeling, fibrosis, and heart failure (HF). Chronic inflammation is believed to drive persistent myofibroblast activity; however, the mechanisms are unclear. We assessed the influence of peripheral blood monocytes on human cardiac myofibroblast activity in a three-dimensional (3D) ECM microenvironment. Human cardiac myofibroblasts isolated from surgical biopsies of the right atrium and left ventricle were seeded into 3D collagen matrices. Peripheral blood monocytes were isolated from healthy human donors and cocultured with myofibroblasts. Monocytes increased myofibroblast activity measured by collagen gel contraction (baseline: 57.6 ± 5.9% vs. coculture: 65.2 ± 7.1% contraction; P matrix metalloproteinase 9 compared with baseline (122.9 ± 10.1 pg/ml and 3,496.0 ± 190.4 pg/ml, respectively, vs. 21.5 ± 16.3 pg/ml and 183.3 ± 43.9 pg/ml; P matrix. Peripheral blood monocyte interaction with human cardiac myofibroblasts stimulates myofibroblast activity through release of TGF-β1. These data implicate inflammation as a potential driver of cardiac fibrosis.

  3. Atrophic cardiac remodeling induced by taurine deficiency in Wistar rats.

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    Mariele Castilho Pansani

    Full Text Available INTRODUCTION: Micronutrient deficiency is observed in heart failure patients. Taurine, for example, represents 50% of total free amino acids in the heart, and in vivo studies have linked taurine deficiency with cardiomyopathy. METHODS: Thirty-four male Wistar rats (body weight = 100 g were weighed and randomly assigned to one of two groups: Control (C or taurine-deficient (T (-. Beta-alanine at a concentration of 3% was added to the animals' water to induce taurine deficiency in the T (- group. On day 30, the rats were individually submitted to echocardiography; morphometrical and histopathological evaluation and metalloproteinase activity, oxidative stress and inflammation evaluation were performed. Tissue samples were collected to determine the taurine concentration in the heart. RESULTS: Taurine deficiency led to decreases in: ventricular wall thickness, left ventricle dry weight, myocyte sectional area, left ventricle posterior wall thickness and ventricular geometry. With regard to heart function, the velocity of the A wave, the ratio between the E and A wave, the ejection fraction, fractional shortening and cardiac output values were decreased in T (- rats, suggesting abnormal diastolic and systolic function. Increased fibrosis, inflammation and increased activation of metalloproteinases were not observed. Oxidative stress was increased in deficient animals. CONCLUSIONS: These data suggest that taurine deficiency promotes structural and functional cardiac alterations with unique characteristics.

  4. Exogenous midkine administration prevents cardiac remodeling in pacing-induced congestive heart failure of rabbits.

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    Harada, Masahide; Hojo, Mayumi; Kamiya, Kaichiro; Kadomatsu, Kenji; Murohara, Toyoaki; Kodama, Itsuo; Horiba, Mitsuru

    2016-01-01

    Midkine (MK), a heparin-binding growth factor, has been shown to prevent cardiac remodeling after ischemic injury through its anti-apoptotic effect. Cell apoptosis is central to the pathophysiology of cardiac remodeling in congestive heart failure (CHF) of ischemic as well as non-ischemic origin. We hypothesized that MK exerts the anti-apoptotic cardioprotective effect in CHF of non-ischemic etiology. MK protein or vehicle (normal saline) was subcutaneously administered in tachycardia-induced CHF rabbits (right ventricular pacing, 350 beats/min, 4 weeks). The vehicle-treated rabbits (n = 19, control) demonstrated severe CHF and high mortality rate, whereas MK (n = 16) demonstrated a well-compensated state and a lower mortality rate. In echocardiography, left ventricular (LV) end-diastolic dimension decreased in MK versus control, whereas LV systolic function increased. In histological analysis (picrosirius red staining), MK decreased collagen deposition area compared with control. TUNEL staining showed that MK prevented cell apoptosis and minimized myocyte loss in the CHF rabbit ventricle, associated with activation of PI3-K/Akt signaling, producing a parallel decrease of Bax/Bcl-2 ratio. MK prevented progression of cardiac remodeling in the CHF rabbit, likely by activation of anti-apoptotic signaling. Exogenous MK application might be a novel therapeutic strategy for CHF due to non-ischemic origin.

  5. Role of mitogen-activated protein kinase pathways in multifactorial adverse cardiac remodeling associated with metabolic syndrome.

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    Asrih, Mohamed; Mach, François; Nencioni, Alessio; Dallegri, Franco; Quercioli, Alessandra; Montecucco, Fabrizio

    2013-01-01

    Metabolic syndrome has been widely associated with an increased risk for acute cardiovascular events. Emerging evidence supports metabolic syndrome as a condition favoring an adverse cardiac remodeling, which might evolve towards heart dysfunction and failure. This pathological remodeling has been described to result from the cardiac adaptive response to clinical mechanical conditions (such as hypertension, dyslipidemia, and hyperglycemia), soluble inflammatory molecules (such as cytokines and chemokines), as well as hormones (such as insulin), characterizing the pathophysiology of metabolic syndrome. Moreover, these cardiac processes (resulting in cardiac hypertrophy and fibrosis) are also associated with the modulation of intracellular signalling pathways within cardiomyocytes. Amongst the different intracellular kinases, mitogen-activated protein kinases (MAPKs) were shown to be involved in heart damage in metabolic syndrome. However, their role remains controversial. In this paper, we will discuss and update evidence on MAPK-mediated mechanisms underlying cardiac adverse remodeling associated with metabolic syndrome.

  6. Role of Mitogen-Activated Protein Kinase Pathways in Multifactorial Adverse Cardiac Remodeling Associated with Metabolic Syndrome

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    Mohamed Asrih

    2013-01-01

    Full Text Available Metabolic syndrome has been widely associated with an increased risk for acute cardiovascular events. Emerging evidence supports metabolic syndrome as a condition favoring an adverse cardiac remodeling, which might evolve towards heart dysfunction and failure. This pathological remodeling has been described to result from the cardiac adaptive response to clinical mechanical conditions (such as hypertension, dyslipidemia, and hyperglycemia, soluble inflammatory molecules (such as cytokines and chemokines, as well as hormones (such as insulin, characterizing the pathophysiology of metabolic syndrome. Moreover, these cardiac processes (resulting in cardiac hypertrophy and fibrosis are also associated with the modulation of intracellular signalling pathways within cardiomyocytes. Amongst the different intracellular kinases, mitogen-activated protein kinases (MAPKs were shown to be involved in heart damage in metabolic syndrome. However, their role remains controversial. In this paper, we will discuss and update evidence on MAPK-mediated mechanisms underlying cardiac adverse remodeling associated with metabolic syndrome.

  7. Cardiac Function Remains Impaired Despite Reversible Cardiac Remodeling after Acute Experimental Viral Myocarditis

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    Peter Moritz Becher

    2017-01-01

    Full Text Available Background. Infection with Coxsackievirus B3 induces myocarditis. We aimed to compare the acute and chronic phases of viral myocarditis to identify the immediate effects of cardiac inflammation as well as the long-term effects after resolved inflammation on cardiac fibrosis and consequently on cardiac function. Material and Methods. We infected C57BL/6J mice with Coxsackievirus B3 and determined the hemodynamic function 7 as well as 28 days after infection. Subsequently, we analyzed viral burden and viral replication in the cardiac tissue as well as the expression of cytokines and matrix proteins. Furthermore, cardiac fibroblasts were infected with virus to investigate if viral infection alone induces profibrotic signaling. Results. Severe cardiac inflammation was determined and cardiac fibrosis was consistently colocalized with inflammation during the acute phase of myocarditis. Declined cardiac inflammation but no significantly improved hemodynamic function was observed 28 days after infection. Interestingly, cardiac fibrosis declined to basal levels as well. Both cardiac inflammation and fibrosis were reversible, whereas the hemodynamic function remains impaired after healed viral myocarditis in C57BL/6J mice.

  8. Apocynin improving cardiac remodeling in chronic renal failure disease is associated with up-regulation of epoxyeicosatrienoic acids.

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    Zhang, Kun; Liu, Yu; Liu, Xiaoqiang; Chen, Jie; Cai, Qingqing; Wang, Jingfeng; Huang, Hui

    2015-09-22

    Cardiac remodeling is one of the most common cardiac abnormalities and associated with a high mortality in chronic renal failure (CRF) patients. Apocynin, a nicotinamide-adenine dinucleotide phosphate (NADPH) oxidase inhibitor, has been showed cardio-protective effects. However, whether apocynin can improve cardiac remodeling in CRF and what is the underlying mechanism are unclear. In the present study, we enrolled 94 participants. In addition, we used 5/6 nephrectomized rats to mimic cardiac remodeling in CRF. Serum levels of epoxyeicosatrienoic acids (EETs) and its mainly metabolic enzyme-soluble epoxide hydrolase (sEH) were measured. The results showed that the serum levels of EETs were significantly decreased in renocardiac syndrome participants (P < 0.05). In 5/6 nephrectomized CRF model, the ratio of left ventricular weight / body weight, left ventricular posterior wall thickness, and cardiac interstitial fibrosis were significantly increased while ejection fraction significantly decreased (P < 0.05). All these effects could partly be reversed by apocynin. Meanwhile, we found during the process of cardiac remodeling in CRF, apocynin significantly increased the reduced serum levels of EETs and decreased the mRNA and protein expressions of sEH in the heart (P < 0.05). Our findings indicated that the protective effect of apocynin on cardiac remodeling in CRF was associated with the up-regulation of EETs. EETs may be a new mediator for the injury of kidney-heart interactions.

  9. Remodeling of the sarcomeric cytoskeleton in cardiac ventricular myocytes during heart failure and after cardiac resynchronization therapy.

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    Lichter, Justin G; Carruth, Eric; Mitchell, Chelsea; Barth, Andreas S; Aiba, Takeshi; Kass, David A; Tomaselli, Gordon F; Bridge, John H; Sachse, Frank B

    2014-07-01

    Sarcomeres are the basic contractile units of cardiac myocytes. Recent studies demonstrated remodeling of sarcomeric proteins in several diseases, including genetic defects and heart failure. Here we investigated remodeling of sarcomeric α-actinin in two models of heart failure, synchronous (SHF) and dyssynchronous heart failure (DHF), as well as a model of cardiac resynchronization therapy (CRT). We applied three-dimensional confocal microscopy and quantitative methods of image analysis to study isolated cells from our animal models. 3D Fourier analysis revealed a decrease of the spatial regularity of the α-actinin distribution in both SHF and DHF versus control cells. The spatial regularity of α-actinin in DHF cells was reduced when compared with SHF cells. The spatial regularity of α-actinin was partially restored after CRT. We found longitudinal depositions of α-actinin in SHF, DHF and CRT cells. These depositions spanned adjacent Z-disks and exhibited a lower density of α-actinin than in the Z-disk. Differences in the occurrence of depositions between the SHF, CRT and DHF models versus control were significant. Also, CRT cells exhibited a higher occurrence of depositions versus SHF, but not DHF cells. Other sarcomeric proteins did not accumulate in the depositions to the same extent as α-actinin. We did not find differences in the expression of α-actinin protein and its encoding gene in our animal models. In summary, our studies indicate that HF is associated with two different types of remodeling of α-actinin and only one of those was reversed after CRT. We suggest that these results can guide us to an understanding of remodeling of structures and function associated with sarcomeres.

  10. Salvianolic acid B functioned as a competitive inhibitor of matrix metalloproteinase-9 and efficiently prevented cardiac remodeling

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    2010-01-01

    Background Infarct-induced left ventricular (LV) remodeling is a deleterious consequence after acute myocardial infarction (MI) which may further advance to congestive heart failure. Therefore, new therapeutic strategies to attenuate the effects of LV remodeling are urgently needed. Salvianolic acid B (SalB) from Salviae mitiorrhizae, which has been widely used in China for the treatment of cardiovascular diseases, is a potential candidate for therapeutic intervention of LV remodeling targeting matrix metalloproteinase-9 (MMP-9). Results Molecular modeling and LIGPLOT analysis revealed in silico docking of SalB at the catalytic site of MMP-9. Following this lead, we expressed truncated MMP-9 which contains only the catalytic domain, and used this active protein for in-gel gelatin zymography, enzymatic analysis, and SalB binding by Biacore. Data generated from these assays indicated that SalB functioned as a competitive inhibitor of MMP-9. In our rat model for cardiac remodeling, western blot, echocardiography, hemodynamic measurement and histopathological detection were used to detect the effects and mechanism of SalB on cardio-protection. Our results showed that in MI rat, SalB selectively inhibited MMP-9 activities without affecting MMP-9 expression while no effect of SalB was seen on MMP-2. Moreover, SalB treatment in MI rat could efficiently increase left ventricle wall thickness, improve heart contractility, and decrease heart fibrosis. Conclusions As a competitive inhibitor of MMP-9, SalB presents significant effects on preventing LV structural damage and preserving cardiac function. Further studies to develop SalB and its analogues for their potential for cardioprotection in clinic are warranted. PMID:20735854

  11. Anti-CCL21 Antibody Attenuates Infarct Size and Improves Cardiac Remodeling After Myocardial Infarction

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    Yi Jiang

    2015-09-01

    Full Text Available Background/Aims: Over-activation of cellular inflammatory effectors adversely affects myocardial function after acute myocardial infarction (AMI. The CC-chemokine CCL21 is, via its receptor CCR7, one of the key regulators of inflammation and immune cell recruitment, participates in various inflammatory disorders, including cardiovascular ones. This study explored the therapeutic effect of an anti-CCL21 antibody in cardiac remodeling after myocardial infarction. Methods and Results: An animal model of AMI generated by left anterior descending coronary artery ligation in C57BL/6 mice resulted in higher levels of circulating CCL21 and cardiac CCR7. Neutralization of CCL21 by intravenous injection of anti-CCL21 monoclonal antibody reduced infarct size after AMI, decreased serum levels of neutrophil and monocyte chemo attractants post AMI, diminished neutrophil and macrophage recruitment in infarcted myocardium, and suppressed MMP-9 and total collagen content in myocardium. Anti-CCL21 treatment also limited cardiac enlargement and improved left ventricular function. Conclusions: Our study indicated that CCL21 was involved in cardiac remodeling post infarction and anti-CCL21 strategies might be useful in the treatment of AMI.

  12. Temporal and Molecular Analyses of Cardiac Extracellular Matrix Remodeling following Pressure Overload in Adiponectin Deficient Mice.

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    Keith Dadson

    Full Text Available Adiponectin, circulating levels of which are reduced in obesity and diabetes, mediates cardiac extracellular matrix (ECM remodeling in response to pressure overload (PO. Here, we performed a detailed temporal analysis of progressive cardiac ECM remodelling in adiponectin knockout (AdKO and wild-type (WT mice at 3 days and 1, 2, 3 and 4 weeks following the induction of mild PO via minimally invasive transverse aortic banding. We first observed that myocardial adiponectin gene expression was reduced after 4 weeks of PO, whereas increased adiponectin levels were detected in cardiac homogenates at this time despite decreased circulating levels of adiponectin. Scanning electron microscopy and Masson's trichrome staining showed collagen accumulation increased in response to 2 and 4 weeks of PO in WT mice, while fibrosis in AdKO mice was notably absent after 2 weeks but highly apparent after 4 weeks of PO. Time and intensity of fibroblast appearance after PO was not significantly different between AdKO and WT animals. Gene array analysis indicated that MMP2, TIMP2, collagen 1α1 and collagen 1α3 were induced after 2 weeks of PO in WT but not AdKO mice. After 4 weeks MMP8 was induced in both genotypes, MMP9 only in WT mice and MMP1α only in AdKO mice. Direct stimulation of primary cardiac fibroblasts with adiponectin induced a transient increase in total collagen detected by picrosirius red staining and collagen III levels synthesis, as well as enhanced MMP2 activity detected via gelatin zymography. Adiponectin also enhanced fibroblast migration and attenuated angiotensin-II induced differentiation to a myofibroblast phenotype. In conclusion, these data indicate that increased myocardial bioavailability of adiponectin mediates ECM remodeling following PO and that adiponectin deficiency delays these effects.

  13. Effects of Growth Hormone on Cardiac Remodeling During Resistance Training in Rats

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    Junqueira, Adriana, E-mail: francispacagnelli@unoeste.br [Universidade do Oeste Paulista (UNOESTE), Presidente Prudente, SP (Brazil); Cicogna, Antônio Carlos [Universidade Estadual Paulista (UNESP), Campus Botucatu, SP (Brazil); Engel, Letícia Estevam; Aldá, Maiara Almeida [Universidade do Oeste Paulista (UNOESTE), Presidente Prudente, SP (Brazil); Tomasi, Loreta Casquel de [Universidade Estadual Paulista (UNESP), Campus Botucatu, SP (Brazil); Giuffrida, Rogério; Giometti, Inês Cristina [Universidade do Oeste Paulista (UNOESTE), Presidente Prudente, SP (Brazil); Freire, Ana Paula Coelho Figueira [Universidade do Oeste Paulista (UNOESTE), Presidente Prudente, SP (Brazil); Universidade Estadual Paulista (UNESP), Campus Presidente Prudente, SP (Brazil); Aguiar, Andreo Fernando [Universidade do Norte do Paraná, UNOPAR, Londrina, PR (Brazil); Pacagnelli, Francis Lopes [Universidade do Oeste Paulista (UNOESTE), Presidente Prudente, SP (Brazil)

    2016-01-15

    Although the beneficial effects of resistance training (RT) on the cardiovascular system are well established, few studies have investigated the effects of the chronic growth hormone (GH) administration on cardiac remodeling during an RT program. To evaluate the effects of GH on the morphological features of cardiac remodeling and Ca2+ transport gene expression in rats submitted to RT. Male Wistar rats were divided into 4 groups (n = 7 per group): control (CT), GH, RT and RT with GH (RTGH). The dose of GH was 0.2 IU/kg every other day for 30 days. The RT model used was the vertical jump in water (4 sets of 10 jumps, 3 bouts/wk) for 30 consecutive days. After the experimental period, the following variables were analyzed: final body weight (FBW), left ventricular weight (LVW), LVW/FBW ratio, cardiomyocyte cross-sectional area (CSA), collagen fraction, creatine kinase muscle-brain fraction (CK-MB) and gene expressions of SERCA2a, phospholamban (PLB) and ryanodine (RyR). There was no significant (p > 0.05) difference among groups for FBW, LVW, LVW/FBW ratio, cardiomyocyte CSA, and SERCA2a, PLB and RyR gene expressions. The RT group showed a significant (p < 0.05) increase in collagen fraction compared to the other groups. Additionally, the trained groups (RT and RTGH) had greater CK-MB levels compared to the untrained groups (CT and GH). GH may attenuate the negative effects of RT on cardiac remodeling by counteracting the increased collagen synthesis, without affecting the gene expression that regulates cardiac Ca{sup 2+} transport.

  14. Post-mortem cardiac diffusion tensor imaging: detection of myocardial infarction and remodeling of myofiber architecture

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    Winklhofer, Sebastian; Berger, Nicole; Stolzmann, Paul [University Hospital Zurich, Institute of Diagnostic and Interventional Radiology, Zurich (Switzerland); University of Zurich, Department of Forensic Medicine and Radiology, Institute of Forensic Medicine, Zurich (Switzerland); Stoeck, Christian T.; Kozerke, Sebastian [Institute for Biomedical Engineering University and ETH Zurich, Zurich (Switzerland); Thali, Michael [University of Zurich, Department of Forensic Medicine and Radiology, Institute of Forensic Medicine, Zurich (Switzerland); Manka, Robert [University Hospital Zurich, Institute of Diagnostic and Interventional Radiology, Zurich (Switzerland); Institute for Biomedical Engineering University and ETH Zurich, Zurich (Switzerland); University Hospital Zurich, Clinic for Cardiology, Zurich (Switzerland); Alkadhi, Hatem [University Hospital Zurich, Institute of Diagnostic and Interventional Radiology, Zurich (Switzerland)

    2014-11-15

    To investigate the accuracy of post-mortem diffusion tensor imaging (DTI) for the detection of myocardial infarction (MI) and to demonstrate the feasibility of helix angle (HA) calculation to study remodelling of myofibre architecture. Cardiac DTI was performed in 26 deceased subjects prior to autopsy for medicolegal reasons. Fractional anisotropy (FA) and mean diffusivity (MD) were determined. Accuracy was calculated on per-segment (AHA classification), per-territory, and per-patient basis, with pathology as reference standard. HAs were calculated and compared between healthy segments and those with MI. Autopsy demonstrated MI in 61/440 segments (13.9 %) in 12/26 deceased subjects. Healthy myocardial segments had significantly higher FA (p < 0.01) and lower MD (p < 0.001) compared to segments with MI. Multivariate logistic regression demonstrated that FA (p < 0.10) and MD (p = 0.01) with the covariate post-mortem time (p < 0.01) predicted MI with an accuracy of 0.73. Analysis of HA distribution demonstrated remodelling of myofibre architecture, with significant differences between healthy segments and segments with chronic (p < 0.001) but not with acute MI (p > 0.05). Post-mortem cardiac DTI enablesdifferentiation between healthy and infarcted myocardial segments by means of FA and MD. HA assessment allows for the demonstration of remodelling of myofibre architecture following chronic MI. (orig.)

  15. Cardiac Myocyte De Novo DNA Methyltransferases 3a/3b Are Dispensable for Cardiac Function and Remodeling after Chronic Pressure Overload in Mice.

    Directory of Open Access Journals (Sweden)

    Thomas G Nührenberg

    Full Text Available Recent studies reported altered DNA methylation in failing human hearts. This may suggest a role for de novo DNA methylation in the development of heart failure. Here, we tested whether cardiomyocyte-specific loss of de novo DNA methyltransferases Dnmt3a and Dnmt3b altered cardiac function and remodeling after chronic left ventricular pressure overload.Mice with specific ablation of Dnmt3a and Dnmt3b expression in cardiomyocytes were generated by crossing floxed Dnmt3afl and Dnmt3bfl alleles with mice expressing Cre recombinase under control of the atrial myosin light chain gene promoter. The efficacy of combined Dnmt3a/3b ablation (DKO was characterized on cardiomyocyte-specific genomic DNA and mRNA levels. Cardiac phenotyping was carried out without (sham or with left ventricular pressure overload induced by transverse aortic constriction (TAC. Under similar conditions, cardiac genome-wide transcriptional profiling was performed and DNA methylation levels of promoters of differentially regulated genes were assessed by pyrosequencing.DKO cardiomyocytes showed virtual absence of targeted Dnmt3a and Dnmt3b mRNA transcripts. Cardiac phenotyping revealed no significant differences between DKO and control mice under sham and TAC conditions. Transcriptome analyses identified upregulation of 44 and downregulation of 9 genes in DKO as compared with control sham mice. TAC mice showed similar changes with substantial overlap of regulated genes compared to sham. Promoters of upregulated genes were largely unmethylated in DKO compared to control mice.The absence of cardiac pathology in the presence of the predicted molecular phenotype suggests that de novo DNA methylation in cardiomyocytes is dispensable for adaptive mechanisms after chronic cardiac pressure overload.

  16. Novel Protective Role of Myeloid Differentiation 1 in Pathological Cardiac Remodelling

    Science.gov (United States)

    Xiong, Xiaojv; Liu, Yu; Mei, Yang; Peng, Jianye; Wang, Zhiqiang; Kong, Bin; Zhong, Peng; Xiong, Liang; Quan, Dajun; Li, Qi; Wang, Guangji; Huang, He

    2017-01-01

    Myeloid differentiation 1 (MD-1), a secreted protein interacting with radioprotective 105 (RP105), plays an important role in Toll-like receptor 4 (TLR4) signalling pathway. Previous studies showed that MD-1 may be restricted in the immune system. In this study, we demonstrated for the first time that MD-1 was highly expressed in both human and animal hearts. We also discovered that cardiac-specific overexpression of MD-1 significantly attenuated pressure overload-induced cardiac hypertrophy, fibrosis, and dysfunction, whereas loss of MD-1 had the opposite effects. Similar results were observed for in vitro angiotensin II-induced neonatal rat cardiomyocyte hypertrophy. The antihypertrophic effects of MD-1 under hypertrophic stimuli were associated with the blockage of MEK-ERK 1/2 and NF-κB signalling. Blocking MEK-ERK 1/2 signalling with a pharmacological inhibitor (U0126) greatly attenuated the detrimental effects observed in MD-1 knockout cardiomyocytes exposed to angiotensin II stimuli. Similar results were observed by blocking NF-κB signalling with a pharmacological inhibitor (BAY11–7082). Our data indicate that MD-1 inhibits cardiac hypertrophy and suppresses cardiac dysfunction during the remodelling process, which is dependent on its modulation of the MEK-ERK 1/2 and NF-κB signalling pathways. Thus, MD-1 might be a novel target for the treatment of pathological cardiac hypertrophy. PMID:28165494

  17. Deubiquitinase BRCC36 protects heart against chronic pressure overload-induced cardiac remodeling in mice

    Institute of Scientific and Technical Information of China (English)

    LI Ru-jun; FANG Wei; ZHU Hua-jiang; ZHANG Feng-xia; XU Ou-fang; XU Li-juan; ZHANG Zhen-gang; GONG Kai-zheng

    2016-01-01

    Emerging evidence has indicated that BRCC 36-mediated K63-linked ubiquitination modification was involved in diverse cellular functions , including endocytosis , apoptosis and DNA damage repair .We previously showed that activation of cGMP/PKG pathway con-tributed to the binding of BRCC36 and the pro-fibrotic factor Smad3.The current study tested the hypothesis that BRCC 36 functions as a negative regulator of transforming growth factor-beta ( TGF-β)/Smad3 pathway and participates in cardiac remodeling .In isolated adult mouse cardiac fibroblasts , we have demonstrated that TGF-β1 treatment significantly increased the expression of BRCC 36.Over-expression BRCC36 suppressed TGF-β1-induced Smad3 phosphorylation, nuclear translocation, extracellular matrix molecular expres-sion and cell proliferation .On the contrary, silencing BRCC36 by transfection of adenovirus-carrying BRCC36 shRNA potentiated to enhance the pro-fibrotic effect of TGF-β.In vivo, under chronic pressure overload condition-induced by transverse aortic constriction , myocardial pro-survival protein Bcl-2 and Mcl-1 expression were significantly decreased and the pro-apoptosis protein Puma was in-creased.However, the cardiac-specific over-expression of BRCC36 significantly increased myocardial Bcl-2 and Mcl-1 and inhibited Puma expression .Interestingly , we also found that sustained pressure overload resulted in a significant myocardial DNA injury in wild type mice, which was characterized by the increase of γH2AX level.However, cardiac-specific BRCC36 over-expression significantly decreased the level of γH2AX in the pressure overloaded heart in the transgenic mice , while effectively enhanced myocardial RAD 51 expression, a marker of DNA damage repair.Furthermore, BRCC36 over-expression effectively attenuated TAC-induced cardiac fibro-sis and remodeling in the transgenic mice , compared with the wild type mice .Collectively , the results have suggested that BRCC 36 ef-fectively protected heart

  18. Impaired autophagy contributes to adverse cardiac remodeling in acute myocardial infarction.

    Directory of Open Access Journals (Sweden)

    Xiaoqian Wu

    Full Text Available OBJECTIVE: Autophagy is activated in ischemic heart diseases, but its dynamics and functional roles remain unclear and controversial. In this study, we investigated the dynamics and role of autophagy and the mechanism(s, if any, during postinfarction cardiac remodeling. METHODS AND RESULTS: Acute myocardial infarction (AMI was induced by ligating left anterior descending (LAD coronary artery. Autophagy was found to be induced sharply 12-24 hours after surgery by testing LC3 modification and Electron microscopy. P62 degradation in the infarct border zone was increased from day 0.5 to day 3, and however, decreased from day 5 until day 21 after LAD ligation. These results indicated that autophagy was induced in the acute phase of AMI, and however, impaired in the latter phase of AMI. To investigate the significance of the impaired autophagy in the latter phase of AMI, we treated the mice with Rapamycin (an autophagy enhancer, 2.0 mg/kg/day or 3-methyladenine (3MA, an autophagy inhibitor, 15 mg/kg/day one day after LAD ligation until the end of experiment. The results showed that Rapamycin attenuated, while 3MA exacerbated, postinfarction cardiac remodeling and dysfunction respectively. In addition, Rapamycin protected the H9C2 cells against oxygen glucose deprivation in vitro. Specifically, we found that Rapamycin attenuated NFκB activation after LAD ligation. And the inflammatory response in the acute stage of AMI was significantly restrained with Rapamycin treatment. In vitro, inhibition of NFκB restored autophagy in a negative reflex. CONCLUSION: Sustained myocardial ischemia impairs cardiomyocyte autophagy, which is an essential mechanism that protects against adverse cardiac remodeling. Augmenting autophagy could be a therapeutic strategy for acute myocardial infarction.

  19. AVE 3085, a novel endothelial nitric oxide synthase enhancer, attenuates cardiac remodeling in mice through the Smad signaling pathway.

    Science.gov (United States)

    Chen, Yili; Chen, Cong; Feng, Cong; Tang, Anli; Ma, Yuedong; He, Xin; Li, Yanhui; He, Jiangui; Dong, Yugang

    2015-03-15

    AVE 3085 is a novel endothelial nitric oxide synthase enhancer. Although AVE 3085 treatment has been shown to be effective in spontaneously restoring endothelial function in hypertensive rats, little is known about the effects and mechanisms of AVE 3085 with respect to cardiac remodeling. The present study was designed to examine the effects of AVE 3085 on cardiac remodeling and the mechanisms underlying the effects of this compound. Mice were subjected to aortic banding to induce cardiac remodeling and were then administered AVE 3085 (10 mg kg day(-1), orally) for 4 weeks. At the end of the treatment, the aortic banding-treated mice exhibited significant elevations in cardiac remodeling, characterized by an increase in left ventricular weight relative to body weight, an increase in the area of collagen deposition, an increase in the mean myocyte diameter, and increases in the gene expressions of the hypertrophic markers atrial natriuretic peptide (ANP) and β-MHC. These indexes were significantly decreased in the AVE 3085-treated mice. Furthermore, AVE 3085 treatment reduced the expression and activation of the Smad signaling pathway in the aortic banding-treated mice. Our data showed that AVE 3085 attenuated cardiac remodeling, and this effect was possibly mediated through the inhibition of Smad signaling.

  20. OSM mitigates post-infarction cardiac remodeling and dysfunction by up-regulating autophagy through Mst1 suppression.

    Science.gov (United States)

    Hu, Jianqiang; Zhang, Lei; Zhao, Zhijing; Zhang, Mingming; Lin, Jie; Wang, Jiaxing; Yu, Wenjun; Man, Wanrong; Li, Congye; Zhang, Rongqing; Gao, Erhe; Wang, Haichang; Sun, Dongdong

    2016-11-04

    The incidence and prevalence of heart failure (HF) in the world are rapidly rising possibly attributed to the worsened HF following myocardial infarction (MI) in recent years. Here we examined the effects of oncostatin M (OSM) on postinfarction cardiac remodeling and the underlying mechanisms involved. MI model was induced using left anterior descending coronary artery (LAD) ligation. In addition, cultured neonatal mouse cardiomyocytes were subjected to simulated MI. Our results revealed that OSM alleviated left ventricular remodeling, promoted cardiac function, restored mitochondrial cristae density and architecture disorders after 4weeks of MI. Enhanced autophagic flux was indicated in cardiomyocytes transduced with Ad-GFP -LC3 in the OSM treated group as compared with the MI group. OSM receptor Oβ knockout blocked the beneficial effects of OSM in postinfarction cardiac remodeling and cardiomyocytes autophagy. OSM pretreatment significantly alleviated left ventricular remodeling and dysfunction in Mst1 transgenic mice, while it failed to reverse further the postinfarction left ventricular dilatation and cardiac function in the Mst1 knockout mice. Our data revealed that OSM alleviated postinfarction cardiac remodeling and dysfunction by enhancing cardiomyocyte autophagy. OSM holds promise as a therapeutic target in treating HF after MI through Oβ receptor by inhibiting Mst1 phosphorylation.

  1. Sodium restriction modulates innate immunity and prevents cardiac remodeling in a rat model of metabolic syndrome.

    Science.gov (United States)

    Jover, Bernard; Reynes, Christelle; Rugale, Caroline; Reboul, Cyril; Jeanson, Laura; Tournier, Michel; Lajoix, Anne Dominique; Desmetz, Caroline

    2017-02-27

    In the view of the relationships between excessive sodium intake, immunity and target organ damage, we hypothesized that reduction in dietary sodium would be beneficial in the prevention of cardiac alterations through a restrained local immunity response in a rat model of metabolic syndrome. Sprague-Dawley rats were fed a 60% fructose diet with either a normal sodium (0.64% NaCl) or a low sodium content (<0.01% NaCl) for 8weeks. After 4weeks, rats were infused or not with angiotensin II (200ng.kg(-1).min(-1), sc) for 4weeks. Tail-cuff blood pressure was determined in conscious rats. Heart and left ventricle weight, cardiomyocyte size, and cardiac fibrosis were evaluated. We performed a transcriptomic analysis in order to identify differentially regulated cardiac mRNAs between normal and low sodium diets. We validated those results using qPCR and immunohistochemistry. Angiotensin II-induced blood pressure rise was blunted (~ 50%) in the low-sodium fed rats while cardiac hypertrophy and fibrosis were prevented. Transcriptomic analysis revealed 66 differentially regulated genes including 13 downregulated genes under the low sodium diet and implicated in the innate immune response. This was confirmed by reduced cardiac macrophages infiltration under the low sodium diet. Dietary sodium restriction prevents structural alterations of the heart of rats with fructose-induced insulin resistance and angiotensin II-hypertension. The reduction of cardiac inflammation and macrophage infiltration suggests that innate immunity has an important role in the beneficial effect of sodium restriction on cardiac remodeling.

  2. Berberine attenuates adverse left ventricular remodeling and cardiac dysfunction after acute myocardial infarction in rats: role of autophagy.

    Science.gov (United States)

    Zhang, Yao-Jun; Yang, Shao-Hua; Li, Ming-Hui; Iqbal, Javaid; Bourantas, Christos V; Mi, Qiong-Yu; Yu, Yi-Hui; Li, Jing-Jing; Zhao, Shu-Li; Tian, Nai-Liang; Chen, Shao-Liang

    2014-12-01

    The present study aimed to test the hypothesis that berberine, a plant-derived anti-oxidant, attenuates adverse left ventricular remodelling and improves cardiac function in a rat model of myocardial infarction (MI). Furthermore, the potential mechanisms that mediated the cardioprotective actions of berberine, in particular the effect on autophagy, were also investigated. Acute MI was induced by ligating the left anterior descending coronary artery of Sprague-Dawley rats. Cardiac function was assessed by transthoracic echocardiography. The protein activity/levels of autophagy related to signalling pathways (e.g. LC-3B, Beclin-1) were measured in myocardial tissue by immunohistochemical staining and western blot. Four weeks after MI, berberine significantly prevented cardiac dysfunction and adverse cardiac remodelling. MI rats treated with low dose berberine (10 mg/kg per day) showed higher left ventricular ejection fraction and fractional shortening than those treated with high-dose berberine (50 mg/kg per day). Both doses reduced interstitial fibrosis and post-MI adverse cardiac remodelling. The cardioprotective action of berberine was associated with increased LC-3B II and Beclin-1 expressions. Furthermore, cardioprotection with berberine was potentially related to p38 MAPK inhibition and phospho-Akt activation. The present in vivo study showed that berberine is effective in promoting autophagy, and subsequently attenuating left ventricular remodelling and cardiac dysfunction after MI. The potential underlying mechanism is augmentation of autophagy through inhibition of p38 MAPK and activation of phospho-Akt signalling pathways.

  3. Developmental remodeling and shortening of the cardiac outflow tract involves myocyte programmed cell death.

    Science.gov (United States)

    Watanabe, M; Choudhry, A; Berlan, M; Singal, A; Siwik, E; Mohr, S; Fisher, S A

    1998-10-01

    The embryonic outflow tract is a simple tubular structure that connects the single primitive ventricle with the aortic sac and aortic arch arteries. This structure undergoes a complex sequence of morphogenetic processes to become the portion of the heart that aligns the right and left ventricles with the pulmonary artery and aorta. Abnormalities of the outflow tract are involved in many clinically significant congenital cardiac defects; however, the cellular and molecular processes governing the development of this important structure are incompletely understood. Histologic and tissue-tagging studies indicate that the outflow tract tissues compact and are incorporated predominantly into a region of the right ventricle. The hypothesis tested in the current study was that cell death or apoptosis in the muscular portion of the outflow tract is an important cellular mechanism for outflow tract shortening. The tubular outflow tract myocardium was specifically marked by infecting myocytes of the chicken embryo heart with a recombinant replication-defective adenovirus expressing beta-galactosidase (beta-gal) under the control of the cytomegalovirus promoter. Histochemical detection of the beta -gal-labeled outflow tract myocytes revealed that the tubular structure shortened to become a compact ring at the level of the pulmonic infundibulum over several days of development (stages 25-32, embryonic days 4-8). The appearance of apoptotic cardiomyocytes was correlated with OFT shortening by two histologic assays, TUNEL labeling of DNA fragments and AnnexinV binding. The rise and fall in the number of apoptotic myocytes detected by histologic analyses paralleled the change in activity levels of Caspase-3, a protease in the apoptotic cascade, measured in outflow tract homogenates. These results suggest that the elimination of myocytes by programmed cell death is one mechanism by which the outflow tract myocardium remodels to form the proper connection between the ventricular

  4. 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...... was associated with the resynchronization ability of CRT. CONCLUSIONS: Patients with severe LV remodeling (EDVI ≥ 90 mL/m(2)) have a poor prognosis following CRT device implantation. This is most likely due to impaired resynchronization efficacy....

  5. Signs of cardiac autonomic imbalance and proarrhythmic remodeling in FTO deficient mice.

    Directory of Open Access Journals (Sweden)

    Luca Carnevali

    Full Text Available In humans, variants of the fat mass and obesity associated (FTO gene have recently been associated with obesity. However, the physiological function of FTO is not well defined. Previous investigations in mice have linked FTO deficiency to growth retardation, loss of white adipose tissue, increased energy metabolism and enhanced systemic sympathetic activation. In this study we investigated for the first time the effects of global knockout of the mouse FTO gene on cardiac function and its autonomic neural regulation. ECG recordings were acquired via radiotelemetry in homozygous knockout (n = 12 and wild-type (n = 8 mice during resting and stress conditions, and analyzed by means of time- and frequency-domain indexes of heart rate variability. In the same animals, cardiac electrophysiological properties (assessed by epicardial mapping and structural characteristics were investigated. Our data indicate that FTO knockout mice were characterized by (i higher heart rate values during resting and stress conditions, (ii heart rate variability changes (increased LF to HF ratio, (iii larger vulnerability to stress-induced tachyarrhythmias, (iv altered ventricular repolarization, and (v cardiac hypertrophy compared to wild-type counterparts. We conclude that FTO deficiency in mice leads to an imbalance of the autonomic neural modulation of cardiac function in the sympathetic direction and to a potentially proarrhythmic remodeling of electrical and structural properties of the heart.

  6. Dysautonomia due to reduced cholinergic neurotransmission causes cardiac remodeling and heart failure.

    Science.gov (United States)

    Lara, Aline; Damasceno, Denis D; Pires, Rita; Gros, Robert; Gomes, Enéas R; Gavioli, Mariana; Lima, Ricardo F; Guimarães, Diogo; Lima, Patricia; Bueno, Carlos Roberto; Vasconcelos, Anilton; Roman-Campos, Danilo; Menezes, Cristiane A S; Sirvente, Raquel A; Salemi, Vera M; Mady, Charles; Caron, Marc G; Ferreira, Anderson J; Brum, Patricia C; Resende, Rodrigo R; Cruz, Jader S; Gomez, Marcus Vinicius; Prado, Vania F; de Almeida, Alvair P; Prado, Marco A M; Guatimosim, Silvia

    2010-04-01

    Overwhelming evidence supports the importance of the sympathetic nervous system in heart failure. In contrast, much less is known about the role of failing cholinergic neurotransmission in cardiac disease. By using a unique genetically modified mouse line with reduced expression of the vesicular acetylcholine transporter (VAChT) and consequently decreased release of acetylcholine, we investigated the consequences of altered cholinergic tone for cardiac function. M-mode echocardiography, hemodynamic experiments, analysis of isolated perfused hearts, and measurements of cardiomyocyte contraction indicated that VAChT mutant mice have decreased left ventricle function associated with altered calcium handling. Gene expression was analyzed by quantitative reverse transcriptase PCR and Western blotting, and the results indicated that VAChT mutant mice have profound cardiac remodeling and reactivation of the fetal gene program. This phenotype was attributable to reduced cholinergic tone, since administration of the cholinesterase inhibitor pyridostigmine for 2 weeks reversed the cardiac phenotype in mutant mice. Our findings provide direct evidence that decreased cholinergic neurotransmission and underlying autonomic imbalance cause plastic alterations that contribute to heart dysfunction.

  7. Time Course of Atrophic Remodeling: Effects of Exercise on Cardiac Morpology and Function

    Science.gov (United States)

    Scott, J. M.; Martin, D.; Caine, T.; Matz, T.; Ploutz-Snyder, L. L.

    2014-01-01

    Early and consistent evaluation of cardiac morphology and function throughout an atrophic stimulus is critically important for the design and optimization of interventions. Exercise training is one intervention that has been shown to confer favorable improvements in LV mass and function during unloading. However, the format and intensity of exercise required to induce optimal cardiac improvements has not been investigated. PURPOSE: This randomized, controlled trial was designed to 1) comprehensively characterize the time course of unloading-induced morpho-functional remodeling, and 2) examine the effects of high intensity exercise training on cardiac structural and functional parameters during unloading. METHODS: Twenty six subjects completed 70 days of head down tilt bed rest (HDBR): 17 were randomized to exercise training (ExBR) and 9 remained sedentary. Exercise consisted of integrated high intensity, continuous, and resistance exercise. We assessed cardiac morphology (left ventricular mass; LVM) and function (speckle-tracking assessment of longitudinal, radial, and circumferential strain and twist) before (BR-2), during (BR7,21,31,70), and following (BR+0, +3) HDBR. Cardiorespiratory fitness (VO2max) was evaluated before (BR- 3), during (BR4,25,46,68) and following (BR+0) HDBR. RESULTS: Sedentary HDBR resulted in a progressive decline in LVM, longitudinal, radial, and circumferential strain, and an increase in twist. ExBR mitigated decreases in LVM and function. Change in twist was significantly related to change in VO2max (R=0.68, premodeling.

  8. Aerobic Training after Myocardial Infarction: Remodeling Evaluated by Cardiac Magnetic Resonance

    Energy Technology Data Exchange (ETDEWEB)

    Izeli, Nataly Lino; Santos, Aurélia Juliana dos; Crescêncio, Júlio César; Gonçalves, Ana Clara Campagnolo Real; Papa, Valéria; Marques, Fabiana [Divisão de Cardiologia do Hospital das Clínicas da Faculdade de Medicina de Ribeirão Preto - USP, Ribeirão Preto, SP (Brazil); Pazin-Filho, Antônio [Divisão de Emergência da Faculdade de Medicina de Ribeirão Preto - USP, Ribeirão Preto, SP (Brazil); Gallo-Júnior, Lourenço; Schmidt, André, E-mail: aschmidt@fmrp.usp.br [Divisão de Cardiologia do Hospital das Clínicas da Faculdade de Medicina de Ribeirão Preto - USP, Ribeirão Preto, SP (Brazil)

    2016-04-15

    Numerous studies show the benefits of exercise training after myocardial infarction (MI). Nevertheless, the effects on function and remodeling are still controversial. To evaluate, in patients after (MI), the effects of aerobic exercise of moderate intensity on ventricular remodeling by cardiac magnetic resonance imaging (CMR). 26 male patients, 52.9 ± 7.9 years, after a first MI, were assigned to groups: trained group (TG), 18; and control group (CG), 8. The TG performed supervised aerobic exercise on treadmill twice a week, and unsupervised sessions on 2 additional days per week, for at least 3 months. Laboratory tests, anthropometric measurements, resting heart rate (HR), exercise test, and CMR were conducted at baseline and follow-up. The TG showed a 10.8% reduction in fasting blood glucose (p = 0.01), and a 7.3-bpm reduction in resting HR in both sitting and supine positions (p < 0.0001). There was an increase in oxygen uptake only in the TG (35.4 ± 8.1 to 49.1 ± 9.6 mL/kg/min, p < 0.0001). There was a statistically significant decrease in the TG left ventricular mass (LVmass) (128.7 ± 38.9 to 117.2 ± 27.2 g, p = 0.0032). There were no statistically significant changes in the values of left ventricular end-diastolic volume (LVEDV) and ejection fraction in the groups. The LVmass/EDV ratio demonstrated a statistically significant positive remodeling in the TG (p = 0.015). Aerobic exercise of moderate intensity improved physical capacity and other cardiovascular variables. A positive remodeling was identified in the TG, where a left ventricular diastolic dimension increase was associated with LVmass reduction.

  9. Low carbohydrate/high-fat diet attenuates cardiac hypertrophy, remodeling, and altered gene expression in hypertension

    Science.gov (United States)

    The effects of dietary fat intake on the development of left ventricular hypertrophy and accompanying structural and molecular remodeling in response to hypertension are not understood. The present study compared the effects of a high-fat versus a low-fat diet on development of left ventricular hype...

  10. Effects of renal sympathetic denervation on post-myocardial infarction cardiac remodeling in rats.

    Directory of Open Access Journals (Sweden)

    Jialu Hu

    Full Text Available OBJECTIVE: To investigate the therapeutic effects of renal denervation (RD on post- myocardial infarction (MI cardiac remodeling in rats, the most optimal time for intervention and the sustainability of these effects. METHODS: One hundred SPF male Wistar rats were randomly assigned to N group (Normal, n=10, MI group(MI, n=20,RD group (RD, n=10, RD3+MI (MI three days after RD, n=20, MI1+RD (RD one day after MI, n=20, MI7+RD (RD seven days after MI, n=20. MI was produced through thoracotomic ligation of the anterior descending artery. RD was performed through laparotomic stripping of the renal arteriovenous adventitial sympathetic nerve. Left ventricular function, hemodynamics, plasma BNP, urine volume, urine sodium excretion and other indicators were measured four weeks after MI. RESULTS: (1 The left ventricular function of the MI group significantly declined (EF<40%, plasma BNP was elevated, urine output was significantly reduced, and 24-hour urine sodium excretion was significantly reduced. (2 Denervation can be achieved by surgically stripping the arteriovenous adventitia, approximately 3 mm from the abdominal aorta. (3 In rats with RD3+MI, MI1+RD and MI7+RD, compared with MI rats respectively, the LVEF was significantly improved (75 ± 8.4%,69 ± 3.8%,73 ± 5.5%, hemodynamic indicators were significantly improved, plasma BNP was significantly decreased, and the urine output was significantly increased (21.3 ± 5 ml,23.8 ± 5.4 ml,25.2 ± 8.7 ml. However, the urinary sodium excretion also increased but without significant difference. CONCLUSIONS: RD has preventive and therapeutic effects on post-MI cardiac remodeling.These effects can be sustained for at least four weeks, but there were no significant differences between denervation procedures performed at different times in the course of illness. Cardiac function, hemodynamics, urine volume and urine sodium excretion in normal rats were not affected by RD.

  11. Cardiac remodeling associated with protein increase and lipid accumulation in early-stage chronic kidney disease in rats.

    Science.gov (United States)

    Kuwahara, Mieko; Bannai, Kenji; Segawa, Hiroko; Miyamoto, Ken-ichi; Yamato, Hideyuki

    2014-09-01

    Chronic kidney disease (CKD) is associated with increased risks of cardiovascular morbidity and mortality. Cardiac remodeling including myocardial fibrosis and hypertrophy is frequently observed in CKD patients. In this study, we investigate the mechanism involved in cardiac hypertrophy associated with CKD using a rat model, by morphological and chemical component changes of the hypertrophic and non-hypertrophic hearts. Sprague-Dawley rats were 4/5 nephrectomized (Nx) at 11 weeks of age and assigned to no treatment and treatment with AST-120, which was reported to affect the cardiac damage, at 18 weeks of age. At 26 weeks of age, the rats were euthanized under anesthesia, and biochemical tests as well as analysis of cardiac condition were performed by histological and spectrophotometric methods. Cardiac hypertrophy and CKD were observed in 4/5 Nx rats even though vascular calcification and myocardial fibrosis were not detected. The increasing myocardial protein was confirmed in hypertrophic hearts by infrared spectroscopy. The absorption of amide I and other protein bands in hypertrophic hearts increased at the same position as in normal cardiac absorption. Infrared spectra also showed that lipid accumulation was also detected in hypertrophic heart. Conversely, the absorptions of protein were obviously reduced in the myocardium of non-hypertrophic heart with CKD compared to that of hypertrophic heart. The lipid associated absorption was also decreased in non-hypertrophic heart. Our results suggest that cardiac remodeling associated with relatively early-stage CKD may be suppressed by reducing increased myocardial protein and ameliorating cardiac lipid load.

  12. Atorvastatin improves cardiac function and remodeling in chronic non-ischemic heart failure: A clinical and pre-clinical study

    Directory of Open Access Journals (Sweden)

    Ibrahim Elmadbouh

    2015-12-01

    Conclusions: Atorvastatin with standard CHF therapy improved cardiac function and remodeling. Cardio-protective “pleiotropic” actions of atorvastatin are anti-inflammatory, anti-fibrotic and anti-oxidative. Thus, atorvastatin has a potential therapeutic value in the management of CHF patients.

  13. Relationship Between Reverse Remodeling and Cardiopulmonary Exercise Capacity in Heart Failure Patients Undergoing Cardiac Resynchronization Therapy

    DEFF Research Database (Denmark)

    Mastenbroek, Mirjam H; Sant, Jetske Van't; Versteeg, Henneke

    2016-01-01

    -defibrillator (mean age 65 ± 11; 73% male) underwent echocardiography and cardiopulmonary exercise testing (CPX) before implantation (baseline) and 6 months after implantation. At baseline, patients also completed a set of questionnaires measuring mental and physical health. The association between echocardiographic......BACKGROUND: Studies on the relationship between left ventricular reverse remodeling and cardiopulmonary exercise capacity in heart failure patients undergoing cardiac resynchronization therapy (CRT) are scarce and inconclusive. METHODS AND RESULTS: Eighty-four patients with a 1st-time CRT...... response (left ventricular end-systolic volume decrease ≥15%) and a comprehensive set of CPX results was examined. Echocardiographic responders (54%) demonstrated higher peak oxygen consumption and better exercise performance than nonresponders at baseline and at 6-month follow-up. Furthermore, only...

  14. Cardiac remodeling following percutaneous mitral valve repair. Initial results assessed by cardiovascular magnetic resonance imaging

    Energy Technology Data Exchange (ETDEWEB)

    Radunski, U.K [University Heart Center, Hamburg (Germany). Cardiology; Franzen, O. [Rigshospitalet, Copenhagen (Denmark). Cardiology; Barmeyer, A. [Klinikum Dortmund (Germany). Kardiologie; and others

    2014-10-15

    Percutaneous mitral valve repair with the MitraClip device (Abbott Vascular, Redwood City, California, USA) is a novel therapeutic option in patients with mitral regurgitation. This study evaluated the feasibility of cardiac volume measurements by cardiovascular magnetic resonance imaging (CMR) to assess reverse myocardial remodeling in patients after MitraClip implantation. 12 patients underwent CMR at baseline (BL) before and at 6 months follow-up (FU) after MitraClip implantation. Cine-CMR was performed in short- and long-axes for the assessment of left ventricular (LV), right ventricular (RV) and left atrial (LA) volumes. Assessment of endocardial contours was not compromised by the device-related artifact. No significant differences in observer variances were observed for LV, RV and LA volume measurements between BL and FU. LV end-diastolic (median 127 [IQR 96-150] vs. 112 [86-150] ml/m{sup 2}; p=0.03) and LV end-systolic (82 [54-91] vs. 69 [48-99] ml/m{sup 2}; p=0.03) volume indices decreased significantly from BL to FU. No significant differences were found for RV end-diastolic (94 [75-103] vs. 99 [77-123] ml/m{sup 2}; p=0.91), RV end-systolic (48 [42-80] vs. 51 [40-81] ml/m{sup 2}; p=0.48), and LA (87 [55-124] vs. 92 [48-137]R ml/m{sup 2}; p=0.20) volume indices between BL and FU. CMR enables the assessment of cardiac volumes in patients after MitraClip implantation. Our CMR findings indicate that percutaneous mitral valve repair results in reverse LV but not in RV or LA remodeling.

  15. Vagus nerve stimulation mitigates intrinsic cardiac neuronal and adverse myocyte remodeling postmyocardial infarction.

    Science.gov (United States)

    Beaumont, Eric; Southerland, Elizabeth M; Hardwick, Jean C; Wright, Gary L; Ryan, Shannon; Li, Ying; KenKnight, Bruce H; Armour, J Andrew; Ardell, Jeffrey L

    2015-10-01

    This paper aims to determine whether chronic vagus nerve stimulation (VNS) mitigates myocardial infarction (MI)-induced remodeling of the intrinsic cardiac nervous system (ICNS), along with the cardiac tissue it regulates. Guinea pigs underwent VNS implantation on the right cervical vagus. Two weeks later, MI was produced by ligating the ventral descending coronary artery. VNS stimulation started 7 days post-MI (20 Hz, 0.9 ± 0.2 mA, 14 s on, 48 s off; VNS-MI, n = 7) and was compared with time-matched MI animals with sham VNS (MI n = 7) vs. untreated controls (n = 8). Echocardiograms were performed before and at 90 days post-MI. At termination, IC neuronal intracellular voltage recordings were obtained from whole-mount neuronal plexuses. MI increased left ventricular end systolic volume (LVESV) 30% (P = 0.027) and reduced LV ejection fraction (LVEF) 6.5% (P < 0.001) at 90 days post-MI compared with baseline. In the VNS-MI group, LVESV and LVEF did not differ from baseline. IC neurons showed depolarization of resting membrane potentials and increased input resistance in MI compared with VNS-MI and sham controls (P < 0.05). Neuronal excitability and sensitivity to norepinephrine increased in MI and VNS-MI groups compared with controls (P < 0.05). Synaptic efficacy, as determined by evoked responses to stimulating input axons, was reduced in VNS-MI compared with MI or controls (P < 0.05). VNS induced changes in myocytes, consistent with enhanced glycogenolysis, and blunted the MI-induced increase in the proapoptotic Bcl-2-associated X protein (P < 0.05). VNS mitigates MI-induced remodeling of the ICNS, correspondingly preserving ventricular function via both neural and cardiomyocyte-dependent actions.

  16. Gender-Based Differences in Cardiac Remodeling and ILK Expression after Myocardial Infarction

    Directory of Open Access Journals (Sweden)

    Renato Rodrigues Sofia

    2014-08-01

    Full Text Available Background: Gender can influence post-infarction cardiac remodeling. Objective: To evaluate whether gender influences left ventricular (LV remodeling and integrin-linked kinase (ILK after myocardial infarction (MI. Methods: Female and male Wistar rats were assigned to one of three groups: sham, moderate MI (size: 20-39% of LV area, and large MI (size: ≥40% of LV area. MI was induced by coronary occlusion, and echocardiographic analysis was performed after six weeks to evaluate MI size as well as LV morphology and function. Real-time RT-PCR and Western blot were used to quantify ILK in the myocardium. Results: MI size was similar between genders. MI resulted in systolic dysfunction and enlargement of end-diastolic as well as end-systolic dimension of LV as a function of necrotic area size in both genders. Female rats with large MI showed a lower diastolic and systolic dilatation than the respective male rats; however, LV dysfunction was similar between genders. Gene and protein levels of ILK were increased in female rats with moderate and large infarctions, but only male rats with large infarctions showed an altered ILK mRNA level. A negative linear correlation was evident between LV dimensions and ILK expression in female rats with large MI. Conclusions: Post-MI ILK expression is altered in a gender-specific manner, and higher ILK levels found in females may be sufficient to improve LV geometry but not LV function.

  17. Gender-Based Differences in Cardiac Remodeling and ILK Expression after Myocardial Infarction

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    Sofia, Renato Rodrigues [Programa de Pós-graduação em Ciências da Reabilitação - Universidade Nove de Julho (Uninove), São Paulo, SP (Brazil); Departamento de Cardiologia - Universidade Federal de São Paulo, São Paulo, SP (Brazil); Serra, Andrey Jorge, E-mail: andreyserra@gmail.com; Silva, Jose Antonio Jr [Programa de Pós-graduação em Ciências da Reabilitação - Universidade Nove de Julho (Uninove), São Paulo, SP (Brazil); Antonio, Ednei Luiz [Departamento de Cardiologia - Universidade Federal de São Paulo, São Paulo, SP (Brazil); Manchini, Martha Trindade [Programa de Pós-graduação em Ciências da Reabilitação - Universidade Nove de Julho (Uninove), São Paulo, SP (Brazil); Oliveira, Fernanda Aparecida Alves de [Departamento de Cardiologia - Universidade Federal de São Paulo, São Paulo, SP (Brazil); Teixeira, Vicente Paulo Castro [Departamento de Patologia - Universidade Federal de São Paulo, São Paulo, SP (Brazil); Tucci, Paulo José Ferreira [Departamento de Cardiologia - Universidade Federal de São Paulo, São Paulo, SP (Brazil)

    2014-08-15

    Gender can influence post-infarction cardiac remodeling. To evaluate whether gender influences left ventricular (LV) remodeling and integrin-linked kinase (ILK) after myocardial infarction (MI). Female and male Wistar rats were assigned to one of three groups: sham, moderate MI (size: 20-39% of LV area), and large MI (size: ≥40% of LV area). MI was induced by coronary occlusion, and echocardiographic analysis was performed after six weeks to evaluate MI size as well as LV morphology and function. Real-time RT-PCR and Western blot were used to quantify ILK in the myocardium. MI size was similar between genders. MI resulted in systolic dysfunction and enlargement of end-diastolic as well as end-systolic dimension of LV as a function of necrotic area size in both genders. Female rats with large MI showed a lower diastolic and systolic dilatation than the respective male rats; however, LV dysfunction was similar between genders. Gene and protein levels of ILK were increased in female rats with moderate and large infarctions, but only male rats with large infarctions showed an altered ILK mRNA level. A negative linear correlation was evident between LV dimensions and ILK expression in female rats with large MI. Post-MI ILK expression is altered in a gender-specific manner, and higher ILK levels found in females may be sufficient to improve LV geometry but not LV function.

  18. High intensity interval and endurance training have opposing effects on markers of heart failure and cardiac remodeling in hypertensive rats.

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    Tanya M Holloway

    Full Text Available There has been re-emerging interest and significant work dedicated to investigating the metabolic effects of high intensity interval training (HIIT in recent years. HIIT is considered to be a time efficient alternative to classic endurance training (ET that elicits similar metabolic responses in skeletal muscle. However, there is a lack of information on the impact of HIIT on cardiac muscle in disease. Therefore, we determined the efficacy of ET and HIIT to alter cardiac muscle characteristics involved in the development of diastolic dysfunction, such as ventricular hypertrophy, fibrosis and angiogenesis, in a well-established rodent model of hypertension-induced heart failure before the development of overt heart failure. ET decreased left ventricle fibrosis by ~40% (P < 0.05, and promoted a 20% (P<0.05 increase in the left ventricular capillary/fibre ratio, an increase in endothelial nitric oxide synthase protein (P<0.05, and a decrease in hypoxia inducible factor 1 alpha protein content (P<0.05. In contrast, HIIT did not decrease existing fibrosis, and HIIT animals displayed a 20% increase in left ventricular mass (P<0.05 and a 20% decrease in cross sectional area (P<0.05. HIIT also increased brain natriuretic peptide by 50% (P<0.05, in the absence of concomitant angiogenesis, strongly suggesting pathological cardiac remodeling. The current data support the longstanding belief in the effectiveness of ET in hypertension. However, HIIT promoted a pathological adaptation in the left ventricle in the presence of hypertension, highlighting the need for further research on the widespread effects of HIIT in the presence of disease.

  19. Transcatheter Closure of Atrial Septal Defects Improves Cardiac Remodeling and Function of Adult Patients with Permanent Atrial Fibrillation

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    Liang Chen; Yuan Bai; Fei-Yu Wang; Zhi-Gang Zhang; Xing-Hua Shan; Tao Chen; Xian-Xian Zhao

    2015-01-01

    Background:Permanent atrial fibrillation (AF) is the most common form of dysrhythmia associated with atrial septal defects (ASDs) in patients older than 40 years.However,little is known about cardiac remodeling after transcatheter closure in patients with permanent AF.This study was designed to compare cardiac events and remodeling effects after transcatheter closure in such patients.Methods:Clinical data of 289 adult patients older than 40 years who underwent ASD closure at our center were analyzed retrospectively.Of them,63 patients with permanent AF were assigned to the case group,and the other 226 patients without permanent AF were assigned to the control group.Cardiac events and changes in left and right cardiac cavity dimensions before the procedure and 6 months after the procedure were compared between the two groups.Results:Patients in the case group were significantly older than those in the control group.The right ventricular (RV) volume and right atrial (RA) volume were decreased significantly in both the groups during a median follow-up period of 6 months after closure (P < 0.001).The left atrial dimensions,left ventricular end-systolic dimensions,left ventricular end-diastolic dimensions and left ventricular ejection fraction showed no significant change before and after the procedure in both the groups.Changes of the RV volume and RA volume in the case group were significantly smaller than those in the control group (P =0.005 and P < 0.001).The New York Heart Association cardiac function was improved in both the groups during the 6 months follow-up period.Conclusions:The transcatheter closure of ASD can improve the cardiac remodeling and cardiac function in patients with or without AF.

  20. Transcatheter Closure of Atrial Septal Defects Improves Cardiac Remodeling and Function of Adult Patients with Permanent Atrial Fibrillation

    Directory of Open Access Journals (Sweden)

    Liang Chen

    2015-01-01

    Full Text Available Background: Permanent atrial fibrillation (AF is the most common form of dysrhythmia associated with atrial septal defects (ASDs in patients older than 40 years. However, little is known about cardiac remodeling after transcatheter closure in patients with permanent AF. This study was designed to compare cardiac events and remodeling effects after transcatheter closure in such patients. Methods: Clinical data of 289 adult patients older than 40 years who underwent ASD closure at our center were analyzed retrospectively. Of them, 63 patients with permanent AF were assigned to the case group, and the other 226 patients without permanent AF were assigned to the control group. Cardiac events and changes in left and right cardiac cavity dimensions before the procedure and 6 months after the procedure were compared between the two groups. Results: Patients in the case group were significantly older than those in the control group. The right ventricular (RV volume and right atrial (RA volume were decreased significantly in both the groups during a median follow-up period of 6 months after closure (P < 0.001. The left atrial dimensions, left ventricular end-systolic dimensions, left ventricular end-diastolic dimensions and left ventricular ejection fraction showed no significant change before and after the procedure in both the groups. Changes of the RV volume and RA volume in the case group were significantly smaller than those in the control group (P = 0.005 and P < 0.001. The New York Heart Association cardiac function was improved in both the groups during the 6 months follow-up period. Conclusions: The transcatheter closure of ASD can improve the cardiac remodeling and cardiac function in patients with or without AF.

  1. Adenosine A2A receptor agonist prevents cardiac remodeling and dysfunction in spontaneously hypertensive male rats after myocardial infarction

    Science.gov (United States)

    da Silva, Jaqueline S; Gabriel-Costa, Daniele; Sudo, Roberto T; Wang, Hao; Groban, Leanne; Ferraz, Emanuele B; Nascimento, José Hamilton M; Fraga, Carlos Alberto M; Barreiro, Eliezer J; Zapata-Sudo, Gisele

    2017-01-01

    Background This work evaluated the hypothesis that 3,4-methylenedioxybenzoyl-2-thienylhydrazone (LASSBio-294), an agonist of adenosine A2A receptor, could be beneficial for preventing cardiac dysfunction due to hypertension associated with myocardial infarction (MI). Methods Male spontaneously hypertensive rats (SHR) were randomly divided into four groups (six animals per group): sham-operation (SHR-Sham), and myocardial infarction rats (SHR-MI) were treated orally either with vehicle or LASSBio-294 (10 and 20 mg.kg−1.d−1) for 4 weeks. Echocardiography and in vivo hemodynamic parameters measured left ventricle (LV) structure and function. Exercise tolerance was evaluated using a treadmill test. Cardiac remodeling was accessed by LV collagen deposition and tumor necrosis factor α expression. Results Early mitral inflow velocity was significantly reduced in the SHR-MI group, and there was significant recovery in a dose-dependent manner after treatment with LASSBio-294. Exercise intolerance observed in the SHR-MI group was prevented by 10 mg.kg−1.d−1 of LASS-Bio-294, and exercise tolerance exceeded that of the SHR-Sham group at 20 mg.kg−1.d−1. LV end-diastolic pressure increased after MI, and this was prevented by 10 and 20 mg.kg−1.d−1 of LASSBio-294. Sarcoplasmic reticulum Ca2+ ATPase levels were restored in a dose-dependent manner after treatment with LASSBio-294. Fibrosis and inflammatory processes were also counteracted by LASSBio-294, with reductions in LV collagen deposition and tumor necrosis factor α expression. Conclusion In summary, oral administration of LASSBio-294 after MI in a dose-dependent manner prevented the development of cardiac dysfunction, demonstrating this compound’s potential as an alternative treatment for heart failure in the setting of ischemic heart disease with superimposed chronic hypertension.

  2. The Nuclear Factor kappaB Inhibitor Pyrrolidine Dithiocarbamate Prevents Cardiac Remodelling and Matrix Metalloproteinase-2 Up-Regulation in Renovascular Hypertension.

    Science.gov (United States)

    Cau, Stefany B A; Guimaraes, Danielle A; Rizzi, Elen; Ceron, Carla S; Gerlach, Raquel F; Tanus-Santos, Jose E

    2015-10-01

    Imbalanced matrix metalloproteinase (MMP) activity is involved in hypertensive cardiac hypertrophy. Pharmacological inhibition of nuclear factor kappaB (NF-кB) with pyrrolidine dithiocarbamate (PDTC) can prevent MMP up-regulation. We suggested that treatment with PDTC could prevent 2-kidney, 1-clip (2K1C) hypertension-induced left ventricular remodelling. Sham-operated controls or 2K1C rats with hypertension received either vehicle or PDTC (100 mg/kg/day) by gavage for 8 weeks. Systolic blood pressure was monitored every week. Histological assessment of left ventricles was carried out with haematoxylin/eosin sections, and fibrosis was quantified in picrosirius red-stained sections. Oxidative stress was evaluated in heart samples with the dihydroethidium probe. Cardiac MMP activity was determined by in situ zymography, and cardiac MMP-2 was assessed by immunofluorescence. 2K1C surgery significantly increased systolic blood pressure in the 2K1C vehicle. PDTC exerted antihypertensive effects after 2 weeks of treatment. Histology revealed increased left ventricular and septum wall thickness associated with augmented myocyte diameter in hypertensive rats, which were reversed by treatment with PDTC. Hypertensive rats developed pronounced cardiac fibrosis with increased interstitial collagen area, increased cardiac reactive oxygen species levels, gelatinase activity and MMP-2 expression. PDTC treatment decreased these alterations. These findings show that PDTC modulates myocardial MMP-2 expression and ameliorates cardiac remodelling in renovascular hypertension. These results suggest that interfering with MMP expression at transcriptional level may be an interesting strategy in the therapy of organ damage associated with hypertension.

  3. Remodeling of intrinsic cardiac neurons: effects of β-adrenergic receptor blockade in guinea pig models of chronic heart disease.

    Science.gov (United States)

    Hardwick, Jean C; Southerland, E Marie; Girasole, Allison E; Ryan, Shannon E; Negrotto, Sara; Ardell, Jeffrey L

    2012-11-01

    Chronic heart disease induces remodeling of cardiac tissue and associated neuronal components. Treatment of chronic heart disease often involves pharmacological blockade of adrenergic receptors. This study examined the specific changes in neuronal sensitivity of guinea pig intrinsic cardiac neurons to autonomic modulators in animals with chronic cardiac disease, in the presence or absence of adrenergic blockage. Myocardial infarction (MI) was produced by ligature of the coronary artery and associated vein on the dorsal surface of the heart. Pressure overload (PO) was induced by a banding of the descending dorsal aorta (∼20% constriction). Animals were allowed to recover for 2 wk and then implanted with an osmotic pump (Alzet) containing either timolol (2 mg·kg(-1)·day(-1)) or vehicle, for a total of 6-7 wk of drug treatment. At termination, intracellular recordings from individual neurons in whole mounts of the cardiac plexus were used to assess changes in physiological responses. Timolol treatment did not inhibit the increased sensitivity to norepinephrine seen in both MI and PO animals, but it did inhibit the stimulatory effects of angiotensin II on the norepinephrine-induced increases in neuronal excitability. Timolol treatment also inhibited the increase in synaptically evoked action potentials observed in PO animals with stimulation of fiber tract bundles. These results demonstrate that β-adrenergic blockade can inhibit specific aspects of remodeling within the intrinsic cardiac plexus. In addition, this effect was preferentially observed with active cardiac disease states, indicating that the β-receptors were more influential on remodeling during dynamic disease progression.

  4. Cell death and serum markers of collagen metabolism during cardiac remodeling in Cavia porcellus experimentally infected with Trypanosoma cruzi.

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    Yagahira E Castro-Sesquen

    Full Text Available We studied cell death by apoptosis and necrosis in cardiac remodeling produced by Trypanosoma cruzi infection. In addition, we evaluated collagen I, III, IV (CI, CIII and CIV deposition in cardiac tissue, and their relationship with serum levels of procollagen type I carboxy-terminal propeptide (PICP and procollagen type III amino-terminal propeptide (PIIINP. Eight infected and two uninfected guinea pigs were necropsied at seven time points up to one year post-infection. Cell death by necrosis and apoptosis was determined by histopathological observation and terminal deoxynucleotidyl transferase dUTP nick end labeling, respectively. Deposition of cardiac collagen types was determined by immunohistochemistry and serum levels of PICP, PIIINP, and anti-T. cruzi IgG1 and IgG2 by ELISA. IgG2 (Th1 response predominated throughout the course of infection; IgG1 (Th2 response was detected during the chronic phase. Cardiac cell death by necrosis predominated over apoptosis during the acute phase; during the chronic phase, both apoptosis and necrosis were observed in cardiac cells. Apoptosis was also observed in lymphocytes, endothelial cells and epicardial adipose tissue, especially in the chronic phase. Cardiac levels of CI, CIII, CIV increased progressively, but the highest levels were seen in the chronic phase and were primarily due to increase in CIII and CIV. High serum levels of PICP and PIIINP were observed throughout the infection, and increased levels of both biomarkers were associated with cardiac fibrosis (p = 0.002 and p = 0.038, respectively. These results confirm the role of apoptosis in cell loss mainly during the chronic phase and the utility of PICP and PIIINP as biomarkers of fibrosis in cardiac remodeling during T. cruzi infection.

  5. Vagal Nerve Stimulation Evoked Heart Rate Changes and Protection from Cardiac Remodeling.

    Science.gov (United States)

    Agarwal, Rahul; Mokelke, Eric; Ruble, Stephen B; Stolen, Craig M

    2016-02-01

    This study investigated whether vagal nerve stimulation (VNS) leads to improvements in ischemic heart failure via heart rate modulation. At 7 ± 1 days post left anterior descending artery (LAD) ligation, 63 rats with myocardial infarctions (MI) were implanted with ECG transmitters and VNS devices (MI + VNS, N = 44) or just ECG transmitters (MI, N = 17). VNS stimulation was active from 14 ± 1 days to 8 ± 1 weeks post MI. The average left ventricular (LV) end diastolic volumes at 8 ± 1 weeks were MI = 672.40 μl and MI + VNS = 519.35 μl, p = 0.03. The average heart weights, normalized to body weight (± std) at 14 ± 1 weeks were MI = 3.2 ± 0.6 g*kg(-1) and MI + VNS = 2.9 ± 0.3 g*kg(-1), p = 0.03. The degree of cardiac remodeling was correlated with the magnitude of acute VNS-evoked heart rate (HR) changes. Further research is required to determine if the acute heart rate response to VNS activation is useful as a heart failure biomarker or as a tool for VNS therapy characterization.

  6. Fermented Wheat Germ Extract (Avemar in the Treatment of Cardiac Remodeling and Metabolic Symptoms in Rats

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    Abishek Iyer

    2011-01-01

    Full Text Available Avemar, a product of industrial fermentation of wheat germ with a standardized content of benzoquinone and plant flavonoids, has been tested as an anti-cancer and immunomodulatory dietary supplement. Proposed mechanisms include anti-oxidant and anti-inflammatory actions. This study has determined whether these actions of Avemar may also be useful in the treatment of cardiovascular diseases. Two experimental rat models of cardiovascular remodeling were used in this project: the deoxycorticosterone acetate (DOCA-salt-induced model of chronic hypertension (study I and a high-carbohydrate/high-fat diet-induced model producing chronic symptoms of the metabolic syndrome and its associated cardiovascular complications (study II. Our results in these rat models of hypertension and diet-induced obesity show that treatment with Avemar improved cardiac function, decreased macrophage infiltration resulting in decreased collagen deposition in the ventricular myocardium, reversed an increased stiffness of the left ventricle in the diseased hearts and attenuated increased plasma malondialdehyde concentrations. In addition to the changes in the heart, Avemar reversed glucose intolerance, normalized systolic blood pressure and decreased visceral fat deposition in rats fed a high-fat/high-carbohydrate diet. In conclusion, the fermented wheat germ extract Avemar has a potential role in attenuating chronic hypertension, diabetes or metabolic syndrome-induced cardiovascular symptoms along with metabolic abnormalities such as glucose tolerance and obesity.

  7. Fermented wheat germ extract (avemar) in the treatment of cardiac remodeling and metabolic symptoms in rats.

    Science.gov (United States)

    Iyer, Abishek; Brown, Lindsay

    2011-01-01

    Avemar, a product of industrial fermentation of wheat germ with a standardized content of benzoquinone and plant flavonoids, has been tested as an anti-cancer and immunomodulatory dietary supplement. Proposed mechanisms include anti-oxidant and anti-inflammatory actions. This study has determined whether these actions of Avemar may also be useful in the treatment of cardiovascular diseases. Two experimental rat models of cardiovascular remodeling were used in this project: the deoxycorticosterone acetate (DOCA)-salt-induced model of chronic hypertension (study I) and a high-carbohydrate/high-fat diet-induced model producing chronic symptoms of the metabolic syndrome and its associated cardiovascular complications (study II). Our results in these rat models of hypertension and diet-induced obesity show that treatment with Avemar improved cardiac function, decreased macrophage infiltration resulting in decreased collagen deposition in the ventricular myocardium, reversed an increased stiffness of the left ventricle in the diseased hearts and attenuated increased plasma malondialdehyde concentrations. In addition to the changes in the heart, Avemar reversed glucose intolerance, normalized systolic blood pressure and decreased visceral fat deposition in rats fed a high-fat/high-carbohydrate diet. In conclusion, the fermented wheat germ extract Avemar has a potential role in attenuating chronic hypertension, diabetes or metabolic syndrome-induced cardiovascular symptoms along with metabolic abnormalities such as glucose tolerance and obesity.

  8. Exogenous nerve growth factor supplementation elevates myocardial immunoreactivity and attenuates cardiac remodeling in pressure-overload rats

    Institute of Scientific and Technical Information of China (English)

    Bing He; and Yuming Li; Fan Ye; Xin Zhou; He Li; Xiaoqing Xun; Xiaoqing Ma; Xudong Liu; Zhihong Wang; Pengxiao Xu

    2012-01-01

    It is postulated that supplementation of exogenous nerve growth factor (NGF) might mediate improvement of the cardiac sympathetic nerve function in heart failure (HF).Local intramuscular injection of NGF near the cardiac sympathetic ganglia could influence the innervation pattern,norepinephrine transporter (NET) gene expression,and improve the cardiac remodeling in experimental HF animals.In this study,we injected NGF into the scalenus medius muscles of Sprague-Dawley rats with abdominal aortic constriction (AC).The nerve innervated pattern,left ventricular morphology,and function following injection in rats with AC were investigated respectively by immunohistochemistry and echocardiography.Levels of mRNA expression of NET,growth associated protein 43 (GAP 43),NGF and its receptors TrkA and p75NTR,and brain natriuretic peptide (BNP) were measured by realtime polymerase chain reaction.The results showed that myocardial NGF mRNA levels were comparable in rats with AC.Short-term supplementation of exogenous NGF raised the myocardial NGF immunoreactivity,but did not cause hyperinnervation and NET mRNA upregulation in the AC rats.Furthermore,myocardial TrkA mRNA was found to be remarkably decreased and p75NTR mRNA was increased.Myocardial TrkA downregulation may play a beneficial effect for avoiding the hyperinnervation,and it is reasonable to postulate that p75NTR can function as an NGF receptor in the absence of TrkA.Interestingly,local NGF administration into the neck muscles near the ganglia could attenuate cardiac remodeling and downregulate BNP mRNA.These results suggest that exogenous NGF can reach the target tissue along the axons anterogradely,and improve the cardiac remodeling.

  9. Effect of Different Styles of Coronary Heart Disease and Its Risk Factors on Cardiac Remodeling and Dysfunction

    Institute of Scientific and Technical Information of China (English)

    Wang Xuelihong; Guo Xuewei; Ma Yushan; Su Shuangshan; Guo Xiangyu

    2006-01-01

    Objectives To evaluate the effect of different styles of coronary heart disease (CHD),different regions of acute myocardial infarction (AMI),its risk factors and branches of coronary stenosis on left ventricular remodeling and dysfunction by applying echocardiography. Methods 251 patients with CHD and 96 patients without CHD (NoCHD) were verified by selective coronary angiography. CHD patients were divided into stable angina pectoris(SAP) 26, unstable angina pectoris(UAP) 53, acute myocardial infarction (AMI) 140 and old myocardial infarction (OMI) 30 based on clinical situation, cTnT, cardiac enzyme and ECG. AMI patients were further divided into subgroups including acute anterior myocardial infarct (Aa,n =53), acute inferior myocardial infarction(Ai, n=54)and Aa+Ai(n=33) based on ECG. Cardiac parameters:end-diastolic interventricular septum thickness (IVSd),end-diastolic left ventricular internal diameter(LVd ),left ventricular mass (LM), end-diastolic left ventricular volume (EDV), end-systolic left ventricular volume (ESV) and left ventricular ejection fraction(LVEF) were measured by ACUSON 128XP/10 echocardiography.Multiples linear regression analyses were performed to test statistical associations between LVEF and the involved branches of coronary stenosis, blood pressure, lipids, glucose and etc after onset of myocardial infarction. Results EDV and ESV were increased and LVEF decreased on patients with AMI,OMI and UAP (P<0.05-0.0001). LM was mainly increased in patients with OMI (P<0.01) and LVd was mainly enlarged in patients with AMI. EF was significantly decreased and EDV, ESV, LM and LVd were remarkably increased in AMI patients with Aa and Aa+Ai. With the multiple linear regression analyses by SPSS software, we found that LVEF was negatively correlated to the involved branches of coronary stenosis as well as to systolic blood pressure after onset of myocardial infarction while there was no significant correlation between LVEF and other factors. LVEF

  10. Sustained cardiac remodeling after a short-term very low calorie diet in type 2 diabetes mellitus patients.

    Science.gov (United States)

    Jonker, Jacqueline T; Snel, Marieke; Hammer, Sebastiaan; Jazet, Ingrid M; van der Meer, Rutger W; Pijl, Hanno; Meinders, A Edo; de Roos, Albert; Smit, Johannes W A; Romijn, Johannes A; Lamb, Hildo J

    2014-01-01

    A very low calorie diet (VLCD) results in cardiac remodeling and improved diastolic function. It is unknown how long these effects sustain after reintroduction of a regular diet. We aimed to assess the long-term effects of initial weight loss by VLCD on cardiac dimensions and function in type 2 diabetes mellitus (T2DM) patients. Fourteen insulin-dependent T2DM patients (mean ± SEM: age 53 ± 2 years; BMI 35 ± 1 kg/m(2)) were treated by a VLCD (450 kcal/day) during 16 weeks. Cardiac function and myocardial triglyceride (TG) content were measured by magnetic resonance imaging and spectroscopy at baseline, after a 16-week VLCD and after 14 months of follow-up on a regular diet. BMI decreased from 35 ± 1 to 28 ± 1 kg/m(2) after VLCD and increased again to 32 ± 1 kg/m(2) at 18 months (both P diet.

  11. 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

  12. Crosstalk between obesity and MMP-9 in cardiac remodelling -a cross-sectional study in apparent treatment-resistant hypertension.

    Science.gov (United States)

    Ritter, Alessandra Mileni Versuti; de Faria, Ana Paula; Barbaro, Natália; Sabbatini, Andréa Rodrigues; Corrêa, Nathália Batista; Brunelli, Veridiana; Amorim, Rivadavio; Modolo, Rodrigo; Moreno, Heitor

    2017-04-01

    The balance between matrix metalloproteinases (MMP) and their tissue inhibitors (TIMP) plays a key role in the development of hypertension and obesity. We aimed to evaluate the levels of MMP-2 and 9 and TIMP-2 and -1 in obese and non-obese apparent treatment-resistant hypertensive subjects (aTRH) and its association with cardiac hypertrophy. This cross-sectional study enrolled 122 subjects and divided into obese aTRH (n = 67) and non-obese (n = 55) group. Clinical and biochemical data were compared between both groups, including office BP, ambulatory BP, plasma MMP-2 and 9, TIMP-2 and 1 and left ventricular mass index (LVMI). We found higher MMP-9 levels and MMP-9/TIMP-1 ratio in obese aTRH subjects but no difference in MMP-2 and TIMP-1 levels. Obesity influenced MMP-9 levels [β = 20.8 SE =8.6, p = 0.02) independently of potential confounders. In addition, we found a positive correlation between MMP-9 and anthropomorphic parameters. Finally, obese aTRH subjects with left ventricular hypertrophy (LVH) had greater MMP-9 levels compared with non-obese with LVH. Our study suggests that MMP-9 levels are influenced by obesity and may directly participate in the progressive LV remodelling process, suggesting a possible role for a higher cardiovascular risk in apparent resistant hypertensive subjects.

  13. Low Intensity Physical Exercise Attenuates Cardiac Remodeling and Myocardial Oxidative Stress and Dysfunction in Diabetic Rats

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    C. Gimenes

    2015-01-01

    Full Text Available We evaluated the effects of a low intensity aerobic exercise protocol on cardiac remodeling and myocardial function in diabetic rats. Wistar rats were assigned into four groups: sedentary control (C-Sed, exercised control (C-Ex, sedentary diabetes (DM-Sed, and exercised diabetes (DM-Ex. Diabetes was induced by intraperitoneal injection of streptozotocin. Rats exercised for 9 weeks in treadmill at 11 m/min, 18 min/day. Myocardial function was evaluated in left ventricular (LV papillary muscles and oxidative stress in LV tissue. Statistical analysis was given by ANOVA or Kruskal-Wallis. Echocardiogram showed diabetic groups with higher LV diastolic diameter-to-body weight ratio and lower posterior wall shortening velocity than controls. Left atrium diameter was lower in DM-Ex than DM-Sed (C-Sed: 5.73±0.49; C-Ex: 5.67±0.53; DM-Sed: 6.41±0.54; DM-Ex: 5.81±0.50 mm; P<0.05 DM-Sed vs C-Sed and DM-Ex. Papillary muscle function was depressed in DM-Sed compared to C-Sed. Exercise attenuated this change in DM-Ex. Lipid hydroperoxide concentration was higher in DM-Sed than C-Sed and DM-Ex. Catalase and superoxide dismutase activities were lower in diabetics than controls and higher in DM-Ex than DM-Sed. Glutathione peroxidase activity was lower in DM-Sed than C-Sed and DM-Ex. Conclusion. Low intensity exercise attenuates left atrium dilation and myocardial oxidative stress and dysfunction in type 1 diabetic rats.

  14. Endothelial cells overexpressing IL-8 receptor reduce cardiac remodeling and dysfunction following myocardial infarction.

    Science.gov (United States)

    Zhao, Xiangmin; Zhang, Wei; Xing, Dongqi; Li, Peng; Fu, Jinyan; Gong, Kaizheng; Hage, Fadi G; Oparil, Suzanne; Chen, Yiu-Fai

    2013-08-15

    The endothelium is a dynamic component of the cardiovascular system that plays an important role in health and disease. This study tested the hypothesis that targeted delivery of endothelial cells (ECs) overexpressing neutrophil membrane IL-8 receptors IL8RA and IL8RB reduces acute myocardial infarction (MI)-induced left ventricular (LV) remodeling and dysfunction and increases neovascularization in the area at risk surrounding the infarcted tissue. MI was created by ligating the left anterior descending coronary artery in 12-wk-old male Sprague-Dawley rats. Four groups of rats were studied: group 1: sham-operated rats without MI or EC transfusion; group 2: MI rats with intravenous vehicle; group 3: MI rats with transfused ECs transduced with empty adenoviral vector (Null-EC); and group 4: MI rats with transfused ECs overexpressing IL8RA/RB (1.5 × 10⁶ cells post-MI). Two weeks after MI, LV function was assessed by echocardiography; infarct size was assessed by triphenyltetrazolium chloride (live tissue) and picrosirus red (collagen) staining, and capillary density and neutrophil infiltration in the area at risk were measured by CD31 and MPO immunohistochemical staining, respectively. When compared with the MI + vehicle and MI-Null-EC groups, transfusion of IL8RA/RB-ECs decreased neutrophil infiltration and pro-inflammatory cytokine expression and increased capillary density in the area at risk, decreased infarct size, and reduced MI-induced LV dysfunction. These findings provide proof of principle that targeted delivery of ECs is effective in repairing injured cardiac tissue. Targeted delivery of ECs to infarcted hearts provides a potential novel strategy for the treatment of acute MI in humans.

  15. 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.

  16. Intramyocardial Delivery of Mesenchymal Stem Cell-Seeded Hydrogel Preserves Cardiac Function and Attenuates Ventricular Remodeling after Myocardial Infarction

    Science.gov (United States)

    Mathieu, Eva; Lamirault, Guillaume; Toquet, Claire; Lhommet, Pierre; Rederstorff, Emilie; Sourice, Sophie; Biteau, Kevin; Hulin, Philippe; Forest, Virginie; Weiss, Pierre

    2012-01-01

    Background To improve the efficacy of bone marrow-derived mesenchymal stem cell (MSC) therapy targeted to infarcted myocardium, we investigated whether a self-setting silanized hydroxypropyl methylcellulose (Si-HPMC) hydrogel seeded with MSC (MSC+hydrogel) could preserve cardiac function and attenuate left ventricular (LV) remodeling during an 8-week follow-up study in a rat model of myocardial infarction (MI). Methodology/Principal Finding Si-HPMC hydrogel alone, MSC alone or MSC+hydrogel were injected into the myocardium immediately after coronary artery ligation in female Lewis rats. Animals in the MSC+hydrogel group showed an increase in cardiac function up to 28 days after MI and a mid-term prevention of cardiac function alteration at day 56. Histological analyses indicated that the injection of MSC+hydrogel induced a decrease in MI size and an increase in scar thickness and ultimately limited the transmural extent of MI. These findings show that intramyocardial injection of MSC+hydrogel induced short-term recovery of ventricular function and mid-term attenuation of remodeling after MI. Conclusion/Significance These beneficial effects may be related to the specific scaffolding properties of the Si-HPMC hydrogel that may provide the ability to support MSC injection and engraftment within myocardium. PMID:23284842

  17. Intramyocardial delivery of mesenchymal stem cell-seeded hydrogel preserves cardiac function and attenuates ventricular remodeling after myocardial infarction.

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    Eva Mathieu

    Full Text Available BACKGROUND: To improve the efficacy of bone marrow-derived mesenchymal stem cell (MSC therapy targeted to infarcted myocardium, we investigated whether a self-setting silanized hydroxypropyl methylcellulose (Si-HPMC hydrogel seeded with MSC (MSC+hydrogel could preserve cardiac function and attenuate left ventricular (LV remodeling during an 8-week follow-up study in a rat model of myocardial infarction (MI. METHODOLOGY/PRINCIPAL FINDING: Si-HPMC hydrogel alone, MSC alone or MSC+hydrogel were injected into the myocardium immediately after coronary artery ligation in female Lewis rats. Animals in the MSC+hydrogel group showed an increase in cardiac function up to 28 days after MI and a mid-term prevention of cardiac function alteration at day 56. Histological analyses indicated that the injection of MSC+hydrogel induced a decrease in MI size and an increase in scar thickness and ultimately limited the transmural extent of MI. These findings show that intramyocardial injection of MSC+hydrogel induced short-term recovery of ventricular function and mid-term attenuation of remodeling after MI. CONCLUSION/SIGNIFICANCE: These beneficial effects may be related to the specific scaffolding properties of the Si-HPMC hydrogel that may provide the ability to support MSC injection and engraftment within myocardium.

  18. 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.

  19. Epigenetic Remodeling in Male Germline Development

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    Na Li

    2016-01-01

    Full Text Available In mammals, germ cells guarantee the inheritance of genetic and epigenetic information across generations and are the origin of a new organism. During embryo development, the blastocyst is formed in the early stage, is comprised of an inner cell mass which is pluripotent, and could give rise to the embryonic stem cells (ESCs. The inner cell mass undergoes demethylation processes and will reestablish a methylated state that is similar to that of somatic cells later in epiblast stage. Primordial germ cells (PGCs will be formed very soon and accompanied by the process of genome-wide demethylation. With the input of male sex determination genes, spermatogonial stem cells (SSCs are generated and undergo the process of spermatogenesis. Spermatogenesis is a delicately regulated process in which various regulations are launched to guarantee normal mitosis and meiosis in SSCs. During all these processes, especially during spermatid development, DNA methylation profile and histone modifications are of crucial importance. In this review, we will discuss the epigenetic modifications from zygote formation to mature sperm generation and their significance to these development processes.

  20. 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.

  1. Novel Sulfur Metabolites of Garlic Attenuate Cardiac Hypertrophy and Remodeling through Induction of Na+/K+-ATPase Expression

    Science.gov (United States)

    Khatua, Tarak N.; Borkar, Roshan M.; Mohammed, Soheb A.; Dinda, Amit K.; Srinivas, R.; Banerjee, Sanjay K.

    2017-01-01

    Epidemiologic studies show an inverse correlation between garlic consumption and progression of cardiovascular disease. However, the molecular basis for the beneficial effect of garlic on the heart is not known. Therefore, the objective of the present study was to (1) investigate the effect of raw garlic on isoproterenol (Iso) induced cardiac hypertrophy (2) find the active metabolites of garlic responsible for the beneficial effect. Cardiac hypertrophy was induced in rats by subcutaneous single injection of Iso 5 mg kg-1 day-1 for 15 days and the effect of garlic (250 mg/kg/day orally) was evaluated. Garlic metabolites in in vivo were identified by LC/MS study. The effect of garlic and its metabolites were evaluated against hypertrophy in H9C2 cells. Garlic normalized cardiac oxidative stress after Iso administration. Cardiac pathology and mitochondrial enzyme activities were improved in hypertrophy heart after garlic administration. Decreased Na+/K+-ATPase protein level that observed in hypertrophy heart was increased after garlic administration. We identified three garlic metabolites in rat serum. To confirm the role of garlic metabolites on cardiac hypertrophy, Na+/K+-ATPase expression and intracellular calcium levels were measured after treating H9C2 cells with raw garlic and two of its active metabolites, allyl methyl sulfide and allyl methyl sulfoxide. Raw garlic and both metabolites increased Na+/K+-ATPase protein level and decreased intracellular calcium levels and cell size in Iso treated H9C2 cells. This antihypertrophic effect of garlic and its sulfur metabolites were lost in H9C2 cells in presence of Na+/K+-ATPase inhibitor. In conclusion, garlic and its active metabolites increased Na+/K+-ATPase in rat heart, and attenuated cardiac hypertrophy and associated remodeling. Our data suggest that identified new garlic metabolites may be useful for therapeutic intervention against cardiac hypertrophy. PMID:28194108

  2. Circulating Endothelial Cells and Endothelial Function predict Major Adverse Cardiac Events and Early Adverse Left Ventricular Remodeling in Patients with ST-Segment Elevation Myocardial Infarction

    Science.gov (United States)

    Magdy, Abdel Hamid; Bakhoum, Sameh; Sharaf, Yasser; Sabry, Dina; El-Gengehe, Ahmed T; Abdel-Latif, Ahmed

    2016-01-01

    Endothelial progenitor cells (EPCs) and circulating endothelial cells (CECs) are mobilized from the bone marrow and increase in the early phase after ST-elevation myocardial infarction (STEMI). The aim of this study was to assess the prognostic significance of CECs and indices of endothelial dysfunction in patients with STEMI. In 78 patients with acute STEMI, characterization of CD34+/VEGFR2+ CECs, and indices of endothelial damage/dysfunction such as brachial artery flow mediated dilatation (FMD) were determined. Blood samples for CECs assessment and quantification were obtained within 24 hours of admission and FMD was assessed during the index hospitalization. At 30 days follow up, the primary composite end point of major cardiac adverse events (MACE) consisting of all-cause mortality, recurrent non-fatal MI, or heart failure and the secondary endpoint of early adverse left ventricular (LV) remodeling were analyzed. The 17 patients (22%) who developed MACE had significantly higher CEC level (P = 0.004), vWF level (P =0.028), and significantly lower FMD (P = 0.006) compared to the remaining patients. Logistic regression analysis showed that CECs level and LV ejection fraction were independent predictors of MACE. The areas under the receiver operating characteristic curves (ROC) for CEC level, FMD, and the logistic model with both markers were 0.73, 0.75, and 0.82 respectively for prediction of the MACE. The 16 patients who developed the secondary endpoint had significantly higher CEC level compared to remaining patients (p =0.038). In conclusion, increased circulating endothelial cells and endothelial dysfunction predicted the occurrence of major adverse cardiac events and adverse cardiac remodeling in patients with STEMI. PMID:26864952

  3. Salvianolic acid A, a novel matrix metalloproteinase-9 inhibitor, prevents cardiac remodeling in spontaneously hypertensive rats.

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    Baohong Jiang

    Full Text Available Cardiac fibrosis is a deleterious consequence of hypertension which may further advance to heart failure and increased matrix metalloproteinase-9 (MMP-9 contributes to the underlying mechanism. Therefore, new therapeutic strategies to attenuate the effects of MMP-9 are urgently needed. In the present study, we characterize salvianolic acid A (SalA as a novel MMP-9 inhibitor at molecular, cellular and animal level. We expressed a truncated form of MMP-9 which contains only the catalytic domain (MMP-9 CD, and used this active protein for enzymatic kinetic analysis and Biacore detection. Data generated from these assays indicated that SalA functioned as the strongest competitive inhibitor of MMP-9 among 7 phenolic acids from Salvia miltiorrhiza. In neonatal cardiac fibroblast, SalA inhibited fibroblast migration, blocked myofibroblast transformation, inhibited secretion of intercellular adhesion molecule (ICAM, interleukin-6 (IL-6 and soluble vascular cell adhesion molecule-1 (sVCAM-1 as well as collagen induced by MMP-9 CD. Functional effects of SalA inhibition on MMP-9 was further confirmed in cultured cardiac H9c2 cell overexpressing MMP-9 in vitro and in heart of spontaneously hypertensive rats (SHR in vivo. Moreover, SalA treatment in SHR resulted in decreased heart fibrosis and attenuated heart hypertrophy. These results indicated that SalA is a novel inhibitor of MMP-9, thus playing an inhibitory role in hypertensive fibrosis. Further studies to develop SalA and its analogues for their potential clinical application of cardioprotection are warranted.

  4. Salvianolic Acid A, a Novel Matrix Metalloproteinase-9 Inhibitor, Prevents Cardiac Remodeling in Spontaneously Hypertensive Rats

    Science.gov (United States)

    Deng, Yanping; Teng, Fukang; Chen, Jing; Xue, Song; Kong, Xiangqian; Luo, Cheng; Shen, Xu; Jiang, Hualiang; Xu, Feng; Yang, Wengang; Yin, Jun; Wang, Yanhui; Chen, Hui; Wu, Wanying; Liu, Xuan; Guo, De-an

    2013-01-01

    Cardiac fibrosis is a deleterious consequence of hypertension which may further advance to heart failure and increased matrix metalloproteinase-9 (MMP-9) contributes to the underlying mechanism. Therefore, new therapeutic strategies to attenuate the effects of MMP-9 are urgently needed. In the present study, we characterize salvianolic acid A (SalA) as a novel MMP-9 inhibitor at molecular, cellular and animal level. We expressed a truncated form of MMP-9 which contains only the catalytic domain (MMP-9 CD), and used this active protein for enzymatic kinetic analysis and Biacore detection. Data generated from these assays indicated that SalA functioned as the strongest competitive inhibitor of MMP-9 among 7 phenolic acids from Salvia miltiorrhiza. In neonatal cardiac fibroblast, SalA inhibited fibroblast migration, blocked myofibroblast transformation, inhibited secretion of intercellular adhesion molecule (ICAM), interleukin-6 (IL-6) and soluble vascular cell adhesion molecule-1 (sVCAM-1) as well as collagen induced by MMP-9 CD. Functional effects of SalA inhibition on MMP-9 was further confirmed in cultured cardiac H9c2 cell overexpressing MMP-9 in vitro and in heart of spontaneously hypertensive rats (SHR) in vivo. Moreover, SalA treatment in SHR resulted in decreased heart fibrosis and attenuated heart hypertrophy. These results indicated that SalA is a novel inhibitor of MMP-9, thus playing an inhibitory role in hypertensive fibrosis. Further studies to develop SalA and its analogues for their potential clinical application of cardioprotection are warranted. PMID:23533637

  5. Recent developments in cardiac pacing.

    Science.gov (United States)

    Rodak, D J

    1995-10-01

    Indications for cardiac pacing continue to expand. Pacing to improve functional capacity, which is now common, relies on careful patient selection and technical improvements, such as complex software algorithms and diagnostic capabilities.

  6. Alterations in the interleukin-1/interleukin-1 receptor antagonist balance modulate cardiac remodeling following myocardial infarction in the mouse.

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    Antonio Abbate

    Full Text Available Healing after acute myocardial infarction (AMI is characterized by an intense inflammatory response and increased Interleukin-1 (IL-1 tissue activity. Genetically engineered mice lacking the IL-1 receptor (IL-1R1-/-, not responsive to IL-1 or the IL-1 receptor antagonist (IL-1Ra, enhanced response to IL-1 have an altered IL-1/IL-1Ra balance that we hypothesize modulates infarct healing and cardiac remodeling after AMI.IL-1R1-/- and IL-1Ra-/- male mice and their correspondent wild-types (WT were subjected to permanent coronary artery ligation or sham surgery. Infarct size (trichrome scar size, apoptotic cell death (TUNEL and left ventricular (LV dimensions and function (echocardiography were measured prior to and 7 days after surgery.When compared with the corresponding WT, IL-1R1-/- mice had significantly smaller infarcts (-25%, less cardiomyocyte apoptosis (-50%, and reduced LV enlargement (LV end-diastolic diameter increase [LVEDD], -20% and dysfunction (LV ejection fraction [LVEF] decrease, -50%, whereas IL-1Ra-/- mice had significantly larger infarcts (+75%, more apoptosis (5-fold increase, and more severe LV enlargement (LVEDD increase,+30% and dysfunction (LVEF decrease, +70%(all P values <0.05.An imbalance in IL-1/IL-1Ra signaling at the IL-1R1 level modulates the severity of cardiac remodeling after AMI in the mouse, with reduced IL-1R1 signaling providing protection and unopposed IL-1R1 signaling providing harm.

  7. Targeted disruption of the heat shock protein 20–phosphodiesterase 4D (PDE4D interaction protects against pathological cardiac remodelling in a mouse model of hypertrophy

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    Tamara P. Martin

    2014-01-01

    Full Text Available Phosphorylated heat shock protein 20 (HSP20 is cardioprotective. Using human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs and a mouse model of pressure overload mediated hypertrophy, we show that peptide disruption of the HSP20–phosphodiesterase 4D (PDE4D complex results in attenuation of action potential prolongation and protection against adverse cardiac remodelling. The later was evidenced by improved contractility, decreased heart weight to body weight ratio, and reduced interstitial and perivascular fibrosis. This study demonstrates that disruption of the specific HSP20–PDE4D interaction leads to attenuation of pathological cardiac remodelling.

  8. Targeted disruption of the heat shock protein 20–phosphodiesterase 4D (PDE4D) interaction protects against pathological cardiac remodelling in a mouse model of hypertrophy

    Science.gov (United States)

    Martin, Tamara P.; Hortigon-Vinagre, Maria P.; Findlay, Jane E.; Elliott, Christina; Currie, Susan; Baillie, George S.

    2014-01-01

    Phosphorylated heat shock protein 20 (HSP20) is cardioprotective. Using human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) and a mouse model of pressure overload mediated hypertrophy, we show that peptide disruption of the HSP20–phosphodiesterase 4D (PDE4D) complex results in attenuation of action potential prolongation and protection against adverse cardiac remodelling. The later was evidenced by improved contractility, decreased heart weight to body weight ratio, and reduced interstitial and perivascular fibrosis. This study demonstrates that disruption of the specific HSP20–PDE4D interaction leads to attenuation of pathological cardiac remodelling. PMID:25426411

  9. Targeted disruption of the heat shock protein 20-phosphodiesterase 4D (PDE4D) interaction protects against pathological cardiac remodelling in a mouse model of hypertrophy.

    Science.gov (United States)

    Martin, Tamara P; Hortigon-Vinagre, Maria P; Findlay, Jane E; Elliott, Christina; Currie, Susan; Baillie, George S

    2014-01-01

    Phosphorylated heat shock protein 20 (HSP20) is cardioprotective. Using human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) and a mouse model of pressure overload mediated hypertrophy, we show that peptide disruption of the HSP20-phosphodiesterase 4D (PDE4D) complex results in attenuation of action potential prolongation and protection against adverse cardiac remodelling. The later was evidenced by improved contractility, decreased heart weight to body weight ratio, and reduced interstitial and perivascular fibrosis. This study demonstrates that disruption of the specific HSP20-PDE4D interaction leads to attenuation of pathological cardiac remodelling.

  10. Glucagon-like peptide-1 and the exenatide analogue AC3174 improve cardiac function, cardiac remodeling, and survival in rats with chronic heart failure

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    Polizzi Clara

    2010-11-01

    Full Text Available Abstract Background Accumulating evidence suggests glucagon-like peptide-1 (GLP-1 exerts cardioprotective effects in animal models of myocardial infarction (MI. We hypothesized that chronic treatment with GLP-1 or the exenatide analog AC3174 would improve cardiac function, cardiac remodeling, insulin sensitivity, and exercise capacity (EC in rats with MI-induced chronic heart failure (CHF caused by coronary artery ligation. Methods Two weeks post-MI, male Sprague-Dawley rats were treated with GLP-1 (2.5 or 25 pmol/kg/min, AC3174 (1.7 or 5 pmol/kg/min or vehicle via subcutaneous infusion for 11 weeks. Cardiac function and morphology were assessed by echocardiography during treatment. Metabolic, hemodynamic, exercise-capacity, and body composition measurements were made at study end. Results Compared with vehicle-treated rats with CHF, GLP-1 or AC3174 significantly improved cardiac function, including left ventricular (LV ejection fraction, and end diastolic pressure. Cardiac dimensions also improved as evidenced by reduced LV end diastolic and systolic volumes and reduced left atrial volume. Vehicle-treated CHF rats exhibited fasting hyperglycemia and hyperinsulinemia. In contrast, GLP-1 or AC3174 normalized fasting plasma insulin and glucose levels. GLP-1 or AC3174 also significantly reduced body fat and fluid mass and improved exercise capacity and respiratory efficiency. Four of 16 vehicle control CHF rats died during the study compared with 1 of 44 rats treated with GLP-1 or AC3174. The cellular mechanism by which GLP-1 or AC3174 exert cardioprotective effects appears unrelated to changes in GLUT1 or GLUT4 translocation or expression. Conclusions Chronic treatment with either GLP-1 or AC3174 showed promising cardioprotective effects in a rat model of CHF. Hence, GLP-1 receptor agonists may represent a novel approach for the treatment of patients with CHF or cardiovascular disease associated with type 2 diabetes.

  11. Development of Bone Remodeling Model for Spaceflight Bone Physiology Analysis

    Science.gov (United States)

    Pennline, James A.; Werner, Christopher R.; Lewandowski, Beth; Thompson, Bill; Sibonga, Jean; Mulugeta, Lealem

    2015-01-01

    Current spaceflight exercise countermeasures do not eliminate bone loss. Astronauts lose bone mass at a rate of 1-2% a month (Lang et al. 2004, Buckey 2006, LeBlanc et al. 2007). This may lead to early onset osteoporosis and place the astronauts at greater risk of fracture later in their lives. NASA seeks to improve understanding of the mechanisms of bone remodeling and demineralization in 1g in order to appropriately quantify long term risks to astronauts and improve countermeasures. NASA's Digital Astronaut Project (DAP) is working with NASA's bone discipline to develop a validated computational model to augment research efforts aimed at achieving this goal.

  12. Renin inhibition improves cardiac function and remodeling after myocardial infarction independent of blood pressure

    NARCIS (Netherlands)

    D. Westermann (Dirk); A. Riad (Alexander); O. Lettau (Olga); A.J.M. Roks (Anton); K. Sawatis (Konstantinos); P.M. Becher (Peter Moritz); F. Escher (Felicitas); A.H.J. Danser (Jan); H.P. Schultheiss (Heinz-Peter); C. Tschöpe (Carsten)

    2008-01-01

    textabstractPharmacological renin inhibition with aliskiren is an effective antihypertensive drug treatment, but it is currently unknown whether aliskiren is able to attenuate cardiac failure independent of its blood pressure-lowering effects. We investigated the effect of aliskiren on cardiac remod

  13. Cardiovascular Development and the Colonizing Cardiac Neural Crest Lineage

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    Paige Snider

    2007-01-01

    Full Text Available Although it is well established that transgenic manipulation of mammalian neural crest-related gene expression and microsurgical removal of premigratory chicken and Xenopus embryonic cardiac neural crest progenitors results in a wide spectrum of both structural and functional congenital heart defects, the actual functional mechanism of the cardiac neural crest cells within the heart is poorly understood. Neural crest cell migration and appropriate colonization of the pharyngeal arches and outflow tract septum is thought to be highly dependent on genes that regulate cell-autonomous polarized movement (i.e., gap junctions, cadherins, and noncanonical Wnt1 pathway regulators. Once the migratory cardiac neural crest subpopulation finally reaches the heart, they have traditionally been thought to participate in septation of the common outflow tract into separate aortic and pulmonary arteries. However, several studies have suggested these colonizing neural crest cells may also play additional unexpected roles during cardiovascular development and may even contribute to a crest-derived stem cell population. Studies in both mice and chick suggest they can also enter the heart from the venous inflow as well as the usual arterial outflow region, and may contribute to the adult semilunar and atrioventricular valves as well as part of the cardiac conduction system. Furthermore, although they are not usually thought to give rise to the cardiomyocyte lineage, neural crest cells in the zebrafish (Danio rerio can contribute to the myocardium and may have different functions in a species-dependent context. Intriguingly, both ablation of chick and Xenopus premigratory neural crest cells, and a transgenic deletion of mouse neural crest cell migration or disruption of the normal mammalian neural crest gene expression profiles, disrupts ventral myocardial function and/or cardiomyocyte proliferation. Combined, this suggests that either the cardiac neural crest

  14. Cardiac remodeling following percutaneous mitral valve repair - initial results assessed by cardiovascular magnetic resonance imaging

    DEFF Research Database (Denmark)

    Radunski, U K; Franzen, O; Barmeyer, A

    2014-01-01

    (CMR) to assess reverse myocardial remodeling in patients after MitraClip implantation. MATERIALS AND METHODS: 12 patients underwent CMR at baseline (BL) before and at 6 months follow-up (FU) after MitraClip implantation. Cine-CMR was performed in short- and long-axes for the assessment of left...

  15. Long-Term Overexpression of Hsp70 Does Not Protect against Cardiac Dysfunction and Adverse Remodeling in a MURC Transgenic Mouse Model with Chronic Heart Failure and Atrial Fibrillation.

    Science.gov (United States)

    Bernardo, Bianca C; Sapra, Geeta; Patterson, Natalie L; Cemerlang, Nelly; Kiriazis, Helen; Ueyama, Tomomi; Febbraio, Mark A; McMullen, Julie R

    2015-01-01

    Previous animal studies had shown that increasing heat shock protein 70 (Hsp70) using a transgenic, gene therapy or pharmacological approach provided cardiac protection in models of acute cardiac stress. Furthermore, clinical studies had reported associations between Hsp70 levels and protection against atrial fibrillation (AF). AF is the most common cardiac arrhythmia presenting in cardiology clinics and is associated with increased rates of heart failure and stroke. Improved therapies for AF and heart failure are urgently required. Despite promising observations in animal studies which targeted Hsp70, we recently reported that increasing Hsp70 was unable to attenuate cardiac dysfunction and pathology in a mouse model which develops heart failure and intermittent AF. Given our somewhat unexpected finding and the extensive literature suggesting Hsp70 provides cardiac protection, it was considered important to assess whether Hsp70 could provide protection in another mouse model of heart failure and AF. The aim of the current study was to determine whether increasing Hsp70 could attenuate adverse cardiac remodeling, cardiac dysfunction and episodes of arrhythmia in a mouse model of heart failure and AF due to overexpression of Muscle-Restricted Coiled-Coil (MURC). Cardiac function and pathology were assessed in mice at approximately 12 months of age. We report here, that chronic overexpression of Hsp70 was unable to provide protection against cardiac dysfunction, conduction abnormalities, fibrosis or characteristic molecular markers of the failing heart. In summary, elevated Hsp70 may provide protection in acute cardiac stress settings, but appears insufficient to protect the heart under chronic cardiac disease conditions.

  16. Effect of the sphingosine kinase 1 selective inhibitor, PF-543 on arterial and cardiac remodelling in a hypoxic model of pulmonary arterial hypertension.

    Science.gov (United States)

    MacRitchie, Neil; Volpert, Giora; Al Washih, Mohammed; Watson, David G; Futerman, Anthony H; Kennedy, Simon; Pyne, Susan; Pyne, Nigel J

    2016-08-01

    Recent studies have demonstrated that the expression of sphingosine kinase 1, the enzyme that catalyses formation of the bioactive lipid, sphingosine 1-phosphate, is increased in lungs from patients with pulmonary arterial hypertension. In addition, Sk1(-/-) mice are protected from hypoxic-induced pulmonary arterial hypertension. Therefore, we assessed the effect of the sphingosine kinase 1 selective inhibitor, PF-543 and a sphingosine kinase 1/ceramide synthase inhibitor, RB-005 on pulmonary and cardiac remodelling in a mouse hypoxic model of pulmonary arterial hypertension. Administration of the potent sphingosine kinase 1 inhibitor, PF-543 in a mouse hypoxic model of pulmonary hypertension had no effect on vascular remodelling but reduced right ventricular hypertrophy. The latter was associated with a significant reduction in cardiomyocyte death. The protection involves a reduction in the expression of p53 (that promotes cardiomyocyte death) and an increase in the expression of anti-oxidant nuclear factor (erythroid-derived 2)-like 2 (Nrf-2). In contrast, RB-005 lacked effects on right ventricular hypertrophy, suggesting that sphingosine kinase 1 inhibition might be nullified by concurrent inhibition of ceramide synthase. Therefore, our findings with PF-543 suggest an important role for sphingosine kinase 1 in the development of hypertrophy in pulmonary arterial hypertension.

  17. Sudden cardiac death in dogs with remodeled hearts is associated with larger beat-to-beat variability of repolarization

    DEFF Research Database (Denmark)

    Thomsen, Morten Bækgaard; Truin, Michiel; van Opstal, Jurren M

    2005-01-01

    Increased proarrhythmia in dogs with chronic AV block (AVB) has been explained by ventricular remodeling causing a decrease in repolarization reserve. Beat-to-beat variability of repolarization (BVR) has been suggested to reflect repolarization reserve, in which high variability represents...... diminished reserve and larger propensity for repolarization-dependent ventricular arrhythmia. A subset of chronic AVB dogs (10%) suffers sudden cardiac death (SCD). With the assumption that repolarization defects constitute a potentially lethal proarrhythmic substrate, we hypothesized that BVR in SCD dogs...... are larger than in matched control chronic AVB dogs. From a population of 200 chronic AVB dogs, initially two groups were chosen retrospectively: 8 dogs that died suddenly (SCD) and 8 control dogs. Control dogs had a longer lifespan after AVB (10 to 18 weeks) than SCD dogs (5 to 10 weeks). All dogs had...

  18. Cardiac remodeling during and after renin-angiotensin system stimulation in Cyp1a1-Ren2 transgenic rats

    DEFF Research Database (Denmark)

    Heijnen, Bart Fj; Pelkmans, Leonie Pj; Danser, Ah Jan

    2013-01-01

    . Hypertrophic genes were highly upregulated, whereas in substantial activation a fibrotic response was absent. Four weeks after withdrawal of I3C, (pro)renin levels were normalized in all IHR. While in adult IHR BP returned to normal, hypertension was sustained in young IHR. Despite the latter, myocardial...... administration of indole-3-carbinol (I3C). Young (four-weeks old) and adult (30-weeks old) IHR were fed I3C for four weeks (leading to systolic BP >200 mmHg). RAS-stimulation was stopped and animals were followed-up for a consecutive period. Cardiac function and geometry was determined echocardiographically...... hypertrophy was fully regressed in both young and adult IHR. We conclude that (pro)renin-induced severe hypertension in IHR causes an age-independent fully reversible myocardial concentric hypertrophic remodeling, despite a continued elevated BP in young IHR....

  19. Inhibiting metalloproteases with PD 166793 in heart failure: impact on cardiac remodeling and beyond.

    Science.gov (United States)

    Kaludercic, Nina; Lindsey, Merry L; Tavazzi, Barbara; Lazzarino, Giuseppe; Paolocci, Nazareno

    2008-01-01

    Metalloproteinases (MMPs, also called matrixins) are extracellular proteolytic enzymes involved in the degradation of both matrix and nonmatrix proteins. Currently, 25 MMPs have been identified in humans, and the overexpression of one or more MMPs has been implicated in several pathologies, spanning from cancer to rheumathoid arthritis to cardiovascular disease. While research over the past 20 years has focused on understanding MMP biology and selectively inhibiting MMP activity, key issues that remain to be addressed include MMP roles in the context of normal versus pathological conditions and whether globally inhibiting MMPs improves or deteriorates overall organ function. In terms of cardiovascular disease, increased MMP expression has been demonstrated in the setting of myocardial ischemia, reperfusion injury, and during the progression to congestive heart failure. MMPs are also major contributors to the progression of atherosclerotic lesions. In this review, we focus on cardiovascular effects produced by PD 166793, a wide-broad spectrum MMP inhibitor, originally developed by Parke-Davis (now Pfizer). We will briefly review its structure, mechanism of action, and inhibitory capacity. Finally, we will illustrate the cardiac contexts, both in vivo and in vitro, in which PD166793 administration has proven beneficial.

  20. Deficiency of ataxia telangiectasia mutated kinase modulates cardiac remodeling following myocardial infarction: involvement in fibrosis and apoptosis.

    Directory of Open Access Journals (Sweden)

    Cerrone R Foster

    Full Text Available Ataxia telangiectasia mutated kinase (ATM is a cell cycle checkpoint protein activated in response to DNA damage. We recently reported that ATM plays a protective role in myocardial remodeling following β-adrenergic receptor stimulation. Here we investigated the role of ATM in cardiac remodeling using myocardial infarction (MI as a model.Left ventricular (LV structure, function, apoptosis, fibrosis, and protein levels of apoptosis- and fibrosis-related proteins were examined in wild-type (WT and ATM heterozygous knockout (hKO mice 7 days post-MI. Infarct sizes were similar in both MI groups. However, infarct thickness was higher in hKO-MI group. Two dimensional M-mode echocardiography revealed decreased percent fractional shortening (%FS and ejection fraction (EF in both MI groups when compared to their respective sham groups. However, the decrease in %FS and EF was significantly greater in WT-MI vs hKO-MI. LV end systolic and diastolic diameters were greater in WT-MI vs hKO-MI. Fibrosis, apoptosis, and α-smooth muscle actin staining was significantly higher in hKO-MI vs WT-MI. MMP-2 protein levels and activity were increased to a similar extent in the infarct regions of both groups. MMP-9 protein levels were increased in the non-infarct region of WT-MI vs WT-sham. MMP-9 protein levels and activity were significantly lower in the infarct region of WT vs hKO. TIMP-2 protein levels similarly increased in both MI groups, whereas TIMP-4 protein levels were significantly lower in the infarct region of hKO group. Phosphorylation of p53 protein was higher, while protein levels of manganese superoxide dismutase were significantly lower in the infarct region of hKO vs WT. In vitro, inhibition of ATM using KU-55933 increased oxidative stress and apoptosis in cardiac myocytes.

  1. Left ventricular geometric remodeling in relation to non-ischemic scar pattern on cardiac magnetic resonance imaging.

    Science.gov (United States)

    Kim, Jiwon; Kochav, Jonathan D; Gurevich, Sergey; Afroz, Anika; Petashnick, Maya; Volo, Samuel; Diaz, Belen; Okin, Peter M; Horn, Evelyn; Devereux, Richard B; Weinsaft, Jonathan W

    2014-12-01

    Left ventricular (LV) remodeling and myocardial fibrosis have been linked to adverse heart failure outcomes. Mid wall late gadolinium enhancement (MW-LGE) on cardiac magnetic resonance (CMR) imaging is well-associated with non-ischemic cardiomyopathy (NICM), but prevalence in ischemic cardiomyopathy (ICM) and association with remodeling are unknown. The population comprised patients with systolic dysfunction [LV ejection fraction (LVEF ≤ 40 %)]. CMR was used to identify MW-LGE, conventionally defined as fibrosis of the mid-myocardial or epicardial aspect of the LV septum. 285 patients were studied. MW-LGE was present in 12 %, and was tenfold more common with NICM (32 %) versus ICM (3 %, p MW-LGE had ICM. LV wall stress was higher (p = 0.02) among patients with, versus those without, MW-LGE despite similar systolic blood pressure (p = 0.24). In multivariate analysis, MW-LGE was associated with CMR-quantified LV end-diastolic volume (p = 0.03) independent of LVEF and mass. Incorporation of clinical and imaging variables demonstrated MW-LGE to be associated with higher LV end-diastolic volume (OR 1.13, CI 1.004-1.27 per 10 ml/m(2), p = 0.04) after controlling for presence of NICM (OR 16.0, CI 5.8-44.1, p MW-LGE can occur in ICM and is a marker of LV chamber dilation irrespective of cardiomyopathic etiology.

  2. TWEAK-Fn14 cytokine-receptor axis: a new player of myocardial remodeling and cardiac failure

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    Tatyana eNovoyatleva

    2014-02-01

    Full Text Available Tumor necrosis factor (TNF has been firmly established as a pathogenic factor in heart failure, a significant socio-economic burden. In this review we will explore the role of other members of the TNF/TNF receptor superfamily (TNFSF/TNFRSF in cardiovascular diseases (CVDs focusing on TWEAK and its receptor Fn14, new players in myocardial remodeling and heart failure. The TWEAK/Fn14 pathway controls a variety of cellular activities such as proliferation, differentiation and apoptosis and has diverse biological functions in pathological mechanisms like inflammation and fibrosis that are associated with CVDs. Furthermore, it has recently been shown that the TWEAK/Fn14 axis is a positive regulator of cardiac hypertrophy and that deletion of Fn14 receptor protects from right heart fibrosis and dysfunction. We discuss the potential use of the TWEAK/Fn14 axis as biomarker for CVDs as well as therapeutic target for future treatment of human heart failure based on supporting data from animal models and in vitro studies. Collectively, existing data strongly suggest the TWEAK/Fn14 axis as a potential new therapeutic target for achieving cardiac protection in patients with CVDs.

  3. S-diclofenac Protects against Doxorubicin-Induced Cardiomyopathy in Mice via Ameliorating Cardiac Gap Junction Remodeling

    Science.gov (United States)

    Zhang, Huili; Zhang, Alian; Guo, Changfa; Shi, Chunzhi; Zhang, Yang; Liu, Qing; Sparatore, Anna; Wang, Changqian

    2011-01-01

    Hydrogen sulfide (H2S), 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-dichlorophenyl)amino] benzeneacetic acid 4-(3H-1,2,dithiol-3-thione-5-yl)phenyl ester), a novel H2S-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 H2S 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 H2S in the pathogenesis of doxorubicin-induced cardiomyopathy. PMID:22039489

  4. S-diclofenac protects against doxorubicin-induced cardiomyopathy in mice via ameliorating cardiac gap junction remodeling.

    Directory of Open Access Journals (Sweden)

    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.

  5. High molecular weight fibroblast growth factor-2 in the human heart is a potential target for prevention of cardiac remodeling.

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    Jon-Jon Santiago

    Full Text Available Fibroblast growth factor 2 (FGF-2 is a multifunctional protein synthesized as high (Hi- and low (Lo- molecular weight isoforms. Studies using rodent models showed that Hi- and Lo-FGF-2 exert distinct biological activities: after myocardial infarction, rat Lo-FGF-2, but not Hi-FGF-2, promoted sustained cardioprotection and angiogenesis, while Hi-FGF-2, but not Lo-FGF-2, promoted myocardial hypertrophy and reduced contractile function. Because there is no information regarding Hi-FGF-2 in human myocardium, we undertook to investigate expression, regulation, secretion and potential tissue remodeling-associated activities of human cardiac (atrial Hi-FGF-2. Human patient-derived atrial tissue extracts, as well as pericardial fluid, contained Hi-FGF-2 isoforms, comprising, respectively, 53%(±20 SD and 68% (±25 SD of total FGF-2, assessed by western blotting. Human atrial tissue-derived primary myofibroblasts (hMFs expressed and secreted predominantly Hi-FGF-2, at about 80% of total. Angiotensin II (Ang II up-regulated Hi-FGF-2 in hMFs, via activation of both type 1 and type 2 Ang II receptors; the ERK pathway; and matrix metalloprotease-2. Treatment of hMFs with neutralizing antibodies selective for human Hi-FGF-2 (neu-AbHi-FGF-2 reduced accumulation of proteins associated with fibroblast-to-myofibroblast conversion and fibrosis, including α-smooth muscle actin, extra-domain A fibronectin, and procollagen. Stimulation of hMFs with recombinant human Hi-FGF-2 was significantly more potent than Lo-FGF-2 in upregulating inflammation-associated proteins such as pro-interleukin-1β and plasminogen-activator-inhibitor-1. Culture media conditioned by hMFs promoted cardiomyocyte hypertrophy, an effect that was prevented by neu-AbHi-FGF-2 in vitro. In conclusion, we have documented that Hi-FGF-2 represents a substantial fraction of FGF-2 in human cardiac (atrial tissue and in pericardial fluid, and have shown that human Hi-FGF-2, unlike Lo-FGF-2, promotes

  6. Modest elevation in BNP in asymptomatic hypertensive patients reflects sub-clinical cardiac remodeling, inflammation and extracellular matrix changes.

    LENUS (Irish Health Repository)

    Phelan, Dermot

    2012-11-01

    In asymptomatic subjects B-type natriuretic peptide (BNP) is associated with adverse cardiovascular outcomes even at levels well below contemporary thresholds used for the diagnosis of heart failure. The mechanisms behind these observations are unclear. We examined the hypothesis that in an asymptomatic hypertensive population BNP would be associated with sub-clinical evidence of cardiac remodeling, inflammation and extracellular matrix (ECM) alterations. We performed transthoracic echocardiography and sampled coronary sinus (CS) and peripheral serum from patients with low (n = 14) and high BNP (n = 27). Peripheral BNP was closely associated with CS levels (r = 0.92, p<0.001). CS BNP correlated significantly with CS levels of markers of collagen type I and III turnover including: PINP (r = 0.44, p = 0.008), CITP (r = 0.35, p = 0.03) and PIIINP (r = 0.35, p = 0.001), and with CS levels of inflammatory cytokines including: TNF-α (r = 0.49, p = 0.002), IL-6 (r = 0.35, p = 0.04), and IL-8 (r = 0.54, p<0.001). The high BNP group had greater CS expression of fibro-inflammatory biomarkers including: CITP (3.8±0.7 versus 5.1±1.9, p = 0.007), TNF-α (3.2±0.5 versus 3.7±1.1, p = 003), IL-6 (1.9±1.3 versus 3.4±2.7, p = 0.02) and hsCRP (1.2±1.1 versus 2.4±1.1, p = 0.04), and greater left ventricular mass index (97±20 versus 118±26 g\\/m(2), p = 0.03) and left atrial volume index (18±2 versus 21±4, p = 0.008). Our data provide insight into the mechanisms behind the observed negative prognostic impact of modest elevations in BNP and suggest that in an asymptomatic hypertensive cohort a peripheral BNP measurement may be a useful marker of an early, sub-clinical pathological process characterized by cardiac remodeling, inflammation and ECM alterations.

  7. Modest elevation in BNP in asymptomatic hypertensive patients reflects sub-clinical cardiac remodeling, inflammation and extracellular matrix changes.

    Directory of Open Access Journals (Sweden)

    Dermot Phelan

    Full Text Available In asymptomatic subjects B-type natriuretic peptide (BNP is associated with adverse cardiovascular outcomes even at levels well below contemporary thresholds used for the diagnosis of heart failure. The mechanisms behind these observations are unclear. We examined the hypothesis that in an asymptomatic hypertensive population BNP would be associated with sub-clinical evidence of cardiac remodeling, inflammation and extracellular matrix (ECM alterations. We performed transthoracic echocardiography and sampled coronary sinus (CS and peripheral serum from patients with low (n = 14 and high BNP (n = 27. Peripheral BNP was closely associated with CS levels (r = 0.92, p<0.001. CS BNP correlated significantly with CS levels of markers of collagen type I and III turnover including: PINP (r = 0.44, p = 0.008, CITP (r = 0.35, p = 0.03 and PIIINP (r = 0.35, p = 0.001, and with CS levels of inflammatory cytokines including: TNF-α (r = 0.49, p = 0.002, IL-6 (r = 0.35, p = 0.04, and IL-8 (r = 0.54, p<0.001. The high BNP group had greater CS expression of fibro-inflammatory biomarkers including: CITP (3.8±0.7 versus 5.1±1.9, p = 0.007, TNF-α (3.2±0.5 versus 3.7±1.1, p = 003, IL-6 (1.9±1.3 versus 3.4±2.7, p = 0.02 and hsCRP (1.2±1.1 versus 2.4±1.1, p = 0.04, and greater left ventricular mass index (97±20 versus 118±26 g/m(2, p = 0.03 and left atrial volume index (18±2 versus 21±4, p = 0.008. Our data provide insight into the mechanisms behind the observed negative prognostic impact of modest elevations in BNP and suggest that in an asymptomatic hypertensive cohort a peripheral BNP measurement may be a useful marker of an early, sub-clinical pathological process characterized by cardiac remodeling, inflammation and ECM alterations.

  8. 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

  9. (Prorenin receptor triggers distinct angiotensin II-independent extracellular matrix remodeling and deterioration of cardiac function.

    Directory of Open Access Journals (Sweden)

    Anne-Mari Moilanen

    Full Text Available BACKGROUND: Activation of the renin-angiotensin-system (RAS plays a key pathophysiological role in heart failure in patients with hypertension and myocardial infarction. However, the function of (prorenin receptor ((PRR is not yet solved. We determined here the direct functional and structural effects of (PRR in the heart. METHODOLOGY/PRINCIPAL FINDINGS: (PRR was overexpressed by using adenovirus-mediated gene delivery in normal adult rat hearts up to 2 weeks. (PRR gene delivery into the anterior wall of the left ventricle decreased ejection fraction (P<0.01, fractional shortening (P<0.01, and intraventricular septum diastolic and systolic thickness, associated with approximately 2-fold increase in left ventricular (PRR protein levels at 2 weeks. To test whether the worsening of cardiac function and structure by (PRR gene overexpression was mediated by angiotensin II (Ang II, we infused an AT(1 receptor blocker losartan via osmotic minipumps. Remarkably, cardiac function deteriorated in losartan-treated (PRR overexpressing animals as well. Intramyocardial (PRR gene delivery also resulted in Ang II-independent activation of extracellular-signal-regulated kinase1/2 phosphorylation and myocardial fibrosis, and the expression of transforming growth factor-β1 and connective tissue growth factor genes. In contrast, activation of heat shock protein 27 phosphorylation and apoptotic cell death by (PRR gene delivery was Ang II-dependent. Finally, (PRR overexpression significantly increased direct protein-protein interaction between (PRR and promyelocytic zinc-finger protein. CONCLUSIONS/SIGNIFICANCE: These results indicate for the first time that (PRR triggers distinct Ang II-independent myocardial fibrosis and deterioration of cardiac function in normal adult heart and identify (PRR as a novel therapeutic target to optimize RAS blockade in failing hearts.

  10. Cardiac resynchronization induces major structural and functional reverse remodeling in patients with New York Heart Association class I/II heart failure

    DEFF Research Database (Denmark)

    St John Sutton, Martin; Ghio, Stefano; Plappert, Ted;

    2009-01-01

    BACKGROUND: Cardiac resynchronization therapy (CRT) improves LV structure, function, and clinical outcomes in New York Heart Association class III/IV heart failure with prolonged QRS. It is not known whether patients with New York Heart Association class I/II systolic heart failure exhibit left...... ventricular (LV) reverse remodeling with CRT or whether reverse remodeling is modified by the cause of heart failure. METHODS AND RESULTS: Six hundred ten patients with New York Heart Association class I/II heart failure, QRS duration > or =120 ms, LV end-diastolic dimension > or =55 mm, and LV ejection...... reduction in LV end-diastolic and end-systolic volume indexes and a 3-fold greater increase in LV ejection fraction in patients with nonischemic causes of heart failure. CONCLUSIONS: CRT in patients with New York Heart Association I/II resulted in major structural and functional reverse remodeling at 1 year...

  11. High-fat Diet Promotes Cardiac Remodeling in an Experimental Model of Obesity

    Directory of Open Access Journals (Sweden)

    Fernando Martins

    2015-01-01

    Full Text Available AbstractBackground:Although nutritional, metabolic and cardiovascular abnormalities are commonly seen in experimental studies of obesity, it is uncertain whether these effects result from the treatment or from body adiposity.Objective:To evaluate the influence of treatment and body composition on metabolic and cardiovascular aspects in rats receiving high saturated fat diet.Methods:Sixteen Wistar rats were used, distributed into two groups, the control (C group, treated with isocaloric diet (2.93 kcal/g and an obese (OB group, treated with high-fat diet (3.64 kcal/g. The study period was 20 weeks. Analyses of nutritional behavior, body composition, glycemia, cholesterolemia, lipemia, systolic arterial pressure, echocardiography, and cardiac histology were performed.Results:High-fat diet associates with manifestations of obesity, accompanied by changes in glycemia, cardiomyocyte hypertrophy, and myocardial interstitial fibrosis. After adjusting for adiposity, the metabolic effects were normalized, whereas differences in morphometric changes between groups were maintained.Conclusion:It was concluded that adiposity body composition has a stronger association with metabolic disturbances in obese rodents, whereas the high-fat dietary intervention is found to be more related to cardiac morphological changes in experimental models of diet-induced obesity.

  12. Getting to the heart of cardiac remodeling; how collagen subtypes may contribute to phenotype.

    Science.gov (United States)

    Collier, P; Watson, C J; van Es, M H; Phelan, D; McGorrian, C; Tolan, M; Ledwidge, M T; McDonald, K M; Baugh, J A

    2012-01-01

    The objective of this study was to investigate the nature and biomechanical properties of collagen fibers within the human myocardium. Targeting cardiac interstitial abnormalities will likely become a major focus of future preventative strategies with regard to the management of cardiac dysfunction. Current knowledge regarding the component structures of myocardial collagen networks is limited, further delineation of which will require application of more innovative technologies. We applied a novel methodology involving combined confocal laser scanning and atomic force microscopy to investigate myocardial collagen within ex-vivo right atrial tissue from 10 patients undergoing elective coronary bypass surgery. Immuno-fluorescent co-staining revealed discrete collagen I and III fibers. During single fiber deformation, overall median values of stiffness recorded in collagen III were 37±16% lower than in collagen I [pretraction, collagen I exhibited greater degrees of elastic recoil [patrial biopsies taken from patients in permanent atrial fibrillation (n=5) versus sinus rhythm (n=5), stiffness of both collagen fiber subtypes was augmented (patrial fibrillation compared to those in sinus rhythm are consistent with recent published findings of increased collagen cross-linking in this setting.

  13. Development and Remodeling of the Vertebrate Blood-Gas Barrier

    Directory of Open Access Journals (Sweden)

    Andrew Makanya

    2013-01-01

    Full Text Available During vertebrate development, the lung inaugurates as an endodermal bud from the primitive foregut. Dichotomous subdivision of the bud results in arborizing airways that form the prospective gas exchanging chambers, where a thin blood-gas barrier (BGB is established. In the mammalian lung, this proceeds through conversion of type II cells to type I cells, thinning, and elongation of the cells as well as extrusion of the lamellar bodies. Subsequent diminution of interstitial tissue and apposition of capillaries to the alveolar epithelium establish a thin BGB. In the noncompliant avian lung, attenuation proceeds through cell-cutting processes that result in remarkable thinning of the epithelial layer. A host of morphoregulatory molecules, including transcription factors such as Nkx2.1, GATA, HNF-3, and WNT5a; signaling molecules including FGF, BMP-4, Shh, and TFG-β and extracellular proteins and their receptors have been implicated. During normal physiological function, the BGB may be remodeled in response to alterations in transmural pressures in both blood capillaries and airspaces. Such changes are mitigated through rapid expression of the relevant genes for extracellular matrix proteins and growth factors. While an appreciable amount of information regarding molecular control has been documented in the mammalian lung, very little is available on the avian lung.

  14. Relationship of cardiac arrhythmias to myocar- dial remodeling and expression of adhesion molecules in patients with mitral valve prolapse

    Directory of Open Access Journals (Sweden)

    A.V. Yagoda

    Conclusion. Myocardial remodeling and dysregulation of cell adhesion proteins are recorded in young patients with MVP and arrhythmias. Relaionship of severity of arrhythmic syndrome to myocardial remodeling and VCAM-1 level was revealed.

  15. Angiotensin II Type 1 Receptor-Mediated Electrical Remodeling in Mouse Cardiac Myocytes.

    Directory of Open Access Journals (Sweden)

    Jeremy Kim

    Full Text Available We recently characterized an autocrine renin angiotensin system (RAS in canine heart. Activation of Angiotensin II Type 1 Receptors (AT1Rs induced electrical remodeling, including inhibition of the transient outward potassium current Ito, prolongation of the action potential (AP, increased calcium entry and increased contractility. Electrical properties of the mouse heart are very different from those of dog heart, but if a similar system existed in mouse, it could be uniquely studied through genetic manipulations. To investigate the presence of a RAS in mouse, we measured APs and Ito in isolated myocytes. Application of angiotensin II (A2 for 2 or more hours reduced Ito magnitude, without affecting voltage dependence, and prolonged APs in a dose-dependent manner. Based on dose-inhibition curves, the fast and slow components of Ito (Ito,fast and IK,slow appeared to be coherently regulated by [A2], with 50% inhibition at an A2 concentration of about 400 nM. This very high K0.5 is inconsistent with systemic A2 effects, but is consistent with an autocrine RAS in mouse heart. Pre-application of the microtubule destabilizing agent colchicine eliminated A2 effects on Ito and AP duration, suggesting these effects depend on intracellular trafficking. Application of the biased agonist SII ([Sar1-Ile4-Ile8]A2, which stimulates receptor internalization without G protein activation, caused Ito reduction and AP prolongation similar to A2-induced changes. These data demonstrate AT1R mediated regulation of Ito in mouse heart. Moreover, all measured properties parallel those measured in dog heart, suggesting an autocrine RAS may be a fundamental feedback system that is present across species.

  16. Cardiac-Restricted IGF-1Ea Overexpression Reduces the Early Accumulation of Inflammatory Myeloid Cells and Mediates Expression of Extracellular Matrix Remodelling Genes after Myocardial Infarction

    Directory of Open Access Journals (Sweden)

    Enrique Gallego-Colon

    2015-01-01

    Full Text Available Strategies to limit damage and improve repair after myocardial infarct remain a major therapeutic goal in cardiology. Our previous studies have shown that constitutive expression of a locally acting insulin-like growth factor-1 Ea (IGF-1Ea propeptide promotes functional restoration after cardiac injury associated with decreased scar formation. In the current study, we investigated the underlying molecular and cellular mechanisms behind the enhanced functional recovery. We observed improved cardiac function in mice overexpressing cardiac-specific IGF-1Ea as early as day 7 after myocardial infarction. Analysis of gene transcription revealed that supplemental IGF-1Ea regulated expression of key metalloproteinases (MMP-2 and MMP-9, their inhibitors (TIMP-1 and TIMP-2, and collagen types (Col 1α1 and Col 1α3 in the first week after injury. Infiltration of inflammatory cells, which direct the remodelling process, was also altered; in particular there was a notable reduction in inflammatory Ly6C+ monocytes at day 3 and an increase in anti-inflammatory CD206+ macrophages at day 7. Taken together, these results indicate that the IGF-1Ea transgene shifts the balance of innate immune cell populations early after infarction, favouring a reduction in inflammatory myeloid cells. This correlates with reduced extracellular matrix remodelling and changes in collagen composition that may confer enhanced scar elasticity and improved cardiac function.

  17. Ablation of C/EBP homologous protein increases the acute phase mortality and doesn't attenuate cardiac remodeling in mice with myocardial infarction.

    Science.gov (United States)

    Luo, Guangjin; Li, Qingman; Zhang, Xiajun; Shen, Liang; Xie, Jiahe; Zhang, Jingwen; Kitakaze, Masafumi; Huang, Xiaobo; Liao, Yulin

    2015-08-14

    Endoplasmic reticulum stress is a proapoptotic and profibrotic stimulus. Ablation of C/EBP homologous protein (CHOP) is reported to reverse cardiac dysfunction by attenuating cardiac endoplasmic reticulum stress in mice with pressure overload or ischemia/reperfusion, but it is unclear whether loss of CHOP also inhibits cardiac remodeling induced by permanent-infarction. In mice with permanent ligation of left coronary artery, we found that ablation of CHOP increased the acute phase mortality. For the mice survived to 4 weeks, left ventricular anterior (LV) wall thickness was larger in CHOP knockout mice than in the wildtype littermates, while no difference was noted on posterior wall thickness, LV dimensions, LV fractional shortening and ejection fraction. Similarly, invasive assessment of LV hemodynamics, morphological analysis of heart and lung weight indexes, myocardial fibrosis and TUNEL-assessed apoptosis showed no significant differences between CHOP knockout mice and their wildtype ones, while in mice with ischemia for 45 min and reperfusion for 1 week, myocardial fibrosis and apoptosis in the infarct area were significantly attenuated in CHOP knockout mice. These findings indicate that ablation of CHOP doesn't ameliorate cardiac remodeling induced by permanent-myocardial infarction, which implicates that early reperfusion is a prerequisite for ischemic myocardium to benefit from CHOP inhibition.

  18. Tenascin-x facilitates myocardial fibrosis and cardiac remodeling through transforming growth factor-β1 and peroxisome proliferator-activated receptor γ in alcoholic cardiomyopathy

    Institute of Scientific and Technical Information of China (English)

    JING Ling; ZHOU Li-jun; ZHANG Feng-min; LI Wei-min; SANG Ying

    2011-01-01

    Background Tenascin-x, an extracellular matrix glycoprotein exclusively expressed in fibroblasts, can mediate fibrosis in the presence of collagen. Therefore, we have investigated its potential role in facilitating myocardial fibrosis and cardiac remodeling via the transforming growth factor-lβ1 and peroxisome proliferator-activated receptor γ(TGFβ1-PPARγ) pathway in alcoholic cardiomyopathy (ACM).Methods Experimental animals were divided into control (group A) and tenascin-x knock-out groups (group B)receiving alcohol. Six months post treatment, cardiac ejections fraction (EF), fractional shortening (FS), left ventricle end-diastole internal diameter (LVEDd) and collagen column fraction (CVF) were observed. Tenascin-x, smad-3, TGFβ1,smad-7 and PPARγ protein expression levels were detected by Western blotting.Results Six months post treatment, EF and FS values were higher in group B than in group A (P <0.05 and P <0.01,respectively), while LVEDd and CVF were lower in group B (P <0.05 and P <0.01, respectively). Tenascin-x, smad-3 and TGFβ1 protein expression levels were higher in group A, while smad-7 and PPARY levels were lower than in group B (P<0.01), as measured by immunohistochemistry and Western blotting. Tenascin-x protein expression was negatively correlated with EF, FS, smad-7 and PPARγ, and positively correlated with LVEDd, CVF, smad-3, and TGFβ1 (P <0.001).Conclusion Tenascin-x is an initiator of myocardial fibrosis and ACM development via upregulation of TGFβ1 and downregulation of PPARγ.

  19. Research Progress of ACE2 against Cardiac Remodeling%ACE2抗心室重构作用的研究进展

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    张培勇

    2013-01-01

    心室重构是心脏对损伤或室壁压力增高的适应性变化,病理性心室重构导致心功能进行性恶化,最终导致心力衰竭.肾素-血管紧张素系统(RAS)通过间接和直接作用在心室重构的发生、发展中发挥重要作用.血管紧张素转换酶2(ACE2)可水解血管紧张素Ⅱ生成血管紧张素-(1-7),负性调节RAS,延缓或逆转病理型心室重构.现对近年来ACE2抗心室重构作用的研究进展进行综述.%Remodeling of the heart which occurs in response to injury and/or an increase in wall stress plays a key role in the progressive deterioration of cardiac function that leads to heart failure. The renin-angiotensin system ( RAS ) is a key regulator in the progress of pathological remodeling, through indirect and direct effects on cells of heart. Angiotensin converting enzyme 2( ACE2 ), which can break down Ang Ⅱ while generating angiotensin-( 1 -7 ), can down-regulate RAS and have an important role against cardiac remodeling. Here is to make a review focusing on advances made in understanding the effects of ACE2 against cardiac remodeling.

  20. Adaptations to iron deficiency: cardiac functional responsiveness to norepinephrine, arterial remodeling, and the effect of beta-blockade on cardiac hypertrophy

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    Walker LeeAnn

    2002-01-01

    Full Text Available Abstract Background Iron deficiency (ID results in ventricular hypertrophy, believed to involve sympathetic stimulation. We hypothesized that with ID 1 intravenous norepinephrine would alter heart rate (HR and contractility, 2 abdominal aorta would be larger and more distensible, and 3 the beta-blocker propanolol would reduce hypertrophy. Methods 1 30 CD rats were fed an ID or replete diet for 1 week or 1 month. Norepinephrine was infused via jugular vein; pressure was monitored at carotid artery. Saline infusions were used as a control. The pressure trace was analyzed for HR, contractility, systolic and diastolic pressures. 2 Abdominal aorta catheters inflated the aorta, while digital microscopic images were recorded at stepwise pressures to measure arterial diameter and distensibility. 3 An additional 10 rats (5 ID, 5 control were given a daily injection of propanolol or saline. After 1 month, the hearts were excised and weighed. Results Enhanced contractility, but not HR, was associated with ID hypertrophic hearts. Systolic and diastolic blood pressures were consistent with an increase in arterial diameter associated with ID. Aortic diameter at 100 mmHg and distensibility were increased with ID. Propanolol was associated with an increase in heart to body mass ratio. Conclusions ID cardiac hypertrophy results in an increased inotropic, but not chronotropic response to the sympathetic neurotransmitter, norepinephrine. Increased aortic diameter is consistent with a flow-dependent vascular remodeling; increased distensibility may reflect decreased vascular collagen content. The failure of propanolol to prevent hypertrophy suggests that ID hypertrophy is not mediated via beta-adrenergic neurotransmission.

  1. Galnt1 is required for normal heart valve development and cardiac function.

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    E Tian

    Full Text Available Congenital heart valve defects in humans occur in approximately 2% of live births and are a major source of compromised cardiac function. In this study we demonstrate that normal heart valve development and cardiac function are dependent upon Galnt1, the gene that encodes a member of the family of glycosyltransferases (GalNAc-Ts responsible for the initiation of mucin-type O-glycosylation. In the adult mouse, compromised cardiac function that mimics human congenital heart disease, including aortic and pulmonary valve stenosis and regurgitation; altered ejection fraction; and cardiac dilation, was observed in Galnt1 null animals. The underlying phenotype is aberrant valve formation caused by increased cell proliferation within the outflow tract cushion of developing hearts, which is first detected at developmental stage E11.5. Developing valves from Galnt1 deficient animals displayed reduced levels of the proteases ADAMTS1 and ADAMTS5, decreased cleavage of the proteoglycan versican and increased levels of other extracellular matrix proteins. We also observed increased BMP and MAPK signaling. Taken together, the ablation of Galnt1 appears to disrupt the formation/remodeling of the extracellular matrix and alters conserved signaling pathways that regulate cell proliferation. Our study provides insight into the role of this conserved protein modification in cardiac valve development and may represent a new model for idiopathic valve disease.

  2. Adenosine A2A  receptor agonist prevents cardiac remodeling and dysfunction in spontaneously hypertensive male rats after myocardial infarction

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    da Silva JS

    2017-03-01

    Full Text Available Jaqueline S da Silva,1 Daniele Gabriel-Costa,1 Roberto T Sudo,1 Hao Wang,2 Leanne Groban,2 Emanuele B Ferraz,3 José Hamilton M Nascimento,3 Carlos Alberto M Fraga,1 Eliezer J Barreiro,1 Gisele Zapata-Sudo1 1Research Program Development of Drugs, Institute of Biomedical Sciences, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil; 2Department of Anesthesiology, Wake Forest School of Medicine, Winston-Salem, NC, USA; 3Institute of Biophysics Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil Background: This work evaluated the hypothesis that 3,4-methylenedioxybenzoyl-2- thienylhydrazone (LASSBio-294, an agonist of adenosine A2A  receptor, could be beneficial for preventing cardiac dysfunction due to hypertension associated with myocardial infarction (MI. Methods: Male spontaneously hypertensive rats (SHR were randomly divided into four groups (six animals per group: sham-operation (SHR-Sham, and myocardial infarction rats (SHR-MI were treated orally either with vehicle or LASSBio-294 (10 and 20 mg.kg-1.d-1 for 4 weeks. Echocardiography and in vivo hemodynamic parameters measured left ventricle (LV structure and function. Exercise tolerance was evaluated using a treadmill test. Cardiac remodeling was accessed by LV collagen deposition and tumor necrosis factor α expression. Results: Early mitral inflow velocity was significantly reduced in the SHR-MI group, and there was significant recovery in a dose-dependent manner after treatment with LASSBio-294. Exercise intolerance observed in the SHR-MI group was prevented by 10 mg.kg-1.d-1 of LASSBio-294, and exercise tolerance exceeded that of the SHR-Sham group at 20 mg.kg-1.d-1. LV end-diastolic pressure increased after MI, and this was prevented by 10 and 20 mg.kg-1.d-1 of LASSBio-294. Sarcoplasmic reticulum Ca2+ ATPase levels were restored in a dose-dependent manner after treatment with LASSBio-294. Fibrosis and inflammatory processes were also

  3. The Combined Effect of Endurance Training and Various Doses of Atorvastatin on Cardiac Remodeling after Myocardial Infarction in Male Rats

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    Hadi Abdi

    2015-12-01

    Full Text Available Introduction: Statins and exercise have beneficial effects in preventing cardiovascular diseases. However, prolonged use of statins particularly at high doses has unpleasant side effects. This study aimed to investigate the combined effect of endurance training and three doses of Atorvastatin on cardiac remodeling after myocardial infarction in male rats.Methods: 75 male wistar rats (weighing 210-250g were randomly divided to 9 groups. Sham, control, endurance training, Atorvastatin (5, 10 and 15 mg/kg, and exercise plus Atorvastatin (5, 10 and 15 mg/kg: Myocardial infarction was induced by subcutaneous injection of isoprenaline (150 mg/kg in two consecutive days. Drug and training intervention was initiated 2 days after infarction and continued for 4 weeks. In order to assess the necrosis lesion and fibrosis tissue, hematoxylin & eosin and masson trichrome staining were used respectively.Results: The combination of endurance training and various doses of Atorvastatin significantly reduced the amount of necrosis and fibrosis tissue compared with the control group (P<0.01. Endurance exercise training alone did not cause significant changes in the extent of necrosis damage, but significantly increased fibrosis tissue compared with the control group (P<0.001. Various doses of Atorvastatin alone significantly reduced necrosis damage (P<0.001, but the difference between these groups and the control group in terms of fibrous tissue was statistically significant only at dose of 15 mg/kg (P<0.001.Conclusion: The results of this study showed that the combination of training and various doses of Atorvastatin are more effective in improving of tissue damage caused by myocardial infarction than exercise and Atorvastatin alone. However, the use of endurance training with medical therapy can not reduce the dose of Atorvastatin.

  4. Effects of Long-term Ramipril on Ventricular Remodeling, Cardiac Function and Survival in Rat Congestive Heart Failure after Myocardial Infarction

    Institute of Scientific and Technical Information of China (English)

    陶则伟; 黄元伟

    2004-01-01

    Objectives The purpose of this study was to investigate the effects of long-term ramipril on ventricular remodeling, cardiac function and survival in rat congestive heart failure after myocardial infarction. Methods Myocardial infarction (MI) was caused by ligation of the left anterior descending coronary artery in rats. 7 days after the surgery, the surviving rats were randomly assigned to the following treatment protocols: 1) MI rats with no therapy, 2) MI rats treated with ramipril 3 mg/kg per day, 3) Sham-operated control rats, and 4) Sham-operated rats treated with ramipril 3 mg/kg per day. At 22 weeks, cardiac hemodynamic parameters such as MAP, LVSP, ±dP/dtmax and LVEDP were measured,and cardiac morphometric parameters such as HW,LVW and LVCA were measured, mRNA of cardiacmolecule genes, such as βMHC, BNP, collagen Ⅰ and Ⅲ, and TGF-β1, were quantified, and survival rates were calculated. Results Compared with sham-operated rats, MI rats without therapy showed significant increases in cardiac morphological parameters as well as in mRAN expressions of cardiac molecule genes (P<0.01); while their hemodynamic parameters were significantly impaired (P<0.01), and survival rate shortened (P<0.05). Compared with MI rats with no therapy, MI rats treated with ramipril showed significant attenuation of mRAN expressions of cardiac molecule genes (P<0.01); while their hemodynamic parameters were significantly impaired (P<0.01), and survival rate shortened (P<0.05). Compared with MI rats with no therapy, MI rats treated with ramipril showed significant attenuation of mRAN expressions of cardiac molecule genes (P<0.01); while their hemodynamic parameters were significantly improved (P<0.05 or P<0.01), and survival rates prolonged (P<0.05). Conclusions Treatment with long-term ramipril may improve LV remodeling, cardiac function and survival in rat congestive heart failure after MI.

  5. Expression of nebulette during early cardiac development.

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    Esham, Michael; Bryan, Kourtney; Milnes, Jennifer; Holmes, William B; Moncman, Carole L

    2007-04-01

    Nebulette, a cardiac homologue of nebulin, colocalizes with alpha-actinin in the pre-myofibrils of spreading cardiomyocytes and has been hypothesized to play a critical role in the formation of the thin-filament-Z-line complex early during myofibrillogenesis. Data from mesodermal explants or whole tissue mounts of developing hearts suggest that the pattern of myofibrillogenesis in situ may differ from observations of spreading cardiomyocytes. To evaluate the role of nebulette in myofibrillogenesis, we have analyzed the expression of nebulette in chicken heart rudiments by immunoblots and immunofluorescence. We detect the 110 kDa nebulette in heart rudiments derived from stage 9-10 using the anti-nebulin mAb, N114, or polyclonal anti-nebulette Abs by immunoblotting. Immunofluorescence analysis of explants stained with anti-nebulette and anti-alpha-actinin Abs demonstrates that both proteins localize along actin filaments in punctate to continuous manner at early stages of cardiac development and later give rise to striations. In both cases, the punctate staining had a periodicity of approximately 1.0 microm indicating a pre-myofibrils distribution at the earliest time points examined. We demonstrate that nebulette is indeed associated with premyofibrils in very early stages of myofibrillogenesis and suggest that nebulette may play an important role in the formation of these structures.

  6. HCM-Linked Δ 160E Cardiac Troponin T Mutation Causes Unique Progressive Structural and Molecular Ventricular Remodeling in Transgenic Mice

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    Moore, Rachel K.; Grinspan, Lauren Tal; Jimenez, Jesus; Guinto, Pia J.; Ertz-Berger, Briar; Tardiff, Jil C.

    2013-01-01

    Hypertrophic cardiomyopathy (HCM) is a primary disease of cardiac muscle, and one of the most common causes of sudden cardiac death (SCD) in young people. Many mutations in cardiac troponin T (cTnT) lead to a complex form of HCM with varying degrees of ventricular hypertrophy and ~65% of all cTnT mutations occur within or flanking the elongated N-terminal TNT1 domain. Biophysical studies have predicted that distal TNT1 mutations, including Δ160E, cause disease by a novel, yet unknown mechanism as compared to N-terminal mutations. To begin to address the specific effects of this commonly observed cTnT mutation we generated two independent transgenic mouse lines carrying variant doses of the mutant transgene. Hearts from the 30% and 70% cTnT Δ160E lines demonstrated a highly unique, dose-dependent disruption in cellular and sarcomeric architecture and a highly progressive pattern of ventricular remodeling. While adult ventricular myocytes isolated from Δ160E transgenic mice exhibited dosage-independent mechanical impairments, decreased sarcoplasmic reticulum calcium load and SERCA2a calcium uptake activity, the observed decreases in calcium transients were dosage-dependent. The latter findings were concordant with measures of calcium regulatory proteins abundance and phosphorylation state. Finally, studies of whole heart physiology in the isovolumic mode demonstrated dose-dependent differences in the degree of cardiac dysfuction. We conclude that the observed clinical severity of the cTnT Δ160E mutation is caused by a combination of direct sarcomeric disruption coupled to a profound disregulation of Ca2+ homeostasis at the cellular level that results in a unique and highly progressive pattern of ventricular remodeling. PMID:23434821

  7. High intensity interval and endurance training have opposing effects on markers of heart failure and cardiac remodeling in hypertensive rats.

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    Holloway, Tanya M; Bloemberg, Darin; da Silva, Mayne L; Simpson, Jeremy A; Quadrilatero, Joe; Spriet, Lawrence L

    2015-01-01

    There has been re-emerging interest and significant work dedicated to investigating the metabolic effects of high intensity interval training (HIIT) in recent years. HIIT is considered to be a time efficient alternative to classic endurance training (ET) that elicits similar metabolic responses in skeletal muscle. However, there is a lack of information on the impact of HIIT on cardiac muscle in disease. Therefore, we determined the efficacy of ET and HIIT to alter cardiac muscle characteristics involved in the development of diastolic dysfunction, such as ventricular hypertrophy, fibrosis and angiogenesis, in a well-established rodent model of hypertension-induced heart failure before the development of overt heart failure. ET decreased left ventricle fibrosis by ~40% (P HIIT did not decrease existing fibrosis, and HIIT animals displayed a 20% increase in left ventricular mass (PHIIT also increased brain natriuretic peptide by 50% (PHIIT promoted a pathological adaptation in the left ventricle in the presence of hypertension, highlighting the need for further research on the widespread effects of HIIT in the presence of disease.

  8. Hypertension is a conditional factor for the development of cardiac hypertrophy in type 2 diabetic mice.

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    Marc van Bilsen

    Full Text Available BACKGROUND: Type 2 diabetes is frequently associated with co-morbidities, including hypertension. Here we investigated if hypertension is a critical factor in myocardial remodeling and the development of cardiac dysfunction in type 2 diabetic db/db mice. METHODS: Thereto, 14-wks-old male db/db mice and non-diabetic db/+ mice received vehicle or angiotensin II (AngII for 4 wks to induce mild hypertension (n = 9-10 per group. Left ventricular (LV function was assessed by serial echocardiography and during a dobutamine stress test. LV tissue was subjected to molecular and (immunohistochemical analysis to assess effects on hypertrophy, fibrosis and inflammation. RESULTS: Vehicle-treated diabetic mice neither displayed marked myocardial structural remodeling nor cardiac dysfunction. AngII-treatment did not affect body weight and fasting glucose levels, and induced a comparable increase in blood pressure in diabetic and control mice. Nonetheless, AngII-induced LV hypertrophy was significantly more pronounced in diabetic than in control mice as assessed by LV mass (increase +51% and +34%, respectively, p<0.01 and cardiomyocyte size (+53% and +31%, p<0.001. This was associated with enhanced LV mRNA expression of markers of hypertrophy and fibrosis and reduced activation of AMP-activated protein kinase (AMPK, while accumulation of Advanced Glycation End products (AGEs and the expression levels of markers of inflammation were not altered. Moreover, AngII-treatment reduced LV fractional shortening and contractility in diabetic mice, but not in control mice. CONCLUSIONS: Collectively, the present findings indicate that type 2 diabetes in its early stage is not yet associated with adverse cardiac structural changes, but already renders the heart more susceptible to hypertension-induced hypertrophic remodeling.

  9. STARS is essential to maintain cardiac development and function in vivo via a SRF pathway.

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    Nelson W Chong

    Full Text Available BACKGROUND: STARS (STriated muscle Activator of Rho Signaling is a sarcomeric protein expressed early in cardiac development that acts as an acute stress sensor for pathological remodeling. However the role of STARS in cardiac development and function is incompletely understood. Here, we investigated the role of STARS in heart development and function in the zebrafish model and in vitro. METHODOLOGY AND PRINCIPAL FINDINGS: Expression of zebrafish STARS (zSTARS first occurs in the somites by the 16 somite stage [17 hours post fertilization (hpf]. zSTARS is expressed in both chambers of the heart by 48 hpf, and also in the developing brain, jaw structures and pectoral fins. Morpholino-induced knockdown of zSTARS alters atrial and ventricular dimensions and decreases ventricular fractional shortening (measured by high-speed video microscopy, with pericardial edema and decreased or absent circulation [abnormal cardiac phenotypes in 126/164 (77% of morpholino-injected embryos vs. 0/152 (0% of control morpholino embryos]. Co-injection of zsrf (serum response factor mRNA rescues the cardiac phenotype of zSTARS knockdown, resulting in improved fractional shortening and ventricular end-diastolic dimensions. Ectopic over-expression of STARS in vitro activates the STARS proximal promoter, which contains a conserved SRF site. Chromatin immunoprecipitation demonstrates that SRF binds to this site in vivo and the SRF inhibitor CCG-1423 completely blocks STARS proximal reporter activity in H9c2 cells. CONCLUSIONS/SIGNIFICANCE: This study demonstrates for the first time that STARS deficiency severely disrupts cardiac development and function in vivo and revealed a novel STARS-SRF feed-forward autoregulatory loop that could play an essential role in STARS regulation and cardiac function.

  10. Features of remodeling of right heart chambers according to tissue Doppler and its correlation with cardiac rhythm disturbance in patients with COPD 2-3 severity

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    O. A. Zhuk

    2014-01-01

    Full Text Available The article presents the study of early sings of dysfunction of right and left chambers of heart in patients with COPD 2 - 3 severity, correlation between structural and electrical remodeling of heart according to the stages of pulmonary hypertension. Standard tissue Doppler echocardiographic parameters and modes were used for the diagnosing. We examined 35 patients with COPD 2 - 3 severity; the control group consisted of 15 patients. The ECG Holter monitoring was made for all patients to identify cardiac rhythm disturbance and correlation with the COPD severity. Standard method of the ECG with modes of tissue Doppler (pulsed wave Tissue Doppler Imaging - PW TDI, color tissue Doppler imaging -TDI, tissue myocardial Doppler - TMD, tissue Tracking - TT, Doppler for evaluation of myocardial strain and myocardial strain rate were made to identify the stage of dysfunction. The results of the study concluded that according to the TDI the dysfunction of right ventricle was more apparent in patients with COPD 3 severity. Pathological arrhythmias were significantly detected in group of patients with COPD 3 severity. In compliance with our observations, the reduce of rapid myocardial strain rates and its inverse proportion with the severity in accordance to the evaluation of longitudinal strain and rate of movement of fibrous ring in tricuspid valve were observed in patients with COPD. Thus the application of the TDI modes for evaluating of early signs of cardiac remodeling in patients with COPD and potential adequate jugulation for preventing chronic cor pulmonale is expedient.

  11. Comparative Characterization of Cardiac Development Specific microRNAs: Fetal Regulators for Future.

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    Yashika Rustagi

    Full Text Available MicroRNAs (miRNAs are small, conserved RNAs known to regulate several biological processes by influencing gene expression in eukaryotes. The implication of miRNAs as another player of regulatory layers during heart development and diseases has recently been explored. However, there is no study which elucidates the profiling of miRNAs during development of heart till date. Very limited miRNAs have been reported to date in cardiac context. In addition, integration of large scale experimental data with computational and comparative approaches remains an unsolved challenge.The present study was designed to identify the microRNAs implicated in heart development using next generation sequencing, bioinformatics and experimental approaches. We sequenced six small RNA libraries prepared from different developmental stages of the heart using chicken as a model system to produce millions of short sequence reads. We detected 353 known and 703 novel miRNAs involved in heart development. Out of total 1056 microRNAs identified, 32.7% of total dataset of known microRNAs displayed differential expression whereas seven well studied microRNAs namely let-7, miR-140, miR-181, miR-30, miR-205, miR-103 and miR-22 were found to be conserved throughout the heart development. The 3'UTR sequences of genes were screened from Gallus gallus genome for potential microRNA targets. The target mRNAs were appeared to be enriched with genes related to cell cycle, apoptosis, signaling pathways, extracellular remodeling, metabolism, chromatin remodeling and transcriptional regulators. Our study presents the first comprehensive overview of microRNA profiling during heart development and prediction of possible cardiac specific targets and has a big potential in future to develop microRNA based therapeutics against cardiac pathologies where fetal gene re-expression is witnessed in adult heart.

  12. Comparative Characterization of Cardiac Development Specific microRNAs: Fetal Regulators for Future.

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    Rustagi, Yashika; Jaiswal, Hitesh K; Rawal, Kamal; Kundu, Gopal C; Rani, Vibha

    2015-01-01

    MicroRNAs (miRNAs) are small, conserved RNAs known to regulate several biological processes by influencing gene expression in eukaryotes. The implication of miRNAs as another player of regulatory layers during heart development and diseases has recently been explored. However, there is no study which elucidates the profiling of miRNAs during development of heart till date. Very limited miRNAs have been reported to date in cardiac context. In addition, integration of large scale experimental data with computational and comparative approaches remains an unsolved challenge.The present study was designed to identify the microRNAs implicated in heart development using next generation sequencing, bioinformatics and experimental approaches. We sequenced six small RNA libraries prepared from different developmental stages of the heart using chicken as a model system to produce millions of short sequence reads. We detected 353 known and 703 novel miRNAs involved in heart development. Out of total 1056 microRNAs identified, 32.7% of total dataset of known microRNAs displayed differential expression whereas seven well studied microRNAs namely let-7, miR-140, miR-181, miR-30, miR-205, miR-103 and miR-22 were found to be conserved throughout the heart development. The 3'UTR sequences of genes were screened from Gallus gallus genome for potential microRNA targets. The target mRNAs were appeared to be enriched with genes related to cell cycle, apoptosis, signaling pathways, extracellular remodeling, metabolism, chromatin remodeling and transcriptional regulators. Our study presents the first comprehensive overview of microRNA profiling during heart development and prediction of possible cardiac specific targets and has a big potential in future to develop microRNA based therapeutics against cardiac pathologies where fetal gene re-expression is witnessed in adult heart.

  13. Remodeling of the metabolome during early frog development.

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    Livia Vastag

    Full Text Available A rapid series of synchronous cell divisions initiates embryogenesis in many animal species, including the frog Xenopus laevis. After many of these cleavage cycles, the nuclear to cytoplasmic ratio increases sufficiently to somehow cause cell cycles to elongate and become asynchronous at the mid-blastula transition (MBT. We have discovered that an unanticipated remodeling of core metabolic pathways occurs during the cleavage cycles and the MBT in X. laevis, as evidenced by widespread changes in metabolite abundance. While many of the changes in metabolite abundance were consistently observed, it was also evident that different female frogs laid eggs with different levels of at least some metabolites. Metabolite tracing with heavy isotopes demonstrated that alanine is consumed to generate energy for the early embryo. dATP pools were found to decline during the MBT and we have confirmed that maternal pools of dNTPs are functionally exhausted at the onset of the MBT. Our results support an alternative hypothesis that the cell cycle lengthening at the MBT is triggered not by a limiting maternal protein, as is usually proposed, but by a decline in dNTP pools brought about by the exponentially increasing demands of DNA synthesis.

  14. The Notch pathway: a novel target for myocardial remodelling therapy?

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    Ferrari, Roberto; Rizzo, Paola

    2014-08-21

    Pathological ventricle remodelling, which follows a cardiac insult, causes heart failure. Despite the existence of multiple pharmaceutical approaches, heart failure is one of the leading causes of death worldwide and there is an urgent need to explore new therapeutic avenues. The Notch pathway is an evolutionary conserved fundamental pathway that regulates cell fate during development as well as throughout postnatal life in self-renewing tissues. In the myocardium, Notch signalling is involved in the modulation of cardiomyocytes survival, cardiac stem cells differentiation, and angiogenesis which are factors known to determine the extent of pathological cardiac remodelling. Modulation of the Notch pathway could become a tool to limit ventricle remodelling and the associated inexorable deterioration of cardiac performance.

  15. Coupling of the Functional Stability of Rat Myocardium and Activity of Lipid Peroxidation in Combined Development of Postinfarction Remodeling and Diabetes Mellitus

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    S. A. Afanasiev

    2016-01-01

    Full Text Available Coupling of the functional stability of rat myocardium and activity of lipid peroxidation processes in combined development of postinfarction remodeling and diabetes mellitus has been studied. The functional stability of myocardium was studied by means of the analysis of inotropic reaction on extrasystolic stimulus, the degree of left ventricular hypertrophy, and the size of scar zone. It was shown that in combined development of postinfarction cardiac remodeling of heart (PICR with diabetes mellitus (DM animal body weight decreased in less degree than in diabetic rats. Animals with combined pathology had no heart hypertrophy. The amplitude of extrasystolic contractions in rats with PICR combined with DM had no differences compared to the control group. In myocardium of rats with PICR combined with DM postextrasystolic potentiation was observed in contrast with the rats with PICR alone. The rats with combined pathology had the decreased value of TBA-active products. Thus, the results of study showed that induction of DM on the stage of the development of postinfarction remodeling increases adaptive ability of myocardium. It is manifested in inhibition of increase of LPO processes activity and maintaining of force-interval reactions of myocardium connected with calcium transport systems of sarcoplasmic reticulum of cardiomyocytes.

  16. 前列地尔对心力衰竭患者心脏功能和心室重构影响%The Effect of Alprostadil on Cardiac Function and Ventricular Remodeling of Patients with Cardiac Failure

    Institute of Scientific and Technical Information of China (English)

    朱鹏程; 林镇荣; 陈庆超; 杨锡泉; 张琳

    2015-01-01

    Objective:To explore the effect of alprostadil on cardiac function and ventricular remodeling of patients with cardiac failure. Method:80 patients with cardiac failure in Overseas Chinese Hospital of Raoping County were divided into research group (n=40) and control group (n=40) randomly from Aug 2013 to May 2015. The research group was treated by alprostadil based on the conventional methods in the control group. There were no differences in the baseline data including age, history, primary disease and ventricular rate between the two groups. Alprostadil was added 10 μg/d for 10-14 days in research group. The differences on cardiac function and ventricular remodeling were compared after 2 weeks after treatment between the two groups. Results:Compared with the control group,there were shorter left ventricular end diastolic diameter,larger left ventricular ejection fraction, longer walking distance in 6 minutes and slower resting heart rate,and higher the total effective rate in the research group,all P<0.01.There were no severe side actions in the research group. Conclusion:It is effective and safe in patients with cardiac failure treated by Alprostadil. Alprostadil could increase cardiac function and improve ventricular remodeling and could be used more popular in patients with cardiac failure.%目的:探讨前列地尔对心力衰竭患者心脏功能和心室重构的影响。方法:将2013年8月至2015年5月广东省潮州市饶平县华侨医院心内科收治的心力衰竭患者80例随机分为对照组和研究组各40例,两组年龄、病程、原发病和心室率等差异无显著性(P >0.05);对照组按常规治疗,研究组在对照组治疗的基础上加用前列地尔10 ug/次,每日1次,持续10-14 d,2周后比较两组治疗前后心脏功能和心室重构的变化。结果:与对照组相比,治疗后研究组的左室舒张末期内径缩小,左室射血分数增高,6 min步行距离延长,静

  17. Pupal remodeling and the evolution and development of alternative male morphologies in horned beetles

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    Moczek Armin P

    2007-08-01

    Full Text Available Abstract Background How novel morphological traits originate and diversify represents a major frontier in evolutionary biology. Horned beetles are emerging as an increasingly popular model system to explore the genetic, developmental, and ecological mechanisms, as well as the interplay between them, in the genesis of novelty and diversity. The horns of beetles originate during a rapid growth phase during the prepupal stage of larval development. Differential growth during this period is either implicitly or explicitly assumed to be the sole mechanism underlying differences in horn expression within and between species. Here I focus on male horn dimorphisms, a phenomenon at the center of many studies in behavioral ecology and evolutionary development, and quantify the relative contributions of a previously ignored developmental process, pupal remodeling, to the expression of male dimorphism in three horned beetle species. Results Prepupal growth is not the only determinant of differences in male horn expression. Instead, following their initial prepupal growth phase, beetles may be extensively remodeled during the subsequent pupal stage in a sex and size-dependent manner. Specifically, male dimorphism in the three Onthophagus species studied here was shaped not at all, partly or entirely by such pupal remodeling rather than differential growth, suggesting that pupal remodeling is phylogenetically widespread, evolutionarily labile, and developmentally flexible. Conclusion This study is the first to document that male dimorphism in horned beetles is the product of two developmentaly dissociated processes: prepupal growth and pupal remodeling. More generally, adult morphology alone appears to provide few clues, if any, as to the relative contributions of both processes to the expression of alternative male morphs, underscoring the importance of developmental studies in efforts aimed at understanding the evolution of adult diversity patterns.

  18. Attenuation of salt-induced cardiac remodeling and diastolic dysfunction by the GPER agonist G-1 in female mRen2.Lewis rats.

    Directory of Open Access Journals (Sweden)

    Jewell A Jessup

    Full Text Available INTRODUCTION: The G protein-coupled estrogen receptor (GPER is expressed in various tissues including the heart. Since the mRen2.Lewis strain exhibits salt-dependent hypertension and early diastolic dysfunction, we assessed the effects of the GPER agonist (G-1, 40 nmol/kg/hr for 14 days or vehicle (VEH, DMSO/EtOH on cardiac function and structure. METHODS: Intact female mRen2.Lewis rats were fed a normal salt (0.5% sodium; NS diet or a high salt (4% sodium; HS diet for 10 weeks beginning at 5 weeks of age. RESULTS: Prolonged intake of HS in mRen2.Lewis females resulted in significantly increased blood pressure, mildly reduced systolic function, and left ventricular (LV diastolic compliance (as signified by a reduced E deceleration time and E deceleration slope, increased relative wall thickness, myocyte size, and mid-myocardial interstitial and perivascular fibrosis. G-1 administration attenuated wall thickness and myocyte hypertrophy, with nominal effects on blood pressure, LV systolic function, LV compliance and cardiac fibrosis in the HS group. G-1 treatment significantly increased LV lusitropy [early mitral annular descent (e'] independent of prevailing salt, and improved the e'/a' ratio in HS versus NS rats (P<0.05 as determined by tissue Doppler. CONCLUSION: Activation of GPER improved myocardial relaxation in the hypertensive female mRen2.Lewis rat and reduced cardiac myocyte hypertrophy and wall thickness in those rats fed a high salt diet. Moreover, these advantageous effects of the GPER agonist on ventricular lusitropy and remodeling do not appear to be associated with overt changes in blood pressure.

  19. The Relationship among Carotid Artery Remodeling, Cardiac Geometry, and Serum N-Terminal Pro-B-Type Natriuretic Peptide Level in Asymptomatic Asians: Sex-Differences and Longitudinal GEE Study.

    Directory of Open Access Journals (Sweden)

    Chen-Yen Chien

    Full Text Available Carotid artery remodeling is known to be associated with a variety of cardiovascular diseases. However, there is limited information regarding gender differences in carotid remodeling. We sought to investigate the associations among blood pressure (BP, carotid artery remodeling and cardiac geometries, and further explore gender differences.In a large cohort of asymptomatic adults undergoing routine health screening with repeated observations, we related measures of carotid artery diameter (CCAD to various BP components, cardiac geometries and blood N-terminal pro-brain natriuretic peptide (NT-proBNP level, both from baseline cross-sectional and longitudinal dataset using generalized estimating equations (GEE.A total of 2,914 person-visits (baseline: n=998, mean age: 47 ± 8.9 years, 34% female were studied (median: 6 ± 1.73 years follow up. We observed that CCAD was larger in men (p=300pg/mL; AUROC: 0.79, CCAD cut-off: 7.95mm, all p<0.05, which remained significant in multi-variate and longitudinal models. There was a prominent sex interaction (p for interaction with age and systolic BP: 0.004 and 0.028 respectively, where the longitudinal associations of age and systolic BP with increasing CCAD as more pronounced in women than men.These data demonstrated that carotid artery remodeling may parallel subclinical biomarker of cardiac dysfunction, and further showed greater effects of aging and higher blood pressure on such remodeling process in women than men. Further study is warranted to understand how this predisposition of elderly hypertensive women to vascular remodeling may play a role in clinical settings.

  20. Development of a postgraduate interventional cardiac nursing curriculum.

    Science.gov (United States)

    Currey, Judy; White, Kevin; Rolley, John; Oldland, Elizabeth; Driscoll, Andrea

    2015-11-01

    Interventional cardiology practices have advanced immensely in the last two decades, but the educational preparation of the workforce in cardiac catheter laboratories has not seen commensurate changes. Although on-the-job training has sufficed in the past, recognition of this workforce as a specialty practice domain now demands specialist educational preparation. The aim of this paper is to present the development of an interventional cardiac nursing curriculum nested within a Master of Nursing Practice in Australia. International and national health educational principles, teaching and learning theories and professional frameworks and philosophies are foundational to the program designed for interventional cardiac specialist nurses. These broader health, educational and professional underpinnings will be described to illustrate their application to the program's theoretical and clinical components. Situating interventional cardiac nursing within a Master's degree program at University provides nurses with the opportunities to develop high level critical thinking and problem solving knowledge and skills.

  1. Chromosome remodeling and differentiation of tetraploid embryos during preimplantation development.

    Science.gov (United States)

    Park, Mi-Ryung; Lee, Ah-Reum; Bui, Hong-Thuy; Park, Chankyu; Park, Keun-Kyu; Cho, Ssang-Goo; Song, Hyuk; Kim, Jae-Hwan; Nguyen, Van Thuan; Kim, Jin-Hoi

    2011-07-01

    Although it is known that the tetraploid embryo contributes only to the placenta, the question of why tetraploid embryos differentiate into placenta remains unclear. To study the effect of electrofusion on the development of mouse tetraploid oocytes, mouse two-cell embryos were fused and cultured in vitro in Chatot-Ziomek-Bavister medium. After electrofusion, two chromosome sets from the tetraploid blastomere were individually duplicated before nuclear fusion. At 8-10 hr after electrofusion, each chromosome set was condensing and the nuclear membrane was breaking down. Around 12-14 hr after electrofusion, the two chromosome sets had combined together and had reached the second mitotic metaphase, at this point with 8n sets of chromosomes. Interestingly, we discovered that expression of OCT4, an inner cell mass cells biomarker, is lost by the tetraploid expanded blastocysts, but that CDX2, a trophectoderm cells biomarker, is strongly expressed at this stage. This observation provides evidence clarifying why tetraploid embryos contribute only to trophectoderm.

  2. Cardiac remodeling as a consequence of atrial fibrillation: An anatomical study of perfusion-fixed human heart specimens

    Institute of Scientific and Technical Information of China (English)

    Christopher D Rolfes; Stephen A Howard; Ryan P Goff; Paul A Iaizzo

    2011-01-01

    Background Atrial fibrillation(AF)causes a continuum of atrial anatomical remodeling.Methods Using a library of perfusion-fixed human hearts,specimens with AF were compared to controls.During this preliminary assessment study,direct measurements were taken of atrial volume,pulmonary vein(PV)circumference,and left atrial(LA)wall thicknesses.Results Hearts with AF typically had larger atrial volumes,as well as a much larger variation in volume compared to controls(range of 59.6-227.1 mL in AF hearts compared to 65.1-115.9 mL in controls).For all hearts,right PVs were larger than left PVs(mean: 171.4±84.6 mm' for right and 118.2±50.1 mm2 for left P<0.005).LA wall thicknesses ranged from 0.7 mm to 3.1 min for both AF and control hearts.Conclusions Hearts with AF had a large range of sizes which is consistent with the progression of atrial remodeling during AF.The large range of thicknesses will influence the amount of energy needed to create transmural lesions during ablation procedures.

  3. microRNAs and Cardiovascular Remodeling.

    Science.gov (United States)

    Ono, Koh

    2015-01-01

    Heart failure (HF) is associated with significant morbidity and mortality attributable largely to structural changes in the heart and with associated cardiac dysfunction. Remodeling is defined as alteration of the mass, dimensions, or shape of the heart (termed cardiac or ventricular remodeling) and vessels (vascular remodeling) in response to hemodynamic load and/or cardiovascular injury in association with neurohormonal activation. Remodeling may be described as physiologic or pathologic; alternatively, remodeling may be classified as adaptive or maladaptive. The importance of remodeling as a pathogenic mechanism has been controversial because factors leading to remodeling as well as the remodeling itself may be major determinants of patients' prognosis. The basic mechanisms of cardiovascular remodeling, and especially the roles of microRNAs in HF progression and vascular diseases, will be reviewed here.

  4. Overlapping Cardiac Programs in Heart Development and Regeneration

    Institute of Scientific and Technical Information of China (English)

    Yi-Song Zhen; Qing Wu; Cheng-Lu Xiao; Nan-Nan Chang; Xu Wang; Lei Lei; Xiaojun Zhu; Jing-Wei Xiong

    2012-01-01

    Gaining cellular and molecular insights into heart development and regeneration will likely provide new therapeutic targets and opportunities for cardiac regenerative medicine,one of the most urgent clinical needs for heart failure.Here we present a review on zebrafish heart development and regeneration,with a particular focus on early cardiac progenitor development and their contribution to building embryonic heart,as well as cellular and molecular programs in adult zebrafish heart regeneration.We attempt to emphasize that the signaling pathways shaping cardiac progenitors in heart development may also be redeployed during the progress of adult heart regeneration.A brief perspective highlights several important and promising research areas in this exciting field.

  5. SR-targeted CaMKII inhibition improves SR Ca2+ handling, but accelerates cardiac remodeling in mice overexpressing CaMKIIδC

    OpenAIRE

    Huke, Sabine; DeSantiago, Jaime; Kaetzel, Marcia A.; Mishra, Shikha; Brown, Joan H.; Dedman, John R.; Bers, Donald M.

    2010-01-01

    Cardiac myocyte overexpression of CaMKIIδC leads to cardiac hypertrophy and heart failure (HF) possibly caused by altered myocyte Ca2+ handling. A central defect might be the marked CaMKII-induced increase in diastolic sarcoplasmic reticulum (SR) Ca2+ leak which decreases SR Ca2+ load and Ca2+ transient amplitude. We hypothesized that inhibition of CaMKII near the SR membrane would decrease the leak, improve Ca2+ handling and prevent the development of contractile dysfunction and HF. To test ...

  6. Onset of hypertension during pregnancy is associated with long-term worse blood pressure control and adverse cardiac remodeling.

    Science.gov (United States)

    Mesquita, Roberto F; Reis, Muriel; Beppler, Ana Paula; Bellinazzi, Vera Regina; Mattos, Sandra S; Lima-Filho, José L; Cipolli, José A; Coelho-Filho, Otavio R; Pio-Magalhães, José A; Sposito, Andrei C; Matos-Souza, José R; Nadruz, Wilson

    2014-11-01

    Up to 20% of women with hypertensive pregnancy disorders might persist with chronic hypertension. This study compared clinical and echocardiographic features between women whose hypertension began as hypertensive pregnancy disorders (PH group) and women whose diagnosis of hypertension did not occur during pregnancy (NPH group). Fifty PH and 100 NPH women were cross-sectionally evaluated by clinical, laboratory, and echocardiography analysis, and the groups were matched by duration of hypertension. PH exhibited lower age (46.6 ± 1.4 vs. 65.3 ± 1.1 years; P < .001), but higher systolic (159.8 ± 3.9 vs. 148.0 ± 2.5 mm Hg; P = .009) and diastolic (97.1 ± 2.4 vs. 80.9 ± 1.3 mm Hg; P < .001) blood pressure than NPH, although used more antihypertensive classes (3.4 ± 0.2 vs. 2.6 ± 0.1; P < .001). Furthermore, PH showed higher left ventricular wall thickness and increased prevalence of concentric hypertrophy than NPH after adjusting for age and blood pressure. In conclusion, this study showed that PH may exhibit worse blood pressure control and adverse left ventricular remodeling compared with NPH.

  7. Improvement of cardiac function and reversal of gap junction remodeling by Neuregulin-1β in volume-overloaded rats with heart failure

    Institute of Scientific and Technical Information of China (English)

    Xue-Hui Wang; Xiao-Zhen Zhuo; Ya-Juan Ni; Min Gong; Ting-Zhong Wang; Qun Lu; Ai-Qun Ma

    2012-01-01

    Objective We performed experiments using Neuregulin-1β (NRG-1β) treatment to determine a mechanism for the protective role derived from its beneficial effects by remodeling gap junctions (GJs) during heart failure (HF). Methods Rat models of HF were established by aortocaval fistula. Forty-eight rats were divided randomly into the HF (HF, n = 16), NRG-1β treatment (NRG, n = 16), and sham operation (S, n = 16) group. The rats in the NRG group were administered NRG-1β (10 μg/kg per day) for 7 days via the tail vein, whereas the other groups were injected with the same doses of saline. Twelve weeks after operation, Connexin 43 (Cx43) expression in single myocytes obtained from the left ventricle was determined by immunocytochemistry. Total protein was extracted from frozen left ventricular tissues for immunoblotting assay, and the ultrastructure of myocytes was observed by transmission electron microscopy. Results Compared with the HF group, the cardiac function of rats in the NRG group was markedly improved, irregular distribution and deceased Cx43 expression were relieved. The ultrastructure of myocytes was seriously damaged in HF rats, and NRG-1β reduced these pathological damages. Conclusions Short-term NRG-1β treatment can rescue pump failure in experimental models of volume overload-induced HF, which is related to the recovery of GJs structure and the improvement of Cx43 expression.

  8. 心脏重构中微 RNA 的作用%The Role of MicroRNAs in the Cardiac Remodeling

    Institute of Scientific and Technical Information of China (English)

    李歆跃(综述); 杨巍(审校)

    2015-01-01

    心脏重构是各类心血管疾病的重要进程之一,包括心肌梗死、瓣膜疾病、心肌炎、扩张型心肌病、心房颤动和心力衰竭等。多项研究发现,微 RNA( miRNA)与此过程息息相关,并且在体内和体外实验模型中都证实了 miRNA 广泛地参与此进程。临床上,miRNA 已作为潜在的诊断指标和治疗靶点被重视。该文就近年的热点及被重点研究的几种 miRNA 进行综述。%Cardiac remodeling is the key process in cardiovascular diseases including myocardial infarc-tion,valvular disease,myocarditis,dilated cardiomyopathy,atrial fibrillation and heart failure.Both in vitro and vivo models have proved that microRNAs play an important role in a wide range of processes.Clinically, miRNAs have been attached much attention as the potential diagnostic biomarkers and novel therapeutic tar-get recently.Here is to make a review of the focal points and mostly studied miRNA in the recent years.

  9. Diverse functions of ATP-dependent chromatin remodeling complexes in development and cancer

    Institute of Scientific and Technical Information of China (English)

    Jiang I. Wu

    2012-01-01

    Mammalian SWI/SNF like Brg1/Brm associated factors (BAF) chromatin-remodeling complexes are able to use energy derived from adenosine triphosphate (ATP) hydrolysis to change chromatin structures and regulate nuclear processes such as transcription.BAF complexes contain multiple subunits and the diverse subunit compositions provide functional specificities to BAF complexes.In this review,we summarize the functions of BAF subunits during mammalian development and in progression of various cancers.The mechanisms underlying the functional diversity and specificities of BAF complexes will be discussed.

  10. Assessment of cardiac remodeling in asymptomatic mitral regurgitation for surgery timing: a comparative study of echocardiography and magnetic resonance imaging

    Directory of Open Access Journals (Sweden)

    Ozdogan Oner

    2010-08-01

    Full Text Available Abstract Background Early surgery is recommended for asymptomatic severe mitral regurgitation (MR, because of increased postoperative left ventricular (LV dysfunction in patients with late surgery. On the other hand, recent reports emphasized a "watchful waiting" process for the determination of the proper time of mitral valve surgery. In our study, we compared magnetic resonance imaging (MRI and transthoracic echocardiography to evaluate the LV and left atrial (LA remodeling; for better definitions of patients that may benefit from early valve surgery. Methods Twenty-one patients with moderate to severe asymptomatic MR were evaluated by echocardiography and MRI. LA and LV ejection fractions (EFs were calculated by echocardiography and MRI. Pulmonary veins (PVs were measured from vein orifices in diastole and systole from the tangential of an imaginary circle that completed LA wall. Right upper PV indices were calculated with the formula; (Right upper PV diastolic diameter- Right upper PV systolic diameter/Right upper PV diastolic diameter. Results In 9 patients there were mismatches between echocardiography and MRI measurements of LV EF. LV EFs were calculated ≥60% by echocardiography, meanwhile 0.05. However, both right upper PV indices (0.16 ± 0.06 vs. 0.24 ± 0.08, p: 0.024 and LA EFs (0.19 ± 0.09 vs. 0.33 ± 0.14, p: 0.025 were significantly decreased in patients with depressed EFs when compared to patients with normal EFs. Conclusions MRI might be preferred when small changes in functional parameters like LV EF, LA EF, and PV index are of clinical importance to disease management like asymptomatic MR patients that we follow up for appropriate surgery timing.

  11. Embryonic Stem Cell-Derived Cardiomyocyte Heterogeneity and the Isolation of Immature and Committed Cells for Cardiac Remodeling and Regeneration

    Directory of Open Access Journals (Sweden)

    Kenneth R. Boheler

    2011-01-01

    Full Text Available Pluripotent stem cells represent one promising source for cell replacement therapy in heart, but differentiating embryonic stem cell-derived cardiomyocytes (ESC-CMs are highly heterogeneous and show a variety of maturation states. In this study, we employed an ESC clonal line that contains a cardiac-restricted ncx1 promoter-driven puromycin resistance cassette together with a mass culture system to isolate ESC-CMs that display traits characteristic of very immature CMs. The cells display properties of proliferation, CM-restricted markers, reduced mitochondrial mass, and hypoxia-resistance. Following transplantation into rodent hearts, bioluminescence imaging revealed that immature cells, but not more mature CMs, survived for at least one month following injection. These data and comparisons with more mature cells lead us to conclude that immature hypoxia resistant ESC-CMs can be isolated in mass in vitro and, following injection into heart, form grafts that may mediate long-term recovery of global and regional myocardial contractile function following infarction.

  12. The chromatin remodeling factor CHD7 controls cerebellar development by regulating reelin expression

    Science.gov (United States)

    Whittaker, Danielle E.; Riegman, Kimberley L.H.; Kasah, Sahrunizam; Mohan, Conor; Yu, Tian; Sala, Blanca Pijuan; Hebaishi, Husam; Caruso, Angela; Marques, Ana Claudia; Michetti, Caterina; Smachetti, María Eugenia Sanz; Shah, Apar; Sabbioni, Mara; Kulhanci, Omer; Tee, Wee-Wei; Reinberg, Danny; Scattoni, Maria Luisa; McGonnell, Imelda; Wardle, Fiona C.; Fernandes, Cathy

    2017-01-01

    The mechanisms underlying the neurodevelopmental deficits associated with CHARGE syndrome, which include cerebellar hypoplasia, developmental delay, coordination problems, and autistic features, have not been identified. CHARGE syndrome has been associated with mutations in the gene encoding the ATP-dependent chromatin remodeler CHD7. CHD7 is expressed in neural stem and progenitor cells, but its role in neurogenesis during brain development remains unknown. Here we have shown that deletion of Chd7 from cerebellar granule cell progenitors (GCps) results in reduced GCp proliferation, cerebellar hypoplasia, developmental delay, and motor deficits in mice. Genome-wide expression profiling revealed downregulated expression of the gene encoding the glycoprotein reelin (Reln) in Chd7-deficient GCps. Recessive RELN mutations have been associated with severe cerebellar hypoplasia in humans. We found molecular and genetic evidence that reductions in Reln expression contribute to GCp proliferative defects and cerebellar hypoplasia in GCp-specific Chd7 mouse mutants. Finally, we showed that CHD7 is necessary for maintaining an open, accessible chromatin state at the Reln locus. Taken together, this study shows that Reln gene expression is regulated by chromatin remodeling, identifies CHD7 as a previously unrecognized upstream regulator of Reln, and provides direct in vivo evidence that a mammalian CHD protein can control brain development by modulating chromatin accessibility in neuronal progenitors. PMID:28165338

  13. The Scaffold Protein Muscle A-Kinase Anchoring Protein β Orchestrates Cardiac Myocyte Hypertrophic Signaling Required for the Development of Heart Failure

    Science.gov (United States)

    Kritzer, Michael D.; Li, Jinliang; Passariello, Catherine L.; Gayanilo, Marjorie; Thakur, Hrishikesh; Dayan, Joseph; Dodge-Kafka, Kimberly; Kapiloff, Michael S.

    2014-01-01

    Background Cardiac myocyte hypertrophy is regulated by an extensive intracellular signal transduction network. In vitro evidence suggests that the scaffold protein muscle A-kinase anchoring protein β (mAKAPβ) serves as a nodal organizer of hypertrophic signaling. However, the relevance of mAKAPβ signalosomes to pathological remodeling and heart failure in vivo remains unknown. Methods and Results Using conditional, cardiac myocyte–specific gene deletion, we now demonstrate that mAKAPβ expression in mice is important for the cardiac hypertrophy induced by pressure overload and catecholamine toxicity. mAKAPβ targeting prevented the development of heart failure associated with long-term transverse aortic constriction, conferring a survival benefit. In contrast to 29% of control mice (n=24), only 6% of mAKAPβ knockout mice (n=31) died in the 16 weeks of pressure overload (P=0.02). Accordingly, mAKAPβ knockout inhibited myocardial apoptosis and the development of interstitial fibrosis, left atrial hypertrophy, and pulmonary edema. This improvement in cardiac status correlated with the attenuated activation of signaling pathways coordinated by the mAKAPβ scaffold, including the decreased phosphorylation of protein kinase D1 and histone deacetylase 4 that we reveal to participate in a new mAKAP signaling module. Furthermore, mAKAPβ knockout inhibited pathological gene expression directed by myocyte-enhancer factor-2 and nuclear factor of activated T-cell transcription factors that associate with the scaffold. Conclusions mAKAPβ orchestrates signaling that regulates pathological cardiac remodeling in mice. Targeting of the underlying physical architecture of signaling networks, including mAKAPβ signalosome formation, may constitute an effective therapeutic strategy for the prevention and treatment of pathological remodeling and heart failure. PMID:24812305

  14. Development of the cardiac conduction system and cardiac anatomy in relation to genesis and treatment of arrhythmias

    NARCIS (Netherlands)

    Jongbloed, Monica Reina Maria

    2006-01-01

    Clinical mapping studies demonstrate that cardiac arrhythmias are often encountered at specific anatomical sites. The anatomical development of the heart and the cardiac conduction system are narrowly related. The thesis starts with a Chapter 1 that provides a general overview of the basics of cardi

  15. Roles of FGFs as Adipokines in Adipose Tissue Development, Remodeling, and Metabolism.

    Science.gov (United States)

    Ohta, Hiroya; Itoh, Nobuyuki

    2014-01-01

    White and brown adipose tissues (BATs), which store and burn lipids, respectively, play critical roles in energy homeostasis. Fibroblast growth factors (FGFs) are signaling proteins with diverse functions in development, metabolism, and neural function. Among 22 FGFs, FGF1, FGF10, and FGF21 play roles as adipokines, adipocyte-secreted proteins, in the development and function of white and BATs. FGF1 is a critical transducer in white adipose tissue (WAT) remodeling. The peroxisome proliferator-activated receptor γ-FGF1 axis is critical for energy homeostasis. FGF10 is essential for embryonic white adipocyte development. FGF21 activates BAT in response to cold exposure. FGF21 also stimulates the accumulation of brown-like cells in WAT during cold exposure and is an upstream effector of adiponectin, which controls systemic energy metabolism. These findings provide new insights into the roles of FGF signaling in white and BATs and potential therapeutic strategies for metabolic disorders.

  16. Deletion of Pr130 Interrupts Cardiac Development in Zebrafish

    Directory of Open Access Journals (Sweden)

    Jie Yang

    2016-11-01

    Full Text Available Protein phosphatase 2 regulatory subunit B, alpha (PPP2R3A, a regulatory subunit of protein phosphatase 2A (PP2A, is a major serine/threonine phosphatase that regulates crucial function in development and growth. Previous research has implied that PPP2R3A was involved in heart failure, and PR130, the largest transcription of PPP2R3A, functioning in the calcium release of sarcoplasmic reticulum (SR, plays an important role in the excitation-contraction (EC coupling. To obtain a better understanding of PR130 functions in myocardium and cardiac development, two pr130-deletion zebrafish lines were generated using clustered regularly interspaced short palindromic repeats (CRISPR/CRISPR-associated proteins (Cas system. Pr130-knockout zebrafish exhibited cardiac looping defects and decreased cardiac function (decreased fractional area and fractional shortening. Hematoxylin and eosin (H&E staining demonstrated reduced cardiomyocytes. Subsequent transmission electron microscopy revealed that the bright and dark bands were narrowed and blurred, the Z- and M-lines were fogged, and the gaps between longitudinal myocardial fibers were increased. Additionally, increased apoptosis was observed in cardiomyocyte in pr130-knockout zebrafish compared to wild-type (WT. Taken together, our results suggest that pr130 is required for normal myocardium formation and efficient cardiac contractile function.

  17. Deletion of Pr130 Interrupts Cardiac Development in Zebrafish

    Science.gov (United States)

    Yang, Jie; Li, Zuhua; Gan, Xuedong; Zhai, Gang; Gao, Jiajia; Xiong, Chenling; Qiu, Xueping; Wang, Xuebin; Yin, Zhan; Zheng, Fang

    2016-01-01

    Protein phosphatase 2 regulatory subunit B, alpha (PPP2R3A), a regulatory subunit of protein phosphatase 2A (PP2A), is a major serine/threonine phosphatase that regulates crucial function in development and growth. Previous research has implied that PPP2R3A was involved in heart failure, and PR130, the largest transcription of PPP2R3A, functioning in the calcium release of sarcoplasmic reticulum (SR), plays an important role in the excitation-contraction (EC) coupling. To obtain a better understanding of PR130 functions in myocardium and cardiac development, two pr130-deletion zebrafish lines were generated using clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated proteins (Cas) system. Pr130-knockout zebrafish exhibited cardiac looping defects and decreased cardiac function (decreased fractional area and fractional shortening). Hematoxylin and eosin (H&E) staining demonstrated reduced cardiomyocytes. Subsequent transmission electron microscopy revealed that the bright and dark bands were narrowed and blurred, the Z- and M-lines were fogged, and the gaps between longitudinal myocardial fibers were increased. Additionally, increased apoptosis was observed in cardiomyocyte in pr130-knockout zebrafish compared to wild-type (WT). Taken together, our results suggest that pr130 is required for normal myocardium formation and efficient cardiac contractile function. PMID:27845735

  18. A case of right renal infarction and subcapsular hematoma that simultaneously developed after cardiac angiography.

    Science.gov (United States)

    Kwon, S H; Cho, H C; Lee, S W; Kim, D Y; Joo, W C; Lee, W H; Song, J H; Kim, M-J

    2009-01-01

    Of the several complications known to develop after cardiac catheterization, simultaneous acute renal infarction and renal subcapsular hematoma is rare. Here, the authors report a case of acute renal infarction with subcapsular hematoma that developed 4 hours after cardiac catheterization.

  19. Study Development of the Cardiac Computer Simulations

    Institute of Scientific and Technical Information of China (English)

    VOLKERHellemanns; ZHANGHong; SEKOUSingare; ZHANGZhen-xi; KONGXiang-yun

    2004-01-01

    The technique of computer simulations is a very efficient method in investigating mechanisms of many diseases. This paper reviews how the simulations of the human heart started as a simple mathematical models in the past and developed to the point where genetic information is needed to do suitable work like finding out new medicaments against heart diseases. Also the Influence of the development of computer performance in the future as well as the data presentation is described.

  20. Autophagy is essential for cardiac morphogenesis during vertebrate development.

    Science.gov (United States)

    Lee, Eunmyong; Koo, Yeon; Ng, Aylwin; Wei, Yongjie; Luby-Phelps, Kate; Juraszek, Amy; Xavier, Ramnik J; Cleaver, Ondine; Levine, Beth; Amatruda, James F

    2014-04-01

    Genetic analyses indicate that autophagy, an evolutionarily conserved lysosomal degradation pathway, is essential for eukaryotic differentiation and development. However, little is known about whether autophagy contributes to morphogenesis during embryogenesis. To address this question, we examined the role of autophagy in the early development of zebrafish, a model organism for studying vertebrate tissue and organ morphogenesis. Using zebrafish that transgenically express the fluorescent autophagy reporter protein, GFP-LC3, we found that autophagy is active in multiple tissues, including the heart, during the embryonic period. Inhibition of autophagy by morpholino knockdown of essential autophagy genes (including atg5, atg7, and becn1) resulted in defects in morphogenesis, increased numbers of dead cells, abnormal heart structure, and reduced organismal survival. Further analyses of cardiac development in autophagy-deficient zebrafish revealed defects in cardiac looping, abnormal chamber morphology, aberrant valve development, and ectopic expression of critical transcription factors including foxn4, tbx5, and tbx2. Consistent with these results, Atg5-deficient mice displayed abnormal Tbx2 expression and defects in valve development and chamber septation. Thus, autophagy plays an essential, conserved role in cardiac morphogenesis during vertebrate development.

  1. Cardiac expression of ms1/STARS, a novel gene involved in cardiac development and disease, is regulated by GATA4.

    Science.gov (United States)

    Ounzain, Samir; Kobayashi, Satoru; Peterson, Richard E; He, Aibin; Motterle, Anna; Samani, Nilesh J; Menick, Donald R; Pu, William T; Liang, Qiangrong; Chong, Nelson W

    2012-05-01

    Ms1/STARS is a novel muscle-specific actin-binding protein that specifically modulates the myocardin-related transcription factor (MRTF)-serum response factor (SRF) regulatory axis within striated muscle. This ms1/STARS-dependent regulatory axis is of central importance within the cardiac gene regulatory network and has been implicated in cardiac development and postnatal cardiac function/homeostasis. The dysregulation of ms1/STARS is associated with and causative of pathological cardiac phenotypes, including cardiac hypertrophy and cardiomyopathy. In order to gain an understanding of the mechanisms governing ms1/STARS expression in the heart, we have coupled a comparative genomic in silico analysis with reporter, gain-of-function, and loss-of-function approaches. Through this integrated analysis, we have identified three evolutionarily conserved regions (ECRs), α, SINA, and DINA, that act as cis-regulatory modules and confer differential cardiac cell-specific activity. Two of these ECRs, α and DINA, displayed distinct regulatory sensitivity to the core cardiac transcription factor GATA4. Overall, our results demonstrate that within embryonic, neonatal, and adult hearts, GATA4 represses ms1/STARS expression with the pathologically associated depletion of GATA4 (type 1/type 2 diabetic models), resulting in ms1/STARS upregulation. This GATA4-dependent repression of ms1/STARS expression has major implications for MRTF-SRF signaling in the context of cardiac development and disease.

  2. Development of the lateral line canal system through a bone remodeling process in zebrafish.

    Science.gov (United States)

    Wada, Hironori; Iwasaki, Miki; Kawakami, Koichi

    2014-08-01

    The lateral line system of teleost fish is composed of mechanosensory receptors (neuromasts), comprising superficial receptors and others embedded in canals running under the skin. Canal diameter and size of the canal neuromasts are correlated with increasing body size, thus providing a very simple system to investigate mechanisms underlying the coordination between organ growth and body size. Here, we examine the development of the trunk lateral line canal system in zebrafish. We demonstrated that trunk canals originate from scales through a bone remodeling process, which we suggest is essential for the normal growth of canals and canal neuromasts. Moreover, we found that lateral line cells are required for the formation of canals, suggesting the existence of mutual interactions between the sensory system and surrounding connective tissues.

  3. MT1-MMP-mediated basement membrane remodeling modulates renal development

    Energy Technology Data Exchange (ETDEWEB)

    Riggins, Karen S.; Mernaugh, Glenda [Department of Cancer Biology, Vanderbilt University Medical Center, Nashville, TN 37232 (United States); Su, Yan; Quaranta, Vito [Division of Nephrology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN 37232 (United States); Koshikawa, Naohiko; Seiki, Motoharu [Division of Cancer Cell Research, Institute of Medical Science, The University of Tokyo, Shirokanedai, Minato-ku, Tokyo 108-8639 (Japan); Pozzi, Ambra [Division of Nephrology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN 37232 (United States); Department of Cancer Biology, Vanderbilt University Medical Center, Nashville, TN 37232 (United States); Department of Research Medicine, Veterans Affairs Hospital, Nashville, TN 37232 (United States); Zent, Roy, E-mail: roy.zent@vanderbilt.edu [Division of Nephrology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN 37232 (United States); Department of Cancer Biology, Vanderbilt University Medical Center, Nashville, TN 37232 (United States); Department of Cell and Developmental Biology, Vanderbilt University Medical Center, Nashville, TN 37232 (United States); Department of Research Medicine, Veterans Affairs Hospital, Nashville, TN 37232 (United States)

    2010-10-15

    Extracellular matrix (ECM) remodeling regulates multiple cellular functions required for normal development and tissue repair. Matrix metalloproteinases (MMPs) are key mediators of this process and membrane targeted MMPs (MT-MMPs) in particular have been shown to be important in normal development of specific organs. In this study we investigated the role of MT1-MMP in kidney development. We demonstrate that loss of MT1-MMP leads to a renal phenotype characterized by a moderate decrease in ureteric bud branching morphogenesis and a severe proliferation defect. The kidneys of MT1-MMP-null mice have increased deposition of collagen IV, laminins, perlecan, and nidogen and the phenotype is independent of the MT-1MMP target, MMP-2. Utilizing in vitro systems we demonstrated that MTI-MMP proteolytic activity is required for renal tubule cells to proliferate in three dimensional matrices and to migrate on collagen IV and laminins. Together these data suggest an important role for MT1-MMP in kidney development, which is mediated by its ability to regulate cell proliferation and migration by proteolytically cleaving kidney basement membrane components.

  4. SWI/SNF Protein Component BAF250a Regulates Cardiac Progenitor Cell Differentiation by Modulating Chromatin Accessibility during Second Heart Field Development*

    Science.gov (United States)

    Lei, Ienglam; Gao, Xiaolin; Sham, Mai Har; Wang, Zhong

    2012-01-01

    ATP-dependent SWI/SNF chromatin remodeling complexes alter the structure of chromatin at specific loci and facilitate tissue-specific gene regulation during development. Several SWI/SNF subunits are required for cardiogenesis. However, the function and mechanisms of SWI/SNF in mediating cardiac progenitor cell (CPC) differentiation during cardiogenesis are not well understood. Our studies of the SWI/SNF chromatin remodeling complex identified that BAF250a, a regulatory subunit of the SWI/SNF, plays a key role in CPC differentiation. BAF250a ablation in mouse second heart field (SHF) led to trabeculation defects in the right ventricle, ventricular septal defect, persistent truncus arteriosus, reduced myocardial proliferation, and embryonic lethality around E13. Using an embryonic stem cell culture system that models the formation and differentiation of SHF CPCs in vivo, we have shown that BAF250a ablation in CPCs specifically inhibits cardiomyocyte formation. Moreover, BAF250a selectively regulates the expression of key cardiac factors Mef2c, Nkx2.5, and Bmp10 in SHF CPCs. Chromatin immunoprecipitation and DNase I digestion assays indicate that BAF250a regulates gene expression by binding selectively to its target gene promoters and recruiting Brg1, the catalytic subunit of SWI/SNF, to modulate chromatin accessibility. Our results thus identify BAF250a-mediated chromatin remodeling as an essential epigenetic mechanism mediating CPC differentiation. PMID:22621927

  5. SWI/SNF protein component BAF250a regulates cardiac progenitor cell differentiation by modulating chromatin accessibility during second heart field development.

    Science.gov (United States)

    Lei, Ienglam; Gao, Xiaolin; Sham, Mai Har; Wang, Zhong

    2012-07-13

    ATP-dependent SWI/SNF chromatin remodeling complexes alter the structure of chromatin at specific loci and facilitate tissue-specific gene regulation during development. Several SWI/SNF subunits are required for cardiogenesis. However, the function and mechanisms of SWI/SNF in mediating cardiac progenitor cell (CPC) differentiation during cardiogenesis are not well understood. Our studies of the SWI/SNF chromatin remodeling complex identified that BAF250a, a regulatory subunit of the SWI/SNF, plays a key role in CPC differentiation. BAF250a ablation in mouse second heart field (SHF) led to trabeculation defects in the right ventricle, ventricular septal defect, persistent truncus arteriosus, reduced myocardial proliferation, and embryonic lethality around E13. Using an embryonic stem cell culture system that models the formation and differentiation of SHF CPCs in vivo, we have shown that BAF250a ablation in CPCs specifically inhibits cardiomyocyte formation. Moreover, BAF250a selectively regulates the expression of key cardiac factors Mef2c, Nkx2.5, and Bmp10 in SHF CPCs. Chromatin immunoprecipitation and DNase I digestion assays indicate that BAF250a regulates gene expression by binding selectively to its target gene promoters and recruiting Brg1, the catalytic subunit of SWI/SNF, to modulate chromatin accessibility. Our results thus identify BAF250a-mediated chromatin remodeling as an essential epigenetic mechanism mediating CPC differentiation.

  6. Molecular mechanism of carvedilol in attenuating the reversion to fetal energy metabolism during cardiac hypertrophy development

    Institute of Scientific and Technical Information of China (English)

    胡琴; 李隆贵

    2003-01-01

    Objective: To explore the molecular regulation mechanism of carvedilol in attenuating the reversion back towards fetal energy metabolism during the development of cardiac hypertrophy induced by coarctation of abdominal aorta (CAA) in male Wistar rats. Methods: Hemodynamic and ventricular remodeling parameters, free fatty acid content in the serum were measured in the experimental animals at 16 weeks after the surgical CAA, the rats receiving carvedilol intervention (CAR) after CAA, and those with sham operation (SH). The expressions of muscle carnitine palmitoyltransferaseⅠ (M-CPTⅠ) and medium chain acyl-CoA dehydrogenase (MCAD) mRNA in the cardiac myocytes from every group were studied with RT-PCR. Results: Significant left ventricular hypertrophy were observed in the rats 16 weeks after coarctation operation (P<0.05), together with significant free fatty acids accumulation and downregulation of M-CPTⅠ and MCAD mRNA (P<0.05) in CAA group. Carvedilol at a dose of 30 mg/kg/d for 12 weeks inhibited the left ventricular hypertrophy induced by pressure overload and enhanced the gene expressions of rate-limiting enzyme (M-CPTⅠ) and key enzyme of fatty acid (MCAD) in the CAR group compared with CAA group (P<0.05). Conclusion: Pressure overload-induced hypertrophy in CAA rats causes the reversion back towards fetal enery metabolism, that is, downregulates the expressions of rate-limiting enzyme and key enzyme of fatty acid oxidation. The intervention therapy with carvedilol, a vasodilating alpha- and beta-adrenoreceptor antagonist, attenuates the reversion of the metabolic gene expression to fetal type through upregulating M-CPTⅠ and MCAD mRNA expressions. Thus, carvedilol may exert cardioprotective effects on heart failure by the mechanism of preserving the adult metabolic gene regulation.

  7. AKAP13 Rho-GEF and PKD-binding domain deficient mice develop normally but have an abnormal response to β-adrenergic-induced cardiac hypertrophy.

    Directory of Open Access Journals (Sweden)

    Matthew J Spindler

    Full Text Available BACKGROUND: A-kinase anchoring proteins (AKAPs are scaffolding molecules that coordinate and integrate G-protein signaling events to regulate development, physiology, and disease. One family member, AKAP13, encodes for multiple protein isoforms that contain binding sites for protein kinase A (PKA and D (PKD and an active Rho-guanine nucleotide exchange factor (Rho-GEF domain. In mice, AKAP13 is required for development as null embryos die by embryonic day 10.5 with cardiovascular phenotypes. Additionally, the AKAP13 Rho-GEF and PKD-binding domains mediate cardiomyocyte hypertrophy in cell culture. However, the requirements for the Rho-GEF and PKD-binding domains during development and cardiac hypertrophy are unknown. METHODOLOGY/PRINCIPAL FINDINGS: To determine if these AKAP13 protein domains are required for development, we used gene-trap events to create mutant mice that lacked the Rho-GEF and/or the protein kinase D-binding domains. Surprisingly, heterozygous matings produced mutant mice at Mendelian ratios that had normal viability and fertility. The adult mutant mice also had normal cardiac structure and electrocardiograms. To determine the role of these domains during β-adrenergic-induced cardiac hypertrophy, we stressed the mice with isoproterenol. We found that heart size was increased similarly in mice lacking the Rho-GEF and PKD-binding domains and wild-type controls. However, the mutant hearts had abnormal cardiac contractility as measured by fractional shortening and ejection fraction. CONCLUSIONS: These results indicate that the Rho-GEF and PKD-binding domains of AKAP13 are not required for mouse development, normal cardiac architecture, or β-adrenergic-induced cardiac hypertrophic remodeling. However, these domains regulate aspects of β-adrenergic-induced cardiac hypertrophy.

  8. Anterior Hox Genes in Cardiac Development and Great Artery Patterning

    Directory of Open Access Journals (Sweden)

    Brigitte Laforest

    2014-03-01

    Full Text Available During early development, the heart tube grows by progressive addition of progenitor cells to the arterial and venous poles. These cardiac progenitor cells, originally identified in 2001, are located in the splanchnic mesoderm in a region termed the second heart field (SHF. Since its discovery, our view of heart development has been refined and it is well established that perturbation in the addition of SHF cells results in a spectrum of congenital heart defects. We have previously shown that anterior Hox genes, including Hoxb1, Hoxa1 and Hoxa3, are expressed in distinct subdomains of the SHF that contribute to atrial and subpulmonary myocardium. It is well known that Hox proteins exert their function through interaction with members of the TALE family, including Pbx and Meis factors. The expression profile of Pbx and Meis factors overlaps with that of anterior Hox factors in the embryonic heart, and recent data suggest that they may interact together during cardiac development. This review aims to bring together recent findings in vertebrates that strongly suggest an important function for Hox, Pbx and Meis factors in heart development and disease.

  9. Structural remodeling and mechanical function in heart failure.

    Science.gov (United States)

    Leonard, Bridget Louise; Smaill, Bruce Henry; LeGrice, Ian John

    2012-02-01

    The cardiac extracellular matrix (ECM) is the three-dimensional scaffold that defines the geometry and muscular architecture of the cardiac chambers and transmits forces produced during the cardiac cycle throughout the heart wall. The cardiac ECM is an active system that responds to the stresses to which it is exposed and in the normal heart is adapted to facilitate efficient mechanical function. There are marked differences in the short- and medium-term changes in ventricular geometry and cardiac ECM that occur as a result of volume overload, hypertension, and ischemic cardiomyopathy. Despite this, there is a widespread view that a common remodeling "phenotype" governs the final progression to end-stage heart failure in different forms of heart disease. In this review article, we make the case that this interpretation is not consistent with the clinical and experimental data on the topic. We argue that there is a need for new theoretical and experimental models that will enable stresses acting on the ECM and resultant deformations to be estimated more accurately and provide better spatial resolution of local signaling mechanisms that are activated as a result. These developments are necessary to link the effects of structural remodeling with altered cardiac mechanical function.

  10. State-of-the-Art Pediatric Hypnosis Training: Remodeling Curriculum and Refining Faculty Development.

    Science.gov (United States)

    Kohen, Daniel P; Kaiser, Pamela; Olness, Karen

    2017-01-01

    Training in pediatric hypnosis has been part of clinical hypnosis education in the United States since 1976. Workshops expanded over time and are now taught by highly experienced pediatric clinicians across the globe. In 1987, a small vanguard of North American faculty, academic pediatricians, and pediatric psychologists taught a 3-day pediatric hypnosis workshop at the national meeting of the Society for Developmental and Behavioral Pediatrics (SDBP). This model of annual tri-level concurrent workshops (introductory, intermediate, and advanced) was sponsored by the SDBP for 24 years. In 2009, the National Pediatric Hypnosis Training Institute (NPHTI) assembled, and in 2010, offered its first annual workshops. This article documents this history of pediatric hypnosis education and describes NPHTI's remodeling and ongoing refinement toward a state-of-the-art curriculum with innovative methodology based upon (1) current research about adult experiential and small group learning; (2) design principles for presentations that maximize adult learning and memory; and (3) evaluations by participants and faculty. These underpinnings-including clinical training videos, individualized learning choices, emphasis on personalized, goal-oriented sessions, and advances in faculty selection, and ongoing development-are applicable to adult training models. Integration of developmental and self-regulation strategies may be more unique to pediatric hypnosis skills training programs. The conclusion proposes expansion of pediatric hypnosis education and elimination of related barriers toward goals that all children learn self-hypnosis (SH) for mind-body health.

  11. Developing cardiac and skeletal muscle share fast-skeletal myosin heavy chain and cardiac troponin-I expression.

    Directory of Open Access Journals (Sweden)

    Kelly C Clause

    Full Text Available Skeletal muscle derived stem cells (MDSCs transplanted into injured myocardium can differentiate into fast skeletal muscle specific myosin heavy chain (sk-fMHC and cardiac specific troponin-I (cTn-I positive cells sustaining recipient myocardial function. We have recently found that MDSCs differentiate into a cardiomyocyte phenotype within a three-dimensional gel bioreactor. It is generally accepted that terminally differentiated myocardium or skeletal muscle only express cTn-I or sk-fMHC, respectively. Studies have shown the presence of non-cardiac muscle proteins in the developing myocardium or cardiac proteins in pathological skeletal muscle. In the current study, we tested the hypothesis that normal developing myocardium and skeletal muscle transiently share both sk-fMHC and cTn-I proteins. Immunohistochemistry, western blot, and RT-PCR analyses were carried out in embryonic day 13 (ED13 and 20 (ED20, neonatal day 0 (ND0 and 4 (ND4, postnatal day 10 (PND10, and 8 week-old adult female Lewis rat ventricular myocardium and gastrocnemius muscle. Confocal laser microscopy revealed that sk-fMHC was expressed as a typical striated muscle pattern within ED13 ventricular myocardium, and the striated sk-fMHC expression was lost by ND4 and became negative in adult myocardium. cTn-I was not expressed as a typical striated muscle pattern throughout the myocardium until PND10. Western blot and RT-PCR analyses revealed that gene and protein expression patterns of cardiac and skeletal muscle transcription factors and sk-fMHC within ventricular myocardium and skeletal muscle were similar at ED20, and the expression patterns became cardiac or skeletal muscle specific during postnatal development. These findings provide new insight into cardiac muscle development and highlight previously unknown common developmental features of cardiac and skeletal muscle.

  12. 体外心脏震波治疗改善心肌梗死后心室重塑研究进展%Research Progress of Extracorporeal Cardiac Shock Wave Therapy Improving Ventricular Remodeling after Myocardial Infarction

    Institute of Scientific and Technical Information of China (English)

    陶四明; 王钰; 郭涛

    2009-01-01

    Ventricular remodeling after myocardial infarction is a pathophysiological process. It is one of the most important risk factors for long-term mortality. Some research has found that many factors participate in, and accelerate the occurance of, ventricular remodeling after myocardial infarction. It was discovered that low-energy extracorporeal shock wave therapy can improve and regulate the function of myocardium during necrosis and can reconstruct the collagen metabolic process. This article reviews the mechanism of ventricular remodeling after myocardial infarction, explains the biological effect of shock wave, and the status of clinical application of extracorporeal cardiac shock wave therapy with the intent of improving ventricular remodeling after myocardial infarction.%急性心肌梗死后左室重构是临床上常见的进行性发展的病理生理过程,是心肌梗死远期心脏性死亡最重要危险因素之一.研究发现有多重因素参与相互促进,共同维持心肌梗死后心室重塑的发生发展.研究发现低能量的体外震波治疗有多项机制调节参与改善和恢复坏死区休眠心肌细胞功能,重新建立胶原代谢平衡,终止和缓解心室重塑发展.现综述心肌梗死后心室重塑发生机制;阐述震波治疗的生物效应及体外心脏震波治疗改善心肌梗死后心室重塑的潜在机制及研究现状.

  13. CTGF knockout does not affect cardiac hypertrophy and fibrosis formation upon chronic pressure overload

    NARCIS (Netherlands)

    Fontes, Magda S C; Kessler, Elise L; van Stuijvenberg, Leonie; Brans, Maike A; Falke, LL; Kok, Bart; Leask, Andrew; van Rijen, HVM; Vos, MA; Goldschmeding, Roel; van Veen, AAB

    2015-01-01

    BACKGROUND: One of the main contributors to maladaptive cardiac remodeling is fibrosis. Connective tissue growth factor (CTGF), a matricellular protein that is secreted into the cardiac extracellular matrix by both cardiomyocytes and fibroblasts, is often associated with development of fibrosis. How

  14. Cell cycle regulation and cytoskeletal remodelling are critical processes in the nutritional programming of embryonic development.

    Directory of Open Access Journals (Sweden)

    Angelina Swali

    Full Text Available Many mechanisms purport to explain how nutritional signals during early development are manifested as disease in the adult offspring. While these describe processes leading from nutritional insult to development of the actual pathology, the initial underlying cause of the programming effect remains elusive. To establish the primary drivers of programming, this study aimed to capture embryonic gene and protein changes in the whole embryo at the time of nutritional insult rather than downstream phenotypic effects. By using a cross-over design of two well established models of maternal protein and iron restriction we aimed to identify putative common "gatekeepers" which may drive nutritional programming.Both protein and iron deficiency in utero reduced the nephron complement in adult male Wistar and Rowett Hooded Lister rats (P<0.05. This occurred in the absence of damage to the glomerular ultrastructure. Microarray, proteomic and pathway analyses identified diet-specific and strain-specific gatekeeper genes, proteins and processes which shared a common association with the regulation of the cell cycle, especially the G1/S and G2/M checkpoints, and cytoskeletal remodelling. A cell cycle-specific PCR array confirmed the down-regulation of cyclins with protein restriction and the up-regulation of apoptotic genes with iron deficiency.The timing and experimental design of this study have been carefully controlled to isolate the common molecular mechanisms which may initiate the sequelae of events involved in nutritional programming of embryonic development. We propose that despite differences in the individual genes and proteins affected in each strain and with each diet, the general response to nutrient deficiency in utero is perturbation of the cell cycle, at the level of interaction with the cytoskeleton and the mitotic checkpoints, thereby diminishing control over the integrity of DNA which is allowed to replicate. These findings offer novel

  15. Challenges and Current Efforts in the Development of Biomarkers for Chronic Inflammatory and Remodeling Conditions of the Lungs.

    Science.gov (United States)

    Grunig, Gabriele; Baghdassarian, Aram; Park, Sung-Hyun; Pylawka, Serhiy; Bleck, Bertram; Reibman, Joan; Berman-Rosenzweig, Erika; Durmus, Nedim

    2015-01-01

    This review discusses biomarkers that are being researched for their usefulness to phenotype chronic inflammatory lung diseases that cause remodeling of the lung's architecture. The review focuses on asthma, chronic obstructive pulmonary disease (COPD), and pulmonary hypertension. Bio-markers of environmental exposure and specific classes of biomarkers (noncoding RNA, metabolism, vitamin, coagulation, and microbiome related) are also discussed. Examples of biomarkers that are in clinical use, biomarkers that are under development, and biomarkers that are still in the research phase are discussed. We chose to present examples of the research in biomarker development by diseases, because asthma, COPD, and pulmonary hypertension are distinct entities, although they clearly share processes of inflammation and remodeling.

  16. Stage-dependent remodeling of the nuclear envelope and lamina during rabbit early embryonic development.

    Science.gov (United States)

    Popken, Jens; Schmid, Volker J; Strauss, Axel; Guengoer, Tuna; Wolf, Eckhard; Zakhartchenko, Valeri

    2016-04-22

    Utilizing 3D structured illumination microscopy, we investigated the quality and quantity of nuclear invaginations and the distribution of nuclear pores during rabbit early embryonic development and identified the exact time point of nucleoporin 153 (NUP153) association with chromatin during mitosis. Contrary to bovine early embryonic nuclei, featuring almost exclusively nuclear invaginations containing a small volume of cytoplasm, nuclei in rabbit early embryonic stages show additionally numerous invaginations containing a large volume of cytoplasm. Small-volume invaginations frequently emanated from large-volume nuclear invaginations but not vice versa, indicating a different underlying mechanism. Large- and small-volume nuclear envelope invaginations required the presence of chromatin, as they were restricted to chromatin-positive areas. The chromatin-free contact areas between nucleolar precursor bodies (NPBs) and large-volume invaginations were free of nuclear pores. Small-volume invaginations were not in contact with NPBs. The number of invaginations and isolated intranuclear vesicles per nucleus peaked at the 4-cell stage. At this stage, the nuclear surface showed highly concentrated clusters of nuclear pores surrounded by areas free of nuclear pores. Isolated intranuclear lamina vesicles were usually NUP153 negative. Cytoplasmic, randomly distributed NUP153-positive clusters were highly abundant at the zygote stage and decreased in number until they were almost absent at the 8-cell stage and later. These large NUP153 clusters may represent a maternally provided NUP153 deposit, but they were not visible as clusters during mitosis. Major genome activation at the 8- to 16-cell stage may mark the switch from a necessity for a deposit to on-demand production. NUP153 association with chromatin is initiated during metaphase before the initiation of the regeneration of the lamina. To our knowledge, the present study demonstrates for the first time major remodeling

  17. The role of muscle loading on bone (Remodeling at the developing enthesis.

    Directory of Open Access Journals (Sweden)

    Alexander M Tatara

    Full Text Available Muscle forces are necessary for the development and maintenance of a mineralized skeleton. Removal of loads leads to malformed bones and impaired musculoskeletal function due to changes in bone (remodeling. In the current study, the development of a mineralized junction at the interface between muscle and bone was examined under normal and impaired loading conditions. Unilateral mouse rotator cuff muscles were paralyzed using botulinum toxin A at birth. Control groups consisted of contralateral shoulders injected with saline and a separate group of normal mice. It was hypothesized that muscle unloading would suppress bone formation and enhance bone resorption at the enthesis, and that the unloading-induced bony defects could be rescued by suppressing osteoclast activity. In order to modulate osteoclast activity, mice were injected with the bisphosphonate alendronate. Bone formation was measured at the tendon enthesis using alizarin and calcein fluorescent labeling of bone surfaces followed by quantitative histomorphometry of histologic sections. Bone volume and architecture was measured using micro computed tomography. Osteoclast surface was determined via quantitative histomorphometry of tartrate resistant acid phosphatase stained histologic sections. Muscle unloading resulted in delayed initiation of endochondral ossification at the enthesis, but did not impair bone formation rate. Unloading led to severe defects in bone volume and trabecular bone architecture. These defects were partially rescued by suppression of osteoclast activity through alendronate treatment, and the effect of alendronate was dose dependent. Similarly, bone formation rate was increased with increasing alendronate dose across loading groups. The bony defects caused by unloading were therefore likely due to maintained high osteoclast activity, which normally decreases from neonatal through mature timepoints. These results have important implications for the treatment of

  18. The development and testing of the nurses' cardiac triage instrument.

    Science.gov (United States)

    Arslanian-Engoren, Cynthia; Hagerty, Bonnie M

    2013-01-01

    Rapid recognition and treatment of myocardial infarction (MI) reduces morbidity and mortality. Although emergency department (ED) nurses are often the first provider to evaluate individuals and are in a prime position to initiate MI guideline recommendations, no valid and reliable instrument was found to quantify their decision-making processes. The purpose of this study was to develop and test the psychometric properties of a new theoretically driven, empirically based instrument for measuring nurses' cardiac triage decisions. Using a descriptive research design, data were collected using a mailed survey. There were 158 ED nurses who completed a mailed questionnaire. Factor analysis revealed three factors (patient presentation, unbiased nurse reasoning process, and nurse action) with good internal consistency (Cronbach's alpha = .903, .809, .718) and sample adequacy (KMO = .758) of the 30-item instrument. The newly developed instrument has the potential to improve patient outcomes surrounding early MI identification and treatment.

  19. Xanthophore migration from the dermis to the epidermis and dermal remodeling during Salamandra salamandra salamandra (L.) larval development.

    Science.gov (United States)

    Pederzoli, Aurora; Gambarelli, Andrea; Restani, Cinzia

    2003-02-01

    During larval development of Salamandra salamandra salamandra chromatophores organize to form the definitive pigment pattern constituted by a black background with yellow patches that are characterized by epidermal xanthophores and dermal iridophores. Simultaneously the dermis undergoes remodeling from the larval stage to that typical of the adult. In the present study we ultrastucturally and immunocytochemically examined skin fragments of S. s. salamandra larvae and juveniles in order to investigate the modalities of xanthophore migration and differentiation in the context of dermal remodeling from the larval to adult stage. Semithin and thin sections showed that the dermis in newly born larvae consists of a compact connective tissue (basement lamella), to which fibroblasts and xanthophores adhere, and of a loose deep collagen layer. As larval development proceeds, fibroblasts and xanthophores invade the basement lamella, skin glands develop and the adult dermis forms. At metamorphosis, xanthophores reach the epidermis crossing through the basal lamina. We examined immunocytochemically the expression of signal molecules, such as fibronectin, vitronectin, beta1-integrin, chondroitin sulfate, E-cadherin, N-cadherin and plasminogen activator, which are known to be involved in regulating morphogenetic events. Their role in dermal remodeling and in pigment pattern formation is discussed.

  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...

  1. Myocardial area at risk after ST-elevation myocardial infarction measured with the late gadolinium enhancement after scar remodeling and T2-weighted cardiac magnetic resonance imaging

    DEFF Research Database (Denmark)

    Lønborg, Jacob; Engstrøm, Thomas; Mathiasen, Anders B;

    2011-01-01

    To evaluate the myocardial area at risk (AAR) measured by the endocardial surface area (ESA) method on late gadolinium enhancement (LGE) cardiovascular magnetic resonance (CMR) when applied after scar remodeling (3 months after index infarction) compared to T2-weighted CMR imaging. One hundred...

  2. Myocardial area at risk after ST-elevation myocardial infarction measured with the late gadolinium enhancement after scar remodeling and T2-weighted cardiac magnetic resonance imaging

    DEFF Research Database (Denmark)

    Lønborg, Jacob; Engstrøm, Thomas; Mathiasen, Anders B;

    2012-01-01

    To evaluate the myocardial area at risk (AAR) measured by the endocardial surface area (ESA) method on late gadolinium enhancement (LGE) cardiovascular magnetic resonance (CMR) when applied after scar remodeling (3 months after index infarction) compared to T2-weighted CMR imaging. One hundred...

  3. PARP-inhibitor treatment prevents hypertension induced cardiac remodeling by favorable modulation of heat shock proteins, Akt-1/GSK-3β and several PKC isoforms.

    Directory of Open Access Journals (Sweden)

    Laszlo Deres

    Full Text Available Spontaneously hypertensive rat (SHR is a suitable model for studies of the complications of hypertension. It is known that activation of poly(ADP-ribose polymerase enzyme (PARP plays an important role in the development of postinfarction as well as long-term hypertension induced heart failure. In this study, we examined whether PARP-inhibitor (L-2286 treatment could prevent the development of hypertensive cardiopathy in SHRs. 6-week-old SHR animals were treated with L-2286 (SHR-L group or placebo (SHR-C group for 24 weeks. Wistar-Kyoto rats were used as aged-matched, normotensive controls (WKY group. Echocardiography was performed, brain-derived natriuretic peptide (BNP activity and blood pressure were determined at the end of the study. We detected the extent of fibrotic areas. The amount of heat-shock proteins (Hsps and the phosphorylation state of Akt-1(Ser473, glycogen synthase kinase (GSK-3β(Ser9, forkhead transcription factor (FKHR(Ser256, mitogen activated protein kinases (MAPKs, and protein kinase C (PKC isoenzymes were monitored. The elevated blood pressure in SHRs was not influenced by PARP-inhibitor treatment. Systolic left ventricular function and BNP activity did not differ among the three groups. L-2286 treatment decreased the marked left ventricular (LV hypertrophy which was developed in SHRs. Interstitial collagen deposition was also decreased by L-2286 treatment. The phosphorylation of extracellular signal-regulated kinase (ERK1/2(Thr183-Tyr185, Akt-1(Ser473, GSK-3β(Ser9, FKHR(Ser256, and PKC ε(Ser729 and the level of Hsp90 were increased, while the activity of PKC α/βII(Thr638/641, ζ/λ(410/403 were mitigated by L-2286 administration. We could detect signs of LV hypertrophy without congestive heart failure in SHR groups. This alteration was prevented by PARP inhibition. Our results suggest that PARP-inhibitor treatment has protective effect already in the early stage of hypertensive myocardial remodeling.

  4. Eccentric and concentric cardiac hypertrophy induced by exercise training: microRNAs and molecular determinants

    OpenAIRE

    Fernandes, T.; Soci, U.P.R.; E.M. Oliveira

    2011-01-01

    Among the molecular, biochemical and cellular processes that orchestrate the development of the different phenotypes of cardiac hypertrophy in response to physiological stimuli or pathological insults, the specific contribution of exercise training has recently become appreciated. Physiological cardiac hypertrophy involves complex cardiac remodeling that occurs as an adaptive response to static or dynamic chronic exercise, but the stimuli and molecular mechanisms underlying transduction of th...

  5. In vivo models of cardiac diseases: application to drug development and screening.

    Science.gov (United States)

    Rokutan, Hirofumi; Anker, Stefan D; Springer, Jochen

    2010-01-01

    Cardiac disease is the top cause of human mortality in the Western world. Current drug therapy for cardiac disease has been established via experimental studies using a variety of in vivo animal models. The purpose of this review is to discuss the features (advantages and limitations) of the mainly used in vivo models of cardiac disease and provide the reader with an overview of how they can be utilized in the development and screening of cardiac drugs. A search for articles focusing on and including in vivo models for the main areas of cardiac diseases was performed on PubMed. We also searched the reference lists of identified articles for further original articles. Large and small animal models including genetically modified ones have made accomplishments in the process of cardiac drug development with different clinical relevance. However, there is still a clear need for lessening the gap between human and experimental models by improving in vivo models.

  6. Role of thyroid hormones in ventricular remodeling.

    Science.gov (United States)

    Rajagopalan, Viswanathan; Gerdes, A Martin

    2015-04-01

    Cardiac remodeling includes alterations in molecular, cellular, and interstitial systems contributing to changes in size, shape, and function of the heart. This may be the result of injury, alterations in hemodynamic load, neurohormonal effects, electrical abnormalities, metabolic changes, etc. Thyroid hormones (THs) serve as master regulators for diverse remodeling processes of the cardiovascular system-from the prenatal period to death. THs promote a beneficial cardiomyocyte shape and improve contractility, relaxation, and survival via reversal of molecular remodeling. THs reduce fibrosis by decreasing interstitial collagen and reduce the incidence and duration of arrhythmias via remodeling ion channel expression and function. THs restore metabolic function and also improve blood flow both by direct effects on the vessel architecture and decreasing atherosclerosis. Optimal levels of THs both in the circulation and in cardiac tissues are critical for normal homeostasis. This review highlights TH-based remodeling and clinically translatable strategies for diverse cardiovascular disorders.

  7. Molecular and immunohistochemical analyses of cardiac troponin T during cardiac development in the Mexican axolotl, Ambystoma mexicanum.

    Science.gov (United States)

    Zhang, C; Pietras, K M; Sferrazza, G F; Jia, P; Athauda, G; Rueda-de-Leon, E; Rveda-de-Leon, E; Maier, J A; Dube, D K; Lemanski, S L; Lemanski, L F

    2007-01-01

    The Mexican axolotl, Ambystoma mexicanum, is an excellent animal model for studying heart development because it carries a naturally occurring recessive genetic mutation, designated gene c, for cardiac nonfunction. The double recessive mutants (c/c) fail to form organized myofibrils in the cardiac myoblasts resulting in hearts that fail to beat. Tropomyosin expression patterns have been studied in detail and show dramatically decreased expression in the hearts of homozygous mutant embryos. Because of the direct interaction between tropomyosin and troponin T (TnT), and the crucial functions of TnT in the regulation of striated muscle contraction, we have expanded our studies on this animal model to characterize the expression of the TnT gene in cardiac muscle throughout normal axolotl development as well as in mutant axolotls. In addition, we have succeeded in cloning the full-length cardiac troponin T (cTnT) cDNA from axolotl hearts. Confocal microscopy has shown a substantial, but reduced, expression of TnT protein in the mutant hearts when compared to normal during embryonic development.

  8. Protein kinase C pathway on cardiac sympathetic nerve neuroplasticity and myocardial interstitial remodeling%心脏交感神经和心肌间质重塑的共同通路——蛋白激酶C途径

    Institute of Scientific and Technical Information of China (English)

    李贺; 周欣; 王坷; 赵丽霞; 王志宏; 李玉明

    2011-01-01

    Cardiac sympathetic nerve and myocardial interstitium play important roles for preservation of heart function. Different extent of the interstitial remodeling and neuroplasticity commonly occur in many kinds of cardiovascular diseases. The abnormalities interact and contribute to progression and worsening of the diseases. There is accumulating evidence suggesting that protein kinase C activation as a regulator involves in and mediates interaction between the neuroplasticity and remodeling under such conditions, which plays a critical role in the nerve dysfunction and myocardial fibrosis.%心脏交感神经和心肌间质对维持正常心功能有重要作用.心血管患病时,两者均发生不同程度的重塑,并互相影响,这些变化对疾病进展发挥重要影响.研究证据显示,两者间的相互作用可能通过蛋白激酶C介导,对交感神经功能异常和心肌纤维化都发挥重要作用.

  9. Low cardiac output predicts development of hepatorenal syndrome and survival in patients with cirrhosis and ascites

    DEFF Research Database (Denmark)

    Krag, A; Bendtsen, F; Henriksen, J H;

    2010-01-01

    OBJECTIVES: Recent studies suggest that cardiac dysfunction precedes development of the hepatorenal syndrome. In this follow-up study, we aimed to investigate the relation between cardiac and renal function in patients with cirrhosis and ascites and the impact of cardiac systolic function...... on survival. Patients and DESIGN: Twenty-four patients with cirrhosis and ascites were included. Cardiac function was investigated by gated myocardial perfusion imaging (MPI) for assessment of cardiac index (CI) and cardiac volumes. The renal function was assessed by determination of glomerular filtration...... (130 (SD 46) vs 78 (SD 29) mumol/l, pdeveloped hepatorenal syndrome type 1 within 3 months was higher in the group with low CI than in the high CI group (43% vs 5%, p = 0.04). Patients with the lowest CI (N = 8) had significantly poorer survival at 3, 9, and 12 months...

  10. Hybrid ECMO for a patient in respiratory failure developing cardiac insufficiency.

    Science.gov (United States)

    Youdle, Jemma; Penn, Sarah; Maunz, Olaf; Simon, Andre

    2016-04-01

    A 45-year-old patient in lung failure treated with veno-venous extracorporeal membrane oxygenation (VV ECMO) developed subsequent right heart failure and required cardiac support.We present a method of upgrading a VV ECMO to a hybrid system for simultaneous support for respiratory and cardiac failure.

  11. Mechanical cardiac remodeling and new-onset atrial fibrillation in long-term follow-up of subjects with chronic Chagas' disease

    Directory of Open Access Journals (Sweden)

    P.R. Benchimol-Barbosa

    2009-03-01

    Full Text Available Atrial fibrillation (AF affects subjects with Chagas' disease and is an indicator of poor prognosis. We investigated clinical, echocardiographic and electrocardiographic variables of Chagas' disease in a long-term longitudinal study as predictors of a new-onset AF episode lasting >24 h, nonfatal embolic stroke and cardiac death. Fifty adult outpatients (34 to 74 years old, 62% females staged according to the Los Andes classification were enrolled. During a follow-up of (mean ± SD 84.2 ± 39.0 months, 9 subjects developed AF (incidence: 3.3 ± 1.0%/year, 5 had nonfatal stroke (incidence: 1.3 ± 1.0%/year, and nine died (mortality rate: 2.3 ± 0.8%/year. The progression rate of left ventricular mass and left ventricular ejection fraction was significantly greater in subjects who experienced AF (16.4 ± 20.0 g/year and -8.6 ± 7.6%/year, respectively than in those who did not (8.2 ± 8.4 g/year; P = 0.03, and -3.0 ± 2.5%/year; P = 0.04, respectively. In univariate analysis, left atrial diameter ≥3.2 cm (P = 0.002, pulmonary arterial hypertension (P = 0.035, frequent premature supraventricular and ventricular contraction counts/24 h (P = 0.005 and P = 0.007, respectively, ventricular couplets/24 h (P = 0.002, and ventricular tachycardia (P = 0.004 were long-term predictors of AF. P-wave signal-averaged ECG revealed a limited long-term predictive value for AF. In chronic Chagas' disease, large left atrial diameter, pulmonary arterial hypertension, frequent supraventricular and ventricular premature beats, and ventricular tachycardia are long-term predictors of AF. The rate of left ventricular mass enlargement and systolic function deterioration impact AF incidence in this population.

  12. Hemodynamics, inflammation, vascular remodeling, and the development and rupture of intracranial aneurysms: a review

    Directory of Open Access Journals (Sweden)

    Francesco Signorelli

    2015-06-01

    Full Text Available The central nervous system is an immunologically active environment where several components of the immune and inflammatory response interact among them and with the constituents of nervous tissue and vasculature in a critically orchestrated manner, influencing physiologic and pathologic processes. In particular, inflammation takes a central role in the pathogenesis of intracranial aneurysms (IAs. The common pathway for aneurysm formation involves endothelial dysfunction and injury, a mounting inflammatory response, vascular smooth muscle cells (VSMCs phenotypic modulation, extracellular matrix remodeling, and subsequent cell death and vessel wall degeneration. We conducted a literature review (1980-2014 by Medline and EMBASE databases using the searching terms "IA" and "cerebral aneurysm" and further search was performed to link the search terms with the following key words: inflammation, hemodynamic(s, remodeling, macrophages, neutrophils, lymphocytes, complement, VSMCs, mast cells, cytokines, and inflammatory biomarkers. The aim of this review was to summarize the most recent and pertinent evidences regarding the articulated processes of aneurysms formation, growth, and rupture. Knowledge of these processes may guide the diagnosis and treatment of these vascular malformations, the most common cause of subarachnoid hemorrhage, which prognosis remains dismal.

  13. ANGPTL2 activity in cardiac pathologies accelerates heart failure by perturbing cardiac function and energy metabolism

    Science.gov (United States)

    Tian, Zhe; Miyata, Keishi; Kadomatsu, Tsuyoshi; Horiguchi, Haruki; Fukushima, Hiroyuki; Tohyama, Shugo; Ujihara, Yoshihiro; Okumura, Takahiro; Yamaguchi, Satoshi; Zhao, Jiabin; Endo, Motoyoshi; Morinaga, Jun; Sato, Michio; Sugizaki, Taichi; Zhu, Shunshun; Terada, Kazutoyo; Sakaguchi, Hisashi; Komohara, Yoshihiro; Takeya, Motohiro; Takeda, Naoki; Araki, Kimi; Manabe, Ichiro; Fukuda, Keiichi; Otsu, Kinya; Wada, Jun; Murohara, Toyoaki; Mohri, Satoshi; Yamashita, Jun K.; Sano, Motoaki; Oike, Yuichi

    2016-01-01

    A cardioprotective response that alters ventricular contractility or promotes cardiomyocyte enlargement occurs with increased workload in conditions such as hypertension. When that response is excessive, pathological cardiac remodelling occurs, which can progress to heart failure, a leading cause of death worldwide. Mechanisms underlying this response are not fully understood. Here, we report that expression of angiopoietin-like protein 2 (ANGPTL2) increases in pathologically-remodeled hearts of mice and humans, while decreased cardiac ANGPTL2 expression occurs in physiological cardiac remodelling induced by endurance training in mice. Mice overexpressing ANGPTL2 in heart show cardiac dysfunction caused by both inactivation of AKT and sarco(endo)plasmic reticulum Ca2+-ATPase (SERCA)2a signalling and decreased myocardial energy metabolism. Conversely, Angptl2 knockout mice exhibit increased left ventricular contractility and upregulated AKT-SERCA2a signalling and energy metabolism. Finally, ANGPTL2-knockdown in mice subjected to pressure overload ameliorates cardiac dysfunction. Overall, these studies suggest that therapeutic ANGPTL2 suppression could antagonize development of heart failure. PMID:27677409

  14. Pharmacotherapy in the cardiac catheterization laboratory: evolution and recent developments

    Directory of Open Access Journals (Sweden)

    Thind GS

    2014-10-01

    Full Text Available Guramrinder S Thind,1 Raunak Parida,1 Nishant Gupta2 1SDM College of Medical Sciences and Hospital, Dharwad, Karnataka, India; 2University of Texas at Houston, Houston, TX, USAAbstract: Many recent innovations have been made in developing new antiplatelet and ­anticoagulant drugs in the last few years, with a total of nine new antithrombotic drugs approved by the Food and Drug Administration after the year 2000. This has revolutionized the medical therapy given to manage acute coronary syndrome and support cardiac catheterization. The concept of dual antiplatelet therapy has been emphasized, and clopidogrel has emerged as the most-popular second antiplatelet drug after aspirin. Newer P2Y12 inhibitors like prasugrel and ticagrelor have been extensively studied and compared to clopidogrel. The role of glycoprotein (Gp IIb/IIIa inhibitors is being redefined. Other alternatives to unfractionated heparin have become available, of which enoxaparin and bivalirudin have been studied the most. Apart from these, many more drugs with novel therapeutic targets are being studied and are currently under development. In this review, current evidence on these drugs is presented and analyzed in a way that would facilitate decision making for the clinician. For this analysis, various high-impact clinical trials, pharmacological studies, meta-analyses, and reviews were accessed through the MEDLINE database. Adopting a unique interdisciplinary approach, an attempt has been made to integrate pharmacological and clinical evidence to better understand and appreciate the pros and cons of each of these classes of drugs. Keywords: acute coronary syndrome, anticoagulants, antiplatelets, percutaneous coronary intervention

  15. Analysis of the endocardium and cardiac jelly in truncal development in the cardiac lethal mutant axolotl Ambystoma mexicanum.

    Science.gov (United States)

    Lemanski, L F; Fitzharris, T P

    1989-05-01

    Recessive mutant gene c in axolotls results in a failure of the heart to function because of abnormal embryonic induction processes. The myocardium in this mutant lacks organized sarcomeric myofibrils. The present study was undertaken to determine if developmental abnormalities were evident in other areas of the heart besides the myocardium. A detailed comparative survey of the structure of developing normal and mutant hearts, including the endocardium, its cellular derivatives, and the extracellular matrix, known as cardiac jelly, showed that in the mutant there are fewer than the normal number of endocardial cells lining the heart lumen, the number of mesenchyme cells is reduced, and the cardiac jelly area is greatly enlarged in the posterior part of the truncus adjacent to the ventricle.

  16. New insights into retinoid signaling in cardiac development and physiology.

    Science.gov (United States)

    Smith, S M; Dickman, E D

    1997-11-01

    Retinoic acid (RA) and the retinoids are potent hormones derived from the nutrient vitamin A; they bind members of the nuclear steroid receptor family (RAR, RXR), which are ligand-dependent trans-activators of target gene transcription. Although classic nutrition studies largely ignored heart as a retinoid target, recent interest in this subject stems from RA's potent cardiac teratogenicity, the identification of retinoid receptors in the heart, and the cardiac malformations observed in retinoid receptor null mutant mice. This review summarizes recent research into retinoid contributions predominantly in the embryonic heart. (Trends Cardiovasc Med 1997;7:324-329). © 1997, Elsevier Science Inc.

  17. Cardiac thrombus developing after an accidental high-voltage electric shock in a child.

    Science.gov (United States)

    Akın, Alper; Bilici, Meki; Demir, Fikri; Gözü Pirinççioğlu, Ayfer; Yavuz, Celal

    2015-01-01

    Electric shock is a condition that may affect various organ systems and potentially cause death. Cardiac findings vary from asymptomatic mild injury to fatal myocardial involvement. Herein we present a five-year-old boy with a cardiac thrombus developing after an accidental electrical shock. Cardiac arrhythmias and evidence of ischemia have been reported after electric shock; we were, however, unable to identify an earlier case report of intracardiac thrombosis related to electric shock. Findings such as elevated cardiac enzymes and systolic dysfunction, which indicate myocardial damage following electric shock, were present in our patient. We think that the cardiac thrombus might have resulted from the myocardial damage and the slowed intracardiac blood flow related to systolic dysfunction. As the thrombus was thought to have been formed through known mechanisms, it was treated traditionally. However, further data regarding the etiology and management of such thrombi is needed.

  18. Development of new anatomy reconstruction software to localize cardiac isochrones to the cardiac surface from the 12 lead ECG.

    Science.gov (United States)

    van Dam, Peter M; Gordon, Jeffrey P; Laks, Michael M; Boyle, Noel G

    2015-01-01

    Non-invasive electrocardiographic imaging (ECGI) of the cardiac muscle can help the pre-procedure planning of the ablation of ventricular arrhythmias by reducing the time to localize the origin. Our non-invasive ECGI system, the cardiac isochrone positioning system (CIPS), requires non-intersecting meshes of the heart, lungs and torso. However, software to reconstruct the meshes of the heart, lungs and torso with the capability to check and prevent these intersections is currently lacking. Consequently the reconstruction of a patient specific model with realistic atrial and ventricular wall thickness and incorporating blood cavities, lungs and torso usually requires additional several days of manual work. Therefore new software was developed that checks and prevents any intersections, and thus enables the use of accurate reconstructed anatomical models within CIPS. In this preliminary study we investigated the accuracy of the created patient specific anatomical models from MRI or CT. During the manual segmentation of the MRI data the boundaries of the relevant tissues are determined. The resulting contour lines are used to automatically morph reference meshes of the heart, lungs or torso to match the boundaries of the morphed tissue. Five patients were included in the study; models of the heart, lungs and torso were reconstructed from standard cardiac MRI images. The accuracy was determined by computing the distance between the segmentation contours and the morphed meshes. The average accuracy of the reconstructed cardiac geometry was within 2mm with respect to the manual segmentation contours on the MRI images. Derived wall volumes and left ventricular wall thickness were within the range reported in literature. For each reconstructed heart model the anatomical heart axis was computed using the automatically determined anatomical landmarks of the left apex and the mitral valve. The accuracy of the reconstructed heart models was well within the accuracy of the used

  19. Nanomaterials for Cardiac Myocyte Tissue Engineering

    Directory of Open Access Journals (Sweden)

    Rodolfo Amezcua

    2016-07-01

    Full Text Available Since their synthesizing introduction to the research community, nanomaterials have infiltrated almost every corner of science and engineering. Over the last decade, one such field has begun to look at using nanomaterials for beneficial applications in tissue engineering, specifically, cardiac tissue engineering. During a myocardial infarction, part of the cardiac muscle, or myocardium, is deprived of blood. Therefore, the lack of oxygen destroys cardiomyocytes, leaving dead tissue and possibly resulting in the development of arrhythmia, ventricular remodeling, and eventual heart failure. Scarred cardiac muscle results in heart failure for millions of heart attack survivors worldwide. Modern cardiac tissue engineering research has developed nanomaterial applications to combat heart failure, preserve normal heart tissue, and grow healthy myocardium around the infarcted area. This review will discuss the recent progress of nanomaterials for cardiovascular tissue engineering applications through three main nanomaterial approaches: scaffold designs, patches, and injectable materials.

  20. The role of patient's profile and allogeneic blood transfusion in development of post-cardiac surgery infections: a retrospective study

    NARCIS (Netherlands)

    Vranken, N.P.; Weerwind, P.W.; Barenbrug, P.J.; Teerenstra, S.; Ganushchak, Y.M.; Maessen, J.G.

    2014-01-01

    OBJECTIVES: We aimed to investigate the association of patient characteristics and allogeneic blood transfusion products in development of post-cardiac surgery nosocomial infections. METHODS: This retrospective study was conducted in 7888 patients undergoing cardiac surgery with median sternotomy an

  1. 先心病心脏重构患者血清血管紧张素转化酶2水平研究%The Serum Levels of Angiotensin-converting Enzyme2 in Patients of Congenital Heart Disease with Cardiac Remodeling

    Institute of Scientific and Technical Information of China (English)

    郭玥; 吕宁; 尹小龙

    2013-01-01

    目的 观察先心病(congenital heart disease,CHD)伴心脏重构(Cardiac remodeling)患者血管紧张素转化酶2 (angiotensin-convertirg enzyrre 2,ACE2)含量和活性的变化,探讨它们与心脏重构的关系.方法 收集被确诊为先心病的患者104例, (其中无心脏重构组80例,合并心脏重构组24例),正常对照组33例.抽取受试者静脉血,应用酶联免疫吸附法(ELISA)检测血清ACE2酶含量,用比色法检测ACE2酶活性的水平,所得实验数据使用SPSS统计软件进行分析.结果 (1)正常对照组、先心病无心脏重构组、先心病心脏重构组ACE2酶含量测定值分别为(15.79± 5.03) U/L、(18.85±6.46) U/L、(14.80±4.58) U/L.正常对照组与先心病无心脏重构组比较,ACE2含量差异有统计学意义(P<0.05);正常对照组与先心病心脏重构组比较,ACE2含量无差异(P>0.05);先心病无心脏重构组与心脏重构组比较,ACE2含量差异有统计学意义(P<0.01); (2)正常对照组、先心病无心脏重构组、先心病心脏重构组ACE2酶活性测定值分别为(1.75±0.82) U/L、(1.85±0.62) U/L、(158±0.52) U/L,3组间比较差异无统计学意义(P>0.05).结论 (1)先心病无心脏重构患者血清中的ACE2酶含量显著升高; (2)先心病无心脏重构患者与心脏重构患者血清中ACE2酶活性无变化.%Objective To observe the Angiotensin-converting enzyme2 (ACE2) protein contents and activity in the serum of patients with Congenital Heart Disease (CHD) combined with cardiac remodeling (CR) , and investigate the correlation of those with cardiac remodeling. Methods 104 patients with Congenital Heart Disease and 33 normal control patients were collected. The patients with congenital heart disease were divided into 80 cases of non-cardiac remodeling group, and 24 cases of cardiac remodeling group. The serum levels of ACE2 protein were detected by enzyme-linked immunosorbent assay ( ELISA) , ACE2 activity was detected by colorimetric

  2. Effect of Shensong Yangxin Capsule on Cardiac Remodelling of Myocardial Infarction Mouse Model%参松养心胶囊对心肌梗死模型小鼠心脏重构的影响

    Institute of Scientific and Technical Information of China (English)

    向家培; 赵劲波; 王勇; 华晓芳; 黄浩; 雷玉华

    2016-01-01

    Objective To investigate the effect of Shensong Yangxin capsule on cardiac remodelling of myocardial infarction mouse model and the possible molecular mechanisms. Methods Adult male C57BL/6J mice were divided into sham operation group(n=10), model control group(n=20)and Shensong Yangxin group(n=20)according to random number table. Left anterior descending branch of coronary artery was ligated to establish myocardic infarction model in the model control group and Shensong Yangxin group. From the 2nd day after the surgery, Shensong Yangxin ( 400 mg . kg-1 ) was intragastrically administered, and the death rate of the mice was observed.Four weeks after the surgery, echocardiography was used to measure the cardiac function;myocardiac infarction area was detected by pathological staining;the expression levels of cardiac remodelling markers and extracellular matrix proteins were detected by RT-PCR. The possible molecular mechanisms were screened by Western blotting. Results As compared with the model control group, Shensong Yangxin significantly reduced the mortality after myocardial infarction in mice(P<0.05), as well as the myocardial infarct size(P<0.05).The mRNA expression levels of cardiac remodelling markers ANP, BNP, and β-MHC and the extracellular matrix proteins(collagenⅠ, collagen Ⅲ, CTGF, TGFβ) decreased significantly in the Shensong Yangxin group as compared with the model control group. Western blotting showed that Shensong Yangxin significantly decreased activation of smad3, and reduced expression level of smad4. Conclusion Shensong Yangxin attenuates cardiac remodelling after myocardial infarction and the mechanism may be related with blockage of smad signaling pathway.%目的:探讨参松养心胶囊对小鼠心肌梗死后心脏重构的影响及其可能的分子机制。方法 C57BL/6J小鼠按照随机数字表法分为假手术组( n=10),模型对照组( n=20)和参松养心组( n=20)。模型对照组和参松养心组采用冠状动

  3. The PAF1 complex component Leo1 is essential for cardiac and neural crest development in zebrafish.

    Science.gov (United States)

    Nguyen, Catherine T; Langenbacher, Adam; Hsieh, Michael; Chen, Jau-Nian

    2010-05-01

    Leo1 is a component of the Polymerase-Associated Factor 1 (PAF1) complex, an evolutionarily conserved protein complex involved in gene transcription regulation and chromatin remodeling. The role of leo1 in vertebrate embryogenesis has not previously been examined. Here, we report that zebrafish leo1 encodes a nuclear protein that has a similar molecular structure to Leo1 proteins from other species. From a genetic screen, we identified a zebrafish mutant defective in the leo1 gene. The truncated Leo1(LA1186) protein lacks a nuclear localization signal and is distributed mostly in the cytoplasm. Phenotypic analysis showed that while the initial patterning of the primitive heart tube is not affected in leo1(LA1186) mutant embryos, the differentiation of cardiomyocytes at the atrioventricular boundary is aberrant, suggesting a requirement for Leo1 in cardiac differentiation. In addition, the expression levels of markers for neural crest-derived cells such as crestin, gch2, dct and mitfa are greatly reduced in leo1(LA1186) mutants, indicating a requirement for Leo1 in maintaining the neural crest population. Consistent with this finding, melanocyte and xanthophore populations are severely reduced, craniofacial cartilage is barely detectable, and mbp-positive glial cells are absent in leo1(LA1186) mutants after three days of development. Taken together, these results provide the first genetic evidence of the requirement for Leo1 in the development of the heart and neural crest cell populations.

  4. Outlined history of the development of the world and Polish cardiac surgery.

    Science.gov (United States)

    Dziatkowiak, A J

    2006-04-01

    It was the dream of humanity to perform surgery on an open non-beating heart. Scientific and medical discoveries five thousand years ago in China, partially adopted by the Western civilization, laid, through ancient Egypt, Mesopotamia, Greece, Rome and, later on in the Renaissance, the foundations for the development of empirical medicine. The 19th and the 20th centuries shoved dynamic scientific and technical development in various fields including medicine and surgery whose importance grew with the necessity to help the patients wounded in the wars. A break-through event in the development of surgery was overcoming of pain and discovery of reasons of infections and the control thereof, and, in the case of cardiology and cardiac surgery, the discoveries in physiology of circulation and the diagnostics of cardiovascular system diseases. This review contains a brief description of medical science in the past centuries, emphasizing the most important discoveries. A focus has been placed on the contribution of general surgery and thoracic surgery to the development of Polish and World cardiac surgery. The I Congress of the Polish Surgeons was held in 1889 in the Austria occupied territory of Cracow, which celebrated its one hundredth anniversary. The main obstacles in the development of clinical cardiac surgery included intratracheal general anesthesia, antisepsis and aseptics, hypothermia, oxygenators, extracorporeal circulation, transfusions, blood clotting and thromboses and cardioplegia. The spectacular heart and aorta surgical operations performed for the first time in the world and in Poland as well as the names of cardiac surgeons employed by the important cardiac surgery centers in Poland have been mentioned. The Department of Heart, Vascular and Transplantology Surgery of Cracow, the role and the share of Fundacja Rozwoju Kardiochirurgii COR AEGRUM in Cracow (COR AEGRUM Foundation for the Development of Cardiac Surgery in Cracow) in the construction of the

  5. Development of Bipotent Cardiac/Skeletal Myogenic Progenitors from MESP1+ Mesoderm

    Directory of Open Access Journals (Sweden)

    Sunny Sun-Kin Chan

    2016-01-01

    Full Text Available The branchiomeric skeletal muscles co-evolved with new chambers of the heart to enable predatory feeding in chordates. These co-evolved tissues develop from a common population in anterior splanchnic mesoderm, referred to as cardiopharyngeal mesoderm (CPM. The regulation and development of CPM are poorly understood. We describe an embryonic stem cell-based system in which MESP1 drives a PDGFRA+ population with dual cardiac and skeletal muscle differentiation potential, and gene expression resembling CPM. Using this system, we investigate the regulation of these bipotent progenitors, and find that cardiac specification is governed by an antagonistic TGFβ-BMP axis, while skeletal muscle specification is enhanced by Rho kinase inhibition. We define transcriptional signatures of the first committed CPM-derived cardiac and skeletal myogenic progenitors, and discover surface markers to distinguish cardiac (PODXL+ from the skeletal muscle (CDH4+ CPM derivatives. These tools open an accessible window on this developmentally and evolutionarily important population.

  6. Molecular switches under TGFβ signalling during progression from cardiac hypertrophy to heart failure.

    Science.gov (United States)

    Heger, J; Schulz, R; Euler, G

    2016-01-01

    Cardiac hypertrophy is a mechanism to compensate for increased cardiac work load, that is, after myocardial infarction or upon pressure overload. However, in the long run cardiac hypertrophy is a prevailing risk factor for the development of heart failure. During pathological remodelling processes leading to heart failure, decompensated hypertrophy, death of cardiomyocytes by apoptosis or necroptosis and fibrosis as well as a progressive dysfunction of cardiomyocytes are apparent. Interestingly, the induction of hypertrophy, cell death or fibrosis is mediated by similar signalling pathways. Therefore, tiny changes in the signalling cascade are able to switch physiological cardiac remodelling to the development of heart failure. In the present review, we will describe examples of these molecular switches that change compensated hypertrophy to the development of heart failure and will focus on the importance of the signalling cascades of the TGFβ superfamily in this process. In this context, potential therapeutic targets for pharmacological interventions that could attenuate the progression of heart failure will be discussed.

  7. Mild hypothermia during global cardiac ischemia opens a window of opportunity to develop heart donation after cardiac death.

    Science.gov (United States)

    Stadelmann, Mathieu; Dornbierer, Monika; Clément, David; Gahl, Brigitta; Dick, Florian; Carrel, Thierry P; Tevaearai, Hendrik T; Longnus, Sarah

    2013-03-01

    Although heart donation after cardiac death (DCD) could greatly improve graft availability, concerns regarding warm ischemic damage typically preclude transplantation. Improving tolerance to warm ischemia may thus open a window of opportunity for DCD hearts. We investigated the hypothesis that, compared with normothermia, mild hypothermia (32° C) initiated after ischemic onset improves cardiac functional recovery upon reperfusion. Isolated, working hearts from adult, male Wistar rats underwent global, no-flow ischemia, and reperfusion (n = 28). After ischemic onset, temperature was maintained at either 37° C for 20 or 30 min or reduced to 32° C for 40, 50, or 60 min. Recovery was measured after 60-min reperfusion. Following normothermic ischemia, recovery of rate-pressure product (RPP; per cent of preischemic value) was almost complete after 20-min ischemia (97 ± 9%), whereas no recovery was detectable after 30-min ischemia. After mildly hypothermic ischemia (32° C), RPP also recovered well after 40 min (86 ± 4%). Markers of metabolism and necrosis were similar in 37° C/20 min and 32° C/40 min groups. Simple reduction in cardiac temperature by a few degrees after the onset of global ischemia dramatically prolongs the interval during which the heart remains resistant to functional deterioration. Preservation of hemodynamic function is associated with improved metabolic recovery and reduced necrosis. The application of mild hypothermia may be a simple first step towards development of clinical protocols for DCD heart recovery.

  8. Retinol dehydrogenase, RDH1l, is essential for the heart development and cardiac performance in zebrafish

    Institute of Scientific and Technical Information of China (English)

    WANG Wei; ZHANG Li-feng; GUI Yong-hao; SONG Hou-yan

    2013-01-01

    Background Retinoic acid (RA) is a potent signaling molecule that plays pleiotropic roles in patterning,morphogenesis,and organogenesis during embryonic development.The synthesis from retinol (vitamin A) to retinoic acid requires two sequential oxidative steps.The first step involves the oxidation of retinol to retinal through the action of retinol dehydrogenases.Retinol dehydrogenases1l (RDH1l) is a novel zebrafish retinol dehydrogenase.Herein we investigated the role of zebrafish RDH1l in heart development and cardiac performance in detail.Methods RDH1l specific morpholino was used to reduce the function of RDH1l in zebrafish.The gene expressions were observed by using whole mount in situ hybridization.Heart rates were observed and recorded under the microscope from 24 to 72 hours post fertilization (hpf).The cardiac performance was analyzed by measuring ventricular shortening fraction (VSF).Results The knock-down of RDH1l led to abnormal neural crest cells migration and reduced numbers of neural crest cells in RDH1l morphant embryos.The reduced numbers of cardiac neural crest cells also can be seen in RDH1l morphant embryos.Furthermore,the morpholino-mediated knock-down of RDH1l resulted in the abnormal heart loop.The left-right determining genes expression pattern was altered in RDH1l morphant embryos.The impaired cardiac performance was observed in RDH1l morphant embryos.Taken together,these data demonstrate that RDH1l is essential for the heart development and cardiac performance in zebrafish.Conclusions RDH1l plays a important role in the neural crest cells development,and then ultimately affects the heart loop and cardiac performance.These results show for the first time that an enzyme involved in the retinol to retinaldehyde conversion participate in the heart development and cardiac performance in zebrafish.

  9. 体外心脏震波对急性心肌梗死模型猪左心室重塑的影响%Effect of extracorporeal cardiac shock wave therapy on left ventricular remodeling in a porcine model of acute myocardial infarction

    Institute of Scientific and Technical Information of China (English)

    陶四明; 郭涛; 王钰; 李建美; 蔡红雁; 羊超

    2012-01-01

    BACKGROUND: Initial studies have confirmed that extracorporeal cardiac shock wave therapy can ameliorate metabolism of ischemia myocardium from the level of gene and cells. However, will the therapy improve the development of post-infarction ventricular remodeling in a morphology level?OBJECTIVE: To explore the effects of extracorporeal cardiac shockwave therapy on the function and morphology of the left ventricle after acute myocardial infarction.METHODS: A total of 25 pigs were randomly divided into three groups: shock wave group, sham shock wave group and sham operation group. Pigs in the shock wave group were treated with extracorporeal cardiac shock wave therapy on 3, 5 and 7 days after the model construction of myocardial infarction. Pigs in the sham shock wave group received the same therapy to the shock wave group except for the shock waves and energy. Sham operation group received the same treatment to the sham shock wave group without constructing the myocardial infarction model.RESULTS AND CONCLUSION: Compared with the sham shockwave group, shockwave therapy significantly reduced the left ventricular end-systolic volume, increased the end-diastolic volume and improved the global left ventricular function (P< 0.001); it significantly improved the ventricular wall motor function in the myocardium of the myocardial infarction border zone and the motion compatibleness of the left ventricular. These findings demonstrate that the early application of effective extracorporeal cardiac shock wave therapy can delay the development to some extent from reversible stage to irreversible stage in the left ventricular remodeling after myocardial infarction.%背景:初期实验已经证实体外心脏震波治疗可从基因和细胞水平改善缺血心肌代谢,但是否在形态学水平也可缓解梗死后心室重塑的发展?目的:观察体外心脏震波对急性心肌梗死后左心室心功能及形态学指标的影响.方法:将25只猪随机分为3组:震

  10. Material-based engineering strategies for cardiac regeneration.

    Science.gov (United States)

    Marion, Mieke H van; Bax, Noortje A M; Spreeuwel, Ariane C C van; van der Schaft, Daisy W J; Bouten, Carlijn V C

    2014-01-01

    Cardiac tissue is composed of muscle and non-muscle cells, surrounded by extracellular matrix (ECM) and spatially organized into a complex three-dimensional (3D) architecture to allow for coordinated contraction and electrical pulse propagation. Despite emerging evidence for cardiomyocyte turnover in mammalian hearts, the regenerative capacity of human cardiac tissue is insufficient to recover from damage, e.g. resulting from myocardial infarction (MI). Instead, the heart 'repairs' lost or injured tissue by ongoing synthesis and remodeling of scar tissue. Conventional therapies and timely (stem) cell delivery to the injured tissue markedly improve short-term function and remodeling, but do not attenuate later stage adverse remodeling, leading to functional deterioration and eventually failure of the heart. Material-based therapies have been successfully used to mechanically support and constrain the post-MI failing heart, preventing it from further remodeling and dilation. When designed to deliver the right microenvironment for endogenous or exogenous cells, as well as the mechanical and topological cues to guide neo-tissue formation, material-based therapies may even reverse remodeling and boost cardiac regeneration. This paper reviews the up-to-date status of material-based cardiac regeneration with special emphasis on 1) the use of bare biomaterials to deliver passive constraints that unload the heart, 2) the use of materials and cells to create engineered cardiac constructs for replacement, support, or regeneration of damaged myocardium, and 3) the development of bio-inspired and bioactive materials that aim to enhance the endogenous regenerative capacity of the heart. As the therapies should function in the infarcted heart, the damaged host environment and engineered in vitro test systems that mimic this environment, are reviewed as well.

  11. Biomarkers to Predict Reverse Remodeling and Myocardial Recovery in Heart Failure.

    Science.gov (United States)

    Motiwala, Shweta R; Gaggin, Hanna K

    2016-10-01

    Left ventricular remodeling appears to be a critical link between cardiac injury and the development and progression of heart failure with reduced ejection fraction (HFrEF). Several drug and device therapies that modify and reverse the remodeling process in patients with HFrEF are closely associated with improvement in clinical outcomes. Reverse remodeling, including partial or complete recovery of systolic function and structure, is possible but its determinants are incompletely understood. Methods to predict reverse remodeling in response to therapy are not well defined. Though non-invasive imaging techniques remain the most widely used methods of assessing reverse remodeling, serum biomarkers are now being investigated as more specific, mechanistically driven, and clinically useful predictors of reverse remodeling. Biomarkers that reflect myocyte stretch and stress, myocyte injury and necrosis, inflammation and fibrosis, and extracellular matrix turnover may be particularly valuable for predicting pathophysiologic changes and prognosis in individual patients. Their use may ultimately allow improved application of precision medicine in chronic HF.

  12. Cardiac GR and MR: From Development to Pathology.

    Science.gov (United States)

    Richardson, Rachel V; Batchen, Emma J; Denvir, Martin A; Gray, Gillian A; Chapman, Karen E

    2016-01-01

    The efficacy of mineralocorticoid receptor (MR) antagonism in the treatment of certain patients with heart failure has highlighted the pivotal role of aldosterone and MR in heart disease. The glucocorticoid (GC) receptor (GR) is also expressed in heart, but the role of cardiac GR had received much less attention until recently. GR and MR are highly homologous in both structure and function, although not in cellular readout. Recent evidence in animal models has uncovered a tonic role for GC action via GR in cardiomyocytes in prevention of heart disease. Here, we review this evidence and the implications for a balance between GR and MR activation in the early life maturation of the heart and its subsequent health and disease.

  13. In utero and lactational 2,3,7,8-tetrachlorodibenzo-p-dioxin exposure: Effects on fetal and adult cardiac gene expression and adult cardiac and renal morphology

    Science.gov (United States)

    The mouse heart is a target of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) during fetal development, and microarray analysis demonstrates significant changes in expression of cardiac genes involved in extracellular matrix (ECM) remodeling. We tested the hypothesis that developmental TCDD exposure wo...

  14. On the development of an integrated bone remodeling law for orthodontic tooth movements models using the Finite Element Method.

    OpenAIRE

    Mengoni, Marlène

    2012-01-01

    One of the guiding principles in orthodontics is to gradually impose progressive and irreversible bone deformations due to remodeling using specific force systems on the teeth. Bone remodeling leads the teeth into new positions with two tissues having a major influence: the periodontal ligament and the alveolar bone. Their mechanical and biological/physiological reactions to orthodontic forces are tightly linked. This mechanical biological coupling can be treated in biomechanical mod...

  15. The morphological development of the locomotor and cardiac muscles of the migratory barnacle goose (Branta leucopsis)

    NARCIS (Netherlands)

    Bishop, CM; Butler, PJ; ElHaj, AJ; Egginton, S; Loonen, MJJE

    1996-01-01

    The masses of the locomotor and cardiac muscles of wild barnacle goose goslings, from a migratory population, were examined systematically during development and their values compared to those of pre-migratory geese. Pre-flight development was typified by approximately linear increases of body, leg,

  16. Development of cardiac parasympathetic neurons, glial cells, and regional cholinergic innervation of the mouse heart.

    Science.gov (United States)

    Fregoso, S P; Hoover, D B

    2012-09-27

    Very little is known about the development of cardiac parasympathetic ganglia and cholinergic innervation of the mouse heart. Accordingly, we evaluated the growth of cholinergic neurons and nerve fibers in mouse hearts from embryonic day 18.5 (E18.5) through postnatal day 21(P21). Cholinergic perikarya and varicose nerve fibers were identified in paraffin sections immunostained for the vesicular acetylcholine transporter (VAChT). Satellite cells and Schwann cells in adjacent sections were identified by immunostaining for S100β calcium binding protein (S100) and brain-fatty acid binding protein (B-FABP). We found that cardiac ganglia had formed in close association to the atria and cholinergic innervation of the atrioventricular junction had already begun by E18.5. However, most cholinergic innervation of the heart, including the sinoatrial node, developed postnatally (P0.5-P21) along with a doubling of the cross-sectional area of cholinergic perikarya. Satellite cells were present throughout neonatal cardiac ganglia and expressed primarily B-FABP. As they became more mature at P21, satellite cells stained strongly for both B-FABP and S100. Satellite cells appeared to surround most cardiac parasympathetic neurons, even in neonatal hearts. Mature Schwann cells, identified by morphology and strong staining for S100, were already present at E18.5 in atrial regions that receive cholinergic innervation at later developmental times. The abundance and distribution of S100-positive Schwann cells increased postnatally along with nerve density. While S100 staining of cardiac Schwann cells was maintained in P21 and older mice, Schwann cells did not show B-FABP staining at these times. Parallel development of satellite cells and cholinergic perikarya in the cardiac ganglia and the increase in abundance of Schwann cells and varicose cholinergic nerve fibers in the atria suggest that neuronal-glial interactions could be important for development of the parasympathetic nervous

  17. Development of new anatomy reconstruction software to localize cardiac isochrones to the cardiac surface from the 12 lead ECG

    NARCIS (Netherlands)

    Dam, P.M. van; Gordon, J.P.; Laks, M.M.; Boyle, N.G.

    2015-01-01

    Non-invasive electrocardiographic imaging (ECGI) of the cardiac muscle can help the pre-procedure planning of the ablation of ventricular arrhythmias by reducing the time to localize the origin. Our non-invasive ECGI system, the cardiac isochrone positioning system (CIPS), requires non-intersecting

  18. Remodeling in the ischemic heart: the stepwise progression for heart

    Directory of Open Access Journals (Sweden)

    J.G. Mill

    2011-09-01

    Full Text Available Abstract Coronary artery disease is the leading cause of death in the developed world and in developing countries. Acute mortality from acute myocardial infarction (MI has decreased in the last decades. However, the incidence of heart failure (HF in patients with healed infarcted areas is increasing. Therefore, HF prevention is a major challenge to the health system in order to reduce healthcare costs and to provide a better quality of life. Animal models of ischemia and infarction have been essential in providing precise information regarding cardiac remodeling. Several of these changes are maladaptive, and they progressively lead to ventricular dilatation and predispose to the development of arrhythmias, HF and death. These events depend on cell death due to necrosis and apoptosis and on activation of the inflammatory response soon after MI. Systemic and local neurohumoral activation has also been associated with maladaptive cardiac remodeling, predisposing to HF. In this review, we provide a timely description of the cardiovascular alterations that occur after MI at the cellular, neurohumoral and electrical level and discuss the repercussions of these alterations on electrical, mechanical and structural dysfunction of the heart. We also identify several areas where insufficient knowledge limits the adoption of better strategies to prevent HF development in chronically infarcted individuals.

  19. Crude oil exposures reveal roles for intracellular calcium cycling in haddock craniofacial and cardiac development

    Science.gov (United States)

    Sørhus, Elin; Incardona, John P.; Karlsen, Ørjan; Linbo, Tiffany; Sørensen, Lisbet; Nordtug, Trond; van der Meeren, Terje; Thorsen, Anders; Thorbjørnsen, Maja; Jentoft, Sissel; Edvardsen, Rolf B.; Meier, Sonnich

    2016-08-01

    Recent studies have shown that crude oil exposure affects cardiac development in fish by disrupting excitation-contraction (EC) coupling. We previously found that eggs of Atlantic haddock (Melanogrammus aeglefinus) bind dispersed oil droplets, potentially leading to more profound toxic effects from uptake of polycyclic aromatic hydrocarbons (PAHs). Using lower concentrations of dispersed crude oil (0.7-7 μg/L ∑PAH), here we exposed a broader range of developmental stages over both short and prolonged durations. We quantified effects on cardiac function and morphogenesis, characterized novel craniofacial defects, and examined the expression of genes encoding potential targets underlying cardiac and craniofacial defects. Because of oil droplet binding, a 24-hr exposure was sufficient to create severe cardiac and craniofacial abnormalities. The specific nature of the craniofacial abnormalities suggests that crude oil may target common craniofacial and cardiac precursor cells either directly or indirectly by affecting ion channels and intracellular calcium in particular. Furthermore, down-regulation of genes encoding specific components of the EC coupling machinery suggests that crude oil disrupts excitation-transcription coupling or normal feedback regulation of ion channels blocked by PAHs. These data support a unifying hypothesis whereby depletion of intracellular calcium pools by crude oil-derived PAHs disrupts several pathways critical for organogenesis in fish.

  20. The Core Subunit of A Chromatin-Remodeling Complex, ZmCHB101, Plays Essential Roles in Maize Growth and Development.

    Science.gov (United States)

    Yu, Xiaoming; Jiang, Lili; Wu, Rui; Meng, Xinchao; Zhang, Ai; Li, Ning; Xia, Qiong; Qi, Xin; Pang, Jinsong; Xu, Zheng-Yi; Liu, Bao

    2016-12-05

    ATP-dependent chromatin remodeling complexes play essential roles in the regulation of diverse biological processes by formulating a DNA template that is accessible to the general transcription apparatus. Although the function of chromatin remodelers in plant development has been studied in A. thaliana, how it affects growth and development of major crops (e.g., maize) remains uninvestigated. Combining genetic, genomic and bioinformatic analyses, we show here that the maize core subunit of chromatin remodeling complex, ZmCHB101, plays essential roles in growth and development of maize at both vegetative and reproductive stages. Independent ZmCHB101 RNA interference plant lines displayed abaxially curling leaf phenotype due to increase of bulliform cell numbers, and showed impaired development of tassel and cob. RNA-seq-based transcriptome profiling revealed that ZmCHB101 dictated transcriptional reprogramming of a significant set of genes involved in plant development, photosynthesis, metabolic regulation, stress response and gene expressional regulation. Intriguingly, we found that ZmCHB101 was required for maintaining normal nucleosome density and 45 S rDNA compaction. Our findings suggest that the SWI3 protein, ZmCHB101, plays pivotal roles in maize normal growth and development via regulation of chromatin structure.

  1. Berberine treatment prevents cardiac dysfunction and remodeling through activation of 5'-adenosine monophosphate-activated protein kinase in type 2 diabetic rats and in palmitate-induced hypertrophic H9c2 cells.

    Science.gov (United States)

    Chang, Wenguang; Zhang, Ming; Meng, Zhaojie; Yu, Yang; Yao, Fan; Hatch, Grant M; Chen, Li

    2015-12-15

    Diabetic cardiomyopathy is the major cause of death in type 2 diabetic patients. Berberine is an isoquinoline alkaloid extract from traditional chinese herbs and its hypoglycemic and hypolipidemic effects make it a promising drug for treatment of type 2 diabetes. We examined if berberine improved cardiac function and attenuated cardiac hypertrophy and fibrosis in high fat diet and streptozotocin induced-type 2 diabetic rats in vivo and reduced expression of hypertrophy markers in palmitate-induced hypertrophic H9c2 cells in vitro. Treatment of diabetic animals with berberine partially improved cardiac function and restored fasting blood insulin, fasting blood glucose, total cholesterol, and triglyceride levels to that of control. In addition, berberine treatment of diabetic animals increased cardiac 5'-adenosine monophosphate-activated protein kinase (AMPK) and protein kinase B (AKT) activation and reduced glycogen synthase kinase 3 beta (GSK3β) activation compared to control. Palmitate incubation of H9c2 cells resulted in cellular hypertrophy and decreased expression of alpha-myosin heavy chain (α-MHC) and increased expression of beta-myosin heavy chain (β-MHC) compared to controls. Berberine treatment of palmitate-incubated H9c2 cells reduced hypertrophy, increased α-MHC expression and decreased β-MHC expression. In addition, berberine treatment of palmitate-incubated H9c2 cells increased AMPK and AKT activation and reduced GSK3β activation. The presence of the AMPK inhibitor Compound C attenuated the effects of berberine. The results strongly indicate that berberine treatment may be protective against the development of diabetic cardiomyopathy.

  2. Part and Parcel of the Cardiac Autonomic Nerve System: Unravelling Its Cellular Building Blocks during Development

    Directory of Open Access Journals (Sweden)

    Anna M. D. Végh

    2016-09-01

    Full Text Available The autonomic nervous system (cANS is essential for proper heart function, and complications such as heart failure, arrhythmias and even sudden cardiac death are associated with an altered cANS function. A changed innervation state may underlie (part of the atrial and ventricular arrhythmias observed after myocardial infarction. In other cardiac diseases, such as congenital heart disease, autonomic dysfunction may be related to disease outcome. This is also the case after heart transplantation, when the heart is denervated. Interest in the origin of the autonomic nerve system has renewed since the role of autonomic function in disease progression was recognized, and some plasticity in autonomic regeneration is evident. As with many pathological processes, autonomic dysfunction based on pathological innervation may be a partial recapitulation of the early development of innervation. As such, insight into the development of cardiac innervation and an understanding of the cellular background contributing to cardiac innervation during different phases of development is required. This review describes the development of the cANS and focuses on the cellular contributions, either directly by delivering cells or indirectly by secretion of necessary factors or cell-derivatives.

  3. Development and Validation of Predictive Models of Cardiac Mortality and Transplantation in Resynchronization Therapy

    Directory of Open Access Journals (Sweden)

    Eduardo Arrais Rocha

    2015-01-01

    Full Text Available Abstract Background: 30-40% of cardiac resynchronization therapy cases do not achieve favorable outcomes. Objective: This study aimed to develop predictive models for the combined endpoint of cardiac death and transplantation (Tx at different stages of cardiac resynchronization therapy (CRT. Methods: Prospective observational study of 116 patients aged 64.8 ± 11.1 years, 68.1% of whom had functional class (FC III and 31.9% had ambulatory class IV. Clinical, electrocardiographic and echocardiographic variables were assessed by using Cox regression and Kaplan-Meier curves. Results: The cardiac mortality/Tx rate was 16.3% during the follow-up period of 34.0 ± 17.9 months. Prior to implantation, right ventricular dysfunction (RVD, ejection fraction < 25% and use of high doses of diuretics (HDD increased the risk of cardiac death and Tx by 3.9-, 4.8-, and 5.9-fold, respectively. In the first year after CRT, RVD, HDD and hospitalization due to congestive heart failure increased the risk of death at hazard ratios of 3.5, 5.3, and 12.5, respectively. In the second year after CRT, RVD and FC III/IV were significant risk factors of mortality in the multivariate Cox model. The accuracy rates of the models were 84.6% at preimplantation, 93% in the first year after CRT, and 90.5% in the second year after CRT. The models were validated by bootstrapping. Conclusion: We developed predictive models of cardiac death and Tx at different stages of CRT based on the analysis of simple and easily obtainable clinical and echocardiographic variables. The models showed good accuracy and adjustment, were validated internally, and are useful in the selection, monitoring and counseling of patients indicated for CRT.

  4. cAMP level modulates scleral collagen remodeling, a critical step in the development of myopia.

    Directory of Open Access Journals (Sweden)

    Yijin Tao

    Full Text Available The development of myopia is associated with decreased ocular scleral collagen synthesis in humans and animal models. Collagen synthesis is, in part, under the influence of cyclic adenosine monophosphate (cAMP. We investigated the associations between cAMP, myopia development in guinea pigs, and collagen synthesis by human scleral fibroblasts (HSFs. Form-deprived myopia (FDM was induced by unilateral masking of guinea pig eyes. Scleral cAMP levels increased selectively in the FDM eyes and returned to normal levels after unmasking and recovery. Unilateral subconjunctival treatment with the adenylyl cyclase (AC activator forskolin resulted in a myopic shift accompanied by reduced collagen mRNA levels, but it did not affect retinal electroretinograms. The AC inhibitor SQ22536 attenuated the progression of FDM. Moreover, forskolin inhibited collagen mRNA levels and collagen secretion by HSFs. The inhibition was reversed by SQ22536. These results demonstrate a critical role of cAMP in control of myopia development. Selective regulation of cAMP to control scleral collagen synthesis may be a novel therapeutic strategy for preventing and treating myopia.

  5. Cell cycle regulation and cytoskeletal remodelling are critical processes in the nutritional programming of embryonic development.

    Science.gov (United States)

    Swali, Angelina; McMullen, Sarah; Hayes, Helen; Gambling, Lorraine; McArdle, Harry J; Langley-Evans, Simon C

    2011-01-01

    Many mechanisms purport to explain how nutritional signals during early development are manifested as disease in the adult offspring. While these describe processes leading from nutritional insult to development of the actual pathology, the initial underlying cause of the programming effect remains elusive. To establish the primary drivers of programming, this study aimed to capture embryonic gene and protein changes in the whole embryo at the time of nutritional insult rather than downstream phenotypic effects. By using a cross-over design of two well established models of maternal protein and iron restriction we aimed to identify putative common "gatekeepers" which may drive nutritional programming.Both protein and iron deficiency in utero reduced the nephron complement in adult male Wistar and Rowett Hooded Lister rats (Pmolecular mechanisms which may initiate the sequelae of events involved in nutritional programming of embryonic development. We propose that despite differences in the individual genes and proteins affected in each strain and with each diet, the general response to nutrient deficiency in utero is perturbation of the cell cycle, at the level of interaction with the cytoskeleton and the mitotic checkpoints, thereby diminishing control over the integrity of DNA which is allowed to replicate. These findings offer novel insight into the primary causes and mechanisms leading to the pathologies which have been identified by previous programming studies.

  6. Daptomycin as supportive treatment option in patients developing mediastinitis after open cardiac surgery

    Directory of Open Access Journals (Sweden)

    Weis Florian

    2012-09-01

    Full Text Available Abstract Background Mediastinitis is a severe complication after cardiac surgery. While improvement of prophylaxis and of medical and surgical therapy has reduced its incidence, the treatment of mediastinitis continues to be a challenging problem. Within this study, we report the successful use of daptomycin as supportive therapy in patients developing mediastinitis after open cardiac surgery. Methods The records of 21 consecutive patients who developed mediastinitis after cardiac surgery were retrospectively reviewed. After diagnosis, all patients received surgical debridement and antibiotic therapy with daptomycin. All patients were followed up to death or discharge. Results Clinical improvement after combined surgical and antibiotic therapy with daptomycin was found in 90.5% of the patients. The median time until clinical improvement occurred was 5 [4/6] days. Daptomycin was well-tolerated and no major adverse events during therapy were observed observed. Conclusions This study provides new and helpful information regarding the beneficial use of daptomycin as supportive treatment option in patients developing mediastinitis after cardiac surgery.

  7. Notch promotes epithelial-mesenchymal transition during cardiac development and oncogenic transformation

    Science.gov (United States)

    Timmerman, Luika A.; Grego-Bessa, Joaquín; Raya, Angel; Bertrán, Esther; Pérez-Pomares, José María; Díez, Juan; Aranda, Sergi; Palomo, Sergio; McCormick, Frank; Izpisúa-Belmonte, Juan Carlos; de la Pompa, José Luis

    2004-01-01

    Epithelial-to-mesenchymal transition (EMT) is fundamental to both embryogenesis and tumor metastasis. The Notch intercellular signaling pathway regulates cell fate determination throughout metazoan evolution, and overexpression of activating alleles is oncogenic in mammals. Here we demonstrate that Notch activity promotes EMT during both cardiac development and oncogenic transformation via transcriptional induction of the Snail repressor, a potent and evolutionarily conserved mediator of EMT in many tissues and tumor types. In the embryonic heart, Notch functions via lateral induction to promote a selective transforming growth factor-β (TGFβ)-mediated EMT that leads to cellularization of developing cardiac valvular primordia. Embryos that lack Notch signaling elements exhibit severely attenuated cardiac snail expression, abnormal maintenance of intercellular endocardial adhesion complexes, and abortive endocardial EMT in vivo and in vitro. Accordingly, transient ectopic expression of activated Notch1 (N1IC) in zebrafish embryos leads to hypercellular cardiac valves, whereas Notch inhibition prevents valve development. Overexpression of N1IC in immortalized endothelial cells in vitro induces EMT accompanied by oncogenic transformation, with corresponding induction of snail and repression of VE-cadherin expression. Notch is expressed in embryonic regions where EMT occurs, suggesting an intimate and fundamental role for Notch, which may be reactivated during tumor metastasis. PMID:14701881

  8. BMPER Promotes Epithelial-Mesenchymal Transition in the Developing Cardiac Cushions.

    Directory of Open Access Journals (Sweden)

    Laura Dyer

    Full Text Available Formation of the cardiac valves is an essential component of cardiovascular development. Consistent with the role of the bone morphogenetic protein (BMP signaling pathway in cardiac valve formation, embryos that are deficient for the BMP regulator BMPER (BMP-binding endothelial regulator display the cardiac valve anomaly mitral valve prolapse. However, how BMPER deficiency leads to this defect is unknown. Based on its expression pattern in the developing cardiac cushions, we hypothesized that BMPER regulates BMP2-mediated signaling, leading to fine-tuned epithelial-mesenchymal transition (EMT and extracellular matrix deposition. In the BMPER-/- embryo, EMT is dysregulated in the atrioventricular and outflow tract cushions compared with their wild-type counterparts, as indicated by a significant increase of Sox9-positive cells during cushion formation. However, proliferation is not impaired in the developing BMPER-/- valves. In vitro data show that BMPER directly binds BMP2. In cultured endothelial cells, BMPER blocks BMP2-induced Smad activation in a dose-dependent manner. In addition, BMP2 increases the Sox9 protein level, and this increase is inhibited by co-treatment with BMPER. Consistently, in the BMPER-/- embryos, semi-quantitative analysis of Smad activation shows that the canonical BMP pathway is significantly more active in the atrioventricular cushions during EMT. These results indicate that BMPER negatively regulates BMP-induced Smad and Sox9 activity during valve development. Together, these results identify BMPER as a regulator of BMP2-induced cardiac valve development and will contribute to our understanding of valvular defects.

  9. Molecular pathogenesis of myocardial remodeling and new potential therapeutic targets in chronic heart failure

    Directory of Open Access Journals (Sweden)

    Distefano Giuseppe

    2012-09-01

    Full Text Available Abstract It is well known that the natural history of chronic heart failure (CHF,regardless of age and aetiology,is characterized by progressive cardiac dysfunction refractory to conventional cardiokinetic, diuretic and peripheral vasodilator therapy. Several previous studies, both in animals and humans, showed that the key pathogenetic element of CHF negative clinical evolution is constituted by myocardial remodeling. This is a complex pathologic process of ultrastructural rearrangement of the heart induced by various neuro-humoral factors released by cardiac fibrocells in response to biomechanical stress connected to chronic haemodynamic overload. Typical features of myocardial remodeling are represented by cardiomyocytes hypertrophy and apoptosis, extracellular matrix alterations, mesenchymal fibrotic and phlogistic processes and by cardiac gene expression modifications with fetal genetic program reactivation. In the last years, increasing knowledge of subtle molecular and cellular mechanisms involved in myocardial remodeling has led to the discovery of some new potential therapeutic targets capable of inducing its regression. In this paper our attention is focused on the possible use of antiapoptotic and antifibrotic agents, and on the fascinating perspectives offered by the development of myocardial gene therapy and, in particular, by myocardial regenerative therapy.

  10. Molecular pathogenesis of myocardial remodeling and new potential therapeutic targets in chronic heart failure.

    Science.gov (United States)

    Distefano, Giuseppe; Sciacca, Pietro

    2012-09-12

    It is well known that the natural history of chronic heart failure (CHF),regardless of age and aetiology,is characterized by progressive cardiac dysfunction refractory to conventional cardiokinetic, diuretic and peripheral vasodilator therapy. Several previous studies, both in animals and humans, showed that the key pathogenetic element of CHF negative clinical evolution is constituted by myocardial remodeling. This is a complex pathologic process of ultrastructural rearrangement of the heart induced by various neuro-humoral factors released by cardiac fibrocells in response to biomechanical stress connected to chronic haemodynamic overload. Typical features of myocardial remodeling are represented by cardiomyocytes hypertrophy and apoptosis, extracellular matrix alterations, mesenchymal fibrotic and phlogistic processes and by cardiac gene expression modifications with fetal genetic program reactivation. In the last years, increasing knowledge of subtle molecular and cellular mechanisms involved in myocardial remodeling has led to the discovery of some new potential therapeutic targets capable of inducing its regression. In this paper our attention is focused on the possible use of antiapoptotic and antifibrotic agents, and on the fascinating perspectives offered by the development of myocardial gene therapy and, in particular, by myocardial regenerative therapy.

  11. Cardiac development : the posterior heart field and atrioventricular reentry tachycardia

    NARCIS (Netherlands)

    Hahurij, Nathan Dominggus

    2011-01-01

    This thesis is separated in two parts (Part I and Part II) in which normal and abnormal heart development are studied and related to congenital heart disease, in particular to the etiology of supraventricular arrhythmias in fetuses and neonates. Part I describes the development of the posterior hear

  12. Changes in short-chain acyl-coA dehydrogenase during rat cardiac development and stress

    OpenAIRE

    Huang, Jinxian; Xu, Lipeng; Huang, Qiuju; Luo, Jiani; Liu, Peiqing; Chen, Shaorui; Yuan, Xi; Lu, Yao; Wang, Ping; Zhou, Sigui

    2015-01-01

    This study was designed to investigate the expression of short-chain acyl-CoA dehydrogenase (SCAD), a key enzyme of fatty acid β-oxidation, during rat heart development and the difference of SCAD between pathological and physiological cardiac hypertrophy. The expression of SCAD was lowest in the foetal and neonatal heart, which had time-dependent increase during normal heart development. In contrast, a significant decrease in SCAD expression was observed in different ages of spontaneously hyp...

  13. The Relationship of Left Ventricular Remodeling and Cardiac Function with Ventricular Arrhythmia in Ischemic Cardiomyopathy%缺血性心肌病左室重构和心功能与室性心律失常的关系

    Institute of Scientific and Technical Information of China (English)

    楚涛

    2012-01-01

    目的:探讨缺血性心肌病(ICM)患者左心室重构和心功能与室性心律失常的关系.方法:120例ICM患者分别按左心功能和左心室舒张末期内径(left ventricle end diastolic dimension,LVEDd)分组,分析各组患者发生室性心律失常的情况.结果:ICM患者的复杂型室性早搏、室内传导阻滞、室性早搏并发室内传导阻滞的发生率与LVEDd有明显相关性,差异有显著性(P<0.05);复杂型室性早搏的发生率与左心功能有关,差异有显著性(P<0.05),而室内传导阻滞以及室性早搏并发室内传导阻滞的发生率与左心功能无关,差异无显著性(P>0.05);简单型室性早搏的发生率与LVEDd和左心功能无关,差异无显著性(P>0.05).结论:ICM患者复杂型室性早搏发生与LVEDd及心功能有明显相关性,LVEDd重度增大者更易发生室性早搏及室内传导阻滞.%Objective: To investigate the relationship of left ventricular remodeling and cardiac function with ventricular arrhythmias in patients with ischemic cardiomyopathy (ICM). Methods; Total 120 cases with ICM were divided into groups according to left ventricle end-diastolic dimension (LVEDd) and left ventricular function, and the occurrence of ventricular arrhythmias in each group was investigated. Results; The occurrence of complex ventricular premature beat, intraventricular block and ventricular premature beat complicated with intraventricular block was related to LVEDd ( P 0. 05). Simple type of ventricular premature beat was not related to LVEDd and left heart function (P > 0. 05). Conclusions: The occurrence of complex ventricular premature beat is related to LVEDd and left heart function. When LVEDd is severe enlargement, ventricular premature beat complicated with intraventricular block is more likely to occur.

  14. Cardiac development: the posterior heart field and atrioventricular reentry tachycardia

    OpenAIRE

    2011-01-01

    This thesis is separated in two parts (Part I and Part II) in which normal and abnormal heart development are studied and related to congenital heart disease, in particular to the etiology of supraventricular arrhythmias in fetuses and neonates. Part I describes the development of the posterior heart field derived venous pole of the heart specifically in correlation to the role of Shox2 and podoplanin in that particular area. Furthermore, the developmental processes in this region seem to hav...

  15. Development of a Charge Adjustment Model for Cardiac Catheterization

    OpenAIRE

    Brennan, Andrew; Gauvreau, Kimberlee; Connor, Jean; O’Connell, Cheryl; David, Sthuthi; Almodovar, Melvin; DiNardo, James; Banka, Puja; Mayer, John E.; Marshall, Audrey C.; Bergersen, Lisa

    2014-01-01

    A methodology that would allow for comparison of charges across institutions has not been developed for catheterization in congenital heart disease. A single institution catheterization database with prospectively collected case characteristics was linked to hospital charges related and limited to an episode of care in the catheterization laboratory for fiscal years 2008–2010. Catheterization charge categories (CCC) were developed to group types of catheterization procedures using a combinati...

  16. O-GlcNAcylation, enemy or ally during cardiac hypertrophy development?

    Science.gov (United States)

    Mailleux, Florence; Gélinas, Roselle; Beauloye, Christophe; Horman, Sandrine; Bertrand, Luc

    2016-12-01

    O-linked attachment of the monosaccharide β-N-acetyl-glucosamine (O-GlcNAcylation) is a post-translational modification occurring on serine and threonine residues, which is evolving as an important mechanism for the regulation of various cellular processes. The present review will, first, provide a general background on the molecular regulation of protein O-GlcNAcylation and will summarize the role of this post-translational modification in various acute cardiac pathologies including ischemia-reperfusion. Then, we will focus on research studies examining protein O-GlcNAcylation in the context of cardiac hypertrophy. A particular emphasis will be laid on the convergent but also divergent actions of O-GlcNAcylation according to the type of hypertrophy investigated, including physiological, pressure overload-induced and diabetes-linked cardiac hypertrophy. In an attempt to distinguish whether O-GlcNAcylation is detrimental or beneficial, this review will present the different O-GlcNAcylated targets involved in hypertrophy development. We will finally argue on potential interest to target O-GlcNAc processes to treat cardiac hypertrophy. This article is part of a Special Issue entitled: The role of post-translational protein modifications on heart and vascular metabolism edited by Jason R.B. Dyck & Jan F.C. Glatz.

  17. Association of Cardiac Development with Assisted Reproductive Technology in Childhood: A Prospective Single-Blind Pilot Study

    Directory of Open Access Journals (Sweden)

    Jie Zhou

    2014-08-01

    Full Text Available Aims: To examine the pattern and extent of cardiovascular developmental alterations among children conceived by assisted reproductive technology (ART and its association with potential confounders. Methods: The present study was a prospective single-blind pilot design lasting 15 months. The ART group was recruited by a non-random, consecutive sample on the basis of the unique personal identification number assigned to ART children, whereas spontaneous conception controls were recruited by a population-based random sample from the same hospital by age. Echocardiography was available for the measurement of 128 ART children and 100 controls with respect to cardiovascular geometric morphology and cardiac function. Results: The majority of cardiac geometric morphology parameters were comparable among the study groups (P>0.05, except for significant increases in left ventricular (LV relative wall thickness (P=0.038, LV mass index (P=0.005 and LV remodeling index (P=0.005 in ART children after adjustment for age, gender, body surface area and heart rate. The results showed similarity in LV systolic function characterized by ejection fraction (P=0.140 and shortening fraction (P=0.167 between the groups. However, ART children had a significant tendency toward a decrease in mitral A (P=0.008 and mitral E′ (P=0.012 compared with controls after adjusting for confounders. Additionally, Cox analysis suggested an independent association (PConclusion: Our findings support the presence of remodeling in the left cardiac geometric morphology and diastolic dysfunction and the absence of any change to the aortocoronary morphometry or systolic function in ART children compared with controls, which may be independently associated with the anthropometrics and perinatal outcomes in addition to the ART procedure.

  18. Cardiac fluid dynamics anticipates heart adaptation.

    Science.gov (United States)

    Pedrizzetti, Gianni; Martiniello, Alfonso R; Bianchi, Valter; D'Onofrio, Antonio; Caso, Pio; Tonti, Giovanni

    2015-01-21

    Hemodynamic forces represent an epigenetic factor during heart development and are supposed to influence the pathology of the grown heart. Cardiac blood motion is characterized by a vortical dynamics, and it is common belief that the cardiac vortex has a role in disease progressions or regression. Here we provide a preliminary demonstration about the relevance of maladaptive intra-cardiac vortex dynamics in the geometrical adaptation of the dysfunctional heart. We employed an in vivo model of patients who present a stable normal heart function in virtue of the cardiac resynchronization therapy (CRT, bi-ventricular pace-maker) and who are expected to develop left ventricle remodeling if pace-maker was switched off. Intra-ventricular fluid dynamics is analyzed by echocardiography (Echo-PIV). Under normal conditions, the flow presents a longitudinal alignment of the intraventricular hemodynamic forces. When pacing is temporarily switched off, flow forces develop a misalignment hammering onto lateral walls, despite no other electro-mechanical change is noticed. Hemodynamic forces result to be the first event that evokes a physiological activity anticipating cardiac changes and could help in the prediction of longer term heart adaptations.

  19. Influence of rosuvastatin in left ventricular remodeling and cardiac function after myocardial infarction in rabbits%瑞舒伐他汀对老年兔心肌梗死左室重构和心功能的影响

    Institute of Scientific and Technical Information of China (English)

    陈丹丹; 李加平

    2013-01-01

    Objective To observe and study correlation influence of rosuvastatin in left ventricular remodeling and cardiac function after myocardial infarction in rabbits. Methods Olderly male New Zealand white rabbits were random divided into control group, myocardial infarction group and rosuvastatin group. Myocardial infarction combination rosuvastatin group were established the left anterior descending coronary artery ligation after infarction model, infarction after the establishment of the model to red easy cutting statin calcium from the gastrointestinal tract infusion 4 weeks group for Rosuvastatin group. Before and after molding respectively, left ventricular end-diastolic diameter (LVDD), left ventricular end-systolic diameter (LVDS), left ventricular short axis shorten rate (LVFS) and left ventricular ejection fraction (LVEF) were measured, postoperation muscle cell scar index and muscle cell apoptosis index (AI) was measured. Results The scores and sham operation group comparison, after the success of the infarction myocardial infarction group and red easy cutting statin group of LVFS, LVEF was decreased, but in a way LVDD, LVDS significantly increased (P <0. 01); In myocardial infarction manufacturing model after the success of 14 and 28 d red easy cutting statin group LVDS below myocardial infarction group (P<0. 05 and 0. 01), however LVFS and LVEF were significantly higher than that of myocardial infarction group (P<0. 01) ; In the infarction model after the establishment of the 28 d Rosuvastatin group myocardial scarring index less than myocardial infarction group (P<0. 05); sham operation group AI significantly lower than easy cutting statin group and myocardial infarction group (P<0. 01), but the myocardial infarction group is obviously higher than that of the red easy cutting statin group (P<0. 05). Conclusion Rosuvastatin for elderly rabbit after myocardial infarction myocardial remodeling and cardiac function in a benign influence, its

  20. In utero and lactational 2,3,7,8-tetrachlorodibenzo-p-dioxin exposure: effects on fetal and adult cardiac gene expression and adult cardiac and renal morphology.

    Science.gov (United States)

    Aragon, Andrea C; Kopf, Phillip G; Campen, Matthew J; Huwe, Janice K; Walker, Mary K

    2008-02-01

    The mouse heart is a target of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) during fetal development, and microarray analysis demonstrates significant changes in expression of cardiac genes involved in extracellular matrix (ECM) remodeling. We tested the hypothesis that developmental TCDD exposure would disrupt cardiac ECM expression and be associated with changes in cardiac morphology in adulthood. In one study, time-pregnant C57BL/6 mice were dosed with corn oil or 1.5, 3.0, or 6.0 microg TCDD/kg on gestation day (GD) 14.5 and sacrificed on GD 17.5, when changes in fetal cardiac mRNA expression were analyzed using quantitative PCR. TCDD induced mRNA expression of genes associated with ECM remodeling (matrix metalloproteinase 9 and 13, preproendothelin-1 [preproET-1]), cardiac hypertrophy (atrial natriuretic peptide, beta-myosin heavy chain, osteopontin), and aryl hydrocarbon receptor (AHR) activation (cytochrome P4501A1, AHR repressor). Further, all TCDD-induced changes required the AHR since gene expression was not altered in AHR knockout fetuses. In a second study, time-pregnant mice were treated with corn oil or 6.0 microg TCDD/kg on GD 14.5, and male offspring were assessed for changes in cardiac gene expression and cardiac and renal morphology at 3 months. All TCDD-induced changes in cardiac gene expression observed fetally, except for preproET-1, remained induced in the hearts of adult male offspring. Adult male offspring of TCDD-exposed dams also displayed cardiac hypertrophy, decreased plasma volume, and mild hydronephrosis. These results demonstrate that in utero and lactational TCDD exposures alter cardiac gene expression and cardiac and renal morphology in adulthood, which may increase the susceptibility to cardiovascular dysfunction.

  1. Influence of cardiac magnetic resonance imaging on the ventricular remodeling after ischemic post-conditioning ST-segment elevation myocardial infarction%心脏核磁共振成像对缺血后处理急性 ST 段抬高型心肌梗死后心室重塑的影响

    Institute of Scientific and Technical Information of China (English)

    陈德华; 郑仕杰; 周敬群; 向常清

    2014-01-01

    目的:探讨心脏核磁共振成像(CMR)对缺血后处理急性 ST 段抬高型心肌梗死(STEMI)后心室重塑的影响。方法选择32例12 h 内行缺血后处理的 STEMI 患者作为实验组及12例健康志愿者作为对照组。2组均于术后6个月行 CMR检查,测量左室心功能指标及梗死心肌面积所占百分比,并以24%为分界值,将实验组又分为无重塑组和重塑组。分析各组间的心功能参数差异,并进行受试者工作特征(ROC)分析。结果与对照组比较,无重塑组与重塑组患者的舒张末期容积(EDV)、收缩末期容积(ESV)和每搏输出量(SV)均明显增加,而射血分数(EF)、PER 和 PFR 均有不同程度的下降,其中重塑组下降的幅度更为显著。ESV 与 EDV 的增大呈线性关系;PFR、PER 和 EF 均随 EDV 的增大而呈线性下降趋势。ROC 分析结果显示,EDV、ESV、EF 和 PFR 的曲线下面积分别为0.741、0.764、0.713和0.743。结论CMR 对预测心室重塑有重要作用,其中 PFR、ESV 和 EDV 可作为独立因子预测心室重塑。%Objective To explore the influence of cardiac magnetic resonance imaging (MRI)on the ventricular remodeling after ischemic post-conditioning ST-segment elevation myocardial infarction (STEMI).Methods 32 STEMI patients treated with ischemic post-conditioning in 12 hours were designed as experimental group,and 12 healthy volunteers were designed as control group.The patients in both groups were given CMR 6 months after surgery,and the left ventricular functional in-dexes and percentage of infarction size were measured.With 24% as the limit value,the experiment group was divided into remodeling and non-remodeling groups.Differences of cardiac functional param-eters and receiver operating characteristic (ROC)were analyzed among groups.Results Compared with control group,end-diastolic volume (EDV),end-systolic volume (ESV)and stroke volume (SV)in remodeling and

  2. TAp63 is important for cardiac differentiation of embryonic stem cells and heart development.

    Science.gov (United States)

    Rouleau, Matthieu; Medawar, Alain; Hamon, Laurent; Shivtiel, Shoham; Wolchinsky, Zohar; Zhou, Huiqing; De Rosa, Laura; Candi, Eleonora; de la Forest Divonne, Stéphanie; Mikkola, Marja L; van Bokhoven, Hans; Missero, Caterina; Melino, Gerry; Pucéat, Michel; Aberdam, Daniel

    2011-11-01

    p63, a member of the p53 family, is essential for skin morphogenesis and epithelial stem cell maintenance. Here, we report an unexpected role of TAp63 in cardiogenesis. p63 null mice exhibit severe defects in embryonic cardiac development, including dilation of both ventricles, a defect in trabeculation and abnormal septation. This was accompanied by myofibrillar disarray, mitochondrial disorganization, and reduction in spontaneous calcium spikes. By the use of embryonic stem cells (ESCs), we show that TAp63 deficiency prevents expression of pivotal cardiac genes and production of cardiomyocytes. TAp63 is expressed by endodermal cells. Coculture of p63-knockdown ESCs with wild-type ESCs, supplementation with Activin A, or overexpression of GATA-6 rescue cardiogenesis. Therefore, TAp63 acts in a non-cell-autonomous manner by modulating expression of endodermal factors. Our findings uncover a critical role for p63 in cardiogenesis that could be related to human heart disease.

  3. Renal sympathetic denervation prevents the development of pulmonary arterial hypertension and cardiac dysfunction in dogs.

    Science.gov (United States)

    Hu, Wei; Yu, Sheng-Bo; Chen, Liao; Guo, Rui-Qiang; Zhao, Qing-Yan

    2015-08-01

    The renin-angiotensin-aldosterone system is activated in pulmonary arterial hypertension (PAH) patients, and this activation may have long-term negative effects on the progression of PAH. The purpose of this study was to evaluate the effects of transcatheter renal sympathetic denervation (RSD) on the development of pulmonary arterial hypertension and cardiac dysfunction in dogs using two-dimensional speckle tracking imaging. Twenty-two dogs were randomly divided into three groups: control group (n = 7), PAH group (n = 8), and PAH + RSD group (n = 7). All dogs were assessed using two-dimensional speckle tracking imaging. The ventricular strain, ventricular synchrony, left ventricular (LV) twist, and torsion rate were analyzed to evaluate cardiac function. After 8 weeks, the right ventricular lateral longitudinal strain and the septum longitudinal strain were reduced in the PAH group compared with the control group (p dogs.

  4. Mitochondria-Targeted Antioxidant Prevents Cardiac Dysfunction Induced by Tafazzin Gene Knockdown in Cardiac Myocytes

    Directory of Open Access Journals (Sweden)

    Quan He

    2014-01-01

    Full Text Available Tafazzin, a mitochondrial acyltransferase, plays an important role in cardiolipin side chain remodeling. Previous studies have shown that dysfunction of tafazzin reduces cardiolipin content, impairs mitochondrial function, and causes dilated cardiomyopathy in Barth syndrome. Reactive oxygen species (ROS have been implicated in the development of cardiomyopathy and are also the obligated byproducts of mitochondria. We hypothesized that tafazzin knockdown increases ROS production from mitochondria, and a mitochondria-targeted antioxidant prevents tafazzin knockdown induced mitochondrial and cardiac dysfunction. We employed cardiac myocytes transduced with an adenovirus containing tafazzin shRNA as a model to investigate the effects of the mitochondrial antioxidant, mito-Tempo. Knocking down tafazzin decreased steady state levels of cardiolipin and increased mitochondrial ROS. Treatment of cardiac myocytes with mito-Tempo normalized tafazzin knockdown enhanced mitochondrial ROS production and cellular ATP decline. Mito-Tempo also significantly abrogated tafazzin knockdown induced cardiac hypertrophy, contractile dysfunction, and cell death. We conclude that mitochondria-targeted antioxidant prevents cardiac dysfunction induced by tafazzin gene knockdown in cardiac myocytes and suggest mito-Tempo as a potential therapeutic for Barth syndrome and other dilated cardiomyopathies resulting from mitochondrial oxidative stress.

  5. The role of acute hyperinsulinemia in the development of cardiac arrhythmias.

    Science.gov (United States)

    Drimba, László; Döbrönte, Róbert; Hegedüs, Csaba; Sári, Réka; Di, Yin; Németh, Joseph; Szilvássy, Zoltán; Peitl, Barna

    2013-05-01

    Patients with perturbed metabolic control are more prone to develop cardiac rhythm disturbances. The main purpose of the present preclinical study was to investigate the possible role of euglycemic hyperinsulinemia in development of cardiac arrhythmias. Euglycemic hyperinsulinemia was induced in conscious rabbits equipped with a right ventricular pacemaker electrode catheter by hyperinsulinemic euglycemic glucose clamp (HEGC) applying two different rates of insulin infusion (5 and 10 mIU/kg/min) and variable rate of glucose infusion to maintain euglycemia (5.5 ± 0.5 mmol/l). The effect of hyperinsulinemia on cardiac electrophysiological parameters was continuously monitored by means of 12-lead surface ECG recording. Arrhythmia incidence was determined by means of programmed electrical stimulation (PES). The possible role of adrenergic activation was investigated by determination of plasma catecholamine levels and intravenous administration of a beta adrenergic blocking agent, metoprolol. All of the measurements were performed during the steady-state period of HEGC and subsequent to metoprolol administration. Both 5 and 10 mIU/kg/min insulin infusion prolonged significantly QTend, QTc, and Tpeak-Tend intervals. The incidence of ventricular arrhythmias generated by PES was increased significantly by euglycemic hyperinsulinemia and exhibited linear relationship to plasma levels of insulin. No alteration on plasma catecholamine levels could be observed; however, metoprolol treatment restored the prolonged QTend, QTc, and Tpeak-Tend intervals and significantly reduced the hyperinsulinemia-induced increase of arrhythmia incidence. Euglycemic hyperinsulinemia can exert proarrhythmic effect presumably due to the enhancement of transmural dispersion of repolarization. Metoprolol treatment may be of benefit in hyperinsulinemia associated with increased incidence of cardiac arrhythmias.

  6. Studies on heart development in normal and cardiac mutant axolotls, Ambystoma Mexicanum, using cellular and molecular biology

    Institute of Scientific and Technical Information of China (English)

    2000-01-01

    @@ The Mexican axolotl (Ambystoma mexicanum) provides and excellent model for studying heart development since it carries a simple recessive cardiac lethal mutation that results in a failure of mutant embryonic myocardium to contract.

  7. Pathophysiology of cardiac hypertrophy and heart failure: signaling pathways and novel therapeutic targets.

    Science.gov (United States)

    Tham, Yow Keat; Bernardo, Bianca C; Ooi, Jenny Y Y; Weeks, Kate L; McMullen, Julie R

    2015-09-01

    The onset of heart failure is typically preceded by cardiac hypertrophy, a response of the heart to increased workload, a cardiac insult such as a heart attack or genetic mutation. Cardiac hypertrophy is usually characterized by an increase in cardiomyocyte size and thickening of ventricular walls. Initially, such growth is an adaptive response to maintain cardiac function; however, in settings of sustained stress and as time progresses, these changes become maladaptive and the heart ultimately fails. In this review, we discuss the key features of pathological cardiac hypertrophy and the numerous mediators that have been found to be involved in the pathogenesis of cardiac hypertrophy affecting gene transcription, calcium handling, protein synthesis, metabolism, autophagy, oxidative stress and inflammation. We also discuss new mediators including signaling proteins, microRNAs, long noncoding RNAs and new findings related to the role of calcineurin and calcium-/calmodulin-dependent protein kinases. We also highlight mediators and processes which contribute to the transition from adaptive cardiac remodeling to maladaptive remodeling and heart failure. Treatment strategies for heart failure commonly include diuretics, angiotensin converting enzyme inhibitors, angiotensin II receptor blockers and β-blockers; however, mortality rates remain high. Here, we discuss new therapeutic approaches (e.g., RNA-based therapies, dietary supplementation, small molecules) either entering clinical trials or in preclinical development. Finally, we address the challenges that remain in translating these discoveries to new and approved therapies for heart failure.

  8. Eccentric and concentric cardiac hypertrophy induced by exercise training: microRNAs and molecular determinants

    Directory of Open Access Journals (Sweden)

    T. Fernandes

    2011-09-01

    Full Text Available Among the molecular, biochemical and cellular processes that orchestrate the development of the different phenotypes of cardiac hypertrophy in response to physiological stimuli or pathological insults, the specific contribution of exercise training has recently become appreciated. Physiological cardiac hypertrophy involves complex cardiac remodeling that occurs as an adaptive response to static or dynamic chronic exercise, but the stimuli and molecular mechanisms underlying transduction of the hemodynamic overload into myocardial growth are poorly understood. This review summarizes the physiological stimuli that induce concentric and eccentric physiological hypertrophy, and discusses the molecular mechanisms, sarcomeric organization, and signaling pathway involved, also showing that the cardiac markers of pathological hypertrophy (atrial natriuretic factor, β-myosin heavy chain and α-skeletal actin are not increased. There is no fibrosis and no cardiac dysfunction in eccentric or concentric hypertrophy induced by exercise training. Therefore, the renin-angiotensin system has been implicated as one of the regulatory mechanisms for the control of cardiac function and structure. Here, we show that the angiotensin II type 1 (AT1 receptor is locally activated in pathological and physiological cardiac hypertrophy, although with exercise training it can be stimulated independently of the involvement of angiotensin II. Recently, microRNAs (miRs have been investigated as a possible therapeutic approach since they regulate the translation of the target mRNAs involved in cardiac hypertrophy; however, miRs in relation to physiological hypertrophy have not been extensively investigated. We summarize here profiling studies that have examined miRs in pathological and physiological cardiac hypertrophy. An understanding of physiological cardiac remodeling may provide a strategy to improve ventricular function in cardiac dysfunction.

  9. Eccentric and concentric cardiac hypertrophy induced by exercise training: microRNAs and molecular determinants.

    Science.gov (United States)

    Fernandes, T; Soci, U P R; Oliveira, E M

    2011-09-01

    Among the molecular, biochemical and cellular processes that orchestrate the development of the different phenotypes of cardiac hypertrophy in response to physiological stimuli or pathological insults, the specific contribution of exercise training has recently become appreciated. Physiological cardiac hypertrophy involves complex cardiac remodeling that occurs as an adaptive response to static or dynamic chronic exercise, but the stimuli and molecular mechanisms underlying transduction of the hemodynamic overload into myocardial growth are poorly understood. This review summarizes the physiological stimuli that induce concentric and eccentric physiological hypertrophy, and discusses the molecular mechanisms, sarcomeric organization, and signaling pathway involved, also showing that the cardiac markers of pathological hypertrophy (atrial natriuretic factor, β-myosin heavy chain and α-skeletal actin) are not increased. There is no fibrosis and no cardiac dysfunction in eccentric or concentric hypertrophy induced by exercise training. Therefore, the renin-angiotensin system has been implicated as one of the regulatory mechanisms for the control of cardiac function and structure. Here, we show that the angiotensin II type 1 (AT1) receptor is locally activated in pathological and physiological cardiac hypertrophy, although with exercise training it can be stimulated independently of the involvement of angiotensin II. Recently, microRNAs (miRs) have been investigated as a possible therapeutic approach since they regulate the translation of the target mRNAs involved in cardiac hypertrophy; however, miRs in relation to physiological hypertrophy have not been extensively investigated. We summarize here profiling studies that have examined miRs in pathological and physiological cardiac hypertrophy. An understanding of physiological cardiac remodeling may provide a strategy to improve ventricular function in cardiac dysfunction.

  10. Cardiomyocyte proliferation in cardiac development and regeneration: a guide to methodologies and interpretations.

    Science.gov (United States)

    Leone, Marina; Magadum, Ajit; Engel, Felix B

    2015-10-01

    The newt and the zebrafish have the ability to regenerate many of their tissues and organs including the heart. Thus, a major goal in experimental medicine is to elucidate the molecular mechanisms underlying the regenerative capacity of these species. A wide variety of experiments have demonstrated that naturally occurring heart regeneration relies on cardiomyocyte proliferation. Thus, major efforts have been invested to induce proliferation of mammalian cardiomyocytes in order to improve cardiac function after injury or to protect the heart from further functional deterioration. In this review, we describe and analyze methods currently used to evaluate cardiomyocyte proliferation. In addition, we summarize the literature on naturally occurring heart regeneration. Our analysis highlights that newt and zebrafish heart regeneration relies on factors that are also utilized in cardiomyocyte proliferation during mammalian fetal development. Most of these factors have, however, failed to induce adult mammalian cardiomyocyte proliferation. Finally, our analysis of mammalian neonatal heart regeneration indicates experiments that could resolve conflicting results in the literature, such as binucleation assays and clonal analysis. Collectively, cardiac regeneration based on cardiomyocyte proliferation is a promising approach for improving adult human cardiac function after injury, but it is important to elucidate the mechanisms arresting mammalian cardiomyocyte proliferation after birth and to utilize better assays to determine formation of new muscle mass.

  11. Development of the hearts of lizards and snakes and perspectives to cardiac evolution.

    Science.gov (United States)

    Jensen, Bjarke; van den Berg, Gert; van den Doel, Rick; Oostra, Roelof-Jan; Wang, Tobias; Moorman, Antoon F M

    2013-01-01

    Birds and mammals both developed high performance hearts from a heart that must have been reptile-like and the hearts of extant reptiles have an unmatched variability in design. Yet, studies on cardiac development in reptiles are largely old and further studies are much needed as reptiles are starting to become used in molecular studies. We studied the growth of cardiac compartments and changes in morphology principally in the model organism corn snake (Pantherophis guttatus), but also in the genotyped anole (Anolis carolinenis and A. sagrei) and the Philippine sailfin lizard (Hydrosaurus pustulatus). Structures and chambers of the formed heart were traced back in development and annotated in interactive 3D pdfs. In the corn snake, we found that the ventricle and atria grow exponentially, whereas the myocardial volumes of the atrioventricular canal and the muscular outflow tract are stable. Ventricular development occurs, as in other amniotes, by an early growth at the outer curvature and later, and in parallel, by incorporation of the muscular outflow tract. With the exception of the late completion of the atrial septum, the adult design of the squamate heart is essentially reached halfway through development. This design strongly resembles the developing hearts of human, mouse and chicken around the time of initial ventricular septation. Subsequent to this stage, and in contrast to the squamates, hearts of endothermic vertebrates completely septate their ventricles, develop an insulating atrioventricular plane, shift and expand their atrioventricular canal toward the right and incorporate the systemic and pulmonary venous myocardium into the atria.

  12. ghrelin调控神经生长因子信号途径介导心肌梗死后神经重构%Ghrelin inhibits cardiac neural remodeling after myocardial infarction in rats

    Institute of Scientific and Technical Information of China (English)

    王广丽; 刘磊; 邓笑伟

    2011-01-01

    Objective Ghrelin is a newly discovered peptide as an endogenous ligand for the growth hormone secretagogue receptor,and has been demonstrated to exert beneficial effect in the cardiovascular system.In the present study,we investigated whether ghrelin administration could inhibit cardiac neural remodeling and sympathetic hyperinnervation after myocardial infarction(MI).Methods Sprague-Dawley rats underwent coronary ligation to induce MI and received rat ghrelin(100μg/kg SC BID)or saline(control).Four weeks after treatment,rats were sacrificed.We examined the expression of nerve growth factor and never markers as well as the mRNA expressions of proinflammatory mediators.We also examined the NF-κB p65 protein and IκBα protein levels by western blot analysis.Results Compared to the control group,ghrelin administration significantly decreased the density of nerve fibers with positive immunostaining for GAP43 and TH,and decreased NGF mRNA and protein levels.Ghrelin also significantly suppressed interleukin-1β,tumor necrosis factor-α,and endothelin-1 mRNA expression,and inhibited NF-κB activation.In the MI rats,the mRNA expression of ET-1 at the non-infarcted zones had a significantly positive correlation with the NGF protein levels.Conclusion Treatment with ghrelin inhibited neural remodeling and sympathetic hyperinnervation,the process may be associated with the inhibition of proinflammatory response and NGF signaling.%目的 ghrelin是最近在胃中分离出来的生长激素释放肽受体的内源性配体,在心血管系统显示出了保护效应.本实验探讨了ghrelin对心肌梗死(MI)后大鼠神经重构的影响及其作用机制.方法 SD大鼠结扎冠状动脉制作MI模型作为对照组,干预组在手术后第1天开始给予ghrelin皮下注射,剂量为100μg/kg,每天两次.对照组开胸后在冠状动脉下穿线,但不结扎,给予盐水作皮下注射.经过4个星期治疗后,处死动物.检测梗死区及梗死边缘区神经生长

  13. SU-E-J-129: Atlas Development for Cardiac Automatic Contouring Using Multi-Atlas Segmentation

    Energy Technology Data Exchange (ETDEWEB)

    Zhou, R; Yang, J; Pan, T; Milgrom, S; Pinnix, C; Shi, A; Yang, J; Liu, Y; Nguyen, Q; Gomez, D; Dabaja, B; Balter, P; Court, L; Liao, Z [MD Anderson Cancer Center, Houston, TX (United States)

    2015-06-15

    Purpose: To develop a set of atlases for automatic contouring of cardiac structures to determine heart radiation dose and the associated toxicity. Methods: Six thoracic cancer patients with both contrast and non-contrast CT images were acquired for this study. Eight radiation oncologists manually and independently delineated cardiac contours on the non-contrast CT by referring to the fused contrast CT and following the RTOG 1106 atlas contouring guideline. Fifteen regions of interest (ROIs) were delineated, including heart, four chambers, four coronary arteries, pulmonary artery and vein, inferior and superior vena cava, and ascending and descending aorta. Individual expert contours were fused using the simultaneous truth and performance level estimation (STAPLE) algorithm for each ROI and each patient. The fused contours became atlases for an in-house multi-atlas segmentation. Using leave-one-out test, we generated auto-segmented contours for each ROI and each patient. The auto-segmented contours were compared with the fused contours using the Dice similarity coefficient (DSC) and the mean surface distance (MSD). Results: Inter-observer variability was not obvious for heart, chambers, and aorta but was large for other structures that were not clearly distinguishable on CT image. The average DSC between individual expert contours and the fused contours were less than 50% for coronary arteries and pulmonary vein, and the average MSD were greater than 4.0 mm. The largest MSD of expert contours deviating from the fused contours was 2.5 cm. The mean DSC and MSD of auto-segmented contours were within one standard deviation of expert contouring variability except the right coronary artery. The coronary arteries, vena cava, and pulmonary vein had DSC<70% and MSD>3.0 mm. Conclusion: A set of cardiac atlases was created for cardiac automatic contouring, the accuracy of which was comparable to the variability in expert contouring. However, substantial modification may need

  14. Tomoregulin-1 prevents cardiac hypertrophy after pressure overload in mice by inhibiting TAK1-JNK pathways

    Directory of Open Access Journals (Sweden)

    Dan Bao

    2015-08-01

    Full Text Available Cardiac hypertrophy is associated with many forms of heart disease, and identifying important modifier genes involved in the pathogenesis of cardiac hypertrophy could lead to the development of new therapeutic strategies. Tomoregulin-1 is a growth factor that is primarily involved in embryonic development and adult central nervous system (CNS function, and it is expressed abnormally in a variety of CNS pathologies. Tomoregulin-1 is also expressed in the myocardium. However, the effects of tomoregulin-1 on the heart, particularly on cardiac hypertrophy, remains unknown. The aim of the study is to examine whether and by what mechanism tomoregulin-1 regulates the development of cardiac hypertrophy induced by pressure overload. In this study, we found that tomoregulin-1 was significantly upregulated in two cardiac hypertrophy models: cTnTR92Q transgenic mice and thoracic aorta constriction (TAC-induced cardiac hypertrophy mice. The transgenic overexpression of tomoregulin-1 increased the survival rate, improved the cardiac geometry and functional parameters of echocardiography, and decreased the degree of cardiac hypertrophy of the TAC mice, whereas knockdown of tomoregulin-1 expression resulted in an opposite phenotype and exacerbated phenotypes of cardiac hypertrophy induced by TAC. A possible mechanism by which tomoregulin-1 regulates the development of cardiac hypertrophy in TAC-induced cardiac hypertrophy is through inhibiting TGFβ non-canonical (TAK1-JNK pathways in the myocardium. Tomoregulin-1 plays a protective role in the modulation of adverse cardiac remodeling from pressure overload in mice. Tomoregulin-1 could be a therapeutic target to control the development of cardiac hypertrophy.

  15. Simulations of trabecular remodeling and fatigue: is remodeling helpful or harmful?

    Science.gov (United States)

    van Oers, René F M; van Rietbergen, Bert; Ito, Keita; Huiskes, Rik; Hilbers, Peter A J

    2011-05-01

    Microdamage-targeted resorption is paradoxal, because it entails the removal of bone from a region that was already overloaded. Under continued intense loading, resorption spaces could potentially cause more damage than they remove. To investigate this problem, we incorporated damage algorithms in a computer-simulation model for trabecular remodeling. We simulated damage accumulation and bone remodeling in a trabecular architecture, for two fatigue regimens, a 'moderate' regimen, and an 'intense' regimen with a higher number of loading cycles per day. Both simulations were also performed without bone remodeling to investigate if remodeling removed or exacerbated the damage. We found that remodeling tends to remove damage under the 'moderate' fatigue regimen, but it exacerbates damage under the 'intense' regimen. This harmful effect of remodeling may play a role in the development of stress fractures.

  16. Chromatin Remodelers: From Function to Dysfunction

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    Gernot Längst

    2015-06-01

    Full Text Available Chromatin remodelers are key players in the regulation of chromatin accessibility and nucleosome positioning on the eukaryotic DNA, thereby essential for all DNA dependent biological processes. Thus, it is not surprising that upon of deregulation of those molecular machines healthy cells can turn into cancerous cells. Even though the remodeling enzymes are very abundant and a multitude of different enzymes and chromatin remodeling complexes exist in the cell, the particular remodeling complex with its specific nucleosome positioning features must be at the right place at the right time in order to ensure the proper regulation of the DNA dependent processes. To achieve this, chromatin remodeling complexes harbor protein domains that specifically read chromatin targeting signals, such as histone modifications, DNA sequence/structure, non-coding RNAs, histone variants or DNA bound interacting proteins. Recent studies reveal the interaction between non-coding RNAs and chromatin remodeling complexes showing importance of RNA in remodeling enzyme targeting, scaffolding and regulation. In this review, we summarize current understanding of chromatin remodeling enzyme targeting to chromatin and their role in cancer development.

  17. Permanent ligation of the left anterior descending coronary artery in mice: a model of post-myocardial infarction remodelling and heart failure.

    Science.gov (United States)

    Muthuramu, Ilayaraja; Lox, Marleen; Jacobs, Frank; De Geest, Bart

    2014-12-02

    Heart failure is a syndrome in which the heart fails to pump blood at a rate commensurate with cellular oxygen requirements at rest or during stress. It is characterized by fluid retention, shortness of breath, and fatigue, in particular on exertion. Heart failure is a growing public health problem, the leading cause of hospitalization, and a major cause of mortality. Ischemic heart disease is the main cause of heart failure. Ventricular remodelling refers to changes in structure, size, and shape of the left ventricle. This architectural remodelling of the left ventricle is induced by injury (e.g., myocardial infarction), by pressure overload (e.g., systemic arterial hypertension or aortic stenosis), or by volume overload. Since ventricular remodelling affects wall stress, it has a profound impact on cardiac function and on the development of heart failure. A model of permanent ligation of the left anterior descending coronary artery in mice is used to investigate ventricular remodelling and cardiac function post-myocardial infarction. This model is fundamentally different in terms of objectives and pathophysiological relevance compared to the model of transient ligation of the left anterior descending coronary artery. In this latter model of ischemia/reperfusion injury, the initial extent of the infarct may be modulated by factors that affect myocardial salvage following reperfusion. In contrast, the infarct area at 24 hr after permanent ligation of the left anterior descending coronary artery is fixed. Cardiac function in this model will be affected by 1) the process of infarct expansion, infarct healing, and scar formation; and 2) the concomitant development of left ventricular dilatation, cardiac hypertrophy, and ventricular remodelling. Besides the model of permanent ligation of the left anterior descending coronary artery, the technique of invasive hemodynamic measurements in mice is presented in detail.

  18. Biomimetic material strategies for cardiac tissue engineering

    Energy Technology Data Exchange (ETDEWEB)

    Prabhakaran, Molamma P., E-mail: nnimpp@nus.edu.sg [Health Care and Energy Materials Laboratory, Nanoscience and Nanotechnology Initiative, Faculty of Engineering, National University of Singapore, 2 Engineering Drive 3, Singapore 117576 (Singapore); Venugopal, J. [Health Care and Energy Materials Laboratory, Nanoscience and Nanotechnology Initiative, Faculty of Engineering, National University of Singapore, 2 Engineering Drive 3, Singapore 117576 (Singapore); Kai, Dan [NUS Graduate School for Integrative Sciences and Engineering, National University of Singapore (Singapore); Ramakrishna, Seeram [Health Care and Energy Materials Laboratory, Nanoscience and Nanotechnology Initiative, Faculty of Engineering, National University of Singapore, 2 Engineering Drive 3, Singapore 117576 (Singapore)

    2011-04-08

    Cardiovascular disease precedes many serious complications including myocardial infarction (MI) and it remains a major problem for the global community. Adult mammalian heart has limited ability to regenerate and compensate for the loss of cardiomyocytes. Restoration of cardiac function by replacement of diseased myocardium with functional cardiomyocytes is an intriguing strategy because it offers a potential cure for MI. Biomaterials are fabricated in nanometer scale dimensions by combining the chemical, biological, mechanical and electrical aspects of material for potential tissue engineering (TE) applications. Synthetic polymers offer advantageous in their ability to tailor the mechanical properties, and natural polymers offer cell recognition sites necessary for cell, adhesion and proliferation. Cardiac tissue engineering (TE) aim for the development of a bioengineered construct that can provide physical support to the damaged cardiac tissue by replacing certain functions of the damaged extracellular matrix and prevent adverse cardiac remodeling and dysfunction after MI. Electrospun nanofibers are applied as heart muscle patches, while hydrogels serve as a platform for controlled delivery of growth factors, prevent mechanical complications and assist in cell recruitment. This article reviews the applications of different natural and synthetic polymeric materials utilized as cardiac patches, injectables or 3D constructs for cardiac TE. Smart organization of nanoscale assemblies with synergistic approaches of utilizing nanofibers and hydrogels could further advance the field of cardiac tissue engineering. Rapid innovations in biomedical engineering and cell biology will bring about new insights in the development of optimal scaffolds and methods to create tissue constructs with relevant contractile properties and electrical integration to replace or substitute the diseased myocardium.

  19. The development of an internet-based outpatient cardiac rehabilitation intervention: a Delphi study

    Directory of Open Access Journals (Sweden)

    Hanley Christine

    2010-06-01

    Full Text Available Abstract Background Face-to-face outpatient cardiac rehabilitation (OCR programs are an important and effective component in the management of cardiovascular disease. However, these programs have low participation rates, especially among patients who live rural or remote. Hence, there is a need to develop OCR programs that provide an alternative to face-to-face contact such as by using the Internet. Only a very limited number of Internet-based OCR programs have been developed and evaluated. Therefore, the purpose of this study was to identify issues that are relevant to the development of an Internet-based OCR intervention. Methods A three-round Delphi study among cardiac rehabilitation experts was conducted. In the first round, 43 experts outlined opinions they had on the development of an online ORC platform into an open-ended electronic questionnaire. In the second round, 42 experts completed a structured (five-point scale electronic questionnaire based on first round results, in which they scored items on their relevance. In the third round, the same experts were asked to re-rate the same items after feedback was given about the group median relevance score to establish a level of consensus. Results After the third round, high consensus was reached in 120 of 162 (74% questionnaire items, of which 93 (57% of 162 items also had high relevance according to the experts. The results indicate that experts strongly agreed on desired website content, data obtained from the patient, and level of interaction with patients that should be part of an Internet-based OCR intervention. Conclusion The high rates of consensus and relevance observed among cardiac rehabilitation experts are an indication that they perceived the development and implementation of an Internet-based ORC intervention as feasible, and as a valuable alternative to face-to-face programs. In many ways the experts indicated that an Internet-based ORC program should mimic a traditional

  20. Cardiac cameras.

    Science.gov (United States)

    Travin, Mark I

    2011-05-01

    Cardiac imaging with radiotracers plays an important role in patient evaluation, and the development of suitable imaging instruments has been crucial. While initially performed with the rectilinear scanner that slowly transmitted, in a row-by-row fashion, cardiac count distributions onto various printing media, the Anger scintillation camera allowed electronic determination of tracer energies and of the distribution of radioactive counts in 2D space. Increased sophistication of cardiac cameras and development of powerful computers to analyze, display, and quantify data has been essential to making radionuclide cardiac imaging a key component of the cardiac work-up. Newer processing algorithms and solid state cameras, fundamentally different from the Anger camera, show promise to provide higher counting efficiency and resolution, leading to better image quality, more patient comfort and potentially lower radiation exposure. While the focus has been on myocardial perfusion imaging with single-photon emission computed tomography, increased use of positron emission tomography is broadening the field to include molecular imaging of the myocardium and of the coronary vasculature. Further advances may require integrating cardiac nuclear cameras with other imaging devices, ie, hybrid imaging cameras. The goal is to image the heart and its physiological processes as accurately as possible, to prevent and cure disease processes.

  1. Leptin as a mediator between obesity and cardiac dysfunction

    Directory of Open Access Journals (Sweden)

    Joanna Karbowska

    2012-05-01

    Full Text Available  Obesity is now recognised as one of the most important risk factors for heart disease. Obese individuals have high circulating levels of leptin, a hormone secreted by adipose tissue and in­volved in energy homeostasis. Growing evidence suggests that leptin may contribute to the development of cardiac dysfunction. In a large prospective study leptin has been shown to be an independent risk factor for coronary heart disease. An independent positive association has also been found between plasma leptin levels and heart rate in hypertensive patients and heart transplant recipients. In animal studies chronic leptin infusion increased heart rate and blood pressure. It has also been demonstrated that circulating leptin levels are elevated in patients with heart failure. The level of plasma leptin was associated with increased myocardial wall thickness and correlated with left ventricular mass, suggesting a role for this hormone in mediating left ventricular hypertrophy in humans. Moreover, leptin directly induced hypertrophy and hyperplasia in human and rodent cardiomyocytes, accompanied by cardiac extracellular matrix remodelling. Leptin may also influence energy substrate utilisation in cardiac tissue.These findings suggest that leptin acting directly or through the sympathetic nervous system may have adverse effects on cardiac structure and function, and that chronic hyperleptinaemia may greatly increase the risk of cardiac disorders. Additional studies are needed to define the role of leptin in cardiac physiology and pathophysiology, nevertheless the reduction in plasma leptin levels with caloric restriction and weight loss may prevent cardiac dysfunction in obese patients.

  2. Gene regulation, alternative splicing, and posttranslational modification of troponin subunits in cardiac development and adaptation: a focused review.

    Science.gov (United States)

    Sheng, Juan-Juan; Jin, Jian-Ping

    2014-01-01

    Troponin plays a central role in regulating the contraction and relaxation of vertebrate striated muscles. This review focuses on the isoform gene regulation, alternative RNA splicing, and posttranslational modifications of troponin subunits in cardiac development and adaptation. Transcriptional and posttranscriptional regulations such as phosphorylation and proteolysis modifications, and structure-function relationships of troponin subunit proteins are summarized. The physiological and pathophysiological significances are discussed for impacts on cardiac muscle contractility, heart function, and adaptations in health and diseases.

  3. Cenderitide-eluting film for potential cardiac patch applications.

    Directory of Open Access Journals (Sweden)

    Xu Wen Ng

    Full Text Available Cenderitide, also known as CD-NP, is a designer peptide developed by combining native mammalian c-type natriuretic peptide (CNP and the C-terminus isolated from the dendroapis natriuretic peptide (DNP of the venom from the green mamba. In early studies, intravenous and subcutaneous infusion of cenderitide was reported to reduce left ventricular (LV mass and ameliorate cardiac remodelling. In this work, biodegradable polymeric films encapsulating CD-NP were developed and were investigated for their in vitro release and degradation characteristics. Subsequently, the bioactivity of released peptide and its effects on human cardiac fibroblast (HCF were explored. We achieved sustained release from three films with low, intermediate and high release profiles for 30 days. Moreover, the bioactivity of released peptide was verified from the elevated production of cyclic guanosine monophospate (cGMP. The CD-NP released from films was able to inhibit the proliferation of hypertrophic HCF as well as suppress DNA synthesis in HCF. Furthermore, the sustained delivery from films showed comparable or superior suppressive actions on hypertrophic HCF compared to daily infusion of CD-NP. The results suggest that these films could be used to inhibit fibrosis and reduce cardiac remodelling via local delivery as cardiac patches.

  4. Cardiac surgery-associated acute kidney injury in a developing country: Prevalence, risk factors and outcome

    OpenAIRE

    2015-01-01

    Little is known about cardiac surgery-associated acute kidney injury (CS-AKI) in children in developing regions of the world. The study aimed to determine the prevalence of CSAKI, associated factors and its impact on mortality and utilization of hospital services. The hospital records of children aged 0-17 years who underwent CS at an Indian hospital were reviewed. CS-AKI was defined as a rise in serum creatinine of ≥0.3 mg/dL in any 48 h and or by urine output

  5. NDR Kinases Are Essential for Somitogenesis and Cardiac Looping during Mouse Embryonic Development.

    Directory of Open Access Journals (Sweden)

    Debora Schmitz-Rohmer

    Full Text Available Studies of mammalian tissue culture cells indicate that the conserved and distinct NDR isoforms, NDR1 and NDR2, play essential cell biological roles. However, mice lacking either Ndr1 or Ndr2 alone develop normally. Here, we studied the physiological consequences of inactivating both NDR1 and NDR2 in mice, showing that the lack of both Ndr1/Ndr2 (called Ndr1/2-double null mutants causes embryonic lethality. In support of compensatory roles for NDR1 and NDR2, total protein and activating phosphorylation levels of the remaining NDR isoform were elevated in mice lacking either Ndr1 or Ndr2. Mice retaining one single wild-type Ndr allele were viable and fertile. Ndr1/2-double null embryos displayed multiple phenotypes causing a developmental delay from embryonic day E8.5 onwards. While NDR kinases are not required for notochord formation, the somites of Ndr1/2-double null embryos were smaller, irregularly shaped and unevenly spaced along the anterior-posterior axis. Genes implicated in somitogenesis were down-regulated and the normally symmetric expression of Lunatic fringe, a component of the Notch pathway, showed a left-right bias in the last forming somite in 50% of all Ndr1/2-double null embryos. In addition, Ndr1/2-double null embryos developed a heart defect that manifests itself as pericardial edemas, obstructed heart tubes and arrest of cardiac looping. The resulting cardiac insufficiency is the likely cause of the lethality of Ndr1/2-double null embryos around E10. Taken together, we show that NDR kinases compensate for each other in vivo in mouse embryos, explaining why mice deficient for either Ndr1 or Ndr2 are viable. Ndr1/2-double null embryos show defects in somitogenesis and cardiac looping, which reveals their essential functions and shows that the NDR kinases are critically required during the early phase of organogenesis.

  6. Reverse right ventricular structural and extracellular matrix remodeling by estrogen in severe pulmonary hypertension.

    Science.gov (United States)

    Nadadur, Rangarajan D; Umar, Soban; Wong, Gabriel; Eghbali, Mansour; Iorga, Andrea; Matori, Humann; Partow-Navid, Rod; Eghbali, Mansoureh

    2012-07-01

    Chronic pulmonary hypertension (PH) leads to right-ventricular failure (RVF) characterized by RV remodeling. Ventricular remodeling is emerging as an important process during heart failure and recovery. Remodeling in RVF induced by PH is not fully understood. Recently we discovered that estrogen (E2) therapy can rescue severe preexisting PH. Here, we focused on whether E2 (42.5 μg·kg(-1)·day(-1), 10 days) can reverse adverse RV structural and extracellular matrix (ECM) remodeling induced by PH using monocrotaline (MCT, 60 mg/kg). RV fibrosis was evident in RVF males. Intact females developed less severe RV remodeling compared with males and ovariectomized (OVX) females. Novel ECM-degrading disintegrin-metalloproteinases ADAM15 and ADAM17 transcripts were elevated ∼2-fold in all RVF animals. E2 therapy reversed RV remodeling in all groups. In vitro, E2 directly inhibited ANG II-induced expression of fibrosis markers as well as the metalloproteinases in cultured cardiac fibroblasts. Estrogen receptor-β agonist diarylpropionitrile (DPN) but not estrogen receptor-α agonist 4,4',4″-(4-propyl-[1H]-pyrazole-1,3,5-triyl)trisphenol (PPT) was as effective as E2 in inhibiting expression of these genes. Expression of ECM-interacting cardiac fetal-gene osteopontin (OPN) also increased ∼9-fold in RVF males. Intact females were partially protected from OPN upregulation (∼2-fold) but OVX females were not. E2 reversed OPN upregulation in all groups. Upregulation of OPN was also reversed in vitro by E2. Plasma OPN was elevated in RVF (∼1.5-fold) and decreased to control levels in the E2 group. RVF resulted in elevated Akt phosphorylation, but not ERK, in the RV, and E2 therapy restored Akt phosphorylation. In conclusion, E2 therapy reverses adverse RV remodeling associated with PH by reversing fibrosis and upregulation of novel ECM enzymes ADAM15, ADAM17, and OPN. These effects are likely mediated through estrogen receptor-β.

  7. PRKAR1A in the development of cardiac myxoma: a study of 110 cases including isolated and syndromic tumors.

    Science.gov (United States)

    Maleszewski, Joseph J; Larsen, Brandon T; Kip, Nefize Sertac; Castonguay, Mathieu C; Edwards, William D; Carney, J Aidan; Kipp, Benjamin R

    2014-08-01

    Cardiac myxoma usually occurs as a solitary mass, but occasionally develops as part of a familial syndrome, the Carney complex (CNC). Two thirds of CNC-associated cardiac myxomas exhibit mutations in PRKAR1A. PRKAR1A mutations occur in both familial and sporadic forms of CNC but have not been described in isolated (nonsyndromic) cardiac myxomas. A total of 127 consecutive cardiac myxomas surgically resected at Mayo Clinic (1993 to 2011) from 110 individuals were studied. Clinical, radiologic, and pathologic findings were reviewed. Of these, 103 patients had isolated cardiac myxomas, and 7 patients had the tumor as a component of CNC. Age and sex distributions were different for CNC (mean 26 y, range 14 to 44 y, 71% female) and non-CNC (mean 62 y, range 18 to 92 y, 63% female) patients. PRKAR1A immunohistochemical analysis (IHC) was performed, and myxoma cell reactivity was graded semiquantitatively. Bidirectional Sanger sequencing was performed in 3 CNC patients and 29 non-CNC patients, to test for the presence of mutations in all coding regions and intron/exon boundaries of the PRKAR1A gene. IHC staining showed that all 7 CNC cases lacked PRKAR1A antigenicity and that 33 (32%) isolated cardiac myxomas were similarly nonreactive. Of tumors subjected to sequencing analysis, 2 (67%) CNC myxomas and 9 (31%) non-CNC myxomas had pathogenic PRKAR1A mutations. No germline mutations were found in 4 non-CNC cases tested. PRKAR1A appears to play a role in the development of both syndromic and nonsyndromic cardiac myxomas. Routine IHC evaluation of cardiac myxomas for PRKAR1A expression may be useful in excluding a diagnosis of CNC.

  8. Kruppel-like factor 2 is required for normal mouse cardiac development.

    Directory of Open Access Journals (Sweden)

    Aditi R Chiplunkar

    Full Text Available Krüppel-like factor 2 (KLF2 is expressed in endothelial cells in the developing heart, particularly in areas of high shear stress, such as the atrioventricular (AV canal. KLF2 ablation leads to myocardial thinning, high output cardiac failure and death by mouse embryonic day 14.5 (E14.5 in a mixed genetic background. This work identifies an earlier and more fundamental role for KLF2 in mouse cardiac development in FVB/N mice. FVB/N KLF2-/- embryos die earlier, by E11.5. E9.5 FVB/N KLF2-/- hearts have multiple, disorganized cell layers lining the AV cushions, the primordia of the AV valves, rather than the normal single layer. By E10.5, traditional and endothelial-specific FVB/N KLF2-/- AV cushions are hypocellular, suggesting that the cells accumulating at the AV canal have a defect in endothelial to mesenchymal transformation (EMT. E10.5 FVB/N KLF2-/- hearts have reduced glycosaminoglycans in the cardiac jelly, correlating with the reduced EMT. However, the number of mesenchymal cells migrating from FVB/N KLF2-/- AV explants into a collagen matrix is reduced considerably compared to wild-type, suggesting that the EMT defect is not due solely to abnormal cardiac jelly. Echocardiography of E10.5 FVB/N KLF2-/- embryos indicates that they have abnormal heart function compared to wild-type. E10.5 C57BL/6 KLF2-/- hearts have largely normal AV cushions. However, E10.5 FVB/N and C57BL/6 KLF2-/- embryos have a delay in the formation of the atrial septum that is not observed in a defined mixed background. KLF2 ablation results in reduced Sox9, UDP-glucose dehydrogenase (Ugdh, Gata4 and Tbx5 mRNA in FVB/N AV canals. KLF2 binds to the Gata4, Tbx5 and Ugdh promoters in chromatin immunoprecipitation assays, indicating that KLF2 could directly regulate these genes. In conclusion, KLF2-/- heart phenotypes are genetic background-dependent. KLF2 plays a role in EMT through its regulation of important cardiovascular genes.

  9. Airway remodeling in asthma: what really matters.

    Science.gov (United States)

    Fehrenbach, Heinz; Wagner, Christina; Wegmann, Michael

    2017-03-01

    Airway remodeling is generally quite broadly defined as any change in composition, distribution, thickness, mass or volume and/or number of structural components observed in the airway wall of patients relative to healthy individuals. However, two types of airway remodeling should be distinguished more clearly: (1) physiological airway remodeling, which encompasses structural changes that occur regularly during normal lung development and growth leading to a normal mature airway wall or as an acute and transient response to injury and/or inflammation, which ultimately results in restoration of a normal airway structures; and (2) pathological airway remodeling, which comprises those structural alterations that occur as a result of either disturbed lung development or as a response to chronic injury and/or inflammation leading to persistently altered airway wall structures and function. This review will address a few major aspects: (1) what are reliable quantitative approaches to assess airway remodeling? (2) Are there any indications supporting the notion that airway remodeling can occur as a primary event, i.e., before any inflammatory process was initiated? (3) What is known about airway remodeling being a secondary event to inflammation? And (4), what can we learn from the different animal models ranging from invertebrate to primate models in the study of airway remodeling? Future studies are required addressing particularly pheno-/endotype-specific aspects of airway remodeling using both endotype-specific animal models and "endotyped" human asthmatics. Hopefully, novel in vivo imaging techniques will be further advanced to allow monitoring development, growth and inflammation of the airways already at a very early stage in life.

  10. Developing competence in cardiac care through the use of blended learning: course members' and mentors' accounts.

    Science.gov (United States)

    Iley, Karen; McInulty, Lorna; Jones, Ian; Yorke, Janelle; Johnson, Martin

    2011-05-01

    The use of blended learning to develop the clinical knowledge and skills of healthcare professionals is increasing. This paper reports the qualitative findings from an evaluation of a blended learning course designed to equip registered nurses with the knowledge and skills required to practice competently in cardiac nursing. The aims of the study were to explore whether a cardiac care course could be successfully delivered mainly online and it had any impact on the students' clinical practice. The sample consisted of course members and their mentors. Data were obtained through focus groups and interviews and analysed using thematic analysis. All students felt they had benefited from undertaking the course. Mentors identified higher levels of confidence and greater depth of knowledge and skills amongst their students. Areas identified for further development by both groups were firstly, the preparation of mentors for their role in supporting the students undertaking an online course and secondly, the expected level of competence that students needed to display in practice. This study indicates online learning is useful in enhancing student competence but may be wrongly seen as requiring less time commitment for both course members and mentors when compared to taught courses.

  11. Vitronectin-binding PAI-1 protects against the development of cardiac fibrosis through interaction with fibroblasts.

    Science.gov (United States)

    Zhong, Jianyong; Yang, Hai-Chun; Kon, Valentina; Fogo, Agnes B; Lawrence, Daniel A; Ma, Ji

    2014-06-01

    Plasminogen activator inhibitor-1 (PAI-1) promotes or abates fibrotic processes occurring in different organs. Binding of PAI-1 to vitronectin, an extracellular matrix component, may inhibit vitronectin-integrin complex-mediated cellular responses in pathophysiological conditions. To investigate the importance of plasmin suppression vs vitronectin-binding pathways of PAI-1 in cardiac fibrosis, we studied uninephrectomized mice fed a high salt diet and infused with angiotensin II (Ang II) together with different PAI-1 variants, including PAI-1AK (AK) that inhibits plasminogen activators but does not bind vitronectin, PAI-1RR (RR) that binds vitronectin but does not have protease inhibitory effects or control PAI-1 (CPAI), the control mutant that has similar molecular backbone and half-life as AK and RR while retaining all functions of native PAI-1. Compared with RR and CPAI, non-vitronectin-binding AK significantly increased expression of cardiac fibroblast marker, periostin (Ang+AK 8.40±3.55 vs Ang+RR 2.23±0.44 and Ang+CPAI 2.33±0.12% positive area, both PPAI-1 against fibrosis, fibroblasts from normal adult human ventricles were stimulated with Ang and different PAI-1 variants. Protease inhibitory AK and CPAI increased supernatant fibronectin, while decreasing plasminogen activator/plasmin activities and matrix metalloproteinase. RR and CPAI variants significantly reduced fibroblast expression of integrin β3, vitronectin level in the supernatant and fibroblast adhesion to vitronectin compared with the non-vitronectin-binding AK. Further, RR and CPAI preserved apoptotic, decreased anti-apoptotic and proliferative activities in fibroblasts. Thus, PAI-1 promotes or protects against development of cardiac fibrosis differentially through the protease inhibitory pathway or through its binding to vitronectin.

  12. Vascular Remodelling and Mesenchymal Transition in Systemic Sclerosis

    Directory of Open Access Journals (Sweden)

    Pier Andrea Nicolosi

    2016-01-01

    Full Text Available Fibrosis of the skin and of internal organs, autoimmunity, and vascular inflammation are hallmarks of Systemic Sclerosis (SSc. The injury and activation of endothelial cells, with hyperplasia of the intima and eventual obliteration of the vascular lumen, are early features of SSc. Reduced capillary blood flow coupled with deficient angiogenesis leads to chronic hypoxia and tissue ischemia, enforcing a positive feed-forward loop sustaining vascular remodelling, further exacerbated by extracellular matrix accumulation due to fibrosis. Despite numerous developments and a growing number of controlled clinical trials no treatment has been shown so far to alter SSc natural history, outlining the need of further investigation in the molecular pathways involved in the pathogenesis of the disease. We review some processes potentially involved in SSc vasculopathy, with attention to the possible effect of sustained vascular inflammation on the plasticity of vascular cells. Specifically we focus on mesenchymal transition, a key phenomenon in the cardiac and vascular development as well as in the remodelling of injured vessels. Recent work supports the role of transforming growth factor-beta, Wnt, and Notch signaling in these processes. Importantly, endothelial-mesenchymal transition may be reversible, possibly offering novel cues for treatment.

  13. Echocardiographic evaluation of pressure overload-induced cardiac remodeling in mice using different ultrasound machines%小动物超声仪与临床用超声仪评价小鼠心脏重构的对比分析

    Institute of Scientific and Technical Information of China (English)

    赵静; 曾智; 颜亮; 纪丽景; 罗滔; 宾建平; 廖禹林

    2011-01-01

    目的 比较不同类型超声仪对小鼠压力负荷下心脏重构的评价结果.方法 C57 BL/6小鼠18只,随机分为假手术(sham)组和主动脉弓缩窄(TAC)组,每组9只.手术8周后,首先应用连接15L8高频探头的临床用西门子超声仪测定TAC组小鼠心功能,并比较清醒和麻醉状态下的差异.然后比较西门子超声仪和小动物用高分辨超声仪(Vevo770)对心功能评价的影响.结果 与清醒状态相比,异氟烷吸入麻醉小鼠的心率和左室短轴缩短率显著降低(P<0.001),而左室内径显著增加(P<0.05).但与相应的sham组比较,两种仪器都可以较敏感地反映TAC组的心脏重构.与西门子超声仪相比,小动物超声仪的分辨率明显增高,并可通过二尖瓣血流频谱图评价左室舒张功能,但暂不能在小鼠清醒状态下评价心功能.结论 麻醉本身会降低心功能,但在反映干预手段对心脏重构的影响程度上与清醒状态下有可比性.高分辨小动物超声仪在评价左室舒张功能方面优于西门子超声仪.%To compare the results of echocardiographic evaluation of pressure overload-induced cardiac remodeling in mice using different ultrasound machines. Methods Eighteen C57 BL/6 mice were randomly divided into the sham-operated and the transverse aortic constriction (TAC) groups (n=9). Eight weeks after the operation, the cardiac function of TAC group was evaluated using Siemens ultrasonic instrument with 15L8 probe and the differences between the awake and anesthetized states were compared. The heart rate, left ventricular (LV) dimensions, systolic and diastolic functions were measured in both sham-operated and TAC groups using the Siemens ultrasonic instrument and a high-resolution ultrasonic imaging system for small animals (Vevo 770). Results Compared with the mice in wakefulness, the anesthetized mice showed significantly decreased heart rate and LV fractional shortening (P<0.001) and markedly increased LV end

  14. Effects of erythropoietin on advanced pulmonary vascular remodelling

    NARCIS (Netherlands)

    van Albada, M. E.; Sarvaas, G. J. du Marchie; Koster, J.; Houwertjes, M. C.; Berger, R. M. F.; Schoemaker, R. G.

    2008-01-01

    Erythropoietin (EPO) mobilises endothelial progenitor cells and promotes neovascularisation in heart failure. The present authors studied the effects of EPO on pulmonary vascular and cardiac remodelling in a model for flow-associated pulmonary arterial hypertension (PAH). PAH was induced in adult ma

  15. Effects of electrical and structural remodeling on atrial fibrillation maintenance: a simulation study.

    Science.gov (United States)

    Krogh-Madsen, Trine; Abbott, Geoffrey W; Christini, David J

    2012-01-01

    Atrial fibrillation, a common cardiac arrhythmia, often progresses unfavourably: in patients with long-term atrial fibrillation, fibrillatory episodes are typically of increased duration and frequency of occurrence relative to healthy controls. This is due to electrical, structural, and contractile remodeling processes. We investigated mechanisms of how electrical and structural remodeling contribute to perpetuation of simulated atrial fibrillation, using a mathematical model of the human atrial action potential incorporated into an anatomically realistic three-dimensional structural model of the human atria. Electrical and structural remodeling both shortened the atrial wavelength--electrical remodeling primarily through a decrease in action potential duration, while structural remodeling primarily slowed conduction. The decrease in wavelength correlates with an increase in the average duration of atrial fibrillation/flutter episodes. The dependence of reentry duration on wavelength was the same for electrical vs. structural remodeling. However, the dynamics during atrial reentry varied between electrical, structural, and combined electrical and structural remodeling in several ways, including: (i) with structural remodeling there were more occurrences of fragmented wavefronts and hence more filaments than during electrical remodeling; (ii) dominant waves anchored around different anatomical obstacles in electrical vs. structural remodeling; (iii) dominant waves were often not anchored in combined electrical and structural remodeling. We conclude that, in simulated atrial fibrillation, the wavelength dependence of reentry duration is similar for electrical and structural remodeling, despite major differences in overall dynamics, including maximal number of filaments, wave fragmentation, restitution properties, and whether dominant waves are anchored to anatomical obstacles or spiralling freely.

  16. Remodeling A School Shop?

    Science.gov (United States)

    Baker, G. E.

    1970-01-01

    Presents guidelines for remodeling a school shop combining major considerations of funds, program changes, class management, and flexibility, with the needs of wiring, painting, and placement of equipment. (Author)

  17. Development of an enzyme-linked immunosorbent assay for detection of chicken osteocalcin and its use in evaluation of perch effects on bone remodeling in caged White Leghorns.

    Science.gov (United States)

    Jiang, S; Cheng, H W; Hester, P Y; Hou, J-F

    2013-08-01

    Osteocalcin (OC) is a sensitive biochemical marker for evaluating bone turnover in mammals. The role of avian OC is less clear because of the need for a chicken assay. Our objectives were to develop an assay using indirect competitive ELISA for detecting chicken serum OC and use the assay to examine the effects of perches on bone remodeling in caged hens. Anti-chicken OC polyclonal antibody was produced by immunization of rabbits with a recombinant OC from Escherichia coli. Chicken OC extracted from bone was used as a coated protein, and purified chicken OC was used for calibration. The limit of detection of the developed OC ELISA was 0.13 ng/mL. The intra- and interassay CV were chickens that never had access to perches during their life cycle. Treatment 2 chickens had perches during the pullet phase (0 to 16.9 wk of age), whereas treatment 3 chickens had perches only during the egg-laying phase of the life cycle (17 to 71 wk of age). Treatment 4 chickens always had access to perches (0 to 71 wk of age). Correlation between the 2 assays was 0.62 (P chicken ELISA were higher than that detected using the Rat-Mid ELISA (P chicken ELISA assay showed that hens with perch access had higher concentrations of serum OC than hens without perches during egg laying (P = 0.04). Pullet access to perches did not affect serum OC levels in 71-wk-old hens (P = 0.15). In conclusion, a chicken OC ELISA has been validated that is sensitive and accurate with adequate discriminatory power for measuring bone remodeling in chickens.

  18. GAJA: 3D CAD methodology for developing a parametric system for the automatic (re)modeling of the cutting components of compound washer dies

    Institute of Scientific and Technical Information of China (English)

    David POTO(C)NIK; Bojan DOL(S)AK; Miran ULBIN

    2013-01-01

    For the designing of cutting-dies is a complex and experience-based process,it is poorly supported by conventional 3D CAD software.Thus,the majority of design activities,including the (re)modeling of those cutting die-components that are directly responsible for performing shaping operations on a sheet-metal stamping part,traditionally still need to be carried-out repetitively,separately,and manually by the designer.To eliminate some of these drawbacks and upgrade the capabilities of conventional 3D CAD software,this paper proposes a new methodology for the development of a parametric system capable of automatically performing a (re)modeling process of compound washer dies' cutting-components.The presented methodology integrates CATIA V5 built-in modules,including Part Design,Assembly Design and Knowledge Advisor,publication mechanism,and compound cutting die-design knowledge.The system developed by this methodology represents an 'intelligent' assembly template composed of two modules GAJA1 and GAJA2,respectively.GAJA1 is responsible for the direct input of the die-design problem regarding the shape,dimensions and material of the stamping part,its extraction in the form of geometric features,and the transferring of relevant design parameters and features to the module GAJA2.GAJA2 interprets the current values for the input parameters and automatically performs the modeling process of cutting die-components,using die-design knowledge and the company's internal design and manufacturing standards.Experimental results show that this system significantly shortens the modeling-time for cutting the die-components,improves the modeling-quality,and enables the training of inexperienced designers.

  19. The pathogenesis and treatment of cardiac atrophy in cancer cachexia.

    Science.gov (United States)

    Murphy, Kate T

    2016-02-15

    Cancer cachexia is a multifactorial syndrome characterized by a progressive loss of skeletal muscle mass associated with significant functional impairment. In addition to a loss of skeletal muscle mass and function, many patients with cancer cachexia also experience cardiac atrophy, remodeling, and dysfunction, which in the field of cancer cachexia is described as cardiac cachexia. The cardiac alterations may be due to underlying heart disease, the cancer itself, or problems initiated by the cancer treatment and, unfortunately, remains largely underappreciated by clinicians and basic scientists. Despite recent major advances in the treatment of cancer, little progress has been made in the treatment of cardiac cachexia in cancer, and much of this is due to lack of information regarding the mechanisms. This review focuses on the cardiac atrophy associated with cancer cachexia, describing some of the known mechanisms and discussing the current and future therapeutic strategies to treat this condition. Above all else, improved awareness of the condition and an increased focus on identification of mechanisms and therapeutic targets will facilitate the eventual development of an effective treatment for cardiac atrophy in cancer cachexia.

  20. Cardiac biomarkers in children with congenital heart disease

    Institute of Scientific and Technical Information of China (English)

    Masaya Sugimoto; Seiko Kuwata; Clara Kurishima; Jeong Hye Kim; Yoich Iwamoto; Hideaki Senzaki

    2015-01-01

    Background: Most congenital heart diseases (CHDs) have specific hemodynamics, including volume and pressure overload, as well as cyanosis and pulmonary hypertension, associated with anatomical abnormalities. Such hemodynamic abnormalities can cause activation of neurohormones, inflammatory cytokines, fibroblasts, and vascular endothelial cells, which in turn contribute to the development of pathologic conditions such as cardiac hypertrophy,fi brosis, and cardiac cell damages and death. Measuring biomarker levels facilitates the prediction of these pathological changes, and provides information about the stress placed on the myocardial cells, the severity of the damage, the responses of neurohumoral factors, and the remodeling of the ventricle. Compared to the ample information on cardiac biomarkers in adult heart diseases, data from children with CHD are still limited. Data sources: We reviewed cardiac biomarkers-specifi cally focusing on troponin as a biomarker of myocardial damage, amino-terminal procollagen type III peptide (PIIIP) as a biomarker of myocardialfi brosis and stromal remodeling, and B-type natriuretic peptide (BNP)/N-terminal proBNP as biomarkers of cardiac load and heart failure, by introducing relevant publications, including our own, on pediatric CHD patients as well as adults. Results: Levels of highly sensitive troponin I are elevated in patients with atrial septal defects (ASDs) and ventricular septal defects (VSDs). PIIIP levels are also elevated in patients with ASD, VSD, pulmonary stenosis, and Tetralogy of Fallot. Measurement of BNP and N-terminal proBNP levels shows good correlation with heart failure score in children. Conclusions: In the treatment of children with CHD requiring delicate care, it is vital to know the specifi c degree of myocardial damage and severity of heart failure. Cardiac biomarkers are useful tools for ascertaining the condition of CHDs with ease and are likely to be useful in determining the appropriate care of

  1. Phosphorylation of pRb by cyclin D kinase is necessary for development of cardiac hypertrophy

    DEFF Research Database (Denmark)

    Hinrichsen, R.; Hansen, A.H.; Busk, P.K.;

    2008-01-01

    OBJECTIVES: A number of stimuli induce cardiac hypertrophy and may lead to cardiomyopathy and heart failure. It is believed that cardiomyocytes withdraw from the cell cycle shortly after birth and become terminally differentiated. However, cell cycle regulatory proteins take part in the development...... of hypertrophy, and it is important to elucidate the mechanisms of how these proteins are involved in the hypertrophic response in cardiomyocytes. MATERIALS AND METHODS, AND RESULTS: In the present study, by immunohistochemistry with a phosphorylation-specific antibody, we found that cyclin D-cdk4....../6-phosphorylated retinoblastoma protein (pRb) during hypertrophy and expression of an unphosphorylatable pRb mutant impaired hypertrophic growth in cardiomyocytes. Transcription factor E2F was activated by hypertrophic elicitors but activation was impaired by pharmacological inhibition of cyclin D-cdk4...

  2. Development and clinical study of mobile 12-lead electrocardiography based on cloud computing for cardiac emergency.

    Science.gov (United States)

    Fujita, Hideo; Uchimura, Yuji; Waki, Kayo; Omae, Koji; Takeuchi, Ichiro; Ohe, Kazuhiko

    2013-01-01

    To improve emergency services for accurate diagnosis of cardiac emergency, we developed a low-cost new mobile electrocardiography system "Cloud Cardiology®" based upon cloud computing for prehospital diagnosis. This comprises a compact 12-lead ECG unit equipped with Bluetooth and Android Smartphone with an application for transmission. Cloud server enables us to share ECG simultaneously inside and outside the hospital. We evaluated the clinical effectiveness by conducting a clinical trial with historical comparison to evaluate this system in a rapid response car in the real emergency service settings. We found that this system has an ability to shorten the onset to balloon time of patients with acute myocardial infarction, resulting in better clinical outcome. Here we propose that cloud-computing based simultaneous data sharing could be powerful solution for emergency service for cardiology, along with its significant clinical outcome.

  3. Vascular Remodeling in Experimental Hypertension

    Directory of Open Access Journals (Sweden)

    Norma R. Risler

    2005-01-01

    Full Text Available The basic hemodynamic abnormality in hypertension is an increased peripheral resistance that is due mainly to a decreased vascular lumen derived from structural changes in the small arteries wall, named (as a whole vascular remodeling. The vascular wall is an active, flexible, and integrated organ made up of cellular (endothelial cells, smooth muscle cells, adventitia cells, and fibroblasts and noncellular (extracellular matrix components, which in a dynamic way change shape or number, or reorganize in response to physiological and pathological stimuli, maintaining the integrity of the vessel wall in physiological conditions or participating in the vascular changes in cardiovascular diseases such as hypertension. Research focused on new signaling pathways and molecules that can participate in the mechanisms of vascular remodeling has provided evidence showing that vascular structure is not only affected by blood pressure, but also by mechanisms that are independent of the increased pressure. This review will provide an overview of the evidence, explaining some of the pathophysiologic mechanisms participating in the development of the vascular remodeling, in experimental models of hypertension, with special reference to the findings in spontaneously hypertensive rats as a model of essential hypertension, and in fructose-fed rats as a model of secondary hypertension, in the context of the metabolic syndrome. The understanding of the mechanisms producing the vascular alterations will allow the development of novel pharmacological tools for vascular protection in hypertensive disease.

  4. Cardiac Hypertrophy and Fibrosis in the Metabolic Syndrome: A Role for Aldosterone and the Mineralocorticoid Receptor

    Directory of Open Access Journals (Sweden)

    Eric E. Essick

    2011-01-01

    Full Text Available Obesity and hypertension, major risk factors for the metabolic syndrome, render individuals susceptible to an increased risk of cardiovascular complications, such as adverse cardiac remodeling and heart failure. There has been much investigation into the role that an increase in the renin-angiotensin-aldosterone system (RAAS plays in the pathogenesis of metabolic syndrome and in particular, how aldosterone mediates left ventricular hypertrophy and increased cardiac fibrosis via its interaction with the mineralocorticoid receptor (MR. Here, we review the pertinent findings that link obesity with elevated aldosterone and the development of cardiac hypertrophy and fibrosis associated with the metabolic syndrome. These studies illustrate a complex cross-talk between adipose tissue, the heart, and the adrenal cortex. Furthermore, we discuss findings from our laboratory that suggest that cardiac hypertrophy and fibrosis in the metabolic syndrome may involve cross-talk between aldosterone and adipokines (such as adiponectin.

  5. Development and application of human virtual excitable tissues and organs: from premature birth to sudden cardiac death.

    Science.gov (United States)

    Holden, Arun V

    2010-12-01

    The electrical activity of cardiac and uterine tissues has been reconstructed by detailed computer models in the form of virtual tissues. Virtual tissues are biophysically and anatomically detailed, and represent quantitatively predictive models of the physiological and pathophysiological behaviours of tissue within an isolated organ. The cell excitation properties are quantitatively reproduced by equations that describe the kinetics of a few dozen proteins. These equations are derived from experimental measurements of membrane potentials, ionic currents, fluxes, and concentrations. Some of the measurements were taken from human cells and human ion channel proteins expressed in non-human cells, but they were mostly taken from cells of other animal species. Data on tissue geometry and architecture are obtained from the diffusion tensor magnetic resonance imaging of ex vivo or post mortem tissue, and are used to compute the spread of current in the tissue. Cardiac virtual tissues are well established and reproduce normal and pathological patterns of cardiac excitation within the atria or ventricles of the human heart. They have been applied to increase the understanding of normal cardiac electrophysiology, to evaluate the candidate mechanisms for re-entrant arrhythmias that lead to sudden cardiac death, and to predict the tissue level effects of mutant or pharmacologically-modified ion channels. The human full-term virtual uterus is still in development. This virtual tissue reproduces the in vitro behaviour of uterine tissue biopsies, and provides possible mechanisms for premature labour.

  6. Development of a Web GIS Application for Visualizing and Analyzing Community Out of Hospital Cardiac Arrest Patterns.

    Science.gov (United States)

    Semple, Hugh; Qin, Han; Sasson, Comilla

    2013-01-01

    Improving survival rates at the neighborhood level is increasingly seen as a priority for reducing overall rates of out-of-hospital cardiac arrest (OHCA) in the United States. Since wide disparities exist in OHCA rates at the neighborhood level, it is important for public health officials and residents to be able to quickly locate neighborhoods where people are at elevated risk for cardiac arrest and to target these areas for educational outreach and other mitigation strategies. This paper describes an OHCA web mapping application that was developed to provide users with interactive maps and data for them to quickly visualize and analyze the geographic pattern of cardiac arrest rates, bystander CPR rates, and survival rates at the neighborhood level in different U.S. cities. The data comes from the CARES Registry and is provided over a period spanning several years so users can visualize trends in neighborhood out-of-hospital cardiac arrest patterns. Users can also visualize areas that are statistical hot and cold spots for cardiac arrest and compare OHCA and bystander CPR rates in the hot and cold spots. Although not designed as a public participation GIS (PPGIS), this application seeks to provide a forum around which data and maps about local patterns of OHCA can be shared, analyzed and discussed with a view of empowering local communities to take action to address the high rates of OHCA in their vicinity.

  7. Electrophysiological and structural remodeling in heart failure modulate arrhythmogenesis. 2D simulation study.

    Directory of Open Access Journals (Sweden)

    Juan F Gomez

    Full Text Available Heart failure is operationally defined as the inability of the heart to maintain blood flow to meet the needs of the body and it is the final common pathway of various cardiac pathologies. Electrophysiological remodeling, intercellular uncoupling and a pro-fibrotic response have been identified as major arrhythmogenic factors in heart failure.In this study we investigate vulnerability to reentry under heart failure conditions by incorporating established electrophysiological and anatomical remodeling using computer simulations.The electrical activity of human transmural ventricular tissue (5 cm × 5 cm was simulated using the human ventricular action potential model Grandi et al. under control and heart failure conditions. The MacCannell et al. model was used to model fibroblast electrical activity, and their electrotonic interactions with myocytes. Selected degrees of diffuse fibrosis and variations in intercellular coupling were considered and the vulnerable window (VW for reentry was evaluated following cross-field stimulation.No reentry was observed in normal conditions or in the presence of HF ionic remodeling. However, defined amount of fibrosis and/or cellular uncoupling were sufficient to elicit reentrant activity. Under conditions where reentry was generated, HF electrophysiological remodeling did not alter the width of the VW. However, intermediate fibrosis and cellular uncoupling significantly widened the VW. In addition, biphasic behavior was observed, as very high fibrotic content or very low tissue conductivity hampered the development of reentry. Detailed phase analysis of reentry dynamics revealed an increase of phase singularities with progressive fibrotic components.Structural remodeling is a key factor in the genesis of vulnerability to reentry. A range of intermediate levels of fibrosis and intercellular uncoupling can combine to favor reentrant activity.

  8. The influence of motor activity on the development of cardiac arrhythmias during experimental emotional stress

    Science.gov (United States)

    Ulyaninskiy, L. S.; Urmancheyeva, T. G.; Stepanyan, Y. P.; Fufacheva, A. A.; Gritsak, A. V.; Kuznetsova, B. A.; Kvitka, A. A.

    1982-01-01

    Experimental emotional stress which can produce various disorders of cardiac rhythm: sinus tachycardia, atrial fibrillation, ventricular, extrasystoles and paroxysmal ventricular tachysystoles was studied. In these conditions the adrenalin content in the blood and myocardium is increased 3 to 4 times. It is found that moderate motor activity leads to a relative decrease of adrenalin in the myocardium and arrest of cardiac arrhythmias.

  9. The development of a new cardiac auscultation test: How do screening and diagnostic skills differ?

    DEFF Research Database (Denmark)

    Nielsen, Tommy; Mølgaard, Henning; Ringsted, Charlotte Vibeke;

    2010-01-01

    BACKGROUND: Newly qualified doctors are expected to be able to conduct a cardiac auscultation unassisted, but studies show conflicting results regarding cardiac auscultation skills. METHODS: A two-part test instrument was designed containing innovative recordings of heart sounds from patients wit...

  10. Association between cardiac biomarkers and the development of ESRD in patients with type 2 diabetes mellitus, anemia, and CKD

    DEFF Research Database (Denmark)

    Desai, Akshay S; Toto, Robert; Jarolim, Petr

    2011-01-01

    In patients with chronic kidney disease (CKD), as in other populations, elevations in cardiac biomarker levels predict increased risk of cardiovascular events. We examined the value of troponin T (TnT) and N-terminal pro-brain natriuretic peptide (NT-pro-BNP) in assessing the risk of developing e...

  11. Decreased KCNE2 expression participates in the development of cardiac hypertrophy

    Institute of Scientific and Technical Information of China (English)

    DENG Jian-xin; LIU Wen-juan; DING Wen-wen; WANG Gang; LIU Jie

    2016-01-01

    AIM:To investigate whether KCNE 2 participates in the development of pathological hypertrophy .METHODS:Bidirectional ma-nipulations of KCNE2 expression were performed by adenoviral overexpression of KCNE 2 or knockdown of KCNE2 with RNA interfer-ence in PE-induced neonatal rat ventricular myocytes .Then overexpression of KCNE 2 in mouse model of left ventricular hypertrophy in-duced by transverse aortic constriction (TAC) by ultrasound microbubble-mediated gene transfer were used to detect the therapeutic function of KCNE2 in the development of hypertrophy .RESULTS:KCNE2 expression was significantly decreased in PE-induced hy-pertrophic cardiomyocytes and in hypertrophic hearts produced by TAC .Knockdown of KCNE2 in cardiomyocytes reproduced hypertro-phy, whereas overexpression of KCNE2 attenuated PE-induced cardiomyocyte hypertrophy .Knockdown of KCNE2 increased calcineurin activity and nuclear NFAT protein level , and pretreatment with nifedipine or FK 506 attenuated decreased KCNE 2-induced cardiomyo-cyte hypertrophy .Overexpression of KCNE 2 in heart by ultrasound microbubble-mediated gene transfer suppressed the development of hypertrophy and activation of calcineurin-NFAT and MAPK pathways in TAC mice .CONCLUSION:These findings demonstrate that cardiac KCNE2 expression is decreased and contributes to the development of hypertrophy via activation of calcineurin -NFAT and MAPK pathways .

  12. A mHealth cardiac rehabilitation exercise intervention: findings from content development studies

    Directory of Open Access Journals (Sweden)

    Pfaeffli Leila

    2012-05-01

    Full Text Available Abstract Background Involving stakeholders and consumers throughout the content and study design ensures interventions are engaging and relevant for end-users. The aim of this paper is to present the content development process for a mHealth (mobile phone and internet-based cardiac rehabilitation (CR exercise intervention. Methods An innovative mHealth intervention was developed with patient input using the following steps: conceptualization, formative research, pre-testing, and pilot testing. Conceptualization, including theoretical and technical aspects, was undertaken by experts. For the formative component, focus groups and interviews with cardiac patients were conducted to discuss their perceptions of a mHealth CR program. A general inductive thematic approach identified common themes. A preliminary library of text and video messages were then developed. Participants were recruited from CR education sessions to pre-test and provide feedback on the content using an online survey. Common responses were extracted and compiled. An iterative process was used to refine content prior to pilot testing and conduct of a randomized controlled trial. Results 38 CR patients and 3 CR nurses participated in the formative research and 20 CR patients participated in the content pre-testing. Participants perceived the mHealth program as an effective approach to inform and motivate patients to exercise. For the qualitative study, 100% (n = 41 of participants thought it to be a good idea, and 11% of participants felt it might not be useful for them, but would be for others. Of the 20 participants who completed the online survey, 17 out of 20 (85% stated they would sign up to a program where they could receive information by video messages on a website, and 12 out of 20 (60% showed interest in a texting program. Some older CR patients viewed technology as a potential barrier as they were unfamiliar with text messaging or did not have mobile phones. Steps to

  13. Bone remodeling as a spatial evolutionary game.

    Science.gov (United States)

    Ryser, Marc D; Murgas, Kevin A

    2017-04-07

    Bone remodeling is a complex process involving cell-cell interactions, biochemical signaling and mechanical stimuli. Early models of the biological aspects of remodeling were non-spatial and focused on the local dynamics at a fixed location in the bone. Several spatial extensions of these models have been proposed, but they generally suffer from two limitations: first, they are not amenable to analysis and are computationally expensive, and second, they neglect the role played by bone-embedded osteocytes. To address these issues, we developed a novel model of spatial remodeling based on the principles of evolutionary game theory. The analytically tractable framework describes the spatial interactions between zones of bone resorption, bone formation and quiescent bone, and explicitly accounts for regulation of remodeling by bone-embedded, mechanotransducing osteocytes. Using tools from the theory of interacting particle systems we systematically classified the different dynamic regimes of the spatial model and identified regions of parameter space that allow for global coexistence of resorption, formation and quiescence, as observed in physiological remodeling. In coexistence scenarios, three-dimensional simulations revealed the emergence of sponge-like bone clusters. Comparison between spatial and non-spatial dynamics revealed substantial differences and suggested a stabilizing role of space. Our findings emphasize the importance of accounting for spatial structure and bone-embedded osteocytes when modeling the process of bone remodeling. Thanks to the lattice-based framework, the proposed model can easily be coupled to a mechanical model of bone loading.

  14. CYP2J2 overexpression protects against arrhythmia susceptibility in cardiac hypertrophy.

    Directory of Open Access Journals (Sweden)

    Christina Westphal

    Full Text Available Maladaptive cardiac hypertrophy predisposes one to arrhythmia and sudden death. Cytochrome P450 (CYP-derived epoxyeicosatrienoic acids (EETs promote anti-inflammatory and antiapoptotic mechanisms, and are involved in the regulation of cardiac Ca(2+-, K(+- and Na(+-channels. To test the hypothesis that enhanced cardiac EET biosynthesis counteracts hypertrophy-induced electrical remodeling, male transgenic mice with cardiomyocyte-specific overexpression of the human epoxygenase CYP2J2 (CYP2J2-TG and wildtype littermates (WT were subjected to chronic pressure overload (transverse aortic constriction, TAC or β-adrenergic stimulation (isoproterenol infusion, ISO. TAC caused progressive mortality that was higher in WT (42% over 8 weeks after TAC, compared to CYP2J2-TG mice (6%. In vivo electrophysiological studies, 4 weeks after TAC, revealed high ventricular tachyarrhythmia inducibility in WT (47% of the stimulation protocols, but not in CYP2J2-TG mice (0%. CYP2J2 overexpression also enhanced ventricular refractoriness and protected against TAC-induced QRS prolongation and delocalization of left ventricular connexin-43. ISO for 14 days induced high vulnerability for atrial fibrillation in WT mice (54% that was reduced in CYP-TG mice (17%. CYP2J2 overexpression also protected against ISO-induced reduction of atrial refractoriness and development of atrial fibrosis. In contrast to these profound effects on electrical remodeling, CYP2J2 overexpression only moderately reduced TAC-induced cardiac hypertrophy and did not affect the hypertrophic response to β-adrenergic stimulation. These results demonstrate that enhanced cardiac EET biosynthesis protects against electrical remodeling, ventricular tachyarrhythmia, and atrial fibrillation susceptibility during maladaptive cardiac hypertrophy.

  15. Knockdown of FABP3 Impairs Cardiac Development in Zebrafish through the Retinoic Acid Signaling Pathway

    Directory of Open Access Journals (Sweden)

    Xuejie Wang

    2013-07-01

    Full Text Available Fatty acid-binding protein 3 (FABP3 is a member of the intracellular lipid-binding protein family, and is primarily expressed in cardiac muscle tissue. Previously, we found that FABP3 is highly expressed in patients with ventricular-septal defects and is often used as a plasma biomarker in idiopathic dilated cardiomyopathy, and may play a significant role in the development of these defects in humans. In the present study, we aimed to investigate the role of FABP3 in the embryonic development of the zebrafish heart, and specifically how morpholino (MO mediated knockdown of FABP3 would affect heart development in this species. Our results revealed that knockdown of FABP3 caused significant impairment of cardiac development observed, including developmental delay, pericardial edema, a linear heart tube phenotype, incomplete cardiac loop formation, abnormal positioning of the ventricles and atria, downregulated expression of cardiac-specific markers and decreased heart rate. Mechanistically, our data showed that the retinoic acid (RA catabolizing enzyme Cyp26a1 was upregulated in FABP3-MO zebrafish, as indicated by in situ hybridization and real-time PCR. On the other hand, the expression level of the RA synthesizing enzyme Raldh2 did not significantly change in FABP3-MO injected zebrafish. Collectively, our results indicated that FABP3 knockdown had significant effects on cardiac development, and that dysregulated RA signaling was one of the mechanisms underlying this effect. As a result, these studies identify FABP3 as a candidate gene underlying the etiology of congenital heart defects.

  16. Development and feasibility of a smartphone, ECG and GPS based system for remotely monitoring exercise in cardiac rehabilitation.

    Directory of Open Access Journals (Sweden)

    Charles Worringham

    Full Text Available BACKGROUND: Despite its efficacy and cost-effectiveness, exercise-based cardiac rehabilitation is undertaken by less than one-third of clinically eligible cardiac patients in every country for which data is available. Reasons for non-participation include the unavailability of hospital-based rehabilitation programs, or excessive travel time and distance. For this reason, there have been calls for the development of more flexible alternatives. METHODOLOGY AND PRINCIPAL FINDINGS: We developed a system to enable walking-based cardiac rehabilitation in which the patient's single-lead ECG, heart rate, GPS-based speed and location are transmitted by a programmed smartphone to a secure server for real-time monitoring by a qualified exercise scientist. The feasibility of this approach was evaluated in 134 remotely-monitored exercise assessment and exercise sessions in cardiac patients unable to undertake hospital-based rehabilitation. Completion rates, rates of technical problems, detection of ECG changes, pre- and post-intervention six minute walk test (6 MWT, cardiac depression and Quality of Life (QOL were key measures. The system was rated as easy and quick to use. It allowed participants to complete six weeks of exercise-based rehabilitation near their homes, worksites, or when travelling. The majority of sessions were completed without any technical problems, although periodic signal loss in areas of poor coverage was an occasional limitation. Several exercise and post-exercise ECG changes were detected. Participants showed improvements comparable to those reported for hospital-based programs, walking significantly further on the post-intervention 6 MWT, 637 m (95% CI: 565-726, than on the pre-test, 524 m (95% CI: 420-655, and reporting significantly reduced levels of cardiac depression and significantly improved physical health-related QOL. CONCLUSIONS AND SIGNIFICANCE: The system provided a feasible and very flexible alternative form of

  17. Cardiomyopathy induced by artificial cardiac pacing: myth or reality sustained by evidence?

    Directory of Open Access Journals (Sweden)

    Andrés Di Leoni Ferrari

    2014-09-01

    Full Text Available Implantable cardiac pacing systems are a safe and effective treatment for symptomatic irreversible bradycardia. Under the proper indications, cardiac pacing might bring significant clinical benefit. Evidences from literature state that the action of the artificial pacing system, mainly when the ventricular lead is located at the apex of the right ventricle, produces negative effects to cardiac structure (remodeling, dilatation and function (dissinchrony. Patients with previously compromised left ventricular function would benefit the least with conventional right ventricle apical pacing, and are exposed to the risk of developing higher incidence of morbidity and mortality for heart failure. However, after almost 6 decades of cardiac pacing, just a reduced portion of patients in general would develop these alterations. In this context, there are not completely clear some issues related to cardiac pacing and the development of this cardiomyopathy. Causality relationships among QRS widening with a left bundle branch block morphology, contractility alterations within the left ventricle, and certain substrates or clinical (previous systolic dysfunction, structural heart disease, time from implant or electrical conditions (QRS duration, percentage of ventricular stimulation are still subjecte of debate. This review analyses contemporary data regarding this new entity, and discusses alternatives of how to use cardiac pacing in this context, emphasizing cardiac resynchronization therapy.

  18. Prevention of liver cancer cachexia-induced cardiac wasting and heart failure

    Science.gov (United States)

    Springer, Jochen; Tschirner, Anika; Haghikia, Arash; von Haehling, Stephan; Lal, Hind; Grzesiak, Aleksandra; Kaschina, Elena; Palus, Sandra; Pötsch, Mareike; von Websky, Karoline; Hocher, Berthold; Latouche, Celine; Jaisser, Frederic; Morawietz, Lars; Coats, Andrew J.S.; Beadle, John; Argiles, Josep M.; Thum, Thomas; Földes, Gabor; Doehner, Wolfram; Hilfiker-Kleiner, Denise; Force, Thomas; Anker, Stefan D.

    2014-01-01

    Aims Symptoms of cancer cachexia (CC) include fatigue, shortness of breath, and impaired exercise capacity, which are also hallmark symptoms of heart failure (HF). Herein, we evaluate the effects of drugs commonly used to treat HF (bisoprolol, imidapril, spironolactone) on development of cardiac wasting, HF, and death in the rat hepatoma CC model (AH-130). Methods and results Tumour-bearing rats showed a progressive loss of body weight and left-ventricular (LV) mass that was associated with a progressive deterioration in cardiac function. Strikingly, bisoprolol and spironolactone significantly reduced wasting of LV mass, attenuated cardiac dysfunction, and improved survival. In contrast, imidapril had no beneficial effect. Several key anabolic and catabolic pathways were dysregulated in the cachectic hearts and, in addition, we found enhanced fibrosis that was corrected by treatment with spironolactone. Finally, we found cardiac wasting and fibrotic remodelling in patients who died as a result of CC. In living cancer patients, with and without cachexia, serum levels of brain natriuretic peptide and aldosterone were elevated. Conclusion Systemic effects of tumours lead not only to CC but also to cardiac wasting, associated with LV-dysfunction, fibrotic remodelling, and increased mortality. These adverse effects of the tumour on the heart and on survival can be mitigated by treatment with either the β-blocker bisoprolol or the aldosterone antagonist spironolactone. We suggest that clinical trials employing these agents be considered to attempt to limit this devastating complication of cancer. PMID:23990596

  19. Disruption of Ah Receptor Signaling during Mouse Development Leads to Abnormal Cardiac Structure and Function in the Adult.

    Directory of Open Access Journals (Sweden)

    Vinicius S Carreira

    Full Text Available The Developmental Origins of Health and Disease (DOHaD Theory proposes that the environment encountered during fetal life and infancy permanently shapes tissue physiology and homeostasis such that damage resulting from maternal stress, poor nutrition or exposure to environmental agents may be at the heart of adult onset disease. Interference with endogenous developmental functions of the aryl hydrocarbon receptor (AHR, either by gene ablation or by exposure in utero to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD, a potent AHR ligand, causes structural, molecular and functional cardiac abnormalities and altered heart physiology in mouse embryos. To test if embryonic effects progress into an adult phenotype, we investigated whether Ahr ablation or TCDD exposure in utero resulted in cardiac abnormalities in adult mice long after removal of the agent. Ten-months old adult Ahr-/- and in utero TCDD-exposed Ahr+/+ mice showed sexually dimorphic abnormal cardiovascular phenotypes characterized by echocardiographic findings of hypertrophy, ventricular dilation and increased heart weight, resting heart rate and systolic and mean blood pressure, and decreased exercise tolerance. Underlying these effects, genes in signaling networks related to cardiac hypertrophy and mitochondrial function were differentially expressed. Cardiac dysfunction in mouse embryos resulting from AHR signaling disruption seems to progress into abnormal cardiac structure and function that predispose adults to cardiac disease, but while embryonic dysfunction is equally robust in males and females, the adult abnormalities are more prevalent in females, with the highest severity in Ahr-/- females. The findings reported here underscore the conclusion that AHR signaling in the developing heart is one potential target of environmental factors associated with cardiovascular disease.

  20. Association between the polymorphism of A9570G in angiotensin I converting enzyme 2 gene and cardiac dysfunction and ventricular remodeling after myocardial infarction%ACE2基因多态性与心肌梗死后心功能不全及心室重构的相关性研究

    Institute of Scientific and Technical Information of China (English)

    陈文忠; 周永健; 周劲东; 李志樑; 徐春生

    2010-01-01

    Objective To determine the effects of polymorphism of A9570G in angiotensin I converting enzyme 2 gene ( ACE2) gene on cardiac dysfunction and ventricular remodeling after myocardial infarction. Methods 252 patients with old myccardial infarction were included in this study. They were classified according to their polymorphisms of ACE 2 gene analyzed by polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP). Echocardiograms were used to determine left ventricular end diastolic diameters (LVEDd) , Left ventricular mass index (LVMI) , mitral flow pattern early diastolic and late diastolic peak flow ratio (E/A) and left ventricular ejection fraction ( LVEF). Results In male, LVEDd, LVMI, and LVEF had significant difference among ACE2 genotypes ( t = 2. 609,3.527and 2.063, P =0.010,0.001 and 0.041), and no significant differences in E/A( t =0.689,P =0.492). In female,LVEDd, LVMI, E/A and LVEF had no significant difference among ACE2 genotypes( F =0. 848, 0.077,0. 985 and 1.611, P = 0. 432,0. 926,0. 377 and 0. 205 ). Conclusion The polymorphism of A9570G in ACE2 gene may be associated with cardiac dysfunction and ventricular remodeling after myocardial infarction in male. ACE 2 gene polymorphism may be a genetic factor on cardiac dysfunction and ventricular remodeling after myocardial infarction.%目的 研究血管紧张素转换酶2基因A9570G多态性与心肌梗死后心功能不全及心室重构的关系.方法 收集252例陈旧性心肌梗死患者,采取外周血2ml提取DNA,多聚酶链扩增反应及限制性内切酶法检测ACE2基因A9570G基因型,按基因型进行分组,采用超声心动图比较不同基因型间患者LVEF,E/A,LVEDd及LVMI的差异.结果 在男性,G基因型组LVEF、LVEDd、LVMI与A基因型组比较,差异有统计学意义(t=2.609、3.527、2.063,P0.05);在女性,3种基因型间患者LVEF、E/A、LVEDd及LVMI差异均无统计学意义(P>0.05).结论 ACE2基因A9570G多态性与男性心肌梗死后

  1. Osteopontin deletion prevents the development of obesity and hepatic steatosis via impaired adipose tissue matrix remodeling and reduced inflammation and fibrosis in adipose tissue and liver in mice.

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    Andoni Lancha

    Full Text Available Osteopontin (OPN is a multifunctional extracellular matrix (ECM protein involved in multiple physiological processes. OPN expression is dramatically increased in visceral adipose tissue in obesity and the lack of OPN protects against the development of insulin resistance and inflammation in mice. We sought to unravel the potential mechanisms involved in the beneficial effects of the absence of OPN. We analyzed the effect of the lack of OPN in the development of obesity and hepatic steatosis induced by a high-fat diet (HFD using OPN-KO mice. OPN expression was upregulated in epididymal white adipose tissue (EWAT and liver in wild type (WT mice with HFD. OPN-KO mice had higher insulin sensitivity, lower body weight and fat mass with reduced adipose tissue ECM remodeling and reduced adipocyte size than WT mice under a HFD. Reduced MMP2 and MMP9 activity was involved in the decreased ECM remodeling. Crown-like structure number in EWAT as well as F4/80-positive cells and Emr1 expression in EWAT and liver increased with HFD, while OPN-deficiency blunted the increase. Moreover, our data show for the first time that OPN-KO under a HFD mice display reduced fibrosis in adipose tissue and liver, as well as reduced oxidative stress in adipose tissue. Gene expression of collagens Col1a1, Col6a1 and Col6a3 in EWAT and liver, as well as the profibrotic cytokine Tgfb1 in EWAT were increased with HFD, while OPN-deficiency prevented this increase. OPN deficiency prevented hepatic steatosis via reduction in the expression of molecules involved in the onset of fat accumulation such as Pparg, Srebf1, Fasn, Mogat1, Dgat2 and Cidec. Furthermore, OPN-KO mice exhibited higher body temperature and improved BAT function. The present data reveal novel mechanisms of OPN in the development of obesity, pointing out the inhibition of OPN as a promising target for the treatment of obesity and fatty liver.

  2. Osteopontin deletion prevents the development of obesity and hepatic steatosis via impaired adipose tissue matrix remodeling and reduced inflammation and fibrosis in adipose tissue and liver in mice.

    Science.gov (United States)

    Lancha, Andoni; Rodríguez, Amaia; Catalán, Victoria; Becerril, Sara; Sáinz, Neira; Ramírez, Beatriz; Burrell, María A; Salvador, Javier; Frühbeck, Gema; Gómez-Ambrosi, Javier

    2014-01-01

    Osteopontin (OPN) is a multifunctional extracellular matrix (ECM) protein involved in multiple physiological processes. OPN expression is dramatically increased in visceral adipose tissue in obesity and the lack of OPN protects against the development of insulin resistance and inflammation in mice. We sought to unravel the potential mechanisms involved in the beneficial effects of the absence of OPN. We analyzed the effect of the lack of OPN in the development of obesity and hepatic steatosis induced by a high-fat diet (HFD) using OPN-KO mice. OPN expression was upregulated in epididymal white adipose tissue (EWAT) and liver in wild type (WT) mice with HFD. OPN-KO mice had higher insulin sensitivity, lower body weight and fat mass with reduced adipose tissue ECM remodeling and reduced adipocyte size than WT mice under a HFD. Reduced MMP2 and MMP9 activity was involved in the decreased ECM remodeling. Crown-like structure number in EWAT as well as F4/80-positive cells and Emr1 expression in EWAT and liver increased with HFD, while OPN-deficiency blunted the increase. Moreover, our data show for the first time that OPN-KO under a HFD mice display reduced fibrosis in adipose tissue and liver, as well as reduced oxidative stress in adipose tissue. Gene expression of collagens Col1a1, Col6a1 and Col6a3 in EWAT and liver, as well as the profibrotic cytokine Tgfb1 in EWAT were increased with HFD, while OPN-deficiency prevented this increase. OPN deficiency prevented hepatic steatosis via reduction in the expression of molecules involved in the onset of fat accumulation such as Pparg, Srebf1, Fasn, Mogat1, Dgat2 and Cidec. Furthermore, OPN-KO mice exhibited higher body temperature and improved BAT function. The present data reveal novel mechanisms of OPN in the development of obesity, pointing out the inhibition of OPN as a promising target for the treatment of obesity and fatty liver.

  3. MCTP2 is a dosage-sensitive gene required for cardiac outflow tract development

    Science.gov (United States)

    Lalani, Seema R.; Ware, Stephanie M.; Wang, Xueqing; Zapata, Gladys; Tian, Qi; Franco, Luis M.; Jiang, Zhengxin; Bucasas, Kristine; Scott, Daryl A.; Campeau, Philippe M.; Hanchard, Neil; Umaña, Luis; Cast, Ashley; Patel, Ankita; Cheung, Sau W.; McBride, Kim L.; Bray, Molly; Craig Chinault, A.; Boggs, Barbara A.; Huang, Miao; Baker, Mariah R.; Hamilton, Susan; Towbin, Jeff; Jefferies, John L.; Fernbach, Susan D.; Potocki, Lorraine; Belmont, John W.

    2013-01-01

    Coarctation of the aorta (CoA) and hypoplastic left heart syndrome (HLHS) have been reported in rare individuals with large terminal deletions of chromosome 15q26. However, no single gene important for left ventricular outflow tract (LVOT) development has been identified in this region. Using array-comparative genomic hybridization, we identified two half-siblings with CoA with a 2.2 Mb deletion on 15q26.2, inherited from their mother, who was mosaic for this deletion. This interval contains an evolutionary conserved, protein-coding gene, MCTP2 (multiple C2-domains with two transmembrane regions 2). Using gene-specific array screening in 146 individuals with non-syndromic LVOT obstructive defects, another individual with HLHS and CoA was found to have a de novo 41 kb intragenic duplication within MCTP2, predicted to result in premature truncation, p.F697X. Alteration of Mctp2 gene expression in Xenopus laevis embryos by morpholino knockdown and mRNA overexpression resulted in the failure of proper OT development, confirming the functional importance of this dosage-sensitive gene for cardiogenesis. Our results identify MCTP2 as a novel genetic cause of CoA and related cardiac malformations. PMID:23773997

  4. Development and Implementation of Discrete Polymeric Microstructural Cues for Applications in Cardiac Tissue Engineering

    Science.gov (United States)

    Pinney, James Richardson

    Chronic fibrosis caused by acute myocardial infarction (MI) leads to increased morbidity and mortality due to cardiac dysfunction. Despite care in the acute setting of MI, subsequent development of scar tissue and a lack of treatments for this maladaptive response lead to a poor prognosis. This has increased burdens on the cost of healthcare due to chronic disability. Here a novel therapeutic strategy that aims to mitigate myocardial fibrosis by utilizing injectable polymeric microstructural cues to attenuate the fibrotic response and improve functional outcomes is presented. Additionally, applications of integrated chemical functionalizations into discrete, micro-scale polymer structures are discussed in the realm of tissue engineering in order to impart enhancements in in vivo localization, three-dimensional manipulation and drug delivery. Polymeric microstructures, termed "microrods" and "microcubes", were fabricated using photolithographic techniques and studied in three-dimensional culture models of the fibrotic environment and by direct injection into the infarct zone of adult Sprague-Dawley rats. In vitro gene expression and functional and histological results were analyzed, showing a dose-dependent down-regulation fibrotic indicators and improvement in cardiac function. Furthermore, iron oxide nanoparticles and functionalized fluorocarbons were incorporated into the polymeric microdevices to promote in situ visualization by magnetic resonance imaging as well as to facilitate the manipulation and alignment of microstructural cues in a tissue-realistic environment. Lastly, successful encapsulation of native MGF peptide within microrods is demonstrated with release over two weeks as a proof of concept in the ability to locally deliver myogenic or supportive pharmacotherapeutics to the injured myocardium. This work demonstrates the efficacy and versatility of discrete microtopographical cues to attenuate the fibrotic response after MI and suggests a novel

  5. 丹红注射液对心肌梗死大鼠心功能和左室重构的改善作用%The improvement effect of Danhong injection on the cardiac function and left ventricular remodeling in myocardial infarction rats

    Institute of Scientific and Technical Information of China (English)

    李骏峰; 王虹; 贾玲; 邢永红; 王育新

    2013-01-01

    目的:探讨丹红注射液(DHI)对心肌梗死大鼠的心功能和左室重构的改善作用.方法:采用冠状动脉结扎法(CAL)制备心肌梗死(MI)模型,观察DHI对大鼠心肌梗死后12周的心脏及肺的解剖学指标、心室的疤痕面积、左心室血流动力学指标、心肌病理指标及凋亡基因水平的影响.结果:心肌梗死后连续12周的DHI治疗可降低心脏和湿肺与体质量的比值、左室舒张末期压力、心肌细胞直径和胶原容积分数(P<0.05),升高左心室内压最大上升速率(P<0.05),但对凋亡基因的异常表达和心室前壁出现梗死疤痕无明显作用(P>0.05).结论:丹红注射液可有效逆转CAL诱导的心肌梗死大鼠的心功能恶化并改善除凋亡外的心室重构.%OBJECTIVE To explore the improving effect of Danhong injection(DHI)on the cardiac function and left ventricular remodeling in myocardial infarction rats. METHODS Coronary artery ligation (CAD was used to induce an in vivo model of myocardial infarction (MI). The experiment observed the influences of DHI on the anatomy indicators of heart and lung, ventricular scar area, left ventricular hemodynamics, myocardial pathological indicators and the levels of apoptotic genes. RESULTS 12 consecutive weeks' treatment of DHI after myocardial infarction could reduce the ratio of HW/BW and WLW/ BW,left ventricular end-diastolic pressure, the diameter of cardiomyocyte and collagen volume fraction (P<0. 05) ,and increase the maximum rate of change of left ventricular pressure(P<0. 05), while caused no changes on the ventricular scar area and the apoptosis. CONCLUSION Danhong injection can attenuate the deterioration of cardiac function and ventricular remodeling (except the apoptosis) in the myocardial infarction rats.

  6. Zebrafish as a Vertebrate Model System to Evaluate Effects of Environmental Toxicants on Cardiac Development and Function

    Science.gov (United States)

    Sarmah, Swapnalee; Marrs, James A.

    2016-01-01

    Environmental pollution is a serious problem of the modern world that possesses a major threat to public health. Exposure to environmental pollutants during embryonic development is particularly risky. Although many pollutants have been verified as potential toxicants, there are new chemicals in the environment that need assessment. Heart development is an extremely sensitive process, which can be affected by environmentally toxic molecule exposure during embryonic development. Congenital heart defects are the most common life-threatening global health problems, and the etiology is mostly unknown. The zebrafish has emerged as an invaluable model to examine substance toxicity on vertebrate development, particularly on cardiac development. The zebrafish offers numerous advantages for toxicology research not found in other model systems. Many laboratories have used the zebrafish to study the effects of widespread chemicals in the environment on heart development, including pesticides, nanoparticles, and various organic pollutants. Here, we review the uses of the zebrafish in examining effects of exposure to external molecules during embryonic development in causing cardiac defects, including chemicals ubiquitous in the environment and illicit drugs. Known or potential mechanisms of toxicity and how zebrafish research can be used to provide mechanistic understanding of cardiac defects are discussed. PMID:27999267

  7. Zebrafish as a Vertebrate Model System to Evaluate Effects of Environmental Toxicants on Cardiac Development and Function

    Directory of Open Access Journals (Sweden)

    Swapnalee Sarmah

    2016-12-01

    Full Text Available Environmental pollution is a serious problem of the modern world that possesses a major threat to public health. Exposure to environmental pollutants during embryonic development is particularly risky. Although many pollutants have been verified as potential toxicants, there are new chemicals in the environment that need assessment. Heart development is an extremely sensitive process, which can be affected by environmentally toxic molecule exposure during embryonic development. Congenital heart defects are the most common life-threatening global health problems, and the etiology is mostly unknown. The zebrafish has emerged as an invaluable model to examine substance toxicity on vertebrate development, particularly on cardiac development. The zebrafish offers numerous advantages for toxicology research not found in other model systems. Many laboratories have used the zebrafish to study the effects of widespread chemicals in the environment on heart development, including pesticides, nanoparticles, and various organic pollutants. Here, we review the uses of the zebrafish in examining effects of exposure to external molecules during embryonic development in causing cardiac defects, including chemicals ubiquitous in the environment and illicit drugs. Known or potential mechanisms of toxicity and how zebrafish research can be used to provide mechanistic understanding of cardiac defects are discussed.

  8. Development of a patch type embedded cardiac function monitoring system using dual microprocessor for arrhythmia detection in heart disease patient.

    Science.gov (United States)

    Jang, Yongwon; Noh, Hyung Wook; Lee, I B; Jung, Ji-Wook; Song, Yoonseon; Lee, Sooyeul; Kim, Seunghwan

    2012-01-01

    A patch type embedded cardiac function monitoring system was developed to detect arrhythmias such as PVC (Premature Ventricular Contraction), pause, ventricular fibrillation, and tachy/bradycardia. The overall system is composed of a main module including a dual processor and a Bluetooth telecommunication module. The dual microprocessor strategy minimizes power consumption and size, and guarantees the resources of embedded software programs. The developed software was verified with standard DB, and showed good performance.

  9. Measuring cardiac efficiency using PET/MRI

    Energy Technology Data Exchange (ETDEWEB)

    Gullberg, Grand [Lawrence Berkeley National Laboratory (United States); Aparici, Carina Mari; Brooks, Gabriel [University of California San Francisco (United States); Liu, Jing; Guccione, Julius; Saloner, David; Seo, Adam Youngho; Ordovas, Karen Gomes [Lawrence Berkeley National Laboratory (United States)

    2015-05-18

    Heart failure (HF) is a complex syndrome that is projected by the American Heart Association to cost $160 billion by 2030. In HF, significant metabolic changes and structural remodeling lead to reduced cardiac efficiency. A normal heart is approximately 20-25% efficient measured by the ratio of work to oxygen utilization (1 ml oxygen = 21 joules). The heart requires rapid production of ATP where there is complete turnover of ATP every 10 seconds with 90% of ATP produced by mitochondrial oxidative metabolism requiring substrates of approximately 30% glucose and 65% fatty acids. In our preclinical PET/MRI studies in normal rats, we showed a negative correlation between work and the influx rate constant for 18FDG, confirming that glucose is not the preferred substrate at rest. However, even though fatty acid provides 9 kcal/gram compared to 4 kcal/gram for glucose, in HF the preferred energy source is glucose. PET/MRI offers the potential to study this maladapted mechanism of metabolism by measuring work in a region of myocardial tissue simultaneously with the measure of oxygen utilization, glucose, and fatty acid metabolism and to study cardiac efficiency in the etiology of and therapies for HF. MRI is used to measure strain and a finite element mechanical model using pressure measurements is used to estimate myofiber stress. The integral of strain times stress provides a measure of work which divided by energy utilization, estimated by the production of 11CO2 from intravenous injection of 11C-acetate, provides a measure of cardiac efficiency. Our project involves translating our preclinical research to the clinical application of measuring cardiac efficiency in patients. Using PET/MRI to develop technologies for studying myocardial efficiency in patients, provides an opportunity to relate cardiac work of specific tissue regions to metabolic substrates, and measure the heterogeneity of LV efficiency.

  10. Development of a scalable suspension culture for cardiac differentiation from human pluripotent stem cells

    Directory of Open Access Journals (Sweden)

    Vincent C. Chen

    2015-09-01

    Full Text Available To meet the need of a large quantity of hPSC-derived cardiomyocytes (CM for pre-clinical and clinical studies, a robust and scalable differentiation system for CM production is essential. With a human pluripotent stem cells (hPSC aggregate suspension culture system we established previously, we developed a matrix-free, scalable, and GMP-compliant process for directing hPSC differentiation to CM in suspension culture by modulating Wnt pathways with small molecules. By optimizing critical process parameters including: cell aggregate size, small molecule concentrations, induction timing, and agitation rate, we were able to consistently differentiate hPSCs to >90% CM purity with an average yield of 1.5 to 2 × 109 CM/L at scales up to 1 L spinner flasks. CM generated from the suspension culture displayed typical genetic, morphological, and electrophysiological cardiac cell characteristics. This suspension culture system allows seamless transition from hPSC expansion to CM differentiation in a continuous suspension culture. It not only provides a cost and labor effective scalable process for large scale CM production, but also provides a bioreactor prototype for automation of cell manufacturing, which will accelerate the advance of hPSC research towards therapeutic applications.

  11. Development of a scalable suspension culture for cardiac differentiation from human pluripotent stem cells.

    Science.gov (United States)

    Chen, Vincent C; Ye, Jingjing; Shukla, Praveen; Hua, Giau; Chen, Danlin; Lin, Ziguang; Liu, Jian-chang; Chai, Jing; Gold, Joseph; Wu, Joseph; Hsu, David; Couture, Larry A

    2015-09-01

    To meet the need of a large quantity of hPSC-derived cardiomyocytes (CM) for pre-clinical and clinical studies, a robust and scalable differentiation system for CM production is essential. With a human pluripotent stem cells (hPSC) aggregate suspension culture system we established previously, we developed a matrix-free, scalable, and GMP-compliant process for directing hPSC differentiation to CM in suspension culture by modulating Wnt pathways with small molecules. By optimizing critical process parameters including: cell aggregate size, small molecule concentrations, induction timing, and agitation rate, we were able to consistently differentiate hPSCs to >90% CM purity with an average yield of 1.5 to 2×10(9) CM/L at scales up to 1L spinner flasks. CM generated from the suspension culture displayed typical genetic, morphological, and electrophysiological cardiac cell characteristics. This suspension culture system allows seamless transition from hPSC expansion to CM differentiation in a continuous suspension culture. It not only provides a cost and labor effective scalable process for large scale CM production, but also provides a bioreactor prototype for automation of cell manufacturing, which will accelerate the advance of hPSC research towards therapeutic applications.

  12. The future of induced pluripotent stem cells for cardiac therapy and drug development.

    Science.gov (United States)

    Thorrez, Lieven; Sampaolesi, Maurilio

    2011-10-01

    The field of stem cell research was revolutionized with the advent of induced pluripotent stem cells. By reprogramming somatic cells to pluripotent stem cells, most ethical concerns associated with the use of embryonic stem cells are overcome, such that many hopes from the stem cell field now seem a step closer to reality. Several methods and cell sources have been described to create induced pluripotent stem cells and we discuss their characteristics in terms of feasibility and efficiency. From these cells, cardiac progenitors and cardiomyocytes can be derived by several protocols and most recent advances as well as remaining limitations are being discussed. However, in the short time period this technology has been around, evidence emerges that induced pluripotent stem cells may be more prone to genetic defects and maintain an epigenetic memory and thus may not be entirely the same as embryonic stem cells. Despite the lack of a complete fundamental understanding of stem cell biology, and even more of ways how to coax them into defined cell types, the technology is quickly adopted by industry. This paper gives an overview of the current applications of induced pluripotent stem cells in cardiovascular drug development and highlights active areas of research towards functional repair of the damaged heart. Adult stem cells have already been taken to clinical trials and we discuss these results in light of potential and hurdles to be taken to move induced pluripotent stem cells to the clinic.

  13. 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.

  14. Cardiac surgery-associated acute kidney injury in a developing country: Prevalence, risk factors and outcome.

    Science.gov (United States)

    Ekure, Ekanem Nsikak; Esezobor, Christopher Imokhuede; Sridhar, Anuradha; Vasudevan, Jyothi; Subramanyan, Rajhavan; Cherian, Kotturathu Mammen

    2015-01-01

    Little is known about cardiac surgery-associated acute kidney injury (CS-AKI) in children in developing regions of the world. The study aimed to determine the prevalence of CSAKI, associated factors and its impact on mortality and utilization of hospital services. The hospital records of children aged 0-17 years who underwent CS at an Indian hospital were reviewed. CS-AKI was defined as a rise in serum creatinine of ≥0.3 mg/dL in any 48 h and or by urine output CS. The study included 323 children with a median age of one year (0.04-17), of whom 22 (6.8%) were neonates and 18.3% had a single ventricle. About 60% of the children had Risk Adjusted Congenital Heart Surgery-I category 1 or 2 interventions. CS-AKI occurred in 39 children (12.1%). Factors associated with CS-AKI were sepsis and intraand post-operative hypotension. In-hospital mortality was six-fold higher in children who developed CS-AKI. CS-AKI was associated with two to three days more of mechanical ventilation and Intensive care unit stay. CS-AKI occurs in children in developing countries, but at a lower frequency mainly due to the predominance of post-neonatal children undergoing less-complex CSs. CS-AKI was associated with higher in-hospital mortality and increased utilization of hospital services. Factors associated with CS-AKI included intraand post-operative hypotension and sepsis.

  15. 甲状腺功能与老年慢性充血性心力衰竭患者心功能、左心室重构的关系研究%Relationship Between Thyroid Function and Cardiac Function/Left Ventricular Remodeling of Elderly Patients With Chronic Congestive Heart Failure

    Institute of Scientific and Technical Information of China (English)

    张萍; 赵东升

    2016-01-01

    目的:探讨甲状腺功能与老年慢性充血性心力衰竭(CHF)患者心功能、左心室重构的关系。方法选取2013年1月—2015年1月衡水市第二人民医院收治的老年(年龄≥60岁)CHF 患者90例作为 CHF 组,另选取同期于衡水市第二人民医院体检的老年非 CHF 者77例作为对照组。比较两组受检者甲状腺功能、心功能及左心室重构指标,比较不同纽约心脏病协会(NYHA)分级 CHF 患者甲状腺功能指标,分析甲状腺功能指标与左心室重构指标的相关性。结果对照组受检者 NYHA 分级均为Ⅰ级,共77例;CHF 组患者 NYHA 分级Ⅱ级37例,Ⅲ级36例,Ⅳ级17例。CHF 组患者促甲状腺素(TSH)、总三碘甲状腺原氨酸(TT3)、总甲状腺素( TT4)、游离三碘甲状腺原氨酸(FT3)、游离甲状腺素(FT4)水平、左心室射血分数(LVEF)低于对照组,左心室收缩末期内径(LVESD)、左心室舒张末期内径(LVEDD)、左心室质量指数(LVMI)高于对照组(P <0.05)。Ⅲ级 CHF 患者 TSH、TT3、FT3水平低于Ⅱ级 CHF 患者(P <0.05);Ⅳ级 CHF 患者 TSH、TT3、TT4、FT3、FT4水平低于Ⅱ级 CHF 患者,TT3、FT3、FT4水平低于Ⅲ级 CHF 患者(P <0.05)。CHF 组患者 TSH 水平与 LVEDD、LVMI 呈负相关(r 值分别为-0.598、-0.566, P <0.05),TT3水平与 LVESD、LVMI 呈负相关( r 值分别为-0.655、-0.832,P <0.05),TT4水平与 LVESD、LVEDD 呈负相关(r 值分别为-0.738、-0.787,P <0.05),FT3水平与 LVMI 呈负相关( r =-0.540,P <0.05), FT4水平与 LVESD 呈负相关(r =-0.547,P <0.05)。结论甲状腺功能与老年 CHF 患者心功能、左心室重构有关,调节甲状腺功能可改善老年 CHF 患者心功能及左心室重构。%Objective To investigate the relationship between thyroid function and cardiac function/ left ventricular remodeling of elderly patients

  16. A case of Hodgkin`s disease presenting a cardiac tamponade during treatment developed a pancytopenia after cessation of chemotherapy

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    Ohta, Shigeru; Iwami, Mika; Narita, Tsutomu; Higashino, Katsumi; Suzuki, Atsushi; Taga, Takashi; Shimada, Morimi [Shiga Univ. of Medical Science, Otsu (Japan)

    1998-10-01

    There had been many reports about cardiac complications of patients with Hodgkin`s disease (HD) after cessation of treatment in Europe and the United States. However, cases of HD accompanied with these complications were extremely rare in Japan. We report a case with HD that developed a cardiac tamponade during the clinical course of chemotherapy and showed a pancytopenia after cessation of chemotherapy. The case was a 14 year-old boy with HD (nodular sclerosis) of anterior upper mediastinum origin. He received modified MOPP therapy and irradiation to the semimantle field and to the mediastinum. The total dose of radiation was 36.3 Gy. He suddenly developed a chest pain, chest discomfort, and dyspnea during the sixth course of chemotherapy. He was diagnosed to have a cardiac tamponade by thoracentesis. The symptoms were improved by continuous transcutaneous drainage. The invasion of HD into the effusion was not detected by cytology, and the chemotherapy was completed after one course. However, he gradually developed a macrocytic anemia and finally developed a pancytopenia. The bone marrow specimen revealed a hypoplasia without evidence of pathological cells. The karyotype of marrow derived cells was normal. With oxymetholone administration, the pancytopenia has improved in four months. He has now been doing well for five years after the cessation of therapy. (author)

  17. 二尖瓣环位移对肥厚性重构患者左室收缩功能的评估作用%Evaluation of left ventricular systolic dysfunction by mitral annular displacement in patients with cardiac hypertrophy and remodeling

    Institute of Scientific and Technical Information of China (English)

    吴卫华; 黄艳; 陆静; 马兰; 魏松霞; 谢晓奕; 刘奇志; 王雷; 杨玲

    2011-01-01

    目的 应用超声二维斑点追踪显像技术测定二尖瓣环位移(MAD),探讨其在评估肥厚性重构所致的早期左室收缩功能减退方面的临床应用价值.方法 选择86例左室射血分数(LVEF)正常(>50%)的各类心肌肥厚(左室壁厚度≥12 mm)患者作为研究对象.采用Philips Sonos iE33超声仪进行检查,先通过M型超声计算出相对室壁厚度(RWT),然后取心尖四腔观分别采集二维和实时三维全容积(RT3D)图像.应用QLAB 6.2在机量化分析软件分别获取MAD相关参数(包括二尖瓣环中点位移和左室长轴缩短率)和经RT3D图像测得左室射血分数(RT3D-LVEF);计算三维心肌重构指标,包括左室舒末容积指数(LVEDVI)和左室质量指数(LVMI).将心肌肥厚患者中RWT<0.45且LVMI在正常范围内的患者归入肥厚正常几何构型组(HNG组),其余归入肥厚重构组(HR组);以46名年龄相匹配的健康志愿者作为正常对照组.结果 HNG组、HR组和正常对照组的RT3D-LVEF均在正常范围内,两两比较差异均无统计学意义(P>0.05).HR组的MAD各值和LVEDVI均显著低于HNG组和正常对照组,差异均有统计学意义(P<0.01或P<0.05);HNG组与正常对照组MAD相关参数值和LVEDVI比较差异均无统计学意义(P>0.05).Bland-Altman分析显示MAD各值的可重复性较高.结论 在心肌肥厚性重构患者中,与LVEF比较,MAD能更早地反映患者的左室收缩功能减退情况.%Objective To investigate the value of mitral annular displacement (MAD) by two-dimensional speckle tracking in evaluating left ventricular systolic dysfunction in patients with cardiac hypertrophy and remodeling.Methods Eightysix patients with cardiac hypertrophy ( left ventricular wall thickness ≥ 12 mm) and normal left ventricular ejection fraction (LVEF) ( > 50% ) were selected.Philips Sonos iE33 ultrasound device was used for examinations.Relative wall thickness (IRWT) was calculated by M mode ultrasound, and two

  18. The impact of juvenile coxsackievirus infection on cardiac progenitor cells and postnatal heart development.

    Science.gov (United States)

    Sin, Jon; Puccini, Jenna M; Huang, Chengqun; Konstandin, Mathias H; Gilbert, Paul E; Sussman, Mark A; Gottlieb, Roberta A; Feuer, Ralph

    2014-07-01

    Coxsackievirus B (CVB) is an enterovirus that most commonly causes a self-limited febrile illness in infants, but cases of severe infection can manifest in acute myocarditis. Chronic consequences of mild CVB infection are unknown, though there is an epidemiologic association between early subclinical infections and late heart failure, raising the possibility of subtle damage leading to late-onset dysfunction, or chronic ongoing injury due to inflammatory reactions during latent infection. Here we describe a mouse model of juvenile infection with a subclinical dose of coxsackievirus B3 (CVB3) which showed no evident symptoms, either immediately following infection or in adult mice. However following physiological or pharmacologically-induced cardiac stress, juvenile-infected adult mice underwent cardiac hypertrophy and dilation indicative of progression to heart failure. Evaluation of the vasculature in the hearts of adult mice subjected to cardiac stress showed a compensatory increase in CD31+ blood vessel formation, although this effect was suppressed in juvenile-infected mice. Moreover, CVB3 efficiently infected juvenile c-kit+ cells, and cardiac progenitor cell numbers were reduced in the hearts of juvenile-infected adult mice. These results suggest that the exhausted cardiac progenitor cell pool following juvenile CVB3 infection may impair the heart's ability to increase capillary density to adapt to increased load.

  19. Developing Indicators of Service Quality Provided for Cardiovascular Patients Hospitalized in Cardiac Care Unit

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    Saber Azami-Aghdash

    2013-03-01

    Full Text Available Introduction: Cardiovascular diseases are among the most prevalent chronic diseases leading to high degrees of mortality and morbidity worldwide and in Iran. The aim of the current study was to determine and develop appropriate indicators for evaluating provided service quality for cardiovascular patients admitted to Cardiac Care Units (CCU in Iran. Methods: In order to determine the indicators for evaluating provided service quality, a four-stage process including reviewing systematic review articles in premier bibliographic databases, interview, performing two rounds of Delphi technique, and holding experts panel by attendance of experts in different fields was adopted. Finally, after recognizing relevant indicators in resources, these indicators were finalized during various stages using ideas of 27 experts in different fields. Results: Among 2800 found articles in the text reviewing phase, 21 articles, which had completely mentioned relevant indicators, were studied and 48 related indicators were extracted. After two interviews with a cardiologist and an epidemiologist, 32 items of the indicators were omitted and replaced by 27 indicators coping with the conditions of Iranian hospitals. Finally, 43 indicators were added into the Delphi phase and after 2 rounds of Delphi with 18 specialists, 7 cases were excluded due to their low scores of applicability. In the experts’ panel stage, 6 items were also omitted and 10 new indicators were developed to replace them. Eventually, 40 indicators were finalized. Conclusion: In this study, some proper indicators for evaluating provided service quality for CCU admissions in Iran were determined. Considering the informative richness of these indicators, they can be used by managers, policy makers, health service providers, and also insurance agencies in order to improve the quality of services, decisions, and policies.

  20. The Arabidopsis SWI2/SNF2 chromatin Remodeler BRAHMA regulates polycomb function during vegetative development and directly activates the flowering repressor gene SVP.

    Science.gov (United States)

    Li, Chenlong; Chen, Chen; Gao, Lei; Yang, Songguang; Nguyen, Vi; Shi, Xuejiang; Siminovitch, Katherine; Kohalmi, Susanne E; Huang, Shangzhi; Wu, Keqiang; Chen, Xuemei; Cui, Yuhai

    2015-01-01

    The chromatin remodeler BRAHMA (BRM) is a Trithorax Group (TrxG) protein that antagonizes the functions of Polycomb Group (PcG) proteins in fly and mammals. Recent studies also implicate such a role for Arabidopsis (Arabidopsis thaliana) BRM but the molecular mechanisms underlying the antagonism are unclear. To understand the interplay between BRM and PcG during plant development, we performed a genome-wide analysis of trimethylated histone H3 lysine 27 (H3K27me3) in brm mutant seedlings by chromatin immunoprecipitation followed by next generation sequencing (ChIP-seq). Increased H3K27me3 deposition at several hundred genes was observed in brm mutants and this increase was partially supressed by removal of the H3K27 methyltransferase CURLY LEAF (CLF) or SWINGER (SWN). ChIP experiments demonstrated that BRM directly binds to a subset of the genes and prevents the inappropriate association and/or activity of PcG proteins at these loci. Together, these results indicate a crucial role of BRM in restricting the inappropriate activity of PcG during plant development. The key flowering repressor gene SHORT VEGETATIVE PHASE (SVP) is such a BRM target. In brm mutants, elevated PcG occupancy at SVP accompanies a dramatic increase in H3K27me3 levels at this locus and a concomitant reduction of SVP expression. Further, our gain- and loss-of-function genetic evidence establishes that BRM controls flowering time by directly activating SVP expression. This work reveals a genome-wide functional interplay between BRM and PcG and provides new insights into the impacts of these proteins in plant growth and development.

  1. The Arabidopsis SWI2/SNF2 chromatin Remodeler BRAHMA regulates polycomb function during vegetative development and directly activates the flowering repressor gene SVP.

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    Chenlong Li

    2015-01-01

    Full Text Available The chromatin remodeler BRAHMA (BRM is a Trithorax Group (TrxG protein that antagonizes the functions of Polycomb Group (PcG proteins in fly and mammals. Recent studies also implicate such a role for Arabidopsis (Arabidopsis thaliana BRM but the molecular mechanisms underlying the antagonism are unclear. To understand the interplay between BRM and PcG during plant development, we performed a genome-wide analysis of trimethylated histone H3 lysine 27 (H3K27me3 in brm mutant seedlings by chromatin immunoprecipitation followed by next generation sequencing (ChIP-seq. Increased H3K27me3 deposition at several hundred genes was observed in brm mutants and this increase was partially supressed by removal of the H3K27 methyltransferase CURLY LEAF (CLF or SWINGER (SWN. ChIP experiments demonstrated that BRM directly binds to a subset of the genes and prevents the inappropriate association and/or activity of PcG proteins at these loci. Together, these results indicate a crucial role of BRM in restricting the inappropriate activity of PcG during plant development. The key flowering repressor gene SHORT VEGETATIVE PHASE (SVP is such a BRM target. In brm mutants, elevated PcG occupancy at SVP accompanies a dramatic increase in H3K27me3 levels at this locus and a concomitant reduction of SVP expression. Further, our gain- and loss-of-function genetic evidence establishes that BRM controls flowering time by directly activating SVP expression. This work reveals a genome-wide functional interplay between BRM and PcG and provides new insights into the impacts of these proteins in plant growth and development.

  2. Metformin Inhibits Angiotensin II-Induced Differentiation of Cardiac Fibroblasts into Myofibroblasts

    OpenAIRE

    Jian Bai; Na Zhang; Ying Hua; Bingjian Wang; Lin Ling; Albert Ferro; Biao Xu

    2013-01-01

    Differentiation of cardiac fibroblasts into myofibroblasts is a critical event in the progression of cardiac fibrosis that leads to pathological cardiac remodeling. Metformin, an antidiabetic agent, exhibits a number of cardioprotective properties. However, much less is known regarding the effect of metformin on cardiac fibroblast differentiation. Thus, in the present study, we examined the effect of metformin on angiotensin (Ang) II-induced differentiation of cardiac fibroblasts into myofibr...

  3. Evidence for a novel mechanism independent of myocardial iron in β-thalassemia cardiac pathogenesis.

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    Ekatherina Stoyanova

    Full Text Available Human β-thalassemia major is one of the most prevalent genetic diseases characterized by decrease/absence of β-globin chain production with reduction of erythrocyte number. The main cause of death of treated β-thalassemia major patients with chronic blood transfusion is early cardiac complications that have been attributed to secondary iron overload despite optimal chelation. Herein, we investigated pathophysiological mechanisms of cardiovascular dysfunction in a severe murine model of β-thalassemia from 6 to 15-months of age in the absence of confounding effects related to transfusion. Our longitudinal echocardiography analysis showed that β-thalassemic mice first display a significant increase of cardiac output in response to limited oxygen-carrying erythrocytes that progressed rapidly to left ventricular hypertrophy and structural remodeling. Following this compensated hypertrophy, β-thalassemic mice developed age-dependent deterioration of left ventricular contractility and dysfunction that led toward decompensated heart failure. Consistently, murine β-thalassemic hearts histopathology revealed cardiac remodeling with increased interstitial fibrosis but virtual absence of myocardial iron deposits. Importantly, development of thalassemic cardiac hypertrophy and dysfunction independently of iron overload has uncoupled these cardiopathogenic processes. Altogether our study on β-thalassemia major hemoglobinopathy points to two successive phases resulting from severe chronic anemia and from secondarily induced mechanisms as pathophysiologic contributors to thalassemic cardiopathy.

  4. EGFR-ras-raf signaling in epidermal stem cells: roles in hair follicle development, regeneration, tissue remodeling and epidermal cancers.

    Science.gov (United States)

    Doma, Eszter; Rupp, Christian; Baccarini, Manuela

    2013-09-25

    The mammalian skin is the largest organ of the body and its outermost layer, the epidermis, undergoes dynamic lifetime renewal through the activity of somatic stem cell populations. The EGFR-Ras-Raf pathway has a well-described role in skin development and tumor formation. While research mainly focuses on its role in cutaneous tumor initiation and maintenance, much less is known about Ras signaling in the epidermal stem cells, which are the main targets of skin carcinogenesis. In this review, we briefly discuss the properties of the epidermal stem cells and review the role of EGFR-Ras-Raf signaling in keratinocyte stem cells during homeostatic and pathological conditions.

  5. Intra-coronary administration of soluble receptor for advanced glycation end-products attenuates cardiac remodeling with decreased myocardial transforming growth factor-β1 expression and fibrosis in minipigs with ischemia-reperfusion injury

    Institute of Scientific and Technical Information of China (English)

    LU Lin; SHEN Wei-feng; ZHANG Qi; XU Yan; ZHU Zheng-bin; GENG Liang; WANG Ling-jie; JIN Cao; CHEN Qiu-jing; Ann Marie Schmidt

    2010-01-01

    Background The cardioprotective effects of soluble receptor for advanced glycation end-products (sRAGE) have not been evaluated in large animals and the underlying mechanisms are not fully understood. This study aimed to evaluate the effects of intra-coronary administration of sRAGE on left ventricular function and myocardial remodeling in a porcine model of ischemia-reperfusion (I/R) injury. Methods Ten male minipigs with I/R injury were randomly allocated to receive intra-coronary administration of sRAGE (sRAGE group, n=5) or saline (control group, n=5). Echocardiography was performed before and 2 months after infarction. Myocardial expression of transforming growth factor (TGF)-β1was determined by immunohistochemistry and fibrosis was evaluated by Sirius red staining. Results As compared with the baseline values in the control animals, left ventricular end-diastolic volume (from (19.5 5.1) to (32.3 5.6) ml, P <0.05) and end-systolic volume (from (8.3 3.2) to (15.2 4.1) ml, P <0.05) were significantly increased, whereas ejection fraction was decreased (from (61.6 13.3)% to (50.2 11.9)%, P<0.05). No obvious change in these parameters was observed in the sRAGE group. Myocardial expression of TGF-β1 was significantly elevated in the infarct and non-infarct regions in the control group, as compared with sRAGE group (both P<0.01). Fibrotic lesions were consistently more prominent in the infarct region of the myocardium in the control animals (P<0.05). Conclusion Intra-coronary sRAGE administration attenuates RAGE-mediated myocardial fibrosis and I/R injury through a TGF-β1-dependent mechanism, suggesting a clinical potential in treating RAGE/ligand-associated cardiovascular diseases.

  6. Mouse Y-Encoded Transcription Factor Zfy2 Is Essential for Sperm Head Remodelling and Sperm Tail Development.

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    Nadege Vernet

    Full Text Available A previous study indicated that genetic information encoded on the mouse Y chromosome short arm (Yp is required for efficient completion of the second meiotic division (that generates haploid round spermatids, restructuring of the sperm head, and development of the sperm tail. Using mouse models lacking a Y chromosome but with varying Yp gene complements provided by Yp chromosomal derivatives or transgenes, we recently identified the Y-encoded zinc finger transcription factors Zfy1 and Zfy2 as the Yp genes promoting the second meiotic division. Using the same mouse models we here show that Zfy2 (but not Zfy1 contributes to the restructuring of the sperm head and is required for the development of the sperm tail. The preferential involvement of Zfy2 is consistent with the presence of an additional strong spermatid-specific promotor that has been acquired by this gene. This is further supported by the fact that promotion of sperm morphogenesis is also seen in one of the two markedly Yp gene deficient models in which a Yp deletion has created a Zfy2/1 fusion gene that is driven by the strong Zfy2 spermatid-specific promotor, but encodes a protein almost identical to that encoded by Zfy1. Our results point to there being further genetic information on Yp that also has a role in restructuring the sperm head.

  7. Renal ischemia/reperfusion-induced cardiac hypertrophy in mice: Cardiac morphological and morphometric characterization

    Science.gov (United States)

    Cirino-Silva, Rogério; Kmit, Fernanda V; Trentin-Sonoda, Mayra; Nakama, Karina K; Panico, Karine; Alvim, Juliana M; Dreyer, Thiago R; Martinho-Silva, Herculano

    2017-01-01

    Background Tissue remodeling is usually dependent on the deposition of extracellular matrix that may result in tissue stiffness and impaired myocardium contraction. Objectives We had previously demonstrated that renal ischemia/reperfusion (I/R) is able to induce development of cardiac hypertrophy in mice. Therefore, we aimed to characterize renal I/R-induced cardiac hypertrophy. Design C57BL/6 J mice were subjected to 60 minutes’ unilateral renal pedicle occlusion, followed by reperfusion (I/R) for 5, 8, 12 or 15 days. Gene expression, protein abundance and morphometric analyses were performed in all time points. Results Left ventricle wall thickening was increased after eight days of reperfusion (p < 0.05). An increase in the number of heart ventricle capillaries and diameter after 12 days of reperfusion (p < 0.05) was observed; an increase in the density of capillaries starting at 5 days of reperfusion (p < 0.05) was also observed. Analyses of MMP2 protein levels showed an increase at 15 days compared to sham (p < 0.05). Moreover, TGF-β gene expression was downregulated at 12 days as well TIMP 1 and 2 (p < 0.05). The Fourier-transform infrared spectroscopy analysis showed that collagen content was altered only in the internal section of the heart (p < 0.05); such data were supported by collagen mRNA levels. Conclusions Renal I/R leads to impactful changes in heart morphology, accompanied by an increase in microvasculature. Although it is clear that I/R is able to induce cardiac remodeling, such morphological changes is present in only a section of the heart tissue.

  8. Monoclonal antibodies to desmin: evidence for stage-dependent intermediate filament immunoreactivity during cardiac and skeletal muscle development.

    Science.gov (United States)

    Fischman, D A; Danto, S I

    1985-01-01

    Monoclonal antibodies reactive with desmin (D3 and D76) have been generated and their specificities validated by immunoblots, RIAs, and immunocytochemistry. No cross-reaction with other IFPs has been observed. The McAbs recognized different epitopes but both reside in the amino-terminal rod domain of desmin. Whereas McAb D3 produces a staining pattern characteristic of desmin throughout the development of cardiac and skeletal muscles, McAb D76 was selectively unreactive with certain regions of early (three days in ovo) embryonic cardiac anlage, with cultured cardiac myocytes derived from 7-day-old embryos, and with skeletal myotubes in early stages of myogenesis in vitro. Positive reactivity of D76 was seen at stages of myofibrillogenesis when the sarcomeres assume lateral alignment. Evidence was presented that differential reactivity of D76 did not result from the biosynthesis of a new desmin isoform or the post-translational modification of an existing protein. We suggest that the appearance of D76 immunoreactivity during striated muscle development represents an unmasking of the epitope by some IF-associated protein. Since this transition during skeletal muscle differentiation occurs during lateral alignment of the myofibrils, this antibody may serve as a useful probe for exploring this reorganization of the contractile apparatus during myogenesis and muscle regeneration.

  9. Insights into the role of maladaptive hexosamine biosynthesis and O-GlcNAcylation in development of diabetic cardiac complications.

    Science.gov (United States)

    Qin, Cheng Xue; Sleaby, Rochelle; Davidoff, Amy J; Bell, James R; De Blasio, Miles J; Delbridge, Leanne M; Chatham, John C; Ritchie, Rebecca H

    2017-02-01

    Diabetes mellitus significantly increases the risk of heart failure, independent of coronary artery disease. The mechanisms implicated in the development of diabetic heart disease, commonly termed diabetic cardiomyopathy, are complex, but much of the impact of diabetes on the heart can be attributed to impaired glucose handling. It has been shown that the maladaptive nutrient-sensing hexosamine biosynthesis pathway (HBP) contributes to diabetic complications in many non-cardiac tissues. Glucose metabolism by the HBP leads to enzymatically-regulated, O-linked attachment of a sugar moiety molecule, β-N-acetylglucosamine (O-GlcNAc), to proteins, affecting their biological activity (similar to phosphorylation). In normal physiology, transient activation of HBP/O-GlcNAc mechanisms is an adaptive, protective means to enhance cell survival; interventions that acutely suppress this pathway decrease tolerance to stress. Conversely, chronic dysregulation of HBP/O-GlcNAc mechanisms has been shown to be detrimental in certain pathological settings, including diabetes and cancer. Most of our understanding of the impact of sustained maladaptive HBP and O-GlcNAc protein modifications has been derived from adipose tissue, skeletal muscle and other non-cardiac tissues, as a contributing mechanism to insulin resistance and progression of diabetic complications. However, the long-term consequences of persistent activation of cardiac HBP and O-GlcNAc are not well-understood; therefore, the goal of this timely review is to highlight current understanding of the role of the HBP pathway in development of diabetic cardiomyopathy.

  10. Weight-bearing locomotion in the developing opossum, Monodelphis domestica following spinal transection: remodeling of neuronal circuits caudal to lesion.

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    Benjamin J Wheaton

    Full Text Available Complete spinal transection in the mature nervous system is typically followed by minimal axonal repair, extensive motor paralysis and loss of sensory functions caudal to the injury. In contrast, the immature nervous system has greater capacity for repair, a phenomenon sometimes called the infant lesion effect. This study investigates spinal injuries early in development using the marsupial opossum Monodelphis domestica whose young are born very immature, allowing access to developmental stages only accessible in utero in eutherian mammals. Spinal cords of Monodelphis pups were completely transected in the lower thoracic region, T10, on postnatal-day (P7 or P28 and the animals grew to adulthood. In P7-injured animals regrown supraspinal and propriospinal axons through the injury site were demonstrated using retrograde axonal labelling. These animals recovered near-normal coordinated overground locomotion, but with altered gait characteristics including foot placement phase lags. In P28-injured animals no axonal regrowth through the injury site could be demonstrated yet they were able to perform weight-supporting hindlimb stepping overground and on the treadmill. When placed in an environment of reduced sensory feedback (swimming P7-injured animals swam using their hindlimbs, suggesting that the axons that grew across the lesion made functional connections; P28-injured animals swam using their forelimbs only, suggesting that their overground hindlimb movements were reflex-dependent and thus likely to be generated locally in the lumbar spinal cord. Modifications to propriospinal circuitry in P7- and P28-injured opossums were demonstrated by changes in the number of fluorescently labelled neurons detected in the lumbar cord following tracer studies and changes in the balance of excitatory, inhibitory and neuromodulatory neurotransmitter receptors' gene expression shown by qRT-PCR. These results are discussed in the context of studies indicating

  11. Transcriptional network analysis for the regulation of left ventricular hypertrophy and microvascular remodeling.

    Science.gov (United States)

    Moreno-Moral, Aida; Mancini, Massimiliano; D'Amati, Giulia; Camici, Paolo; Petretto, Enrico

    2013-12-01

    Hypertension and cardiomyopathies share maladaptive changes of cardiac morphology, eventually leading to heart failure. These include left ventricular hypertrophy (LVH), myocardial fibrosis, and structural remodeling of coronary microcirculation, which is the morphologic hallmark of coronary microvascular dysfunction. To pinpoint the complex molecular mechanisms and pathways underlying LVH-associated cardiac remodeling independent of blood pressure effects, we employed gene network approaches to the rat heart. We used the Spontaneously Hypertensive Rat model showing many features of human hypertensive cardiomyopathy, for which we collected histological and histomorphometric data of the heart and coronary vasculature, and genome-wide cardiac gene expression. Here, we provide a large catalogue of gene co-expression networks in the heart that are significantly associated with quantitative variation in LVH, microvascular remodeling, and fibrosis-related traits. Many of these networks were significantly conserved to human idiopathic and/or ischemic cardiomyopathy patients, suggesting a potential role for these co-expressed genes in human heart disease.

  12. Embryonic Lethality Due to Arrested Cardiac Development in Psip1/Hdgfrp2 Double-Deficient Mice.

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    Hao Wang

    Full Text Available Hepatoma-derived growth factor (HDGF related protein 2 (HRP2 and lens epithelium-derived growth factor (LEDGF/p75 are closely related members of the HRP2 protein family. LEDGF/p75 has been implicated in numerous human pathologies including cancer, autoimmunity, and infectious disease. Knockout of the Psip1 gene, which encodes for LEDGF/p75 and the shorter LEDGF/p52 isoform, was previously shown to cause perinatal lethality in mice. The function of HRP2 was by contrast largely unknown. To learn about the role of HRP2 in development, we knocked out the Hdgfrp2 gene, which encodes for HRP2, in both normal and Psip1 knockout mice. Hdgfrp2 knockout mice developed normally and were fertile. By contrast, the double deficient mice died at approximate embryonic day (E 13.5. Histological examination revealed ventricular septal defect (VSD associated with E14.5 double knockout embryos. To investigate the underlying molecular mechanism(s, RNA recovered from ventricular tissue was subjected to RNA-sequencing on the Illumina platform. Bioinformatic analysis revealed several genes and biological pathways that were significantly deregulated by the Psip1 knockout and/or Psip1/Hdgfrp2 double knockout. Among the dozen genes known to encode for LEDGF/p75 binding factors, only the expression of Nova1, which encodes an RNA splicing factor, was significantly deregulated by the knockouts. However the expression of other RNA splicing factors, including the LEDGF/p52-interacting protein ASF/SF2, was not significantly altered, indicating that deregulation of global RNA splicing was not a driving factor in the pathology of the VSD. Tumor growth factor (Tgf β-signaling, which plays a key role in cardiac morphogenesis during development, was the only pathway significantly deregulated by the double knockout as compared to control and Psip1 knockout samples. We accordingly speculate that deregulated Tgf-β signaling was a contributing factor to the VSD and prenatal lethality

  13. Fermitins, the orthologs of mammalian Kindlins, regulate the development of a functional cardiac syncytium in Drosophila melanogaster.

    Directory of Open Access Journals (Sweden)

    James H Catterson

    Full Text Available The vertebrate Kindlins are an evolutionarily conserved family of proteins critical for integrin signalling and cell adhesion. Kindlin-2 (KIND2 is associated with intercalated discs in mice, suggesting a role in cardiac syncytium development; however, deficiency of Kind2 leads to embryonic lethality. Morpholino knock-down of Kind2 in zebrafish has a pleiotropic effect on development that includes the heart. It therefore remains unclear whether cardiomyocyte Kind2 expression is required for cardiomyocyte junction formation and the development of normal cardiac function. To address this question, the expression of Fermitin 1 and Fermitin 2 (Fit1, Fit2, the two Drosophila orthologs of Kind2, was silenced in Drosophila cardiomyocytes. Heart development was assessed in adult flies by immunological methods and videomicroscopy. Silencing both Fit1 and Fit2 led to a severe cardiomyopathy characterised by the failure of cardiomyocytes to develop as a functional syncytium and loss of synchrony between cardiomyocytes. A null allele of Fit1 was generated but this had no impact on the heart. Similarly, the silencing of Fit2 failed to affect heart function. In contrast, the silencing of Fit2 in the cardiomyocytes of Fit1 null flies disrupted syncytium development, leading to severe cardiomyopathy. The data definitively demonstrate a role for Fermitins in the development of a functional cardiac syncytium in Drosophila. The findings also show that the Fermitins can functionally compensate for each other in order to control syncytium development. These findings support the concept that abnormalities in cardiomyocyte KIND2 expression or function may contribute to cardiomyopathies in humans.

  14. Vessel remodelling, pregnancy hormones and extravillous trophoblast function.

    Science.gov (United States)

    Chen, Jessie Z-J; Sheehan, Penelope M; Brennecke, Shaun P; Keogh, Rosemary J

    2012-02-26

    During early human pregnancy, extravillous trophoblast (EVT) cells from the placenta invade the uterine decidual spiral arterioles and mediate the remodelling of these vessels such that a low pressure, high blood flow can be supplied to the placenta. This is essential to facilitate normal growth and development of the foetus. Defects in remodelling can manifest as the serious pregnancy complication pre-eclampsia. During the period of vessel remodelling three key pregnancy-associated hormones, human chorionic gonadotrophin (hCG), progesterone (P(4)) and oestradiol (E(2)), are found in high concentrations at the maternal-foetal interface. Potentially these hormones may control EVT movement and thus act as regulators of vessel remodelling. This review will discuss what is known about how these hormones affect EVT proliferation, migration and invasion during vascular remodelling and the potential relationship between hCG, P(4), E(2) and the development of pre-eclampsia.

  15. Basement membrane zone remodeling during appendageal development in human fetal skin. The absence of type VII collagen is associated with gelatinase-A (MMP2) activity.

    Science.gov (United States)

    Karelina, T V; Bannikov, G A; Eisen, A Z

    2000-02-01

    protein correlates directly with the presence of Gel A-activity at the BMZ. Gel A appears to play a major role in appendageal development and contributes to remodeling of the BMZ during fetal skin morphogenesis.

  16. A peptide vaccine targeting angiotensin II attenuates the cardiac dysfunction induced by myocardial infarction

    Science.gov (United States)

    Watanabe, Ryo; Suzuki, Jun-ichi; Wakayama, Kouji; Maejima, Yasuhiro; Shimamura, Munehisa; Koriyama, Hiroshi; Nakagami, Hironori; Kumagai, Hidetoshi; Ikeda, Yuichi; Akazawa, Hiroshi; Morishita, Ryuichi; Komuro, Issei; Isobe, Mitsuaki

    2017-01-01

    A peptide vaccine targeting angiotensin II (Ang II) was recently developed as a novel treatment for hypertension to resolve the problem of noncompliance with pharmacotherapy. Ang II plays a crucial role in the pathogenesis of cardiac remodeling after myocardial infarction (MI), which causes heart failure. In the present study, we examined whether the Ang II vaccine is effective in preventing heart failure. The injection of the Ang II vaccine in a rat model of MI attenuated cardiac dysfunction in association with an elevation in the serum anti-Ang II antibody titer. Furthermore, any detrimental effects of the Ang II vaccine were not observed in the rats that underwent sham operations. Treatment with immunized serum from Ang II vaccine-injected rats significantly suppressed post-MI cardiac dysfunction in MI rats and Ang II-induced remodeling-associated signaling in cardiac fibroblasts. Thus, our present study demonstrates that the Ang II vaccine may provide a promising novel therapeutic strategy for preventing heart failure. PMID:28266578

  17. The role of cardiac magnetic resonance imaging following acute myocardial infarction

    Energy Technology Data Exchange (ETDEWEB)

    Wong, Dennis T.L.; Richardson, James D.; Puri, Rishi; Nelson, Adam J.; Teo, Karen S.L.; Worthley, Matthew I. [Royal Adelaide Hospital, Cardiovascular Research Centre, Adelaide (Australia); University of Adelaide, Department of Medicine, Adelaide (Australia); Bertaso, Angela G. [Royal Adelaide Hospital, Cardiovascular Research Centre, Adelaide (Australia); Worthley, Stephen G. [Royal Adelaide Hospital, Cardiovascular Research Centre, Adelaide (Australia); University of Adelaide, Department of Medicine, Adelaide (Australia); Cardiovascular Investigational Unit, Adelaide, SA (Australia)

    2012-08-15

    Advances in the management of myocardial infarction have resulted in substantial reductions in morbidity and mortality. However, after acute treatment a number of diagnostic and prognostic questions often remain to be answered, whereby cardiac imaging plays an essential role. For example, some patients will sustain early mechanical complications after infarction, while others may develop significant ventricular dysfunction. Furthermore, many individuals harbour a significant burden of residual coronary disease for which clarification of functional ischaemic status and/or viability of the suspected myocardial territory is required. Cardiac magnetic resonance (CMR) imaging is well positioned to fulfil these requirements given its unparalleled capability in evaluating cardiac function, stress ischaemia testing and myocardial tissue characterisation. This review will focus on the utility of CMR in resolving diagnostic uncertainty, evaluating early complications following myocardial infarction, assessing inducible ischaemia, myocardial viability, ventricular remodelling and the emerging role of CMR-derived measures as endpoints in clinical trials. (orig.)

  18. Platelet-derived growth factor involvement in myocardial remodeling following infarction.

    Science.gov (United States)

    Zhao, Wenyuan; Zhao, Tieqiang; Huang, Valerie; Chen, Yuanjian; Ahokas, Robert A; Sun, Yao

    2011-11-01

    Cardiac remodeling occurs in the infarcted heart (MI). The underlying regulatory mechanisms are under investigation. Platelet-derived growth factor (PDGF) is a family of growth factors that stimulates cell growth, differentiation and migration. Herein, we sought to determine whether PDGF is involved in cardiac repair/remodeling following MI. The temporal and spatial expressions of PDGF isoforms (A, B, C and D) and PDGF receptor (PDGFR)-α and β as well as cell types expressing PDGF were examined in the infarcted rat heart. Sham-operated rats served as controls. We found that the normal myocardium expressed all PDGF isoforms, and cell types expressing PDGF were primarily interstitial cells. Following MI, PDGF-A and D were significantly increased in the infarcted myocardium during 6 weeks of the observation period and cells expressing PDGF-A and D were primarily endothelial cells, macrophages and myofibroblasts (myoFb). PDGF-B and C expressions were, however, reduced in the infarcted heart. In the noninfarcted myocardium, PDGF-D expression was increased in the late stage of MI and cells expressing PDGF-D were predominantly fibroblasts. Both PDGFR-α and β were significantly increased in the infarcted myocardium in the early and late stages of MI and in the noninfarcted myocardium in the late stage of MI. Enhanced PDGF-A, PDGF-D and PDGFR are coincident with angiogenesis, and inflammatory and fibrogenic responses in the infarcted myocardium, suggesting their regulation on cardiac repair. Elevated PDGF-D in the noninfarcted myocardium suggests its involvement in the development of interstitial fibrosis that appears in the late stage of MI.

  19. Human bone marrow-derived adult stem cells for post-myocardial infarction cardiac repair: current status and future directions.

    Science.gov (United States)

    Wei, H M; Wong, P; Hsu, L F; Shim, W

    2009-10-01

    Stem cell-based cell therapy has emerged as a potentially therapeutic option for patients with acute myocardial infarction (AMI) and heart failure. With the completion of a number of trials using bone marrow (BM)-derived adult stem cells, critical examination of the overall clinical benefits, limitations and potential side effects of this revolutionary treatment will pave the way for future clinical research. At present, clinical trials have been conducted almost exclusively using BM stem cells. The primary endpoints of these trials are mainly safety and feasibility, with secondary endpoints in the efficacy of post-myocardial infarction (MI) cardiac repair. Intervention with BM-derived cells was mainly carried out by endogenously-mobilised BM cells with granulocyte-colony stimulating factor, and more frequently, by intracoronary infusion or direct intramyocardial injection of autologous BM cells. While these studies have been proven safe and feasible without notable side effects, mixed outcomes in terms of clinical benefits have been reported. The major clinical benefits observed are improved cardiac contractile function and suppressed left ventricular negative remodelling, including reduced infarct size and improved cardiac perfusion of infarct zone. Moderate and transient clinical benefits have been mostly observed in studies with intracoronary infusion or direct intramyocardial injection of BM cells. These effects are widely considered to be indirect effects of implanted cells in association with paracrine factors, cell fusion, passive ventricular remodelling, or the responses of endogenous cardiac stem cells. In contrast, evidence of cardiac regeneration characterised by differentiation of implanted stem cells into cardiomyocytes and other cardiac cell lineages, is weak or lacking. To elucidate a clear risk-benefit of this exciting therapy, future studies on the mechanisms of cardiac cell therapy will need to focus on confirming the ideal cell types in relation

  20. Chromatin Remodeling and Plant Immunity.

    Science.gov (United States)

    Chen, W; Zhu, Q; Liu, Y; Zhang, Q

    2017-01-01

    Chromatin remodeling, an important facet of the regulation of gene expression in eukaryotes, is performed by two major types of multisubunit complexes, covalent histone- or DNA-modifying complexes, and ATP-dependent chromosome remodeling complexes. Snf2 family DNA-dependent ATPases constitute the catalytic subunits of ATP-dependent chromosome remodeling complexes, which accounts for energy supply during chromatin remodeling. Increasing evidence indicates a critical role of chromatin remodeling in the establishment of long-lasting, even transgenerational immune memory in plants, which is supported by the findings that DNA methylation, histone deacetylation, and histone methylation can prime the promoters of immune-related genes required for disease defense. So what are the links between Snf2-mediated ATP-dependent chromosome remodeling and plant immunity, and what mechanisms might support its involvement in disease resistance?

  1. Development of Electrically Conductive Double-Network Hydrogels via One-Step Facile Strategy for Cardiac Tissue Engineering.

    Science.gov (United States)

    Yang, Boguang; Yao, Fanglian; Hao, Tong; Fang, Wancai; Ye, Lei; Zhang, Yabin; Wang, Yan; Li, Junjie; Wang, Changyong

    2016-02-18

    Cardiac tissue engineering is an effective method to treat the myocardial infarction. However, the lack of electrical conductivity of biomaterials limits their applications. In this work, a homogeneous electronically conductive double network (HEDN) hydrogel via one-step facile strategy is developed, consisting of a rigid/hydrophobic/conductive network of chemical crosslinked poly(thiophene-3-acetic acid) (PTAA) and a flexible/hydrophilic/biocompatible network of photo-crosslinking methacrylated aminated gelatin (MAAG). Results suggest that the swelling, mechanical, and conductive properties of HEDN hydrogel can be modulated via adjusting the ratio of PTAA network to MAAG network. HEDN hydrogel has Young's moduli ranging from 22.7 to 493.1 kPa, and its conductivity (≈10(-4) S cm(-1)) falls in the range of reported conductivities for native myocardium tissue. To assess their biological activity, the brown adipose-derived stem cells (BADSCs) are seeded on the surface of HEDN hydrogel with or without electrical stimulation. Our data show that the HEDN hydrogel can support the survival and proliferation of BADSCs, and that it can improve the cardiac differentiation efficiency of BADSCs and upregulate the expression of connexin 43. Moreover, electrical stimulation can further improve this effect. Overall, it is concluded that the HEDN hydrogel may represent an ideal scaffold for cardiac tissue engineering.

  2. Longstanding hyperthyroidism is associated with normal or enhanced intrinsic cardiomyocyte function despite decline in global cardiac function.

    Directory of Open Access Journals (Sweden)

    Nathan Y Weltman

    Full Text Available Thyroid hormones (THs play a pivotal role in cardiac homeostasis. TH imbalances alter cardiac performance and ultimately cause cardiac dysfunction. Although short-term hyperthyroidism typically leads to heightened left ventricular (LV contractility and improved hemodynamic parameters, chronic hyperthyroidism is associated with deleterious cardiac consequences including increased risk of arrhythmia, impaired cardiac reserve and exercise capacity, myocardial remodeling, and occasionally heart failure. To evaluate the long-term consequences of chronic hyperthyroidism on LV remodeling and function, we examined LV isolated myocyte function, chamber function, and whole tissue remodeling in a hamster model. Three-month-old F1b hamsters were randomized to control or 10 months TH treatment (0.1% grade I desiccated TH. LV chamber remodeling and function was assessed by echocardiography at 1, 2, 4, 6, 8, and 10 months of treatment. After 10 months, terminal cardiac function was assessed by echocardiography and LV hemodynamics. Hyperthyroid hamsters exhibited significant cardiac hypertrophy and deleterious cardiac remodeling characterized by myocyte lengthening, chamber dilatation, decreased relative wall thickness, increased wall stress, and increased LV interstitial fibrotic deposition. Importantly, hyperthyroid hamsters demonstrated significant LV systolic and diastolic dysfunction. Despite the aforementioned remodeling and global cardiac decline, individual isolated cardiac myocytes from chronically hyperthyroid hamsters had enhanced function when compared with myocytes from untreated age-matched controls. Thus, it appears that long-term hyperthyroidism may impair global LV function, at least in part by increasing interstitial ventricular fibrosis, in spite of normal or enhanced intrinsic cardiomyocyte function.

  3. Development of a unidimensional composite measure of neuropsychological functioning in older cardiac surgery patients with good measurement precision.

    Science.gov (United States)

    Jones, Richard N; Rudolph, James L; Inouye, Sharon K; Yang, Frances M; Fong, Tamara G; Milberg, William P; Tommet, Douglas; Metzger, Eran D; Cupples, L Adrienne; Marcantonio, Edward R

    2010-12-01

    The objective of this analysis was to develop a measure of neuropsychological performance for cardiac surgery and to assess its psychometric properties. Older patients (n = 210) underwent a neuropsychological battery using nine assessments. The number of factors was identified with variable reduction methods. Factor analysis methods based on item response theory were used to evaluate the measure. Modified parallel analysis supported a single factor, and the battery formed an internally consistent set (coefficient alpha = .82). The developed measure provided a reliable, continuous measure (reliability > .90) across a broad range of performance (-1.5 SDs to +1.0 SDs) with minimal ceiling and floor effects.

  4. [Advances in cardiac pacing].

    Science.gov (United States)

    de Carranza, María-José Sancho-Tello; Fidalgo-Andrés, María Luisa; Ferrer, José Martínez; Mateas, Francisco Ruiz

    2012-01-01

    This article contains a review of the current status of remote monitoring and follow-up involving cardiac pacing devices and of the latest developments in cardiac resynchronization therapy. In addition, the most important articles published in the last year are discussed.

  5. Remodeling with the sun

    Energy Technology Data Exchange (ETDEWEB)

    Bodzin, S. [ed.

    1997-05-01

    Remodeling is the perfect time to improve daylighting, direct gain heating and shading with passive solar techniques. It can also provide the best opportunity to add solar water heating or even photoboltaics to a home. This article describes addition of such energy efficient plans to a home in terms of what is needed and what the benefits are: adding windows, North glass, east and west glass, south glass, daylighting, the roof, shingles and roofing tiles, walls and floors, solar hot water, photovoltaics. Two side bars discuss the sunplace: a passive solar room and angles and overhangs.

  6. Cardiac arrest

    Science.gov (United States)

    ... Article.jsp. Accessed June 16, 2014. Myerburg RJ, Castellanos A. Approach to cardiac arrest and life-threatening ... PA: Elsevier Saunders; 2011:chap 63. Myerburg RJ, Castellanos A. Cardiac arrest and audden aardiac death. In: ...

  7. Assembly of the cardiac intercalated disk during pre- and postnatal development of the human heart.

    Directory of Open Access Journals (Sweden)

    Arnold Vreeker

    Full Text Available BACKGROUND: In cardiac muscle, the intercalated disk (ID at the longitudinal cell-edges of cardiomyocytes provides as a macromolecular infrastructure that integrates mechanical and electrical coupling within the heart. Pathophysiological disturbance in composition of this complex is well known to trigger cardiac arrhythmias and pump failure. The mechanisms underlying assembly of this important cellular domain in human heart is currently unknown. METHODS: We collected 18 specimens from individuals that died from non-cardiovascular causes. Age of the specimens ranged from a gestational age of 15 weeks through 11 years postnatal. Immunohistochemical labeling was performed against proteins comprising desmosomes, adherens junctions, the cardiac sodium channel and gap junctions to visualize spatiotemporal alterations in subcellular location of the proteins. RESULTS: Changes in spatiotemporal localization of the adherens junction proteins (N-cadherin and ZO-1 and desmosomal proteins (plakoglobin, desmoplakin and plakophilin-2 were identical in all subsequent ages studied. After an initial period of diffuse and lateral labelling, all proteins were fully localized in the ID at approximately 1 year after birth. Nav1.5 that composes the cardiac sodium channel and the gap junction protein Cx43 follow a similar pattern but their arrival in the ID is detected at (much later stages (two years for Nav1.5 and seven years for Cx43, respectively. CONCLUSION: Our data on developmental maturation of the ID in human heart indicate that generation of the mechanical junctions at the ID precedes that of the electrical junctions with a significant difference in time. In addition arrival of the electrical junctions (Nav1.5 and Cx43 is not uniform since sodium channels localize much earlier than gap junction channels.

  8. Prenatal programming: adverse cardiac programming by gestational testosterone excess

    Science.gov (United States)

    Vyas, Arpita K.; Hoang, Vanessa; Padmanabhan, Vasantha; Gilbreath, Ebony; Mietelka, Kristy A.

    2016-01-01

    Adverse events during the prenatal and early postnatal period of life are associated with development of cardiovascular disease in adulthood. Prenatal exposure to excess testosterone (T) in sheep induces adverse reproductive and metabolic programming leading to polycystic ovarian syndrome, insulin resistance and hypertension in the female offspring. We hypothesized that prenatal T excess disrupts insulin signaling in the cardiac left ventricle leading to adverse cardiac programming. Left ventricular tissues were obtained from 2-year-old female sheep treated prenatally with T or oil (control) from days 30–90 of gestation. Molecular markers of insulin signaling and cardiac hypertrophy were analyzed. Prenatal T excess increased the gene expression of molecular markers involved in insulin signaling and those associated with cardiac hypertrophy and stress including insulin receptor substrate-1 (IRS-1), phosphatidyl inositol-3 kinase (PI3K), Mammalian target of rapamycin complex 1 (mTORC1), nuclear factor of activated T cells –c3 (NFATc3), and brain natriuretic peptide (BNP) compared to controls. Furthermore, prenatal T excess increased the phosphorylation of PI3K, AKT and mTOR. Myocardial disarray (multifocal) and increase in cardiomyocyte diameter was evident on histological investigation in T-treated females. These findings support adverse left ventricular remodeling by prenatal T excess. PMID:27328820

  9. Prenatal programming: adverse cardiac programming by gestational testosterone excess.

    Science.gov (United States)

    Vyas, Arpita K; Hoang, Vanessa; Padmanabhan, Vasantha; Gilbreath, Ebony; Mietelka, Kristy A

    2016-06-22

    Adverse events during the prenatal and early postnatal period of life are associated with development of cardiovascular disease in adulthood. Prenatal exposure to excess testosterone (T) in sheep induces adverse reproductive and metabolic programming leading to polycystic ovarian syndrome, insulin resistance and hypertension in the female offspring. We hypothesized that prenatal T excess disrupts insulin signaling in the cardiac left ventricle leading to adverse cardiac programming. Left ventricular tissues were obtained from 2-year-old female sheep treated prenatally with T or oil (control) from days 30-90 of gestation. Molecular markers of insulin signaling and cardiac hypertrophy were analyzed. Prenatal T excess increased the gene expression of molecular markers involved in insulin signaling and those associated with cardiac hypertrophy and stress including insulin receptor substrate-1 (IRS-1), phosphatidyl inositol-3 kinase (PI3K), Mammalian target of rapamycin complex 1 (mTORC1), nuclear factor of activated T cells -c3 (NFATc3), and brain natriuretic peptide (BNP) compared to controls. Furthermore, prenatal T excess increased the phosphorylation of PI3K, AKT and mTOR. Myocardial disarray (multifocal) and increase in cardiomyocyte diameter was evident on histological investigation in T-treated females. These findings support adverse left ventricular remodeling by prenatal T excess.

  10. Influence of telmisartan on morning peak of blood pressure and cardiac remodeling in aged patients with hypertension%替米沙坦对老年高血压患者血压晨峰与心脏重构的影响

    Institute of Scientific and Technical Information of China (English)

    周咏梅; 陶剑虹

    2012-01-01

    目的:探讨替米沙坦对老年高血压患者血压晨峰现象及心脏重构的影响.方法:120例老年高血压患者根据血压晨峰是否超过23.58mmHg分为晨峰组(60例)与非晨峰组(60例),均予以替米沙坦80~160mg/d治疗6月,治疗前后行动态血压、心脏超声检查.结果:与血压非晨峰组比较,晨峰组左室肥厚发生率(36.7%比51.6%)、左房内径扩大率(26.7%比41.7%)明显升高(P均<0.01);与治疗前比较,晨峰组经替米沙坦治疗6月后收缩压(SBP)差值[(32.7±4.2) mmHg比(21.2±6.7) mmHg]、舒张压(DBP)差值[(20.3±3.6)mmHg比(13.5±7.4) mmHg]明显降低(P<0.01),而非晨峰组SBP、DBP差值较治疗前无明显降低(P>0.05),两组替米沙坦治疗6月后左室重量指数均明显降低(P<0.05).结论:老年高血压患者血压晨峰程度与心脏重构密切相关,替米沙坦能有效控制老年高血压患者晨峰现象,逆转左室肥厚.%Objective: To investigate influence of telmisartan on morning peak of blood pressure and cardiac remodeling in aged patients with hypertension. Methods: According to morning peak of blood pressure≥23. 58 mmHg or not, a total of 120 aged patients with hypertension were divided into morning peak of blood pressure group (observe group, n = 60) and non-morning peak of blood pressure group (control group, n = 60). Both groups received telmis-artan 80~160 mg/d for six months and underwent ambulatory blood pressure monitoring and echocardiography examination before and after treatment. Results: Compared with control group, incidence rates of left ventricular hypertrophy (36.7% vs. 51.6%) and left atrial enlargement rate (26.7% vs. 41.7%) significantly increased in observe group, P0. 05). After six- month telmisartan treatment, left ventricular mass indexes of the two groups significantly decreased (P<0. 05). Conclusion: Morning peak of blood pressure is closely correlated with cardiac remodeling in aged patients with hypertension

  11. 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.

  12. Biomaterials for cardiac regeneration

    CERN Document Server

    Ruel, Marc

    2015-01-01

    This book offers readers a comprehensive biomaterials-based approach to achieving clinically successful, functionally integrated vasculogenesis and myogenesis in the heart. Coverage is multidisciplinary, including the role of extracellular matrices in cardiac development, whole-heart tissue engineering, imaging the mechanisms and effects of biomaterial-based cardiac regeneration, and autologous bioengineered heart valves. Bringing current knowledge together into a single volume, this book provides a compendium to students and new researchers in the field and constitutes a platform to allow for future developments and collaborative approaches in biomaterials-based regenerative medicine, even beyond cardiac applications. This book also: Provides a valuable overview of the engineering of biomaterials for cardiac regeneration, including coverage of combined biomaterials and stem cells, as well as extracellular matrices Presents readers with multidisciplinary coverage of biomaterials for cardiac repair, including ...

  13. The development and application of a high-sensitivity immunoassay for cardiac myosin–binding protein C

    Science.gov (United States)

    Marjot, Jack; Liebetrau, Christoph; Goodson, Robert J.; Kaier, Thomas; Weber, Ekkehard; Heseltine, Peter; Marber, Michael S.

    2016-01-01

    Cardiac troponins (cTns) are released and cleared slowly after myocardial injury. Cardiac myosin–binding protein C (cMyC) is a similar cardiac-restricted protein that has more rapid release and clearance kinetics. Direct comparisons are hampered by the lack of an assay for cMyC that matches the sensitivity of the contemporary assays for cTnI and cTnT. Using a novel pair of monoclonal antibodies, we generated a sensitive assay for MyC on the Erenna platform (Singulex) and compared serum concentrations with those of cTnI (Abbott) and cTnT (Roche) in stable ambulatory cardiac patients without evidence of acute cardiac injury or significant coronary artery stenoses. The assay for cMyC had a lower limit of detection of 0.4 ng/L, a lower limit of quantification (LLoQ) of 1.2 ng/L (LLoQ at 20% coefficient of variation [CV]) and reasonable recovery (107.1 ± 3.7%; mean ± standard deviation), dilutional linearity (101.0 ± 7.7%), and intraseries precision (CV, 11 ± 3%) and interseries precision (CV, 13 ± 3%). In 360 stable patients, cMyC was quantifiable in 359 patients and compared with cTnT and cTnI measured using contemporary high-sensitivity assays. cMyC concentration (median, 12.2 ng/L; interquartile range [IQR], 7.9–21.2 ng/L) was linearly correlated with those for cTnT (median, <3.0 ng/L; IQR, <3.0–4.9 ng/L; R = 0.56, P < 0.01) and cTnI (median, 2.10 ng/L; IQR, 1.3–4.2 ng/L; R = 0.77, P < 0.01) and showed similar dependencies on age, renal function, and left ventricular function. We have developed a high-sensitivity assay for cMyC. Concentrations of cMyC in clinically stable patients are highly correlated with those of cTnT and cTnI. This high correlation may enable ratiometric comparisons between biomarkers to distinguish clinical instability. PMID:26713894

  14. Functional Alterations of Ion Channels From Cardiac Fibroblasts in Heart Diseases

    Directory of Open Access Journals (Sweden)

    Gracious R. Ross

    2016-11-01

    Full Text Available In an aged population, cardiovascular disease is the leading cause of fatality and morbidity. Age-related fibrotic remodeling of the heart contributes to progressive myocardial dysfunction. Cardiac fibroblasts (CF, responsible for the maintenance of extracellular matrix and fibrosis process, play an important role in cardiac health and disease. CFs influence myocardial function by their chemical, electrical and mechanical interactions with cardiomyocytes through extracellular matrix deposition or secretion of cytokines and growth factors. These, in turn, are modulated by ion channels, macromolecular pores in the plasma membrane that allow selective ionic fluxes of major ions like K+, Ca2+, Na+ or Cl-, which affect membrane potential and cellular signal transduction. The importance of ion channels in modulating various functions of CFs, including proliferation, differentiation, secretion and apoptosis, is being recognized from recent studies of CFs from animal models and tissue from patients with various cardiac pathologies. Understanding the role of ion channels in CFs under physiological conditions and their alterations in age-related cardiac diseases may help facilitate development of novel therapeutic strategies to limit cardiac fibrosis and its adverse effect on myocardial function. This narrative review summarizes the knowledge gained thus far on ion channels in CFs and their relationship with cardiac diseases in human and experimental animal models.

  15. Alternative splicing in the differentiation of human embryonic stem cells into cardiac precursors.

    Directory of Open Access Journals (Sweden)

    Nathan Salomonis

    2009-11-01

    Full Text Available The role of alternative splicing in self-renewal, pluripotency and tissue lineage specification of human embryonic stem cells (hESCs is largely unknown. To better define these regulatory cues, we modified the H9 hESC line to allow selection of pluripotent hESCs by neomycin resistance and cardiac progenitors by puromycin resistance. Exon-level microarray expression data from undifferentiated hESCs and cardiac and neural precursors were used to identify splice isoforms with cardiac-restricted or common cardiac/neural differentiation expression patterns. Splice events for these groups corresponded to the pathways of cytoskeletal remodeling, RNA splicing, muscle specification, and cell cycle checkpoint control as well as genes with serine/threonine kinase and helicase activity. Using a new program named AltAnalyze (http://www.AltAnalyze.org, we identified novel changes in protein domain and microRNA binding site architecture that were predicted to affect protein function and expression. These included an enrichment of splice isoforms that oppose cell-cycle arrest in hESCs and that promote calcium signaling and cardiac development in cardiac precursors. By combining genome-wide predictions of alternative splicing with new functional annotations, our data suggest potential mechanisms that may influence lineage commitment and hESC maintenance at the level of specific splice isoforms and microRNA regulation.

  16. Electrical and myocardial remodeling in primary aldosteronism

    Directory of Open Access Journals (Sweden)

    Mario eCurione

    2014-11-01

    Full Text Available Objective and design: primary aldosteronism (PA represents the most common cause of secondary hypertension. An higher risk of cardiovascular events has been reported in patients with PA than otherwise similar patients with essential hypertension (EH. At today few studies has been investigated the electrocardiographic changes in PA patients compared to EH patients.Methods: to investigate the electrocardiographic changes and heart remodeling in PA we enrolled 61 consecutive patients, 30 with PA (12 with aldosterone producing adenoma-APA and 18 with bilateral adrenal hyperplasia-IHA and 30 with EH. In all subjects electrelectrocardiographic parameters were evaluated from 12-lead electrocardiograms and heart remodeling with echocardiogram.Results: no significant differences in age, sex , body mass index (BMI and blood pressure were found in two groups. The P wave and PR interval duration were significantly prolonged in patientswith PA respect to EH (p< 0.003 and p< 0.002, respectively. First degree atrioventricular block was present in 16% patient with PA and only in 3.2% patients with EH. In PA patients the interventricular septum thickness (IVST correlated with left ventricular mass indecized (LVMi (r= 0.54; p< 0.04, and with PR duration (r= 0.51; p< 0.03. Left ventricular hypertrophy (LVH was present in 53% patients with PA and in 26% patients with EH (χ2 p<0.03.Conclusions: in this case-control study, patients with PA show more anatomic and electrical heart remodeling than those with EH. We hypothesize that in patients with PA these cardiac changes may play a role for the increased risk of future cardiovascular events.

  17. To Remodel or To Build?

    Science.gov (United States)

    Rosenblum, Todd

    2009-01-01

    The question of remodeling an existing house to make it wheelchair accessible or building a new barrier-free house is a difficult decision. This article presents some initial questions and considerations followed by a list of pros and cons for remodeling an existing house vs. building a new house.

  18. Myocardial scaffold-based cardiac tissue engineering: application of coordinated mechanical and electrical stimulations.

    Science.gov (United States)

    Wang, Bo; Wang, Guangjun; To, Filip; Butler, J Ryan; Claude, Andrew; McLaughlin, Ronald M; Williams, Lakiesha N; de Jongh Curry, Amy L; Liao, Jun

    2013-09-03

    Recently, we developed an optimal decellularization protocol to generate 3D porcine myocardial scaffolds, which preserve the natural extracellular matrix structure, mechanical anisotropy, and vasculature templates and also show good cell recellularization and differentiation potential. In this study, a multistimulation bioreactor was built to provide coordinated mechanical and electrical stimulation for facilitating stem cell differentiation and cardiac construct development. The acellular myocardial scaffolds were seeded with mesenchymal stem cells (10(6) cells/mL) by needle injection and subjected to 5-azacytidine treatment (3 μmol/L, 24 h) and various bioreactor conditioning protocols. We found that after 2 days of culturing with mechanical (20% strain) and electrical stimulation (5 V, 1 Hz), high cell density and good cell viability were observed in the reseeded scaffold. Immunofluorescence staining demonstrated that the differentiated cells showed a cardiomyocyte-like phenotype by expressing sarcomeric α-actinin, myosin heavy chain, cardiac troponin T, connexin-43, and N-cadherin. Biaxial mechanical testing demonstrated that positive tissue remodeling took place after 2 days of bioreactor conditioning (20% strain + 5 V, 1 Hz); passive mechanical properties of the 2 day and 4 day tissue constructs were comparable to those of the tissue constructs produced by stirring reseeding followed by 2 weeks of static culturing, implying the effectiveness and efficiency of the coordinated simulations in promoting tissue remodeling. In short, the synergistic stimulations might be beneficial not only for the quality of cardiac construct development but also for patients by reducing the waiting time in future clinical scenarios.

  19. No-Regrets Remodeling, 2nd Edition

    Energy Technology Data Exchange (ETDEWEB)

    None

    2013-12-01

    No-Regrets Remodeling, sponsored by Oak Ridge National Laboratory, is an informative publication that walks homeowners and/or remodelers through various home remodeling projects. In addition to remodeling information, the publication provides instruction on how to incorporate energy efficiency into the remodeling process. The goal of the publication is to improve homeowner satisfaction after completing a remodeling project and to provide the homeowner with a home that saves energy and is comfortable and healthy.

  20. Suppression of NLRP3 Inflammasome Activation Ameliorates Chronic Kidney Disease-Induced Cardiac Fibrosis and Diastolic Dysfunction

    Science.gov (United States)

    Bugyei-Twum, Antoinette; Abadeh, Armin; Thai, Kerri; Zhang, Yanling; Mitchell, Melissa; Kabir, Golam; Connelly, Kim A.

    2016-01-01

    Cardiac fibrosis is a common finding in patients with chronic kidney disease. Here, we investigate the cardio-renal effects of theracurmin, a novel formulation of the polyphenolic compound curcumin, in a rat model of chronic kidney disease. Briefly, Sprague-Dawley rats were randomized to undergo sham or subtotal nephrectomy (SNx) surgery. At 3 weeks post surgery, SNx animals were further randomized to received theracurmin via once daily oral gavage or vehicle for 5 consecutive weeks. At 8 weeks post surgery, cardiac function was assessed via echocardiography and pressure volume loop analysis, followed by LV and renal tissue collection for analysis. SNx animals developed key hallmarks of renal injury including hypertension, proteinuria, elevated blood urea nitrogen, and glomerulosclerosis. Renal injury in SNx animals was also associated with significant diastolic dysfunction, macrophage infiltration, and cardiac NLRP3 inflammasome activation. Treatment of SNx animals with theracurmin improved structural and functional manifestations of cardiac injury associated with renal failure and also attenuated cardiac NLRP3 inflammasome activation and mature IL-1β release. Taken together, our findings suggest a significant role for the NLRP3 inflammasome in renal injury-induced cardiac dysfunction and presents inflammasome attenuation as a unique strategy to prevent adverse cardiac remodeling in the setting of chronic kidney disease. PMID:28000751

  1. Precocious appearance of cardiac troponin T pre-mRNAs during early avian embryonic skeletal muscle development in ovo.

    Science.gov (United States)

    Swiderski, R E; Solursh, M

    1990-07-01

    Cardiac troponin T (cTNT), a component of the muscle contractile apparatus, is transiently expressed in skeletal muscle during avian limb development. While cTNT was first detected immunohistochemically in limb buds undergoing overt myogenic differentiation (Hamburger and Hamilton stage 26, about 5 days in ovo), RNA blot analyses of early, predifferentiated wing buds have revealed the presence of cTNT transcripts in limb buds as early as stage 23 (4 days in ovo). Steady-state cTNT poly(A) RNAs of stage 22 through stage 37 fore- and hindlimbs were compared using both cTNT cDNA and cTNT intron-specific probes. In the predifferentiated state, two incompletely processed RNAs (3.8 and 2.4 kb) were expressed in the absence of the mature cTNT transcript, while a third pre-mRNA (3.5 kb) appeared concomitantly with the mature mRNA as differentiation and development proceeded. In addition, a population of unique cTNT transcripts were expressed in a proximal to distal manner in wing buds which had undergone initial overt myogenic differentiation (stage 26). Some of the cTNT pre-mRNAs observed in premyogenic limbs appeared to accumulate stably in a tissue-specific manner, based on their absence from the cardiac poly(A) RNA population. These results suggest that the appearance of cardiac troponin T mRNA, as well as the polypeptide, may be regulated at multiple levels including RNA processing, stability, and/or translation during early skeletal muscle myogenesis.

  2. Global microRNA profiles and signaling pathways in the development of cardiac hypertrophy

    Energy Technology Data Exchange (ETDEWEB)

    Feng, H.J.; Ouyang, W.; Liu, J.H.; Sun, Y.G.; Hu, R.; Huang, L.H.; Xian, J.L. [Southern Medical University, Department of Nuclear Medicine, Zhujiang Hospital, Guangzhou, China, Department of Nuclear Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou (China); Jing, C.F.; Zhou, M.J. [Sun Yat-Sen University, South China Sea Marine Biotechnology, National Engineering Research Center, Guangzhou, China, National Engineering Research Center, South China Sea Marine Biotechnology, Sun Yat-Sen University, Guangzhou (China)

    2014-04-11

    Hypertrophy is a major predictor of progressive heart disease and has an adverse prognosis. MicroRNAs (miRNAs) that accumulate during the course of cardiac hypertrophy may participate in the process. However, the nature of any interaction between a hypertrophy-specific signaling pathway and aberrant expression of miRNAs remains unclear. In this study, Spague Dawley male rats were treated with transverse aortic constriction (TAC) surgery to mimic pathological hypertrophy. Hearts were isolated from TAC and sham operated rats (n=5 for each group at 5, 10, 15, and 20 days after surgery) for miRNA microarray assay. The miRNAs dysexpressed during hypertrophy were further analyzed using a combination of bioinformatics algorithms in order to predict possible targets. Increased expression of the target genes identified in diverse signaling pathways was also analyzed. Two sets of miRNAs were identified, showing different expression patterns during hypertrophy. Bioinformatics analysis suggested the miRNAs may regulate multiple hypertrophy-specific signaling pathways by targeting the member genes and the interaction of miRNA and mRNA might form a network that leads to cardiac hypertrophy. In addition, the multifold changes in several miRNAs suggested that upregulation of rno-miR-331*, rno-miR-3596b, rno-miR-3557-5p and downregulation of rno-miR-10a, miR-221, miR-190, miR-451 could be seen as biomarkers of prognosis in clinical therapy of heart failure. This study described, for the first time, a potential mechanism of cardiac hypertrophy involving multiple signaling pathways that control up- and downregulation of miRNAs. It represents a first step in the systematic discovery of miRNA function in cardiovascular hypertrophy.

  3. 6:2 Chlorinated polyfluorinated ether sulfonate, a PFOS alternative, induces embryotoxicity and disrupts cardiac development in zebrafish embryos.

    Science.gov (United States)

    Shi, Guohui; Cui, Qianqian; Pan, Yitao; Sheng, Nan; Sun, Sujie; Guo, Yong; Dai, Jiayin

    2017-04-01

    As an alternative to perfluorooctanesulfonate (PFOS), 6:2 chlorinated polyfluorinated ether sulfonate (commercial name: F-53B) has been used as a mist suppressant in Chinese electroplating industries for over 30 years. It has been found in the environment and fish, and one acute assay indicated F-53B was moderately toxic. However, the toxicological information on this compound was incomplete and insufficient for assessment of their environment impact. The object of this study was to examine the developmental toxicity of F-53B using zebrafish embryos. Zebrafish embryos were incubated in 6-well plates with various concentrations of F-53B (1.5, 3, 6, and 12mg/L) from 6 to 132h post fertilization (hpf). Results showed that F-53B exposure induced developmental toxicity, including delayed hatching, increased occurrence of malformations, and reduced survival. Malformations, including pericardial and yolk sac edemas, abnormal spines, bent tails, and uninflated swim bladders, appeared at 84 hpf, and increased with time course and dose. A decrease in survival percentages was noted in the 6 and 12mg/L F-53B-treated groups at 132 hpf. Continuous exposure to 3mg/L F-53B resulted in high accumulation levels in zebrafish embryos, suggesting an inability for embryos to eliminate this compound and a high cumulative risk to fish. We also examined the cardiac function of embryos at specific developmental stages following exposure to different concentrations, and found that F-53B induced cardiac toxicity and reduced heart rate. Even under low F-53B concentration, o-dianisidine staining results showed significant decrease of relative erythrocyte number at 72 hpf before the appearance of observed effects of F-53B on the heart. To elucidate the underlying molecular changes, genes involved in normal cardiac development were analyzed using real-time qPCR in the whole-body of zebrafish embryos. F-53B inhibited the mRNA expression of β-catenin (ctnnb2) and wnt3a. The mRNA levels of

  4. Effects of multi-intervention RAAS on ventricular remodeling and serum K+ concentration in the chronic cardiac insufficiency rats%多重干预RAAS对大鼠慢性心功能不全心室重构及血钾的影响

    Institute of Scientific and Technical Information of China (English)

    陈斗佳; 陈娅; 吴伦宽

    2011-01-01

    目的 探讨多重干预RAAS对大鼠慢性心功能不全心室重构及血钾的影响.方法 实验采用缩窄大鼠腹主动脉法建立慢性压力负荷致心功能不全动物模型,选6周龄20只雌性SD大鼠,随机分4组(每组5只),B组(手术模型组)、C组(卡托普利组)、D组(卡托普利+缬沙坦组)、E组(卡托普利+缬沙坦+螺内酯组),另随机抽取5只同龄雌性SD大鼠假手术作为对照(A组).给药8周后用Doppler超声心动图检测大鼠心脏结构和心功能各项参数的变化,放射免疫法测定血浆Ang Ⅱ,ALDO浓度,并生化检测血钾水平.结果 腹主动脉结扎后第9周,与A组比较,B组舒张末期室间隔厚度(IVSTD)、舒张末期左室后壁厚度(LVPWTD)、相对室壁厚度(RWT)、左室重量(LVM)、左室重量与体重比(LVM/BW)均显著提高(P<0.05);C、D、E组与B组相比,LVM,LVM/BW下降显著(P<0.05).各药物干预组(C、D、E)血浆Ang Ⅱ,ALDO水平明显低于B组(P<0.05),以联合应用螺内酯组明显.各药物干预组与A组和B组相比较,血钾水平差异无显著性(P>0.05).结论 联合应用卡托普利、缬沙坦及螺内酯多重干预RAAS能明显改善大鼠慢性心功能不全心室重构,对血钾无明显影响.%Objective To explore the effects of multi-intervention RAAS on ventricular remodeling and serum K+ concentration in the chronic pressure overload heart due to cardiac insufficiency in rats. Methods To establish chronic cardiac insufficiency animal models with suprarenal abdominal aortic banding in rats. Six-week old female Sprague-Dawley rats were enrolled and the suprarenal abdominal aorta was ligated by 4-0 nylon suture against a needle (outer diameter 0. 7 mm). Twenty female rats were randomized into four groups (n = 5), including operated rats (group B), and Captopriltreated rats ( group C), Captopril + Valsartan treatment rats ( group D) and Captopril + Valsartan + Spironolactone treatment rats (group E), which were treated by

  5. Data analysis in cardiac arrhythmias.

    Science.gov (United States)

    Rodrigo, Miguel; Pedrón-Torecilla, Jorge; Hernández, Ismael; Liberos, Alejandro; Climent, Andreu M; Guillem, María S

    2015-01-01

    Cardiac arrhythmias are an increasingly present in developed countries and represent a major health and economic burden. The occurrence of cardiac arrhythmias is closely linked to the electrical function of the heart. Consequently, the analysis of the electrical signal generated by the heart tissue, either recorded invasively or noninvasively, provides valuable information for the study of cardiac arrhythmias. In this chapter, novel cardiac signal analysis techniques that allow the study and diagnosis of cardiac arrhythmias are described, with emphasis on cardiac mapping which allows for spatiotemporal analysis of cardiac signals.Cardiac mapping can serve as a diagnostic tool by recording cardiac signals either in close contact to the heart tissue or noninvasively from the body surface, and allows the identification of cardiac sites responsible of the development or maintenance of arrhythmias. Cardiac mapping can also be used for research in cardiac arrhythmias in order to understand their mechanisms. For this purpose, both synthetic signals generated by computer simulations and animal experimental models allow for more controlled physiological conditions and complete access to the organ.

  6. Remodeling of endogenous mammary epithelium by breast cancer stem cells.

    Science.gov (United States)

    Parashurama, Natesh; Lobo, Neethan A; Ito, Ken; Mosley, Adriane R; Habte, Frezghi G; Zabala, Maider; Smith, Bryan R; Lam, Jessica; Weissman, Irving L; Clarke, Michael F; Gambhir, Sanjiv S

    2012-10-01

    Poorly regulated tissue remodeling results in increased breast cancer risk, yet how breast cancer stem cells (CSC) participate in remodeling is unknown. We performed in vivo imaging of changes in fluorescent, endogenous duct architecture as a metric for remodeling. First, we quantitatively imaged physiologic remodeling of primary branches of the developing and regenerating mammary tree. To assess CSC-specific remodeling events, we isolated CSC from MMTV-Wnt1 (mouse mammary tumor virus long-term repeat enhancer driving Wnt1 oncogene) breast tumors, a well studied model in which tissue remodeling affects tumorigenesis. We confirm that CSC drive tumorigenesis, suggesting a link between CSC and remodeling. We find that normal, regenerating, and developing gland maintain a specific branching pattern. In contrast, transplantation of CSC results in changes in the branching patterns of endogenous ducts while non-CSC do not. Specifically, in the presence of CSC, we identified an increased number of branches, branch points, ducts which have greater than 40 branches (5/33 for CSC and 0/39 for non-CSC), and histological evidence of increased branching. Moreover, we demonstrate that only CSC implants invade into surrounding stroma with structures similar to developing mammary ducts (nine for CSC and one for non-CSC). Overall, we demonstrate a novel approach for imaging physiologic and pathological remodeling. Furthermore, we identify unique, CSC-specific, remodeling events. Our data suggest that CSC interact with the microenvironment differently than non-CSC, and that this could eventually be a therapeutic approach for targeting CSC.

  7. EXPERIMENT STUDY OF CARDIOMYOCYTE APOPTOSIS AND CARDIOMYOCYTE PROLIFERATION DURING THE DEVELOPMENT OF CARDIAC HYPERTROPHY IN SPONTANEOUSLY HYPERTENSIVE RATS

    Institute of Scientific and Technical Information of China (English)

    江立生; 方宁远; 高天; 孟超

    2005-01-01

    Objective To investigate the effect and significance of cardiomyocyte apoptosis and cardiomyocyte proliferation on cardiac hypertrophy by observing the dynamic changes of them during the development of cardiac hypertrophy in spontaneously hypertensive rats (SHR). Methods Hearts were excised from SHR and Wistar-Kyoto rats(WKY) at different ages. Cardiac hypertrophic index (CHI) was calculated as the radio of heart weight to body weight; Cardiomyocyte apoptosis was identified by in situ TDT-mediated dUTP nick end labeling (TUNEL); Localization and expression of proliferating cell nuclear antigen (PCNA) were examined by immunohistochemistry. Results Compared with age-matched WKY, CHI in SHR was significantly increased at 12 weeks old and 24 weeks old (3. 604 ± 0. 089 vs 2. 997 ± 0. 166, P<0.01; 4. 156 ± 0. 385 vs 3. 119 ± 0. 208, P < 0. 01 ) ,and CHI in SHR was increased little by little with the age increasing and attained plaiform since 20 weeks old. In contrast with age-matched WKY, cardiomyocyte apoptotic index (APOI) in SHR at 12 weeks was not increased significantly (4. 248 ± 1. 592 vs 3. 678 ± 0. 856, P > 0. 05 ), but decreased markedly when their age were 24 weeks (3. 207 ± 1. 794 vs 5. 494 ± 1. 372, P <0. 05); APOI in SHR at 12 weeks old, 16 weeks old, 20 weeks old and 24weeks old were 4. 248 ± 1. 592, 5. 707 ± 1. 322, 7. 436 ± 1. 128, 3. 207 ± 1. 794, respectively. On the other hand,APOI in SHR from 12 weeks old to 20 weeks old increased gradually, and attained peak at 20 weeks old, but decreased markedly after 20 weeks old ( P <0. 01 ). Compared with age-matched WKY, the rate of cardiomyocyte PCNA positive labeling (PCNAR) in SHR at 12 weeks old and 24 weeks old didn' t have obvious difference. Conclusion Imbalance of cardiomyocyte apoptosis and cardiomyocyte proliferation existed during the development of cardiac hypertrophy in spontaneously hypertensive rats.

  8. miRNA调节心脏发育的信号网络%miRNA Regulatory Networks in Cardiac Development

    Institute of Scientific and Technical Information of China (English)

    刘怀钰

    2011-01-01

    心脏是整个生命过程中精确的功能调控器官.任何对心脏结构和功能的微弱干抚都会造成致命性的结果.最近研究表明在心血管的发育和疾病中,miRNAs控制了这一过程中的基因表达.进入心脏循环系统的miRNAs为基因提供了一个互动的监管系统,并控制心脏基因的表达图谱.miRNAs的调控网络的发现,有利于治疗心脏疾病保护心脏功能.主要讨论了miRNA在心脏成型和功能中发挥的调节作用.%The heart requires precise functionality on a second-to-second basis throughout the lifespan of the organism. Any weak disturbance to the structure and function of heart would lead to fatal result. Recent studies had revealed central roles for miRNAs as governors of gene expression during cardiovascular development and disease. The integration of miRNAs into the genetic circuitry of the heart provided a rich and robust array of regulatory interactions to control cardiac gene expression. miRNA regulatory networks also offered opportunities for therapeutically modulating cardiac function through the manipulation of pathogenic and protective miRNAs. The roles of miRNAs as regulators of cardiac form and function were discussed.

  9. [Age-related features of intracellular calcium homeostasis in rat cardiomyocites in postinfarction heart remodeling].

    Science.gov (United States)

    Afanas'ev, S A; Kondrat'eva, D S; Putrova, O D; Perchatkin, V A; Repin, A N

    2010-01-01

    Research results of features of an intracellular calcium homeostasis in 4 and 12-month's rat cardiomyocites at postinfarction cardiosclerosis are presented. It is shown that the myocardium of animals in the old rats group is more susceptible to extrasystolic impacts. In the pathology conditions additional extrasystolic influences also had the expressed age specificity of inotropic response. The data testifying to almost identical dynamics of postextrasystolic cycles of intact myocardium in animals of investigated age groups has been obtained. The different postextrasystolic potentiation in the remodeled myocardium in old and young rats testified to different of sarcoplasmic reticulum ability to accumulate additional calcium ions. The conclusion was made that the myocardium of animals in the old rats group has more chance for development of hemodynamic significant disturbance of cardiac rhythm as a consequence of age-related changes processes of the electromechanical coupling in cardiomyocites.

  10. Differences in coronary artery disease by CT angiography between patients developing unstable angina pectoris vs. major adverse cardiac events

    Energy Technology Data Exchange (ETDEWEB)

    Schlett, Christopher L. [Cardiac MR PET CT Program, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, MA (United States); Department of Diagnostic and Interventional Radiology, University Hospital Heidelberg (Germany); Nance, John W. Jr. [Heart and Vascular Center, Medical University of South Carolina, Charleston, SC (United States); The Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins Hospital, Baltimore, MD (United States); Schoepf, U. Joseph, E-mail: schoepf@musc.edu [Heart and Vascular Center, Medical University of South Carolina, Charleston, SC (United States); O’Brien, Terrence X. [Heart and Vascular Center, Medical University of South Carolina, Charleston, SC (United States); The Ralph H. Johnson Veterans Affairs Medical Center, Charleston, SC (United States); Ebersberger, Ullrich [Heart and Vascular Center, Medical University of South Carolina, Charleston, SC (United States); Department of Cardiology and Intensive Care Medicine, Heart Centre Munich-Bogenhausen, Munich (Germany); Headden, Gary F. [Heart and Vascular Center, Medical University of South Carolina, Charleston, SC (United States); Hoffmann, Udo [Cardiac MR PET CT Program, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, MA (United States); Bamberg, Fabian [Cardiac MR PET CT Program, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, MA (United States); Department of Radiology, University of Munich, Grosshadern Campus, and Munich Heart Alliance, Munich (Germany); Department of Radiology, University of Tuebingen (Germany)

    2014-07-15

    Highlights: • Patients developing UAP had overall more atherosclerosis as patients without any events. • Patients developing MACE had only more mixed plaque as those developing UAP. • Different atherosclerotic plaque components by CTA carry different prognostic value. - Abstract: Objective: CT angiography (CTA) has prognostic value in patients. But it is unknown whether differences in atherosclerosis by CTA predict the development of unstable angina pectoris (UAP) vs. major adverse cardiac events (MACE). Methods: We followed patients undergoing CTA as part of their acute chest pain work-up. Primary outcome was the development of UAP or MACE (cardiac death, myocardial infarction, revascularization) during a minimum follow-up of 12-months. CTAs were assessed for extent and composition of coronary plaque and stenosis. Ordinal regression with a 3-level outcome (no events, UAP, MACE) was applied. Results: Among 315 patients, 22 developed UAP and 31 MACE. While UAP patients had higher atherosclerosis burden with respect to all assessed features compared to patients with no events (p ≤ 0.02), only mixed plaque extent was significantly different between UAP and MACE patients (p = 0.02). The odds ratio was 4.55 for being in a higher disease-level comparing patients with low extent to those with no mixed plaque, and 3.02 comparing patients with high to those with low. These findings remained after adjustments for potential confounders. Conclusion: The extent of mixed coronary plaque is different between patients who develop UAP vs. MACE, supporting the hypothesis that it is a more culprit morphology.

  11. Implantable defibrillators improve survival in patients with mildly symptomatic heart failure receiving cardiac resynchronization therapy

    DEFF Research Database (Denmark)

    Gold, Michael R; Daubert, Jean-Claude; Abraham, William T;

    2013-01-01

    Cardiac resynchronization therapy (CRT) decreases mortality, improves functional status, and induces reverse left ventricular remodeling in selected populations with heart failure. These benefits have been noted with both CRT-pacemakers as well as those devices with defibrillator backup (CRT...

  12. microRNA-21通过促进成纤维细胞的增殖和分化调节心肌梗死后的心脏重塑%MicroRNA-21 Regulates Cardiac Remodeling by Promoting Proliferation and Differentiation of Fibroblast after Myocardial Infarction

    Institute of Scientific and Technical Information of China (English)

    郭东; 张闽红; 肖清萍; 刘建文

    2014-01-01

    R-21 were measured by quantitative real-time PCR in the various myocardial tissues. The cardiac fibroblasts transfected with miR-21 mimic were over-expressed miR-21. The proliferation was assessed by immunostaining for 5-ethynyl-2’-deoxyuridine (EdU). Western blot assay was used to detect the expression ofα-SMA and Smad7 in the cardiac fibroblasts,and compared with control group and blank group. Results The expression of miR-21 was significantly increased in border area in MI group than that of sham group [(6.043 ± 0.231)×10-4 vs(1.620±0.451)×10-4,P<0.01]. There was a higher expression of miR-21 in miR-21 mimic group than that of control group and blank group [(4.839±0.705)×10-4 vs(1.143±0.064)×10-4 vs(1.017±0.201)×10-4,P<0.01]. The EdU positive rate was significantly higher in miR-21 mimic group than that of control group and blank group[(27.892±1.645)%vs(12.553 ± 1.227)% vs(13.946 ± 1.550)%,P<0.01]. The expression of α-SMA was significantly increased in miR-21 mimic group, while the expression of Smad7, a target gene of miR-21, was significantly decreased. Conclusion The over-expression of miR-21 in cardiac fibroblasts disrupts TGF-βsignaling pathway by reducing the expression of Smad7, which promotes the proliferation and differentiation of cardiac fibroblast, and finally regulates cardiac remodeling after myocardial infarction.

  13. [Development of multi-channels cardiac electrophysiological polygraph with LabVIEW as software platform and its clinical application].

    Science.gov (United States)

    Fan, Shounian; Jiang, Yi; Jiang, Chenxi; Yang, Tianhe; Zhang, Chengyun; Liu, Junshi; Wu, Qiang; Zheng, Yaxi; Liu, Xiaoqiao

    2004-10-01

    Polygraph has become a necessary instrument in interventional cardiology and fundamental research of medicine up to the present. In this study, a LabView development system (DS) (developed by NI in U.S.) used as software platform, a DAQ data acquisition module and universal computer used as hardware platform, were creatively coupled with our self-made low noise multi-channels preamplifier to develop Multi-channels electrocardiograph. The device possessed the functions such as real time display of physiological process, digit highpass and lowpass, 50Hz filtered and gain adjustment, instant storing, random playback and printing, and process control stimulation. Besides, it was small-sized, economically practical and easy to operate. It could advance the spread of cardiac intervention treatment in hospitals.

  14. Effects of valsartan on left ventricular remodeling and cardiac function in patients with essential hypertension using echocardiography with automated segmental motion analysis and free angle model%自动室壁分区运动分析与全方位M型超声心动图评价缬沙坦对高血压左心室重构及心脏整体功能的影响

    Institute of Scientific and Technical Information of China (English)

    赖小今; 梁燕; 朱峻; 陶杰; 陈重; 邓旦; 廖明松

    2010-01-01

    Objective To assess the effects of valsartan on left ventricular remodeling and cardiac functions in patients with essential hypertension using echocardiography with automated segmental motion analysis(ASMA)and free angle model(FAM).Methods The parameters about the cardiac morphology and function of the 178cases with essential hypertension were observed before and per three months(total about twelve months)after valsartan treated(80 mg/day)using echocardiography with ASMA-FAM,and the blood pressure values and patients' symptoms were observed at the same time.Results The patients' symptoms were improved,and the values of the patients blood pressure were decreased gradually after using valsartan two weeks,and they were to steady after five weeks.The values of left ventricle diameter,wall thickness,and left ventricular mass index were be decreased after treated six months(P<0.05),and they were be decreased obviously after treated one year(P<0.01),the left ventricular wall kinestate,cardiac functions were improved(P<0.01).Conclusions The left ventricular remodeling and the cardiac functions in patients with essential hypertension are improved obviously after using valsartan treated twelve months.The cardiac structures,left ventricle wall kinestate,and cardiac functions can be evaluated overall and objectively using echocardiography with ASMA-FAM.%目的 探讨自动室壁分区运动分析(ASMA)与全方位M型超声心动图(FAM)技术评价血管紧张素Ⅱ受体拮抗剂缬沙坦对原发性高血压左室重构及心脏整体功能的影响.方法 原发性高血压患者178例,应用缬沙坦80 mg/d口服治疗,疗程12个月.观察治疗过程中患者血压及症状体征的变化情况,并分别在治疗前及治疗后每3个月分阶段应用ASMA-FAM技术观察心脏形态学及心脏整体功能变化情况.结果 在治疗缬沙坦2周后血压开始下降,5周后趋于平稳;心腔径、室壁厚度及左室质量指数等在治疗3月后开始降低(P<0

  15. Port Access Cardiac Surgery.

    Science.gov (United States)

    Viganó, Mario; Minzioni, Gaetano; Spreafico, Patrizio; Rinaldi, Mauro; Pasquino, Stefano; Ceriana, Piero; Locatelli, Alessandro

    2000-10-01

    The port-access technique for cardiac surgery was recently developed at Stanford University in California as a less invasive method to perform some cardiac operations. The port-access system has been described in detail elsewhere. It is based on femoral arterial and venous access for cardiopulmonary bypass (CPB) and on the adoption of a specially designed triple-lumen catheter described originally by Peters, and subsequently modified and developed in the definitive configuration called the endoaortic clamp.

  16. Nonenzymatic biomimetic remodeling of phospholipids in synthetic liposomes.

    Science.gov (United States)

    Brea, Roberto J; Rudd, Andrew K; Devaraj, Neal K

    2016-08-02

    Cell membranes have a vast repertoire of phospholipid species whose structures can be dynamically modified by enzymatic remodeling of acyl chains and polar head groups. Lipid remodeling plays important roles in membrane biology and dysregulation can lead to disease. Although there have been tremendous advances in creating artificial membranes to model the properties of native membranes, a major obstacle has been developing straightforward methods to mimic lipid membrane remodeling. Stable liposomes are typically kinetically trapped and are not prone to exchanging diacylphospholipids. Here, we show that reversible chemoselective reactions can be harnessed to achieve nonenzymatic spontaneous remodeling of phospholipids in synthetic membranes. Our approach relies on transthioesterification/acyl shift reactions that occur spontaneously and reversibly between tertiary amides and thioesters. We demonstrate exchange and remodeling of both lipid acyl chains and head groups. Using our synthetic model system we demonstrate the ability of spontaneous phospholipid remodeling to trigger changes in vesicle spatial organization, composition, and morphology as well as recruit proteins that can affect vesicle curvature. Membranes capable of chemically exchanging lipid fragments could be used to help further understand the specific roles of lipid structure remodeling in biological membranes.

  17. The chromatin remodeler SPLAYED regulates specific stress signaling pathways.

    Directory of Open Access Journals (Sweden)

    Justin W Walley

    2008-12-01

    Full Text Available Organisms are continuously exposed to a myriad of environmental stresses. Central to an organism's survival is the ability to mount a robust transcriptional response to the imposed stress. An emerging mechanism of transcriptional control involves dynamic changes in chromatin structure. Alterations in chromatin structure are brought about by a number of different mechanisms, including chromatin modifications, which covalently modify histone proteins; incorporation of histone variants; and chromatin remodeling, which utilizes ATP hydrolysis to alter histone-DNA contacts. While considerable insight into the mechanisms of chromatin remodeling has been gained, the biological role of chromatin remodeling complexes beyond their function as regulators of cellular differentiation and development has remained poorly understood. Here, we provide genetic, biochemical, and biological evidence for the critical role of chromatin remodeling in mediating plant defense against specific biotic stresses. We found that the Arabidopsis SWI/SNF class chromatin remodeling ATPase SPLAYED (SYD is required for the expression of selected genes downstream of the jasmonate (JA and ethylene (ET signaling pathways. SYD is also directly recruited to the promoters of several of these genes. Furthermore, we show that SYD is required for resistance against the necrotrophic pathogen Botrytis cinerea but not the biotrophic pathogen Pseudomonas syringae. These findings demonstrate not only that chromatin remodeling is required for selective pathogen resistance, but also that chromatin remodelers such as SYD can regulate specific pathways within biotic stress signaling networks.

  18. Over-phosphorylation of FKBP12.6, phospholamban,relating to exacerbation of cardiac arrhythmias and failure

    Institute of Scientific and Technical Information of China (English)

    De-zaiDAI

    2004-01-01

    AIM: Cardiac arrhythmias occur severely in diseased and failing hearts and remain an important cause of mortality in cardiovascular disorders. It was intended to explore mechanisms of abnormal ion channels underlying cardiac arrhythmias and failure and in responses to drug interventions. METHODS: Chronic infarction plus isoproterenol (ISO) medication or L-thyroxin (THY) repetitive medication promote cardiac remodeling and exaggerated

  19. How to develop a clinic for sudden cardiac arrest survivors and families of non-survivors.

    Science.gov (United States)

    Abrams, Dominic J

    2017-01-01

    The investigation of the aetiology of sudden cardiac arrest or death in a young person combines features of a traditional clinical medical examination with those of forensic medicine. Nuances of the immediate peri-event history, when available, can be paramount. New genetic tools have greatly improved the yield of such investigations, but they must be carefully interpreted by genetic specialists. The approach to surviving patients, their family members, and to family members of non-survivors is best achieved in a structured programme that includes all appropriate specialists and support personnel. As an example, this may include all appropriate paediatric and internal medicine specialists, a geneticist, a genetic counsellor, a clinical psychologist, nurse specialist(s), and a programme coordinator. This family-centred strategy affords the patient, if surviving, and all family members the necessary emotional and medical support while at the same time providing the necessary diagnostic and therapeutic approaches.

  20. Arrhythmogenesis in the remodeled heart : the role of spatially dispersed Cx43 expression

    NARCIS (Netherlands)

    Boulaksil, M.

    2010-01-01

    The heart is able to adapt to new, often pathologic, conditions, so-called cardiac remodeling. Although initially adequate, these adaptations could can become maladaptive over time. One of the adaptations of the heart during pathology is ventricular hypertrophy, which may go hand in hand with an inc

  1. Role of inflammation in the development of cardiac autonomic disfunction in patients with systemic lupus erythematosus

    Directory of Open Access Journals (Sweden)

    D. S. Novikova

    2008-01-01

    Full Text Available Objective. To evaluate role of inflammation in pathogenesis of cardiac autonomic dysfunction assessed by heart rate variability (HRV analyses, in patients (pts with systemic lupus erythematosus (SLE. Material and methods. 75 female pts with SLE aged before 55 years were included. Control group consisted of 32 healthy women of comparable age. Clinical symptoms, activity degree and main cardiovascular risk factors were assessed. Common carotid duplex scanning with measurement of intima-media thickness, echocardiography, 24 h ECG ambulatory recording with determination of time domain parameters, evaluation of serum inflammation markers level (CRP, IL-6, TNFa were performed. Results. HRV time domain parameters adjusted by McanNN - SDNNn%, SDNNin%, rMSSDn%, pNN50% in women with SLE were lower than in healthy control. HRV parameters inversely correlated with inflammation markers in SLE (p<0,05. SLE pts were divided into 4 groups: 1 (n=12 - pts with low HRV parameters and high level of IL-6; 2 (n=13 - low HRV and normal IL-6; 3 (n=6 - normal HRV and high IL-6; 4 (n=44 - normal HRV and IL-6. SLEDA1 2K, left atrium size, levels of markers of inflammation in group 1 were higher, then in group 4 (p<0,05. Hypertension, dyslipidemia, smoking and subclinical atherosclerosis of carotid arteries were more frequent in group 2 compared to group 4 (p<0,05. Conclusion. These results suggest important role of autoimmune inflammation in pathogenesis of cardiac autonomic dysfunction in SLE pts with high disease activity and traditional cardiovascular risk factor, atherosclerotic changes - in low SLE activity. HRV, traditional cardiovascular risk factors and inflammatory markers combined measurement can help to identify subjects at risk of cardiovascular mortality among SLE pts.

  2. Induction of antibodies reactive to cardiac myosin and development of heart alterations in cruzipain-immunized mice and their offspring.

    Science.gov (United States)

    Giordanengo, L; Maldonado, C; Rivarola, H W; Iosa, D; Girones, N; Fresno, M; Gea, S

    2000-11-01

    Human and murine infection with Trypanosoma cruzi parasite is usually accompanied by strong humoral and cellular immune response to cruzipain, a parasite immunodominant antigen. In the present study we report that the immunization of mice with cruzipain devoid of enzymatic activity, was able to induce antibodies which bind to a 223-kDa antigen from a mouse heart extract. We identified this protein as the mouse cardiac myosin heavy chain by sequencing analysis. The study of IgG isotype profile revealed the occurrence of all IgG isotypes against cruzipain and myosin. IgG1 showed the strongest reactivity against cruzipain, whereas IgG2a was the main isotype against myosin. Anti-cruzipain antibodies purified by immunoabsorption recognized the cardiac myosin heavy chain, suggesting cross-reactive epitopes between cruzipain and myosin. Autoimmune response in mice immunized with cruzipain was associated to heart conduction disturbances. In addition, ultrastructural findings revealed severe alterations of cardiomyocytes and IgG deposit on heart tissue of immunized mice. We investigated whether antibodies induced by cruzipain transferred from immunized mothers to their offsprings could alter the heart function in the pups. All IgG isotypes against cruzipain derived from transplacental crossing were detected in pups' sera. Electrocardiographic studies performed in the offsprings born to immunized mothers revealed conduction abnormalities. These results provide strong evidence for a pathogenic role of autoimmune response induced by a purified T. cruzi antigen in the development of experimental Chagas' disease.

  3. Improved troponin T ELISA specific for cardiac troponin T isoform: assay development and analytical and clinical validation.

    Science.gov (United States)

    Müller-Bardorff, M; Hallermayer, K; Schröder, A; Ebert, C; Borgya, A; Gerhardt, W; Remppis, A; Zehelein, J; Katus, H A

    1997-03-01

    The first generation of troponin T ELISA (TnT 1) can yield false-positive results in patients with severe skeletal muscle injury. Therefore, a cardiac-specific second-generation troponin T ELISA (TnT 2) was developed, in which the cross-reactive antibody 1B10 has been replaced by a high-affinity cardiac-specific antibody M11.7. No cross-reactivity of TnT 2 was observed with purified skeletal muscle troponin T (1000 micrograms/L) or in test samples from 43 marathon runners and 24 patients with rhabdomyolysis and highly increased creatine kinase. TnT 2 was increased > 0.2 microgram/L in 5 of 40 patients with renal failure and in 4 of 20 muscular dystrophy patients. The detection limit is 0.012 microgram/L. Day-to-day imprecision (CV) within the range 0.19-14.89 micrograms/L was error of estimate (Sey) of 1.18, 0.01 micrograms/L, and 0.81 microgram/L, respectively.

  4. Development of a mobile HIS/PACS workstation to assist critical cardiac patients in an intensive care unit

    Science.gov (United States)

    Gutierrez, Marco A.; Cestari, Idagene A.; Hamamoto, Gina; Bacht, Simão; Rebelo, Marina S.; Silva, João E. M. M.; Lage, Silvia G.

    2008-03-01

    The current study describes the experience in the implementation of a mobile HIS/PACS workstation to assist critical cardiac patients in an Intensive Care Unit (ICU). Recently, mobile devices connected to a WiFi network were incorporated to the Hospital information System, providing the same functionalities of common desktop counterpart. However, the use of commercially devices like PDAs and Pocket PCs presented a series of problems that are more emphasized in the ICUs 1) low autonomy of the batteries, which need constant recharges; 2) low robustness of the devices; 3) insufficient display area to show medical images and vital signals; 4) data entry remains a major problem and imposes an extra time consumption to the staff; 5) high cost when fully equipped with WiFi connection, optical reader to access bar codes and memory. To address theses problems we developed a mobile workstation (MedKart) that provides access the HIS and PACS systems, with all resources and an ergonomic and practical design to be used by physicians and nurses inside the ICU. The system fulfills the requirements to assist, in the point-of-care, critical cardiac patients in Intensive Care Units.

  5. Cardiac Sarcoidosis.

    Science.gov (United States)

    Birnie, David; Ha, Andrew C T; Gula, Lorne J; Chakrabarti, Santabhanu; Beanlands, Rob S B; Nery, Pablo

    2015-12-01

    Studies suggest clinically manifest cardiac involvement occurs in 5% of patients with pulmonary/systemic sarcoidosis. The principal manifestations of cardiac sarcoidosis (CS) are conduction abnormalities, ventricular arrhythmias, and heart failure. Data indicate that an 20% to 25% of patients with pulmonary/systemic sarcoidosis have asymptomatic (clinically silent) cardiac involvement. An international guideline for the diagnosis and management of CS recommends that patients be screened for cardiac involvement. Most studies suggest a benign prognosis for patients with clinically silent CS. Immunosuppression therapy is advocated for clinically manifest CS. Device therapy, with implantable cardioverter defibrillators, is recommended for some patients.

  6. Changes in microRNAs expression are involved in age-related atrial structural remodeling and atrial fibrillation

    Institute of Scientific and Technical Information of China (English)

    XU Guo-jun; GAN Tian-yi; TANG Bao-peng; CHEN Zu-heng; Mahemuti Ailiman; ZHOU Xian-hui; JIANG Tao

    2013-01-01

    Background Small noncoding microRNAs regulate gene expression in cardiac development and disease and have been implicated in the aging process and in the regulation of extracellular matrix proteins.However,their role in age-related cardiac remodeling and atrial fibrillation (AF) was not well understood.The present study was designed to decipher molecular mechanisms underlying age-related atrial structural remodeling and AF.Methods Three groups of dogs were studied:adult and aged dogs in sinus rhythm and with persistent AF induced by rapid atrial pacing.The expressions of microRNAs were measured by quantitative real-time polymerase chain reaction.Pathohistological and ultrastructural changes were tested by light and electron microscopy.Apoptosis index of myocytes was detected by TUNEL.Results Samples of atrial tissue showed the abnormal pathohistological and ultrastructural changes,the accelerated fibrosis,and apoptosis with aging and/or in AF dogs.Compared to the adult group,the expressions of microRNAs-21 and -29 were significantly increased,whereas the expressions of microRNAs-1 and-133 showed obvious downregulation tendency in the aged group.Compared to the aged group,the expressions of microRNAs-1,-21,and-29 was significantly increased in the old group in AF; contrastingly,the expressions of microRNA-133 showed obvious downregulation tendency.Conclusion These multiple aberrantly expressed microRNAs may be responsible for modulating the transition from adaptation to pathological atrial remodeling with aging and/or in AF.

  7. Optical coherence tomography provides an ability to assess mechanical property of cardiac wall of developing outflow tract in embryonic heart in vivo

    Science.gov (United States)

    Li, Peng; Wang, Ruikang K.

    2012-12-01

    Knowledge of the biomechanical/elastic property of the cardiac wall is of fundamental importance in improving our understanding of cardiac development, particularly the interaction between the wall dynamics and hemodynamics in the developing outflow tract (OFT). We describe a method that employs optical coherence tomography (OCT) as a means to noninvasively measure the local elastic property of the cardiac wall in vivo. The method uses a time-lapse sequence of OCT images that represent the dynamic behavior of the OFT longitudinal section to calculate the regional wall pulse wave velocity (PWV), upon which the Young's modulus of the cardiac wall is deduced by the use of the Moens-Korteweg equation. The experimental results show that the foot-to-foot PWV ranges from 3.2 to 6.6 mm/s with a mean of 4.7 mm/s, and the averaged Young's modulus is 0.36 Pa, both of which are comparable to the documented values of stage HH17 atrioventricular canal tissue. The proposed method that provides the quantitative mechanical assessment may play a significant role in the understanding of the cardiac development.

  8. MicroRNA与心血管重构%MicroRNA and cardiovascular remodeling

    Institute of Scientific and Technical Information of China (English)

    邓璧

    2013-01-01

    MicroRNA is a short (18-25 nuucleotides) and single-stranded non-coding RNA which is involved in almost all pathological and physiological process of diseases.Cardiovascular remodeling is the pathological basis of development of multiple cardiovascular diseases,in which microRNA plays an important role.In cardiac diseases,microRNAs affect myocardial cell hypertrophy,apoptosis,and interstitial fibrosis through a variety of mechanisms.In vascular remodeling diseases,microRNAs regulate proliferation and secretion of vascular smooth muscle cells through multiple signaling pathways.%MicroRNA为短小(18~25个核苷酸组成)单链非编码RNAs,几乎参与所有疾病的病理生理过程.心血管重构是多种心血管疾病发生与发展的病理基础,而microRNA在心血管重构中起重要调控作用.在心肌性疾病中,microRNA通过多种机制影响心肌细胞肥大、凋亡和间质纤维化;在血管重构性疾病中,不同microRNA通过多条信号通路调节血管平滑肌细胞增殖和分泌.

  9. Activation of common signaling pathways during remodeling of the heart and the bladder.

    Science.gov (United States)

    Koeck, Ivonne; Burkhard, Fiona C; Monastyrskaya, Katia

    2016-02-15

    The heart and the urinary bladder are hollow muscular organs, which can be afflicted by pressure overload injury due to pathological conditions such as hypertension and bladder outlet obstruction. This increased outflow resistance induces hypertrophy, marked by dramatic changes in the organs' phenotype and function. The end result in both the heart and the bladder can be acute organ failure due to advanced fibrosis and the subsequent loss of contractility. There is emerging evidence that microRNAs (miRNAs) play an important role in the pathogenesis of heart failure and bladder dysfunction. MiRNAs are endogenous non-coding single-stranded RNAs, which regulate gene expression and control adaptive and maladaptive organ remodeling processes. This Review summarizes the current knowledge of molecular alterations in the heart and the bladder and highlights common signaling pathways and regulatory events. The miRNA expression analysis and experimental target validation done in the heart provide a valuable source of information for investigators working on the bladder and other organs undergoing the process of fibrotic remodeling. Aberrantly expressed miRNA are amendable to pharmacological manipulation, offering an opportunity for development of new therapies for cardiac and bladder hypertrophy and failure.

  10. Effect of dihydrofolate reductase gene knock-down on the expression of heart and neural crest derivatives expressed transcript 2 in zebrafish cardiac development

    Institute of Scientific and Technical Information of China (English)

    SUN Shu-na; GUI Yong-hao; WANG Yue-xiang; QIAN Lin-xi; JIANG Qiu; LIU Dong; SONG Hou-yan

    2007-01-01

    Background Folic acid is very important for embryonic development and dihydrofolate reductase is one of the key enzymes in the process of folic acid performing its biological function. Therefore, the dysfunction of dihydrofolate reductase can inhibit the function of folic acid and finally cause the developmental malformations. In this study, we observed the abnormal cardiac phenotypes in dihydrofolate reductase (DHFR) gene knock-down zebrafish embryos,investigated the effect of DHFR on the expression of heart and neural crest derivatives expressed transcript 2 (HAND2)and explored the possible mechanism of DHFR knock-down inducing zebrafish cardiac malformations.Methods Morpholino oligonucleotides were microinjected into fertilized eggs to knock down the functions of DHFR or HAND2. Full length of HAND2 mRNA which was transcribed in vitro was microinjected into fertilized eggs to overexpress HAND2. The cardiac morphologies, the heart rates and the ventricular shortening fraction were observed and recorded under the microscope at 48 hours post fertilization. Whole-mount in situ hybridization and real-time PCR were performed to detect HAND2 expression.Results DHFR or HAND2 knock-down caused the cardiac malformation in zebrafish. The expression of HAND2 was obviously reduced in DHFR knock-down embryos (P<0.05). Microinjecting HAND2 mRNA into fertilized eggs can induce HAND2 overexpression. HAND2 overexpression rescued the cardiac malformation phenotypes of DHFR knock-down embryos.Conclusions DHFR plays a crucial role in cardiac development. The down-regulation of HAND2 caused by DHFR knock-down is the possible mechanism of DHFR knock-down inducing the cardiac malformation.

  11. Evidence of structural remodeling in the dyssynchronous failing heart.

    Science.gov (United States)

    Helm, Patrick A; Younes, Laurent; Beg, Mirza F; Ennis, Daniel B; Leclercq, Christophe; Faris, Owen P; McVeigh, Elliot; Kass, David; Miller, Michael I; Winslow, Raimond L

    2006-01-01

    Ventricular remodeling of both geometry and fiber structure is a prominent feature of several cardiac pathologies. Advances in MRI and analytical methods now make it possible to measure changes of cardiac geometry, fiber, and sheet orientation at high spatial resolution. In this report, we use diffusion tensor imaging to measure the geometry, fiber, and sheet architecture of eight normal and five dyssynchronous failing canine hearts, which were explanted and fixed in an unloaded state. We apply novel computational methods to identify statistically significant changes of cardiac anatomic structure in the failing and control heart populations. The results demonstrate significant regional differences in geometric remodeling in the dyssynchronous failing heart versus control. Ventricular chamber dilatation and reduction in wall thickness in septal and some posterior and anterior regions are observed. Primary fiber orientation showed no significant change. However, this result coupled with the local wall thinning in the septum implies an altered transmural fiber gradient. Further, we observe that orientation of laminar sheets become more vertical in the early-activated septum, with no significant change of sheet orientation in the late-activated lateral wall. Measured changes in both fiber gradient and sheet structure will affect both the heterogeneity of passive myocardial properties as well as electrical activation of the ventricles.

  12. Effects of Perindopril on Left Ventricular Remodeling and Osteopontin Expression in Rats With Myocardial Infarction

    Institute of Scientific and Technical Information of China (English)

    2007-01-01

    To observe the effects of perindopril on left ventricular remodeling and myocardial osteopontin expression in rats with myocardial infarction. Methods In this study male adult SD rats were randomly divided into 3groups: sham-operation group, MI-saline group and MI-perindopril group. Left anterior descending artery was ligated to generate myocardial infarction. Perindopril (2 mg/kg body weight/day) was administered from the next day of MI.Four weeks later, left ventricular diameter (LVEDD and LVESD) and left ventricular ejection fraction was estimated with echocardiography, LVSP, LVEDP and ± dp/dtmax was detected with hemodynamic measurement, cardiomyocyte diameter and interstitial fibrosis infiltration were evaluated with histological methods, and myocardium osteopontin protein expression level was detected with western blot. Results ①Compared with the sham-operation group, all rats with MI developed significant systolic and diastolic dysfunction, as was indicated by decreased LVEF, LVSP and ± dp/dtmax, as well as increased LVEDP. ②Rats with MI showed significantly dilated left ventricles and higher ventricular weight / body weight ratio, significantly increased cardiomyocyte diameter and marked interstitial fibrosis in the non-infarction area. ③Perindopril treatment partly prevented cardiac dysfunction and left ventricular remodeling as indicated by the parameters mentioned above. ④No osteopontin protein was detected in myocardium of sham-operation rats. In rats with MI, high level osteopontin protein expression was significantly inhibited by perindopril treatment. Conclusions In rats with MI, perindopril treatment significantly prevented left ventricular remodeling and myocardium osteopontin protein expression.

  13. Rat Heterotopic Heart Transplantation Model to Investigate Unloading-Induced Myocardial Remodeling

    Science.gov (United States)

    Fu, Xuebin; Segiser, Adrian; Carrel, Thierry P.; Tevaearai Stahel, Hendrik T.; Most, Henriette

    2016-01-01

    Unloading of the failing left ventricle in order to achieve myocardial reverse remodeling and improvement of contractile function has been developed as a strategy with the increasing frequency of implantation of left ventricular assist devices in clinical practice. But, reverse remodeling remains an elusive target, with high variability and exact mechanisms still largely unclear. The small animal model of heterotopic heart transplantation (hHTX) in rodents has been widely implemented to study the effects of complete and partial unloading on cardiac failing and non-failing tissue to better understand the structural and molecular changes that underlie myocardial recovery. We herein review the current knowledge on the effects of volume unloading the left ventricle via different methods of hHTX in rats, differentiating between changes that contribute to functional recovery and adverse effects observed in unloaded myocardium. We focus on methodological aspects of heterotopic transplantation, which increase the correlation between the animal model and the setting of the failing unloaded human heart. Last, but not least, we describe the late use of sophisticated techniques to acquire data, such as small animal MRI and catheterization, as well as ways to assess unloaded hearts under “reloaded” conditions. While giving regard to certain limitations, heterotopic rat heart transplantation certainly represents the crucial model to mimic unloading-induced changes in the heart and as such the intricacies and challenges deserve highest consideration. Careful translational research will further improve our knowledge of the reverse remodeling process and how to potentiate its effect in order to achieve recovery of contractile function in more patients.

  14. Knock-in Mice Harboring a Ca2+ Desensitizing Mutation in Cardiac Troponin C Develop Early Onset Dilated Cardiomyopathy

    Directory of Open Access Journals (Sweden)

    Bradley K McConnell

    2015-08-01

    Full Text Available The physiological consequences of aberrant Ca2+ binding and exchange with cardiac myofilaments are not clearly understood. In order to examine the effect of decreasing Ca2+ sensitivity of cTnC on cardiac function, we generated knock-in mice carrying a D73N mutation (not known to be associated with heart disease in human patients in cTnC. The D73N mutation was engineered into the regulatory N-domain of cTnC in order to reduce Ca2+ sensitivity of reconstituted thin filaments by increasing the rate of Ca2+ dissociation. In addition, the D73N mutation drastically blunted the extent of Ca2+ desensitization of reconstituted thin filaments induced by cTnI pseudo-phosphorylation. Compared to wild-type mice, heterozygous knock-in mice carrying the D73N mutation exhibited a substantially decreased Ca2+ sensitivity of force development in skinned ventricular trabeculae. Kaplan-Meier survival analysis revealed that median survival time for knock-in mice was twelve weeks. Echocardiographic analysis revealed that knock-in mice exhibited increased left ventricular dimensions with thinner walls. Echocardiographic analysis also revealed that measures of systolic function, such as ejection fraction and fractional shortening, were dramatically reduced in knock-in mice. In addition, knock-in mice displayed electrophysiological abnormalities, namely prolonged QRS and QT intervals. Furthermore, ventricular myocytes isolated from knock-in mice did not respond to β-adrenergic stimulation. Thus, knock-in mice developed pathological features similar to those observed in human patients with dilated cardiomyopathy (DCM. In conclusion, our results suggest that decreasing Ca2+ sensitivity of the regulatory N-domain of cTnC is sufficient to trigger the development of DCM.

  15. Extracellular Matrix Remodeling During the Progression of Volume Overload-Induced Heart Failure

    Science.gov (United States)

    Hutchinson, Kirk R.; Stewart, James A.; Lucchesi, Pamela A.

    2009-01-01

    Volume overload-induced heart failure results in progressive left ventricular remodeling characterized by chamber dilation, eccentric cardiac myocyte hypertrophy and changes in extracellular matrix (ECM) remodeling changes. The ECM matrix scaffold is an important determinant of the structural integrity of the myocardium and actively participates in force transmission across the LV wall. In response to this hemodynamic overload, the ECM undergoes a distinct pattern of remodeling that differs from pressure overload. Once thought to be a static entity, the ECM is now regarded to be a highly adaptive structure that is dynamically regulated by mechanical stress, neurohormonal activation, inflammation and oxidative stress, that result in alterations in collagen and other matrix components and a net change in matrix metalloproteinase (MMP) expression and activation. These changes dictate overall ECM turnover during volume overload hear failure progression. This review will discuss the cellular and molecular mechanisms that dictate the temporal patterns of ECM remodeling during heart disease progression. PMID:19524591

  16. Cardiac Malpositions

    Energy Technology Data Exchange (ETDEWEB)

    Yoo, Shi Joon; Im, Chung Gie; Yeon, Kyung Mo; Hasn, Man Chung [Seoul National University College of Medicine, Seoul (Korea, Republic of)

    1979-06-15

    Cardiac Malposition refers to any position of the heart other than a left-sided heart in a situs solitus individual. Associated cardiac malformations are so complex that even angiocardiographic and autopsy studies may not afford an accurate information. Although the terms and classifications used to describe the internal cardiac anatomy and their arterial connections in cardiac malpositions differ and tend to be confusing, common agreement exists on the need for a segmental approach to diagnosis. Authors present 18 cases of cardiac malpositions in which cardiac catheterization and angiocardiography were done at the Department of Radiology, Seoul National University Hospital between 1971 and 1979. Authors analyzed the clinical, radiographic, operative and autopsy findings with the emphasis on the angiocardiographic findings. The results are as follows: 1. Among 18 cases with cardiac malpositions, 6 cases had dextrocardia with situs inversus, 9 cases had dextrocardia with situs solitus and 3 cases had levocardia with situs inversus. 2. There was no genuine exception to visceroatrial concordance rule. 3. Associated cardiac malpositions were variable and complex with a tendency of high association of transposition and double outlet varieties with dextrocardia in situs solitus and levocardia in situs inversus. Only one in 6 cases of dextrocardia with situs inversus had pure transposition. 4. In two cases associated pulmonary atresia was found at surgery which was not predicted by angiocardiography. 5. Because many of the associated complex lesions can be corrected surgically provided the diagnosis is accurate, the selective biplane angiocardiography with or without cineradiography is essential.

  17. 经胸微创封堵治疗对先天性心脏病患者心脏重构的近期影响%Short-term effect of minimally invasive transthoracic closure on cardiac remodeling in patients with congenital heart disease

    Institute of Scientific and Technical Information of China (English)

    王海永; 陈辉; 阳玉晶; 胡江苇; 李安桂; 杜振宗; 宋剑非

    2015-01-01

    transthoracic closure can effectively improve the short-term cardiac remodeling of patients with congenital heart disease.

  18. Extracellular matrix remodelling in myocardial hypertrophy and failure : focus on osteopontin.

    Science.gov (United States)

    Francia, Pietro; Uccellini, Arianna; Frattari, Alessandra; Modestino, Anna; Ricotta, Agnese; Balla, Cristina; Scialla, Ludovica; Volpe, Massimo

    2009-12-01

    Cardiac remodelling refers to molecular and cellular changes of the myocardium, as well as adapting alterations in size, shape and function of the heart in response to changing loading conditions. It represents the final common pathway of different heart diseases, and is recognized as a crucial aspect of cardiac and myocardial dysfunction and a well established determinant of the clinical course of heart failure.Osteopontin is an extracellular matrix glycoprotein secreted by osteoblasts, osteoclasts, macrophages, T cells, vascular smooth muscle cells, fibroblasts and cardiomyocytes. Osteopontin is not expressed in healthy cardiac tissue, although its expression can be triggered by pressure or volume overload, hypoxia and angiotensin II. Indeed, osteopontin has been reported in macrophages and interstitial tissues early after myocardial infarction and in cardiac macrophage-like cells of inflammatory lesions in experimental models of cardiomyopathy. Pressure overload is associated with osteopontin overexpression as well. Indeed, myocardial osteopontin messenger RNA is upregulated in rats following renovascular hypertension or aortic banding. In humans, a significant correlation exists between increased osteopontin immunoreactivity in cardiac myocytes and impaired left ventricular function or cardiomyocyte hypertrophy in patients with dilated cardiomyopathy.The present article focuses on the role of osteopontin in myocardial hypertrophy and remodelling. In general, evidence supports the concept that osteopontin plays a crucial role in extracellular matrix remodelling following myocardial adaptation to hypertrophic, inflammatory and neurohormonal stimuli in the overloaded heart.

  19. Development of a Comprehensive Sequencing Assay for Inherited Cardiac Condition Genes.

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    Pua, Chee Jian; Bhalshankar, Jaydutt; Miao, Kui; Walsh, Roddy; John, Shibu; Lim, Shi Qi; Chow, Kingsley; Buchan, Rachel; Soh, Bee Yong; Lio, Pei Min; Lim, Jaclyn; Schafer, Sebastian; Lim, Jing Quan; Tan, Patrick; Whiffin, Nicola; Barton, Paul J; Ware, James S; Cook, Stuart A

    2016-02-01

    Inherited cardiac conditions (ICCs) are characterised by marked genetic and allelic heterogeneity and require extensive sequencing for genetic characterisation. We iteratively optimised a targeted gene capture panel for ICCs that includes disease-causing, putatively pathogenic, research and phenocopy genes (n = 174 genes). We achieved high coverage of the target region on both MiSeq (>99.8% at ≥ 20× read depth, n = 12) and NextSeq (>99.9% at ≥ 20×, n = 48) platforms with 100% sensitivity and precision for single nucleotide variants and indels across the protein-coding target on the MiSeq. In the final assay, 40 out of 43 established ICC genes informative in clinical practice achieved complete coverage (100 % at ≥ 20×). By comparison, whole exome sequencing (WES; ∼ 80×), deep WES (∼ 500×) and whole genome sequencing (WGS; ∼ 70×) had poorer performance (88.1, 99.2 and 99.3% respectively at ≥ 20×) across the ICC target. The assay described here delivers highly accurate and affordable sequencing of ICC genes, complemented by accessible cloud-based computation and informatics. See Editorial in this issue (DOI: 10.1007/s12265-015-9667-8 ).

  20. Selection and collection of multi parameter physiological data for cardiac rhythm diagnostic algorithm development

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    Bostock, J.; Weller, P. [School of Informatics, City University London, London EC1V 0HB (United Kingdom); Cooklin, M., E-mail: jbostock1@msn.co [Cardiovascular Directorate, Guy' s and St. Thomas' NHS Foundation Trust, London, SE1 7EH (United Kingdom)

    2010-07-01

    Automated diagnostic algorithms are used in implantable cardioverter-defibrillators (ICD's) to detect abnormal heart rhythms. Algorithms misdiagnose and improved specificity is needed to prevent inappropriate therapy. Knowledge engineering (KE) and artificial intelligence (AI) could improve this. A pilot study of KE was performed with artificial neural network (ANN) as AI system. A case note review analysed arrhythmic events stored in patients ICD memory. 13.2% patients received inappropriate therapy. The best ICD algorithm had sensitivity 1.00, specificity 0.69 (p<0.001 different to gold standard). A subset of data was used to train and test an ANN. A feed-forward, back-propagation network with 7 inputs, a 4 node hidden layer and 1 output had sensitivity 1.00, specificity 0.71 (p<0.001). A prospective study was performed using KE to list arrhythmias, factors and indicators for which measurable parameters were evaluated and results reviewed by a domain expert. Waveforms from electrodes in the heart and thoracic bio-impedance; temperature and motion data were collected from 65 patients during cardiac electrophysiological studies. 5 incomplete datasets were due to technical failures. We concluded that KE successfully guided selection of parameters and ANN produced a usable system and that complex data collection carries greater risk of technical failure, leading to data loss.

  1. The role of late I Na in development of cardiac arrhythmias.

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    Antzelevitch, Charles; Nesterenko, Vladislav; Shryock, John C; Rajamani, Sridharan; Song, Yejia; Belardinelli, Luiz

    2014-01-01

    Late I Na is an integral part of the sodium current, which persists long after the fast-inactivating component. The magnitude of the late I Na is relatively small in all species and in all types of cardiomyocytes as compared with the amplitude of the fast sodium current, but it contributes significantly to the shape and duration of the action potential. This late component had been shown to increase in several acquired or congenital conditions, including hypoxia, oxidative stress, and heart failure, or due to mutations in SCN5A, which encodes the α-subunit of the sodium channel, as well as in channel-interacting proteins, including multiple β subunits and anchoring proteins. Patients with enhanced late I Na exhibit the type-3 long QT syndrome (LQT3) characterized by high propensity for the life-threatening ventricular arrhythmias, such as Torsade de Pointes (TdP), as well as for atrial fibrillation. There are several distinct mechanisms of arrhythmogenesis due to abnormal late I Na, including abnormal automaticity, early and delayed after depolarization-induced triggered activity, and dramatic increase of ventricular dispersion of repolarization. Many local anesthetic and antiarrhythmic agents have a higher potency to block late I Na as compared with fast I Na. Several novel compounds, including ranolazine, GS-458967, and F15845, appear to be the most selective inhibitors of cardiac late I Na reported to date. Selective inhibition of late I Na is expected to be an effective strategy for correcting these acquired and congenital channelopathies.

  2. Combining experimental and mathematical modeling to reveal mechanisms of macrophage-dependent left ventricular remodeling

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    Dai Qiuxia

    2011-05-01

    Full Text Available Abstract Background Progressive remodeling of the left ventricle (LV following myocardial infarction (MI can lead to congestive heart failure, but the underlying initiation factors remain poorly defined. The objective of this study, accordingly, was to determine the key factors and elucidate the regulatory mechanisms of LV remodeling using integrated computational and experimental approaches. Results By examining the extracellular matrix (ECM gene expression and plasma analyte levels in C57/BL6J mice LV post-MI and ECM gene responses to transforming growth factor (TGF-β1 in cultured cardiac fibroblasts, we found that key factors in LV remodeling included macrophages, fibroblasts, transforming growth factor-β1, matrix metalloproteinase-9 (MMP-9, and specific collagen subtypes. We established a mathematical model to study LV remodeling post-MI by quantifying the dynamic balance between ECM construction and destruction. The mathematical model incorporated the key factors and demonstrated that TGF-β1 stimuli and MMP-9 interventions with different strengths and intervention times lead to different LV remodeling outcomes. The predictions of the mathematical model fell within the range of experimental measurements for these interventions, providing validation for the model. Conclusions In conclusion, our results demonstrated that the balance between ECM synthesis and degradation, controlled by interactions of specific key factors, determines the LV remodeling outcomes. Our mathematical model, based on the balance between ECM construction and destruction, provides a useful tool for studying the regulatory mechanisms and for predicting LV remodeling outcomes.

  3. Cardiac Imaging in Heart Failure with Comorbidities.

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    Wong, Chiew; Chen, Sylvia; Iyngkaran, Pupalan

    2017-01-01

    Imaging modalities stand at the frontiers for progress in congestive heart failure (CHF) screening, risk stratification and monitoring. Advancements in echocardiography (ECHO) and Magnetic Resonance Imaging (MRI) have allowed for improved tissue characterizations, cardiac motion analysis, and cardiac performance analysis under stress. Common cardiac comorbidities such as hypertension, metabolic syndromes and chronic renal failure contribute to cardiac remodeling, sharing similar pathophysiological mechanisms starting with interstitial changes, structural changes and finally clinical CHF. These imaging techniques can potentially detect changes earlier. Such information could have clinical benefits for screening, planning preventive therapies and risk stratifying patients. Imaging reports have often focused on traditional measures without factoring these novel parameters. This review is aimed at providing a synopsis on how we can use this information to assess and monitor improvements for CHF with comorbidities.

  4. Sudden cardiac death after acute ST elevation myocardial infarction: insight from a developing country

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    Rao, Hygriv B; Sastry, B K S; Korabathina, Radhika; Raju, Krishnam P

    2012-01-01

    Background There is no data concerning sudden cardiac death (SCD) following acute ST elevation myocardial infarction (STEMI) in India. We assessed the incidence and factors influencing SCD following STEMI. Methods Patients with STEMI admitted in our hospital from 2006 to 2009 were prospectively entered into a database. In the period 2010–2011