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Sample records for genes improves cardiac

  1. Stem cell factor gene transfer improves cardiac function after myocardial infarction in swine.

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    Ishikawa, Kiyotake; Fish, Kenneth; Aguero, Jaume; Yaniz-Galende, Elisa; Jeong, Dongtak; Kho, Changwon; Tilemann, Lisa; Fish, Lauren; Liang, Lifan; Eltoukhy, Ahmed A; Anderson, Daniel G; Zsebo, Krisztina; Costa, Kevin D; Hajjar, Roger J

    2015-01-01

    Stem cell factor (SCF), a ligand of the c-kit receptor, is a critical cytokine, which contributes to cell migration, proliferation, and survival. It has been shown that SCF expression increases after myocardial infarction (MI) and may be involved in cardiac repair. The aim of this study was to determine whether gene transfer of membrane-bound human SCF improves cardiac function in a large animal model of MI. A transmural MI was created by implanting an embolic coil in the left anterior descending artery in Yorkshire pigs. One week after the MI, the pigs received direct intramyocardial injections of either a recombinant adenovirus encoding for SCF (Ad.SCF, n=9) or β-gal (Ad.β-gal, n=6) into the infarct border area. At 3 months post-MI, ejection fraction increased by 12% relative to baseline after Ad.SCF therapy, whereas it decreased by 4.2% (P=0.004) in pigs treated with Ad.β-gal. Preload-recruitable stroke work was significantly higher in pigs after SCF treatment (Ad.SCF, 55.5±11.6 mm Hg versus Ad.β-gal, 31.6±12.6 mm Hg, P=0.005), indicating enhanced cardiac function. Histological analyses confirmed the recruitment of c-kit(+) cells as well as a reduced degree of apoptosis 1 week after Ad.SCF injection. In addition, increased capillary density compared with pigs treated with Ad.β-gal was found at 3 months and suggests an angiogenic role of SCF. Local overexpression of SCF post-MI induces the recruitment of c-kit(+) cells at the infarct border area acutely. In the chronic stages, SCF gene transfer was associated with improved cardiac function in a preclinical model of ischemic cardiomyopathy. © 2014 American Heart Association, Inc.

  2. SUMO-1 gene transfer improves cardiac function in a large-animal model of heart failure.

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    Tilemann, Lisa; Lee, Ahyoung; Ishikawa, Kiyotake; Aguero, Jaume; Rapti, Kleopatra; Santos-Gallego, Carlos; Kohlbrenner, Erik; Fish, Kenneth M; Kho, Changwon; Hajjar, Roger J

    2013-11-13

    Recently, the impact of small ubiquitin-related modifier 1 (SUMO-1) on the regulation and preservation of sarcoplasmic reticulum calcium adenosine triphosphatase (SERCA2a) function was discovered. The amount of myocardial SUMO-1 is decreased in failing hearts, and its knockdown results in severe heart failure (HF) in mice. In a previous study, we showed that SUMO-1 gene transfer substantially improved cardiac function in a murine model of pressure overload-induced HF. Toward clinical translation, we evaluated in this study the effects of SUMO-1 gene transfer in a swine model of ischemic HF. One month after balloon occlusion of the proximal left anterior descending artery followed by reperfusion, the animals were randomized to receive either SUMO-1 at two doses, SERCA2a, or both by adeno-associated vector type 1 (AAV1) gene transfer via antegrade coronary infusion. Control animals received saline infusions. After gene delivery, there was a significant increase in the maximum rate of pressure rise [dP/dt(max)] that was most pronounced in the group that received both SUMO-1 and SERCA2a. The left ventricular ejection fraction (LVEF) improved after high-dose SUMO-1 with or without SERCA2a gene delivery, whereas there was a decline in LVEF in the animals receiving saline. Furthermore, the dilatation of LV volumes was prevented in the treatment groups. SUMO-1 gene transfer therefore improved cardiac function and stabilized LV volumes in a large-animal model of HF. These results support the critical role of SUMO-1 in SERCA2a function and underline the therapeutic potential of SUMO-1 for HF patients.

  3. Ameliorated stress related proteins are associated with improved cardiac function by sarcoplasmic reticulum calcium ATPase gene transfer in heart failure

    Institute of Scientific and Technical Information of China (English)

    Zhi-Qing Fu; Xiao-Ying Li; Xiao-Chun Lu; Ya-Fei Mi; Tao Liu; Wei-Hua Ye

    2012-01-01

    Background Previous studies showed that overexpression of sarco-endoplasmic reticulum calcium ATPase (SERCA2a) in a variety of heart failure (HF) models was associated with greatly enhanced cardiac performance. However, it still undefined the effect of SERCA2a overexpression on the systemic inflammatory response and neuro-hormonal factors. Methods A rapid right ventricular pacing model of experimental HF was used in beagles. Then the animals underwent recombinant adeno-associated virus 1 (rAAV1) mediated gene transfection by direct intra-myocardium injection. HF animals were randomized to receive the SERCA2a gene, enhanced green fluorescent protein (control) gene, or equivalent phosphate buffered saline. Thirty days after gene delivery, the cardiac function was evaluated by echocardiographic testing. The protein level of SERCA2a was measured by western blotting. The proteomic analysis of left ventricular (LV) sample was determined using two-dimensional (2-D) gel electrophoresis and MALDI-TOF-MS. The serum levels of the systemic inflammatory and neuro-hormonal factors were assayed using radioimmunoassay kits. Results The cardiac function improved after SERCA- 2a gene transfer due to the significantly increased SERCA2a protein level. Beagles treated with SERCA2a had significantly decreased serum levels of the inflammatory markers (interleukin-6 and tumor necrosis factor-α) and neuro-hormonal factors (brain natriuretic peptide, endothelin-1 and angiotensin Ⅱ) compared with HF animals. The myocardial proteomic analysis showed that haptoglobin heavy chain, heat shock protein (alpha-crystallin-related, B6) were down-regulated, and galectin-1 was up-regulated in SERCA2a group compared with HF group, companied by up-regulated contractile proteins and NADH dehydrogenase. Conclusions These findings demonstrate that regional intramyocardial injections of rAAV1-SERCA2a vectors may improve global LV function, correlating with reverse activation of the systemic inflammatory

  4. Improvement in cardiac function after sarcoplasmic reticulum Ca2+-ATPase gene transfer in a beagle heart failure model

    Institute of Scientific and Technical Information of China (English)

    MI Ya-fei; LI Xiao-ying; TANG Li-jiang; LU Xiao-chun; FU Zhi-qing; YE Wei-hua

    2009-01-01

    Background Heart failure (HF) is a major cause of morbidity and mortality worldwide, but current treatment modalities cannot reverse the underlying pathological state of the heart. Gene-based therapies are emerging as promising therapeutic modalities in HF patients. Our previous studies have shown that recombinant adeno-associated viral (rAAV) gene transfer of Sarco-endoplasmic reticulum calcium ATPase (SERCA2a) can be effective in treating rats with chronic heart failure (CHF). The aim of this study was to examine the effects of SERCA2a gene transfer in a large HF animal model.Methods HF was induced in beagles by rapid right ventricular pacing (230 beats/min) for 30 days. A reduced rate ventricular pacing (180 beats/min) was continued for another 30 days. The beagles were assigned to four groups: (a) control group (n=4); (b) HF group (n=4); (c) enhanced green fluorescent protein group (n=4); and (d) SERCA2.a group (n=4). rAAVl-EGFP (lx1012 μg) and rAAVl-SERCA2a (lx1012 μg) were delivered intramyocardially. SERCA2.a expression was assessed by Western blotting and immunohistochemistry.Results Following 30 days of SERCA2a gene transfer in HF beagles its protein expression was significantly higher than in the HF group than in the control group (P <0.05). Heart function improved along with the increase in SERCA2a expression. Left ventricular systolic function significantly improved, including the ejection fraction, left ventricular systolic pressure, maximal rate of rise of left ventricular pressure (+dp/dtmax), and the maximal rate of decline of left ventricular pressure (-dp/dtmax) (P <0.05). Left ventricular end-diastole pressure significantly decreased (P <0.05). The expression of SERCA2a in the myocardial tissue was higher in the SERCA2a group than in the HF group (P<0.05). Conclusions Intramyocardial injection of rAAVl-SERCA2a can improve the cardiac function in beagles induced with HE We expect further studies on SERCA2a's long-term safety, efficacy, dosage

  5. Stem cell therapy with overexpressed VEGF and PDGF genes improves cardiac function in a rat infarct model.

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    Hiranmoy Das

    Full Text Available BACKGROUND: Therapeutic potential was evaluated in a rat model of myocardial infarction using nanofiber-expanded human cord blood derived hematopoietic stem cells (CD133+/CD34+ genetically modified with VEGF plus PDGF genes (VIP. METHODS AND FINDINGS: Myocardial function was monitored every two weeks up to six weeks after therapy. Echocardiography revealed time dependent improvement of left ventricular function evaluated by M-mode, fractional shortening, anterior wall tissue velocity, wall motion score index, strain and strain rate in animals treated with VEGF plus PDGF overexpressed stem cells (VIP compared to nanofiber expanded cells (Exp, freshly isolated cells (FCB or media control (Media. Improvement observed was as follows: VIP>Exp> FCB>media. Similar trend was noticed in the exercise capacity of rats on a treadmill. These findings correlated with significantly increased neovascularization in ischemic tissue and markedly reduced infarct area in animals in the VIP group. Stem cells in addition to their usual homing sites such as lung, spleen, bone marrow and liver, also migrated to sites of myocardial ischemia. The improvement of cardiac function correlated with expression of heart tissue connexin 43, a gap junctional protein, and heart tissue angiogenesis related protein molecules like VEGF, pNOS3, NOS2 and GSK3. There was no evidence of upregulation in the molecules of oncogenic potential in genetically modified or other stem cell therapy groups. CONCLUSION: Regenerative therapy using nanofiber-expanded hematopoietic stem cells with overexpression of VEGF and PDGF has a favorable impact on the improvement of rat myocardial function accompanied by upregulation of tissue connexin 43 and pro-angiogenic molecules after infarction.

  6. Gene transfer strategies for augmenting cardiac function.

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    Peppel, K; Koch, W J; Lefkowitz, R J

    1997-07-01

    Recent transgenic as well as gene-targeted animal models have greatly increased our understanding of the molecular mechanisms of normal and compromised heart function. These studies have raised the possibility of using somatic gene transfer as a means for improving cardiac function. DNA transfer to a significant portion of the myocardium has thus far been difficult to accomplish. This review describes current efforts to achieve myocardial gene transfer in several model systems, with particular emphasis placed on adenovirus-mediated gene delivery, its possibilities, and current limitations. (Trend Cardiovasc Med 1997;7:145-150). © 1997, Elsevier Science Inc.

  7. Reduction of sympathetic activity via adrenal-targeted GRK2 gene deletion attenuates heart failure progression and improves cardiac function after myocardial infarction.

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    Lymperopoulos, Anastasios; Rengo, Giuseppe; Gao, Erhe; Ebert, Steven N; Dorn, Gerald W; Koch, Walter J

    2010-05-21

    Chronic heart failure (HF) is characterized by sympathetic overactivity and enhanced circulating catecholamines (CAs), which significantly increase HF morbidity and mortality. We recently reported that adrenal G protein-coupled receptor kinase 2 (GRK2) is up-regulated in chronic HF, leading to enhanced CA release via desensitization/down-regulation of the chromaffin cell alpha(2)-adrenergic receptors that normally inhibit CA secretion. We also showed that adrenal GRK2 inhibition decreases circulating CAs and improves cardiac inotropic reserve and function. Herein, we hypothesized that adrenal-targeted GRK2 gene deletion before the onset of HF might be beneficial by reducing sympathetic activation. To specifically delete GRK2 in the chromaffin cells of the adrenal gland, we crossed PNMTCre mice, expressing Cre recombinase under the chromaffin cell-specific phenylethanolamine N-methyltransferase (PNMT) gene promoter, with floxedGRK2 mice. After confirming a significant ( approximately 50%) reduction of adrenal GRK2 mRNA and protein levels, the PNMT-driven GRK2 knock-out (KO) offspring underwent myocardial infarction (MI) to induce HF. At 4 weeks post-MI, plasma levels of both norepinephrine and epinephrine were reduced in PNMT-driven GRK2 KO, compared with control mice, suggesting markedly reduced post-MI sympathetic activation. This translated in PNMT-driven GRK2 KO mice into improved cardiac function and dimensions as well as amelioration of abnormal cardiac beta-adrenergic receptor signaling at 4 weeks post-MI. Thus, adrenal-targeted GRK2 gene KO decreases circulating CAs, leading to improved cardiac function and beta-adrenergic reserve in post-MI HF. GRK2 inhibition in the adrenal gland might represent a novel sympatholytic strategy that can aid in blocking HF progression.

  8. Gene therapy to treat cardiac arrhythmias.

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    Bongianino, Rossana; Priori, Silvia G

    2015-09-01

    Gene therapy to treat electrical dysfunction of the heart is an appealing strategy because of the limited therapeutic options available to manage the most-severe cardiac arrhythmias, such as ventricular tachycardia, ventricular fibrillation, and asystole. However, cardiac genetic manipulation is challenging, given the complex mechanisms underlying arrhythmias. Nevertheless, the growing understanding of the molecular basis of these diseases, and the development of sophisticated vectors and delivery strategies, are providing researchers with adequate means to target specific genes and pathways involved in disorders of heart rhythm. Data from preclinical studies have demonstrated that gene therapy can be successfully used to modify the arrhythmogenic substrate and prevent life-threatening arrhythmias. Therefore, gene therapy might plausibly become a treatment option for patients with difficult-to-manage acquired arrhythmias and for those with inherited arrhythmias. In this Review, we summarize the preclinical studies into gene therapy for acquired and inherited arrhythmias of the atria or ventricles. We also provide an overview of the technical advances in the design of constructs and viral vectors to increase the efficiency and safety of gene therapy and to improve selective delivery to target organs.

  9. Gene transfer to promote cardiac regeneration.

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    Collesi, Chiara; Giacca, Mauro

    2016-12-01

    There is an impelling need to develop new therapeutic strategies for patients with myocardial infarction and heart failure. Leading from the large quantity of new information gathered over the last few years on the mechanisms controlling cardiomyocyte proliferation during embryonic and fetal life, it is now possible to devise innovative therapies based on cardiac gene transfer. Different protein-coding genes controlling cell cycle progression or cardiomyocyte specification and differentiation, along with microRNA mimics and inhibitors regulating pre-natal and early post-natal cell proliferation, are amenable to transformation in potential therapeutics for cardiac regeneration. These gene therapy approaches are conceptually revolutionary, since they are aimed at stimulating the intrinsic potential of differentiated cardiac cells to proliferate, rather than relying on the implantation of exogenously expanded cells to achieve tissue regeneration. For efficient and prolonged cardiac gene transfer, vectors based on the Adeno-Associated Virus stand as safe, efficient and reliable tools for cardiac gene therapy applications.

  10. Reducing RBM20 activity improves diastolic dysfunction and cardiac atrophy.

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    Hinze, Florian; Dieterich, Christoph; Radke, Michael H; Granzier, Henk; Gotthardt, Michael

    2016-12-01

    Impaired diastolic filling is a main contributor to heart failure with preserved ejection fraction (HFpEF), a syndrome with increasing prevalence and no treatment. Both collagen and the giant sarcomeric protein titin determine diastolic function. Since titin's elastic properties can be adjusted physiologically, we evaluated titin-based stiffness as a therapeutic target. We adjusted RBM20-dependent cardiac isoform expression in the titin N2B knockout mouse with increased ventricular stiffness. A ~50 % reduction of RBM20 activity does not only maintain cardiac filling in diastole but also ameliorates cardiac atrophy and thus improves cardiac function in the N2B-deficient heart. Reduced RBM20 activity partially normalized gene expression related to muscle development and fatty acid metabolism. The adaptation of cardiac growth was related to hypertrophy signaling via four-and-a-half lim-domain proteins (FHLs) that translate mechanical input into hypertrophy signals. We provide a novel link between cardiac isoform expression and trophic signaling via FHLs and suggest cardiac splicing as a therapeutic target in diastolic dysfunction. Increasing the length of titin isoforms improves ventricular filling in heart disease. FHL proteins are regulated via RBM20 and adapt cardiac growth. RBM20 is a therapeutic target in diastolic dysfunction.

  11. A novel needleless liquid jet injection methodology for improving direct cardiac gene delivery: An optimization of parameters, AAV mediated therapy and investigation of host responses in ischemic heart failure

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    Fargnoli, Anthony Samuel

    Heart disease remains the leading cause of mortality and morbidity worldwide, with 22 million new patients diagnosed annually. Essentially, all present therapies have significant cost burden to the healthcare system, yet fail to increase survival rates. One key employed strategy is the genetic reprogramming of cells to increase contractility via gene therapy, which has advanced to Phase IIb Clinical Trials for advanced heart failure patients. It has been argued that the most significant barrier preventing FDA approval are resolving problems with safe, efficient myocardial delivery, whereby direct injection in the infarct and remote tissue areas is not clinically feasible. Here, we aim to: (1) Improve direct cardiac gene delivery through the development of a novel liquid jet device approach (2) Compare the new method against traditional IM injection with two different vector constructions and evaluate outcome (3) Evaluate the host response resulting from both modes of direct cardiac injection, then advance a drug/gene combination with controlled release nanoparticle formulations.

  12. Improving cardiac myocytes performance by CNTs platforms

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    Valentina eMartinelli

    2013-09-01

    Full Text Available The application of nanotechnology to the cardiovascular system has increasingly caught scientists’ attention as a potentially powerful tool for the development of new generation devices able to interface, repair or boost the performance of cardiac tissue. Carbon nanotubes (CNTs are considered as promising materials for nanomedicine applications in general and have been recently tested towards excitable cell growth. CNTs are cylindrically shaped structures made up of rolled-up graphene sheets, with unique electrical, thermal and mechanical properties, able to effectively conducting electrical current in electrochemical interfaces. CNTs-based scaffolds have been recently found to support the in vitro growth of cardiac cells: in particular, their ability to improve cardiomyocytes proliferation, maturation and electrical behavior are making CNTs extremely attractive for the development and exploitation of interfaces able to impact on cardiac cells physiology and function.

  13. Synergistic activation of cardiac genes by myocardin and Tbx5.

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    Chunbo Wang

    Full Text Available Myocardial differentiation is associated with the activation and expression of an array of cardiac specific genes. However, the transcriptional networks that control cardiac gene expression are not completely understood. Myocardin is a cardiac and smooth muscle-specific expressed transcriptional coactivator of Serum Response Factor (SRF and is able to potently activate cardiac and smooth muscle gene expression during development. We hypothesize that myocardin discriminates between cardiac and smooth muscle specific genes by associating with distinct co-factors. Here, we show that myocardin directly interacts with Tbx5, a member of the T-box family of transcription factors involved in the Holt-Oram syndrome. Tbx5 synergizes with myocardin to activate expression of the cardiac specific genes atrial natriuretic factor (ANF and alpha myosin heavy chain (α-MHC, but not that of smooth muscle specific genes SM22 or smooth muscle myosin heavy chain (SM-MHC. We found that this synergistic activation of shared target genes is dependent on the binding sites for Tbx5, T-box factor-Binding Elements (TBEs. Myocardin and Tbx5 physically interact and their interaction domains were mapped to the basic domain and the coil domain of myocardin and Tbx5, respectively. Our analysis demonstrates that the Tbx5G80R mutation, which leads to the Holt-Oram syndrome in humans, failed to synergize with myocardin to activate cardiac gene expression. These data uncover a key role for Tbx5 and myocardin in establishing the transcriptional foundation for cardiac gene activation and suggest that the interaction of myocardin and Tbx5 maybe involved in cardiac development and diseases.

  14. Transplantation of 5-azacytidine treated cardiac fibroblasts improves cardiac function of infarct hearts in rats

    Institute of Scientific and Technical Information of China (English)

    TANG Cheng-chun; MA Gan-shan; CHEN Ji-yuan

    2010-01-01

    Background Cellular cardiomyoplasty by transplantation of various cell types has been investigated as potential treatments for the improvement of cardiac function after myocardial injury. A major barrier for the clinical application of cell transplantation is obtaining sufficiently large quantities of suitable cells. AIIogeneic cellular cardiomyoplasty may provide an alternative source of abundant, transplantable, myogenic cells by in vitro manipulation of cardiac fibroblasts using chemicals including 5-azacytidine. This study evaluated cardiomyogenic differentiation of cardiac fibroblasts, their survival in myocardial scar tissue, and the effect of the implanted cells on heart function.Methods Primary cardiac fibroblasts from neonatal rats were treated with 5-azacytidine (10 μmol/L) or control.Treatment of 5-azacytidine caused myogenic differentiation of cultured cardiac fibroblasts, as defined by elongation and fusion into multinucleated myotubes with sarcomeric structures as identified by electron microscopy, and positive immunostaining for cardiac specific proteins, troponin I and β-myosin heavy chain (β-MHC) and the gap junction protein connexin 43. The myogenic cells (1.0x106) were transplanted into the infarcted myocardium 2 weeks after coronary artery occlusion.Results By 1 month after transplantation, the converted fibroblasts gave rise to a cluster of cardiac-like muscle cells that in the hearts occupied a large part of the scar with positive immunostaining for the myogenic proteins troponin I and β-MHC. Engrafted cells also expressed the gap junction protein connexin 43 in a disorganized manner. There was no positive staining in the control hearts treated with injections of culture medium. Heart function was evaluated at 6 weeks after myocardial injury with echocardiographic and hemodynamic measurements. Improvement in cardiac function was seen in the hearts transplanted with the 5-azacytidine-treated cardiac fibroblasts which was absent in the

  15. Caffeine exposure alters cardiac gene expression in embryonic cardiomyocytes

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    Fang, Xiefan; Mei, Wenbin; Barbazuk, William B.; Rivkees, Scott A.

    2014-01-01

    Previous studies demonstrated that in utero caffeine treatment at embryonic day (E) 8.5 alters DNA methylation patterns, gene expression, and cardiac function in adult mice. To provide insight into the mechanisms, we examined cardiac gene and microRNA (miRNA) expression in cardiomyocytes shortly after exposure to physiologically relevant doses of caffeine. In HL-1 and primary embryonic cardiomyocytes, caffeine treatment for 48 h significantly altered the expression of cardiac structural genes (Myh6, Myh7, Myh7b, Tnni3), hormonal genes (Anp and BnP), cardiac transcription factors (Gata4, Mef2c, Mef2d, Nfatc1), and microRNAs (miRNAs; miR208a, miR208b, miR499). In addition, expressions of these genes were significantly altered in embryonic hearts exposed to in utero caffeine. For in utero experiments, pregnant CD-1 dams were treated with 20–60 mg/kg of caffeine, which resulted in maternal circulation levels of 37.3–65.3 μM 2 h after treatment. RNA sequencing was performed on embryonic ventricles treated with vehicle or 20 mg/kg of caffeine daily from E6.5-9.5. Differential expression (DE) analysis revealed that 124 genes and 849 transcripts were significantly altered, and differential exon usage (DEU) analysis identified 597 exons that were changed in response to prenatal caffeine exposure. Among the DE genes identified by RNA sequencing were several cardiac structural genes and genes that control DNA methylation and histone modification. Pathway analysis revealed that pathways related to cardiovascular development and diseases were significantly affected by caffeine. In addition, global cardiac DNA methylation was reduced in caffeine-treated cardiomyocytes. Collectively, these data demonstrate that caffeine exposure alters gene expression and DNA methylation in embryonic cardiomyocytes. PMID:25354728

  16. Technical solutions to improve cardiac regenerative therapy

    NARCIS (Netherlands)

    van Slochteren, F.J.

    2014-01-01

    The therapeutic options for patients suffering from ischemic heart disease (IHD) are limited, and worldwide 23 million patients suffer from heart failure (HF). Therefore there is a strong need for alternative therapies for IHD. Since cardiac regenerative therapies have shown promising results in bas

  17. Human paraoxonase gene cluster overexpression alleviates angiotensin II-induced cardiac hypertrophy in mice.

    Science.gov (United States)

    Pei, Jian-Fei; Yan, Yun-Fei; Tang, Xiaoqiang; Zhang, Yang; Cui, Shen-Shen; Zhang, Zhu-Qin; Chen, Hou-Zao; Liu, De-Pei

    2016-11-01

    Cardiac hypertrophy is the strongest predictor of the development of heart failure, and anti-hypertrophic treatment holds the key to improving the clinical syndrome and increasing the survival rates for heart failure. The paraoxonase (PON) gene cluster (PC) protects against atherosclerosis and coronary artery diseases. However, the role of PC in the heart is largely unknown. To evaluate the roles of PC in cardiac hypertrophy, transgenic mice carrying the intact human PON1, PON2, and PON3 genes and their flanking sequences were studied. We demonstrated that the PC transgene (PC-Tg) protected mice from cardiac hypertrophy induced by Ang II; these mice had reduced heart weight/body weight ratios, decreased left ventricular wall thicknesses and increased fractional shortening compared with wild-type (WT) control. The same protective tendency was also observed with an Apoe (-/-) background. Mechanically, PC-Tg normalized the disequilibrium of matrix metalloproteinases (MMPs)/tissue inhibitors of MMPs (TIMPs) in hypertrophic hearts, which might contribute to the protective role of PC-Tg in cardiac fibrosis and, thus, protect against cardiac remodeling. Taken together, our results identify a novel anti-hypertrophic role for the PON gene cluster, suggesting a possible strategy for the treatment of cardiac hypertrophy through elevating the levels of the PON gene family.

  18. Proteasome inhibition slightly improves cardiac function in mice with hypertrophic cardiomyopathy.

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    Schlossarek, Saskia; Singh, Sonia R; Geertz, Birgit; Schulz, Herbert; Reischmann, Silke; Hübner, Norbert; Carrier, Lucie

    2014-01-01

    A growing line of evidence indicates a dysfunctional ubiquitin-proteasome system (UPS) in cardiac diseases. Anti-hypertrophic effects and improved cardiac function have been reported after treatment with proteasome inhibitors in experimental models of cardiac hypertrophy. Here we tested whether proteasome inhibition could also reverse the disease phenotype in a genetically-modified mouse model of hypertrophic cardiomyopathy (HCM), which carries a mutation in Mybpc3, encoding the myofilament protein cardiac myosin-binding protein C. At 7 weeks of age, homozygous mutant mice (KI) have 39% higher left ventricular mass-to-body-weight ratio and 29% lower fractional area shortening (FAS) than wild-type (WT) mice. Both groups were treated with epoxomicin (0.5 mg/kg/day) or vehicle for 1 week via osmotic minipumps. Epoxomicin inhibited the chymotrypsin-like activity by ~50% in both groups. All parameters of cardiac hypertrophy (including the fetal gene program) were not affected by epoxomicin treatment in both groups. In contrast, FAS was 12% and 35% higher in epoxomicin-treated than vehicle-treated WT and KI mice, respectively. To identify which genes or pathways could be involved in this positive effect, we performed a transcriptome analysis in KI and WT neonatal cardiac myocytes, treated or not with the proteasome inhibitor MG132 (1 μM, 24 h). This revealed 103 genes (four-fold difference; 5% FDR) which are commonly regulated in both KI and WT cardiac myocytes. Thus, even in genetically-modified mice with manifest HCM, proteasome inhibition showed beneficial effects, at least with regard to cardiac function. Targeting the UPS in cardiac diseases remains therefore a therapeutic option.

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

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    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.

  20. Inhibition of neutrophil activity improves cardiac function after cardiopulmonary bypass

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    Grünwald Frank

    2007-10-01

    Full Text Available Abstract Background The arterial in line application of the leukocyte inhibition module (LIM in the cardiopulmonary bypass (CPB limits overshooting leukocyte activity during cardiac surgery. We studied in a porcine model whether LIM may have beneficial effects on cardiac function after CPB. Methods German landrace pigs underwent CPB (60 min myocardial ischemia; 30 min reperfusion without (group I; n = 6 or with LIM (group II; n = 6. The cardiac indices (CI and cardiac function were analyzed pre and post CPB with a Swan-Ganz catheter and the cardiac function analyzer. Neutrophil labeling with technetium, scintigraphy, and histological analyses were done to track activated neutrophils within the organs. Results LIM prevented CPB-associated increase of neutrophil counts in peripheral blood. In group I, the CI significantly declined post CPB (post: 3.26 ± 0.31; pre: 4.05 ± 0.45 l/min/m2; p 2; p = 0.23. Post CPB, the intergroup difference showed significantly higher CI values in the LIM group (p Conclusion Our data provides strong evidence that LIM improves perioperative hemodynamics and cardiac function after CPB by limiting neutrophil activity and inducing accelerated sequestration of neutrophils in the spleen.

  1. Expression profiling reveals differences in metabolic gene expression between exercise-induced cardiac effects and maladaptive cardiac hypertrophy

    DEFF Research Database (Denmark)

    Strøm, Claes C; Aplin, Mark; Ploug, Thorkil

    2005-01-01

    While cardiac hypertrophy elicited by pathological stimuli eventually leads to cardiac dysfunction, exercise-induced hypertrophy does not. This suggests that a beneficial hypertrophic phenotype exists. In search of an underlying molecular substrate we used microarray technology to identify cardiac...... by quantitative PCR. The exercise program resulted in cardiac hypertrophy without impaired cardiac function. Principal component analysis identified an exercise-induced change in gene expression that was distinct from the program observed in maladaptive hypertrophy. Statistical analysis identified 267 upregulated...... genes and 62 downregulated genes in response to exercise. Expression changes in genes encoding extracellular matrix proteins, cytoskeletal elements, signalling factors and ribosomal proteins mimicked changes previously described in maladaptive hypertrophy. Our most striking observation...

  2. Cardiac gene therapy: from concept to reality.

    Science.gov (United States)

    Kratlian, Razmig Garo; Hajjar, Roger J

    2012-03-01

    Heart failure is increasing in incidence throughout the world, especially in industrialized countries. Although the current therapeutic modalities have been successful in stabilizing the course of heart failure, morbidity and mortality remain quite high and there remains a great need for innovative breakthroughs that will offer new treatment strategies for patients with advanced forms of the disease. The past few years have witnessed a greater understanding of the molecular underpinnings of the failing heart, paving the way for novel strategies in modulating the cellular environment. As such, gene therapy has recently emerged as a powerful tool offering the promise of a new paradigm for alleviating heart failure. Current gene therapy research for heart failure is focused on exploring potential cellular targets and preclinical and clinical studies are ongoing toward the realization of this goal. Efforts also include the development of sophisticated viral vectors and vector delivery methods for efficient transduction of cardiomyocytes.

  3. Exercise improves cardiac autonomic function in obesity and diabetes.

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    Voulgari, Christina; Pagoni, Stamatina; Vinik, Aaron; Poirier, Paul

    2013-05-01

    Physical activity is a key element in the prevention and management of obesity and diabetes. Regular physical activity efficiently supports diet-induced weight loss, improves glycemic control, and can prevent or delay type 2 diabetes diagnosis. Furthermore, physical activity positively affects lipid profile, blood pressure, reduces the rate of cardiovascular events and associated mortality, and restores the quality of life in type 2 diabetes. However, recent studies have documented that a high percentage of the cardiovascular benefits of exercise cannot be attributed solely to enhanced cardiovascular risk factor modulation. Obesity in concert with diabetes is characterized by sympathetic overactivity and the progressive loss of cardiac parasympathetic influx. These are manifested via different pathogenetic mechanisms, including hyperinsulinemia, visceral obesity, subclinical inflammation and increased thrombosis. Cardiac autonomic neuropathy is an underestimated risk factor for the increased cardiovascular morbidity and mortality associated with obesity and diabetes. The same is true for the role of physical exercise in the restoration of the heart cardioprotective autonomic modulation in these individuals. This review addresses the interplay of cardiac autonomic function in obesity and diabetes, and focuses on the importance of exercise in improving cardiac autonomic dysfunction. Copyright © 2013 Elsevier Inc. All rights reserved.

  4. Gene therapy during cardiac surgery: role of surgical technique to minimize collateral organ gene expression.

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    Katz, Michael G; Swain, JaBaris D; Fargnoli, Anthony S; Bridges, Charles R

    2010-12-01

    Effective gene therapy for heart failure has not yet been achieved clinically. The aim of this study is to quantitatively assess the cardiac isolation efficiency of the molecular cardiac surgery with recirculating delivery (MCARD™) and to evaluate its efficacy as a means to limit collateral organ gene expression. 10(14) genome copies (GC) of recombinant adeno-associated viral vector 6 encoding green fluorescent protein under control of the cytomegalovirus promoter was delivered to the nine arrested sheep hearts. Blood samples were assessed using real-time quantitative polymerase chain reaction (RT QPCR). Collateral organ gene expression was assessed at four-weeks using immunohistochemical staining. The blood vector GC concentration in the cardiac circuit during complete isolation trended from 9.59±0.73 to 9.05±0.65 (log GC/cm(3)), and no GC were detectable in the systemic circuit (P800-fold (P99% isolation efficiency. Conversely, incomplete isolation resulted in equalization of vector GC concentration in the circuits, leading to robust collateral organ gene expression. MCARD™ is an efficient, clinically translatable myocardial delivery platform for cardiac specific gene therapy. The cardiac surgical techniques utilized are critically important to limit collateral organ gene expression.

  5. Improvement of cardiac function after kidney transplantation with dilated cardiomyopathy and long dialysis vintage.

    Science.gov (United States)

    Mimura, Imari; Kawarazaki, Hiroo; Momose, Toshimitsu; Shibagaki, Yugo; Fujita, Toshiro

    2009-12-01

    Patients with long dialysis vintage have low cardiac output for various reasons. Although kidney transplantation is known to improve cardiac mortality, patients are sometimes evaluated as contraindicated for transplantation because of cardiac risk. We successfully performed kidney transplantation for a patient with a long dialysis vintage and dilated cardiomyopathy. Sequential (123)I-metaiodobenzylguanidine ((123)I-MIBG) scintigraphy suggested that amelioration of uraemia improved cardiac function. Kidney transplantation for patients with severely impaired cardiac function is safe and effective under careful perioperative monitoring irrespective of dialysis vintage. Sequential (123)I-MIBG scintigraphy can be used as an evaluation tool for the improvement in cardiac function.

  6. Cardiac ryanodine receptor gene (hRyR2) mutation underlying catecholaminergic polymorphic ventricular tachycardia in a Chinese adolescent presenting with sudden cardiac arrest and cardiac syncope

    Institute of Scientific and Technical Information of China (English)

    Ngai-Shing Mok; Ching-Wan Lam; Nai-Chung Fong; Yim-Wo Hui; Yuen-Choi Choi; Kwok-Yin Chan

    2006-01-01

    @@ Sudden cardiac death (SCD) in children and adolescents is uncommon and yet it is devastating for both victim's family and the society.Recently, it was increasingly recognized that SCD in young patients with structurally normal heart may be caused by inheritable primary electrical diseases due to the malfunction of cardiac ion channels, a disease entity known as the ion channelopathies.Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a specific form of ion channelopathy which can cause cardiac syncope or SCD in young patients by producing catecholamine-induced bi-directional ventricular tachycardia (BiVT), polymorphic VT and ventricular fibrillation (VF) during physical exertion or emotion.1-7 We reported here an index case of CPVT caused by cardiac ryanodine receptor gene (hRyR2)mutation which presented as cardiac syncope and sudden cardiac arrest in a Chinese adolescent female.

  7. Biologically improved nanofibrous scaffolds for cardiac tissue engineering

    Energy Technology Data Exchange (ETDEWEB)

    Bhaarathy, V. [Centre for Nanofibers and Nanotechnology, NUSNNI, Faculty of Engineering, National University of Singapore, 117576 (Singapore); Department of Nanoscience and Technology, School of Physical Sciences, Bharathiar University, Coimbatore 641046 (India); Lee Kong Chian School of Medicine, Nanyang Technological University, 138673 (Singapore); Venugopal, J., E-mail: nnijrv@nus.edu.sg [Centre for Nanofibers and Nanotechnology, NUSNNI, Faculty of Engineering, National University of Singapore, 117576 (Singapore); Gandhimathi, C. [Centre for Nanofibers and Nanotechnology, NUSNNI, Faculty of Engineering, National University of Singapore, 117576 (Singapore); Ponpandian, N.; Mangalaraj, D. [Department of Nanoscience and Technology, School of Physical Sciences, Bharathiar University, Coimbatore 641046 (India); Ramakrishna, S. [Centre for Nanofibers and Nanotechnology, NUSNNI, Faculty of Engineering, National University of Singapore, 117576 (Singapore)

    2014-11-01

    Nanofibrous structure developed by electrospinning technology provides attractive extracellular matrix conditions for the anchorage, migration and differentiation of stem cells, including those responsible for regenerative medicine. Recently, biocomposite nanofibers consisting of two or more polymeric blends are electrospun more tidily in order to obtain scaffolds with desired functional and mechanical properties depending on their applications. The study focuses on one such an attempt of using copolymer Poly(L-lactic acid)-co-poly (ε-caprolactone) (PLACL), silk fibroin (SF) and Aloe Vera (AV) for fabricating biocomposite nanofibrous scaffolds for cardiac tissue engineering. SEM micrographs of fabricated electrospun PLACL, PLACL/SF and PLACL/SF/AV nanofibrous scaffolds are porous, beadless, uniform nanofibers with interconnected pores and obtained fibre diameter in the range of 459 ± 22 nm, 202 ± 12 nm and 188 ± 16 nm respectively. PLACL, PLACL/SF and PLACL/SF/AV electrospun mats obtained at room temperature with an elastic modulus of 14.1 ± 0.7, 9.96 ± 2.5 and 7.0 ± 0.9 MPa respectively. PLACL/SF/AV nanofibers have more desirable properties to act as flexible cell supporting scaffolds compared to PLACL for the repair of myocardial infarction (MI). The PLACL/SF and PLACL/SF/AV nanofibers had a contact angle of 51 ± 12° compared to that of 133 ± 15° of PLACL alone. Cardiac cell proliferation was increased by 21% in PLACL/SF/AV nanofibers compared to PLACL by day 6 and further increased to 42% by day 9. Confocal analysis for cardiac expression proteins myosin and connexin 43 was observed better by day 9 compared to all other nanofibrous scaffolds. The results proved that the fabricated PLACL/SF/AV nanofibrous scaffolds have good potentiality for the regeneration of infarcted myocardium in cardiac tissue engineering. - Highlights: • Fabricated nanofibrous scaffolds are porous, beadless and uniform structures. • PLACL/SF/AV nanofibers improve the

  8. 21 CFR 862.1163 - Cardiac allograft gene expression profiling test system.

    Science.gov (United States)

    2010-04-01

    ... HUMAN SERVICES (CONTINUED) MEDICAL DEVICES CLINICAL CHEMISTRY AND CLINICAL TOXICOLOGY DEVICES Clinical Chemistry Test Systems § 862.1163 Cardiac allograft gene expression profiling test system....

  9. No cytogenetic evidence for involvement of gene(s) at 2p16 in sporadic cardiac myxomas : cytogenetic changes in ten sporadic cardiac myxomas

    NARCIS (Netherlands)

    Dijkhuizen, Trijnie; Jong, Bauke de; Meuzelaar, Jacobus J; Molenaar, Willemina M; Berg, Eva van den

    2001-01-01

    Cardiac myxomas are significant causes of cardiovascular morbidity and mortality. Their genetic background is presently unknown. Recently, linkage analysis in cardiac myxomas of Carney complex patients has indicated that 2p16 and 17q2 might carry genes responsible for the development of hereditary c

  10. No cytogenetic evidence for involvement of gene(s) at 2p16 in sporadic cardiac myxomas : cytogenetic changes in ten sporadic cardiac myxomas

    NARCIS (Netherlands)

    Dijkhuizen, Trijnie; Jong, Bauke de; Meuzelaar, Jacobus J; Molenaar, Willemina M; van den Berg, Eva

    2001-01-01

    Cardiac myxomas are significant causes of cardiovascular morbidity and mortality. Their genetic background is presently unknown. Recently, linkage analysis in cardiac myxomas of Carney complex patients has indicated that 2p16 and 17q2 might carry genes responsible for the development of hereditary c

  11. 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.

  12. SPECT imaging of cardiac reporter gene expression in living rabbits

    Institute of Scientific and Technical Information of China (English)

    LIU Ying; LAN Xiaoli; ZHANG Liang; WU Tao; JIANG Rifeng; ZHANG Yongxue

    2009-01-01

    This work is to demonstrate feasibility of imaging the expression of herpes simplex virus 1-thymidine ki-nase (HSV1-tk) reporter gene in rabbits myocardium by using the reporter probe 131I-2'-fluoro-2'-deoxy-1-β-D- arabi-nofuranosyl-5-iodouracil (131I-FIAU) and SPECT. Rabbits of the study group received intramyocardial injection of Ad5-tk and control group received aseptic saline injection. Two sets of experiments were performed on the study group. Rabbits of the 1st set were injected with 131I-FIAU 600 μCi at Day 2 after intramyocardial transfection of Ad5-tk in 1×109, 5×108, 1×108, 5×107 and 1×107 pfu, and heart SPECT imaging was done at different hours. Rabbits of the 2nd were transferred various titers of Ad5-tk (1×109, 5×108, 1×108, 5×107, 1×107 pfu) to determine the threshold and optimal viral titer needed for detection of gene expression. Two days later, 131I-FIAU was injected and heart SPECT imaging was performed at 6, 24 and 48 h, before killing them for gamma counting of the hearts. Reverse tran-scription-polymerase chain reaction (RT-PCR) was used to verify the transferred HSV1-tk gene expression. Semi-quantitative analysis derived of region of interest (ROI) of SPECT images and RT-PCR images was performed and the relationship of SPECT images with ex vivo gamma counting and mRNA level were evaluated. SPECT images conformed 131I-FIAU accumulation in rabbits injected with Ad5-tk in the anterolateral wall. The optimal images qual-ity was obtained at 24~48 h for different viral titers. The highest radioactivity in the focal myocardium was seen at 6 h, and then declined with time. The threshold was 5×107 pfu of virus titer. The result could be set better in 1~5×108 pfu by SPECT analysis and gamma counting. ROI-derived semi-quantitative study on SPECT images correlated well with ex vivo gamma counting and mRNA levels from RT-PCR analysis. The HSV1-tk/131I-FIAU reporter gene/reporter probe system is feasible for cardiac SPECT reporter gene imaging

  13. 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.

  14. Identification of genes regulated during mechanical load-induced cardiac hypertrophy

    Science.gov (United States)

    Johnatty, S. E.; Dyck, J. R.; Michael, L. H.; Olson, E. N.; Abdellatif, M.; Schneider, M. (Principal Investigator)

    2000-01-01

    Cardiac hypertrophy is associated with both adaptive and adverse changes in gene expression. To identify genes regulated by pressure overload, we performed suppressive subtractive hybridization between cDNA from the hearts of aortic-banded (7-day) and sham-operated mice. In parallel, we performed a subtraction between an adult and a neonatal heart, for the purpose of comparing different forms of cardiac hypertrophy. Sequencing more than 100 clones led to the identification of an array of functionally known (70%) and unknown genes (30%) that are upregulated during cardiac growth. At least nine of those genes were preferentially expressed in both the neonatal and pressure over-load hearts alike. Using Northern blot analysis to investigate whether some of the identified genes were upregulated in the load-independent calcineurin-induced cardiac hypertrophy mouse model, revealed its incomplete similarity with the former models of cardiac growth. Copyright 2000 Academic Press.

  15. Identification of genes regulated during mechanical load-induced cardiac hypertrophy

    Science.gov (United States)

    Johnatty, S. E.; Dyck, J. R.; Michael, L. H.; Olson, E. N.; Abdellatif, M.; Schneider, M. (Principal Investigator)

    2000-01-01

    Cardiac hypertrophy is associated with both adaptive and adverse changes in gene expression. To identify genes regulated by pressure overload, we performed suppressive subtractive hybridization between cDNA from the hearts of aortic-banded (7-day) and sham-operated mice. In parallel, we performed a subtraction between an adult and a neonatal heart, for the purpose of comparing different forms of cardiac hypertrophy. Sequencing more than 100 clones led to the identification of an array of functionally known (70%) and unknown genes (30%) that are upregulated during cardiac growth. At least nine of those genes were preferentially expressed in both the neonatal and pressure over-load hearts alike. Using Northern blot analysis to investigate whether some of the identified genes were upregulated in the load-independent calcineurin-induced cardiac hypertrophy mouse model, revealed its incomplete similarity with the former models of cardiac growth. Copyright 2000 Academic Press.

  16. Improved detection of cardiac fibrosis : Biomarkers and novel imaging techniques

    NARCIS (Netherlands)

    Jong, S. de

    2015-01-01

    Cardiac cells are embedded in a collagen network that provides strength in the heart against tension that occurs during contraction and relaxation. In almost every cardiac disease increased collagen (fibrosis) is observed. Fibrosis has adverse effects on cardiac pump function and increases the risk

  17. Protocol guided bleeding management improves cardiac surgery patient outcomes.

    Science.gov (United States)

    Pearse, B L; Smith, I; Faulke, D; Wall, D; Fraser, J F; Ryan, E G; Drake, L; Rapchuk, I L; Tesar, P; Ziegenfuss, M; Fung, Y L

    2015-10-01

    Excessive bleeding is a risk associated with cardiac surgery. Treatment invariably requires transfusion of blood products; however, the transfusion itself may contribute to postoperative sequelae. Our objective was to analyse a quality initiative designed to provide an evidenced-based approach to bleeding management. A retrospective analysis compared blood product transfusion and patient outcomes 15 months before and after implementation of a bleeding management protocol. The protocol incorporated point-of-care coagulation testing (POCCT) with ROTEM and Multiplate to diagnose the cause of bleeding and monitor treatment. Use of the protocol led to decreases in the incidence of transfusion of PRBCs (47·3% vs. 32·4%; P bleeding (5·6% vs. 3·4; P = 0·01), superficial chest wound (3·3% vs. 1·4%; P = 0·002), leg wound infection (4·6% vs. 2·0%; P bleeding management protocol supported by POCCT in a cardiac surgery programme was associated with significant reductions in the transfusion of allogeneic blood products, improved outcomes and reduced cost. © 2015 International Society of Blood Transfusion.

  18. Identification of a core set of genes that signifies pathways underlying cardiac hypertrophy

    DEFF Research Database (Denmark)

    Strom, C.C.; Kruhoffer, M.; Knudsen, Steen

    2004-01-01

    Although the molecular signals underlying cardiac hypertrophy have been the subject of intense investigation, the extent of common and distinct gene regulation between different forms of cardiac hypertrophy remains unclear. We hypothesized that a general and comparative analysis of hypertrophic...... gene expression, using microarray technology in multiple models of cardiac hypertrophy, including aortic banding, myocardial infarction, an arteriovenous shunt and pharmacologically induced hypertrophy, would uncover networks of conserved hypertrophy-specific genes and identify novel genes involved...... in hypertrophic signalling. From gene expression analyses (8740 probe sets, n = 46) of rat ventricular RNA, we identified a core set of 139 genes with consistent differential expression in all hypertrophy models as compared to their controls, including 78 genes not previously associated with hypertrophy and 61...

  19. Identification of a core set of genes that signifies pathways underlying cardiac hypertrophy

    DEFF Research Database (Denmark)

    Strøm, Claes C; Kruhøffer, Mogens; Knudsen, Steen

    2004-01-01

    Although the molecular signals underlying cardiac hypertrophy have been the subject of intense investigation, the extent of common and distinct gene regulation between different forms of cardiac hypertrophy remains unclear. We hypothesized that a general and comparative analysis of hypertrophic...... gene expression, using microarray technology in multiple models of cardiac hypertrophy, including aortic banding, myocardial infarction, an arteriovenous shunt and pharmacologically induced hypertrophy, would uncover networks of conserved hypertrophy-specific genes and identify novel genes involved...... in hypertrophic signalling. From gene expression analyses (8740 probe sets, n = 46) of rat ventricular RNA, we identified a core set of 139 genes with consistent differential expression in all hypertrophy models as compared to their controls, including 78 genes not previously associated with hypertrophy and 61...

  20. Leonurine (SCM-198) improves cardiac recovery in rat during chronic infarction.

    Science.gov (United States)

    Liu, XinHua; Pan, LiLong; Gong, QiHai; Zhu, YiZhun

    2010-12-15

    Leonurine, an alkaloid typically found in Herba leonuri, is known to have both antioxidant and cardioprotective properties. In the present study, we investigated the cardioprotective mechanism of leonurine the in vivo rat model of chronic myocardial ischemia and in vitro H9c2 cardiac myocyte model of oxidative stress. Myocardial ischemia was induced by ligating the left anterior descending coronary artery. Rats were divided into sham, myocardial ischemia+saline, and myocardial ischemia+leonurine (15 mg/kg/day). Cardiac function was recorded by catheterization. Apoptosis-related factor vascular endothelial growth factor (VEGF), survivin, Bcl-2 and Bax and pro-survival signaling pathways Akt, hypoxia inducible factor (HIF)-1α were measured by Western blotting or RT-PCR. Our results showed leonurine significantly improved myocardial function as evidenced by the decreased left ventricle end-diastolic pressure and the increased +dP/dt. Interestingly, leonurine increased the phosphorylation of Akt, the protein and gene expression of Bcl-2, but it reduced the protein and gene expression of Bax in vivo. Meanwhile leonurine significantly increased Akt phosphorylation in a concentration-dependent manner in H9c2 cardiac myocyte induced by oxidative stress in vitro, which was abolished by a phosphoinositide 3-kinase (PI3K) inhibitor, LY294002. Furthermore, leonurine not only increased the expression of HIF-1α but also the expression of survivin and VEGF. The results of present study demonstrated, for the first time that leonurine has potent anti-apoptotic effects after chronic myocardial ischemia mediated by activating the PI3K/Akt signaling pathway. Angiogenic mechanisms may be partially responsible for such an effect, which needs to be studied further.

  1. Regulation of Cardiac Gene Expression by GATA-4/5/6.

    Science.gov (United States)

    Evans, T

    1997-04-01

    The identification of nuclear regulatory proteins provides great promise for advancing our understanding of the transcriptional control of cardiac gene expression. Three new members of the GATA family of DNA-binding transcription factors were recently discovered and designated GATA-4/5/6. On the basis of expression patterns, the identification of candidate cardiac target genes and the current understanding of how other GATA factors function in the hematopoietic system, it appears that these genes are important for regulating programs of cardiac development and terminal differentiation. Indeed, a functional role for GATA-4/5/6 in activating the cardiac differentiation program was demonstrated in cell culture and embryonic systems; however, recent results obtained in embryonic stem (ES) cells with a targeted mutation of GATA-4 raise new questions regarding specificity of action among the three genes. The future direction of research in the field is discussed; understanding GATA-4/5/6 function and regulation is likely to provide important insight into the specification and/or differentiation of cardiac progenitors, development and morphogenesis of the heart, and regulation of cardiac-specific gene expression. (Trends Cardiovasc Med 1997;7:75-83). © 1997, Elsevier Science Inc.

  2. 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.

  3. Improvements to cardiovascular gene ontology.

    Science.gov (United States)

    Lovering, Ruth C; Dimmer, Emily C; Talmud, Philippa J

    2009-07-01

    Gene Ontology (GO) provides a controlled vocabulary to describe the attributes of genes and gene products in any organism. Although one might initially wonder what relevance a 'controlled vocabulary' might have for cardiovascular science, such a resource is proving highly useful for researchers investigating complex cardiovascular disease phenotypes as well as those interpreting results from high-throughput methodologies. GO enables the current functional knowledge of individual genes to be used to annotate genomic or proteomic datasets. In this way, the GO data provides a very effective way of linking biological knowledge with the analysis of the large datasets of post-genomics research. Consequently, users of high-throughput methodologies such as expression arrays or proteomics will be the main beneficiaries of such annotation sets. However, as GO annotations increase in quality and quantity, groups using small-scale approaches will gradually begin to benefit too. For example, genome wide association scans for coronary heart disease are identifying novel genes, with previously unknown connections to cardiovascular processes, and the comprehensive annotation of these novel genes might provide clues to their cardiovascular link. At least 4000 genes, to date, have been implicated in cardiovascular processes and an initiative is underway to focus on annotating these genes for the benefit of the cardiovascular community. In this article we review the current uses of Gene Ontology annotation to highlight why Gene Ontology should be of interest to all those involved in cardiovascular research.

  4. The Early-Onset Myocardial Infarction Associated PHACTR1 Gene Regulates Skeletal and Cardiac Alpha-Actin Gene Expression.

    Directory of Open Access Journals (Sweden)

    Annina Kelloniemi

    Full Text Available The phosphatase and actin regulator 1 (PHACTR1 locus is a very commonly identified hit in genome-wide association studies investigating coronary artery disease and myocardial infarction (MI. However, the function of PHACTR1 in the heart is still unknown. We characterized the mechanisms regulating Phactr1 expression in the heart, used adenoviral gene delivery to investigate the effects of Phactr1 on cardiac function, and analyzed the relationship between MI associated PHACTR1 allele and cardiac function in human subjects. Phactr1 mRNA and protein levels were markedly reduced (60%, P<0.01 and 90%, P<0.001, respectively at 1 day after MI in rats. When the direct myocardial effects of Phactr1 were studied, the skeletal α-actin to cardiac α-actin isoform ratio was significantly higher (1.5-fold, P<0.05 at 3 days but 40% lower (P<0.05 at 2 weeks after adenovirus-mediated Phactr1 gene delivery into the anterior wall of the left ventricle. Similarly, the skeletal α-actin to cardiac α-actin ratio was lower at 2 weeks in infarcted hearts overexpressing Phactr1. In cultured neonatal cardiac myocytes, adenovirus-mediated Phactr1 overexpression for 48 hours markedly increased the skeletal α-actin to cardiac α-actin ratio, this being associated with an enhanced DNA binding activity of serum response factor. Phactr1 overexpression exerted no major effects on the expression of other cardiac genes or LV structure and function in normal and infarcted hearts during 2 weeks' follow-up period. In human subjects, MI associated PHACTR1 allele was not associated significantly with cardiac function (n = 1550. Phactr1 seems to regulate the skeletal to cardiac α-actin isoform ratio.

  5. A recirculating cooling system for improved topical cardiac hypothermia.

    Science.gov (United States)

    Rosenfeldt, F L; Fambiatos, A; Pastoriza-Pinol, J; Stirling, G R

    1981-10-01

    A simple system is described that recirculates cooling fluid for topical cardiac hypothermia. This disposable system can produce a flow of 1,500 ml/min at 2 degrees to 4 degrees C. The recirculating cooler produced significantly lower myocardial temperatures than a conventional fluid-discard system in 22 patients having coronary operation. This system has been used as part of the technique of hypothermic cardioplegia in more than 600 patients. During various cardiac procedures, septal temperatures were maintained well below 20 degrees C for 60 minutes or more without the need to reinfuse the cardioplegic solution.

  6. 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...

  7. Evaluation of the ACT intervention to improve nurses' cardiac triage decisions.

    Science.gov (United States)

    Arslanian-Engoren, Cynthia; Hagerty, Bonnie; Eagle, Kim A

    2010-10-01

    Emergency department (ED) nurses are in a key position to initiate life-saving recommendations for myocardial infarction, which include a physician-read electrocardiogram (ECG) within 10 min of ED arrival. Using a quasi-experimental, one-group pretest-posttest design, the authors evaluated the preliminary effectiveness of the Aid to Cardiac Triage (ACT) intervention to improve ED nurses' cardiac triage decisions. Charts of all women who received an ED ECG 3 months before ( n = 171) and after (n = 184) the intervention and who were at least 18 years of age were reviewed. A 1-hr educational session was conducted to improve nurses' (n = 23) cardiac triage decisions. Postintervention, the proportion of women receiving an ECG within 10 min of ED arrival improved, as did the odds of women receiving a timely ECG. Preliminary evaluation of the ACT intervention indicates its effectiveness at improving ED nurses' cardiac triage decisions and obtaining a 10-min physician-read ECG.

  8. Research on the relativity between gene polymorphism and children cardiac insufficiency.

    Science.gov (United States)

    He, X-H; Li, C-L; Ling, N; Wang, Q-W; Wang, Z-Z; An, X-J

    2017-08-01

    We analyzed the relationship between Mink-S27 gene polymorphism and children with cardiac insufficiency. From April 2013 to April 2015, we enrolled 73 cases of children with cardiac insufficiency for this study, and all 73 were placed in the observation group. 76 normal cases were selected for the control group. Restriction fragment length polymorphism (RFLP) was used to make polymorphism analysis of the Mink-S27. Our results showed no significant differences in Mink-S27 genotype and allele distribution in both observation and control groups (p>0.05). In lesion samples collected from children with cardiac insufficiency, we detected significant difference in AA, CC genotype frequency and allele frequency between the observation group and the control group (prelatively high. GNAS2 gene polymorphism was associated with the prevalence of cardiac insufficiency in children. And also the patients' condition was correlated to the frequency of different genotypes and alleles.

  9. Common variation in fatty acid metabolic genes and risk of incident sudden cardiac arrest

    NARCIS (Netherlands)

    R.N. Lemaitre (Rozenn ); C.O. Johnson (Catherine); S. Hesselson (Stephanie); N. Sotoodhenia (Nona); B. McKnight (Barbara); C.M. Sitlani (Colleen); D. Rea (Dan); I.B. King (Irena); P.-Y. Kwok (Pui-Yan); A. Mak (Angel); G. Li (Guo); J. Brody (Jennifer); E.B. Larson (Eric); D. Mozaffarian (Dariush); B.M. Psaty (Bruce); A. Huertas-Vazquez (Adriana); J.-C. Tardif (Jean-Claude); C.M. Albert (Christine); L.-P. Lyytikäinen (Leo-Pekka); D.E. Arking (Dan); S. Kääb (Stefan); H.V. Huikuri (Heikki); B.P. Krijthe (Bouwe); M. Eijgelsheim (Mark); Y.A. Wang (Ying); K. Reinier (Kyndaron); T. Lehtimäki (Terho); S.L. Pulit (Sara); R. Brugada (Ramon); M. Müller-Nurasyid (Martina); C. Newton-Cheh (Christopher); P.J. Karhunen (Pekka); B.H.Ch. Stricker (Bruno); P. Goyette (Philippe); J.I. Rotter (Jerome); S.S. Chugh (Sumeet); A. Chakravarti (Aravinda); X. Jouven (Xavier); D.S. Siscovick (David)

    2014-01-01

    textabstractBackground There is limited information on genetic factors associated with sudden cardiac arrest (SCA). Objective To assess the association of common variation in genes in fatty acid pathways with SCA risk. Methods We selected 85 candidate genes and 1155 single nucleotide polymorphisms (

  10. Differentially expressed genes in embryonic cardiac tissues of mice lacking Folr1 gene activity

    Directory of Open Access Journals (Sweden)

    Schwartz Robert J

    2007-11-01

    Full Text Available Abstract Background Heart anomalies are the most frequently observed among all human congenital defects. As with the situation for neural tube defects (NTDs, it has been demonstrated that women who use multivitamins containing folic acid peri-conceptionally have a reduced risk for delivering offspring with conotruncal heart defects 123. Cellular folate transport is mediated by a receptor or binding protein and by an anionic transporter protein system. Defective function of the Folr1 (also known as Folbp1; homologue of human FRα gene in mice results in inadequate transport, accumulation, or metabolism of folate during cardiovascular morphogenesis. Results We have observed cardiovascular abnormalities including outflow tract and aortic arch arterial defects in genetically compromised Folr1 knockout mice. In order to investigate the molecular mechanisms underlying the failure to complete development of outflow tract and aortic arch arteries in the Folr1 knockout mouse model, we examined tissue-specific gene expression difference between Folr1 nullizygous embryos and morphologically normal heterozygous embryos during early cardiac development (14-somite stage, heart tube looping (28-somite stage, and outflow track septation (38-somite stage. Microarray analysis was performed as a primary screening, followed by investigation using quantitative real-time PCR assays. Gene ontology analysis highlighted the following ontology groups: cell migration, cell motility and localization of cells, structural constituent of cytoskeleton, cell-cell adhesion, oxidoreductase, protein folding and mRNA processing. This study provided preliminary data and suggested potential candidate genes for further description and investigation. Conclusion The results suggested that Folr1 gene ablation and abnormal folate homeostasis altered gene expression in developing heart and conotruncal tissues. These changes affected normal cytoskeleton structures, cell migration and

  11. Olmesartan attenuates cardiac hypertrophy and improves cardiac diastolic function in spontaneously hypertensive rats through inhibition of calcineurin pathway.

    Science.gov (United States)

    Fu, Mingqiang; Zhou, Jingmin; Xu, Jianfeng; Zhu, Hongmin; Liao, Jianquan; Cui, Xiaotong; Sun, Aijun; Fu, Michael; Zou, Yunzeng; Hu, Kai; Ge, Junbo

    2014-03-01

    To test whether olmesartan ameliorates cardiac diastolic dysfunction in spontaneously hypertensive rats (SHRs) through calcineurin pathway. Twenty-four male SHRs of 6 months were divided into saline- (n = 12) and olmesartan-treated (n = 12) groups. Age-matched WKY (n = 12) rats served as controls. Saline (10 mL·kg·d) or the same volume of olmesartan liquor (2.5 mg·kg·d) was administered by gavage for 3 months. Heart rate, systolic blood pressure, cardiac structure, and function and histological studies were determined. Expression of calcineurin and downstream NFAT3 were also detected. Compared with age-matched Wistar Kyoto rats, SHRs of 6 months exhibited evident cardiac hypertrophy and diastolic dysfunction as demonstrated by elevated systolic blood pressure and E/E', decreased E/A and E'/A', while F, left ventricular ejection fraction and fractional shortening remained unimpaired. Treatment with olmesartan significantly decreased systolic blood pressure and ventricular hypertrophy, attenuated fibrosis, and improved diastolic function (all P olmesartan group compared with the other 2 groups (both P olmesartan on cardiac structure and diastolic dysfunction, and it may be mediated through calcineurin pathway. This indicates a new therapeutic target for diastolic dysfunction.

  12. Stem cell factor gene transfer promotes cardiac repair after myocardial infarction via in situ recruitment and expansion of c-kit+ cells.

    Science.gov (United States)

    Yaniz-Galende, Elisa; Chen, Jiqiu; Chemaly, Elie; Liang, Lifan; Hulot, Jean-Sebastien; McCollum, LaTronya; Arias, Teresa; Fuster, Valentin; Zsebo, Krisztina M; Hajjar, Roger J

    2012-11-09

    There is growing evidence that the myocardium responds to injury by recruiting c-kit(+) cardiac progenitor cells to the damage tissue. Even though the ability of exogenously introducing c-kit(+) cells to injured myocardium has been established, the capability of recruiting these cells through modulation of local signaling pathways by gene transfer has not been tested. To determine whether stem cell factor gene transfer mediates cardiac regeneration in a rat myocardial infarction model, through survival and recruitment of c-kit(+) progenitors and cell-cycle activation in cardiomyocytes, and explore the mechanisms involved. Infarct size, cardiac function, cardiac progenitor cells recruitment, fibrosis, and cardiomyocyte cell-cycle activation were measured at different time points in controls (n=10) and upon stem cell factor gene transfer (n=13) after myocardial infarction. We found a regenerative response because of stem cell factor overexpression characterized by an enhancement in cardiac hemodynamic function: an improvement in survival; a reduction in fibrosis, infarct size and apoptosis; an increase in cardiac c-kit(+) progenitor cells recruitment to the injured area; an increase in cardiomyocyte cell-cycle activation; and Wnt/β-catenin pathway induction. Stem cell factor gene transfer induces c-kit(+) stem/progenitor cell expansion in situ and cardiomyocyte proliferation, which may represent a new therapeutic strategy to reverse adverse remodeling after myocardial infarction.

  13. 53. Improved outcome of cardio-pulmonary arrest in post-operative cardiac children resuscitated in critical care setup

    Directory of Open Access Journals (Sweden)

    Hussam Hamadah

    2015-10-01

    Conclusions: The current outcome of cardio-pulmonary arrest in post-operative cardiac children has improved. Majority of cardiac arrest were successfully resuscitated with ROSC and 80% survived to discharge. The current result reflects significant improvement in the reported outcome of children who had cardio-pulmonary arrest in post-operative cardiac children in PCICU setup.

  14. Nanowires and Electrical Stimulation Synergistically Improve Functions of hiPSC Cardiac Spheroids.

    Science.gov (United States)

    Richards, Dylan J; Tan, Yu; Coyle, Robert; Li, Yang; Xu, Ruoyu; Yeung, Nelson; Parker, Arran; Menick, Donald R; Tian, Bozhi; Mei, Ying

    2016-07-13

    The advancement of human induced pluripotent stem-cell-derived cardiomyocyte (hiPSC-CM) technology has shown promising potential to provide a patient-specific, regenerative cell therapy strategy to treat cardiovascular disease. Despite the progress, the unspecific, underdeveloped phenotype of hiPSC-CMs has shown arrhythmogenic risk and limited functional improvements after transplantation. To address this, tissue engineering strategies have utilized both exogenous and endogenous stimuli to accelerate the development of hiPSC-CMs. Exogenous electrical stimulation provides a biomimetic pacemaker-like stimuli that has been shown to advance the electrical properties of tissue engineered cardiac constructs. Recently, we demonstrated that the incorporation of electrically conductive silicon nanowires to hiPSC cardiac spheroids led to advanced structural and functional development of hiPSC-CMs by improving the endogenous electrical microenvironment. Here, we reasoned that the enhanced endogenous electrical microenvironment of nanowired hiPSC cardiac spheroids would synergize with exogenous electrical stimulation to further advance the functional development of nanowired hiPSC cardiac spheroids. For the first time, we report that the combination of nanowires and electrical stimulation enhanced cell-cell junction formation, improved development of contractile machinery, and led to a significant decrease in the spontaneous beat rate of hiPSC cardiac spheroids. The advancements made here address critical challenges for the use of hiPSC-CMs in cardiac developmental and translational research and provide an advanced cell delivery vehicle for the next generation of cardiac repair.

  15. Combination of European System for Cardiac Operative Risk Evaluation (EuroSCORE) and Cardiac Surgery Score (CASUS) to Improve Outcome Prediction in Cardiac Surgery.

    Science.gov (United States)

    Doerr, Fabian; Heldwein, Matthias B; Bayer, Ole; Sabashnikov, Anton; Weymann, Alexander; Dohmen, Pascal M; Wahlers, Thorsten; Hekmat, Khosro

    2015-08-17

    BACKGROUND We hypothesized that the combination of a preoperative and a postoperative scoring system would improve the accuracy of mortality prediction and therefore combined the preoperative 'additive EuroSCORE' (European system for cardiac operative risk evaluation) with the postoperative 'additive CASUS' (Cardiac Surgery Score) to form the 'modified CASUS'. MATERIAL AND METHODS We included all consecutive adult patients after cardiac surgery during January 2007 and December 2010 in our prospective study. Our single-centre study was conducted in a German general referral university hospital. The original additive and the 'modified CASUS' were tested using calibration and discrimination statistics. We compared the area under the curve (AUC) of the receiver characteristic curves (ROC) by DeLong's method and calculated overall correct classification (OCC) values. RESULTS The mean age among the total of 5207 patients was 67.2 ± 10.9 years. Whilst the ICU mortality was 5.9% we observed a mean length of ICU stay of 4.6 ± 7.0 days. Both models demonstrated excellent discriminatory power (mean AUC of 'modified CASUS': ≥ 0.929; 'additive CASUS': ≥ 0.920), with no significant differences according to DeLong. Neither model showed a significant p-value (cardiac surgery by combining a preoperative and a postoperative scoring system. A separate calculation of the two individual elements is therefore recommended.

  16. Rational promoter selection for gene transfer into cardiac cells

    NARCIS (Netherlands)

    Maass, A; Langer, SJ; Oberdorf-Maass, S; Bauer, S; Neyses, L; Leinwand, LA

    2003-01-01

    Cardiomyocytes (CMCs) are extremely difficult to transfect with non-viral techniques, but they are efficiently infected by adenoviruses. The most commonly used promoters to drive protein expression in cardiac myocytes are of viral origin, since they are believed to be constitutively active and minim

  17. 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.

  18. Biologically improved nanofibrous scaffolds for cardiac tissue engineering.

    Science.gov (United States)

    Bhaarathy, V; Venugopal, J; Gandhimathi, C; Ponpandian, N; Mangalaraj, D; Ramakrishna, S

    2014-11-01

    Nanofibrous structure developed by electrospinning technology provides attractive extracellular matrix conditions for the anchorage, migration and differentiation of stem cells, including those responsible for regenerative medicine. Recently, biocomposite nanofibers consisting of two or more polymeric blends are electrospun more tidily in order to obtain scaffolds with desired functional and mechanical properties depending on their applications. The study focuses on one such an attempt of using copolymer Poly(l-lactic acid)-co-poly (ε-caprolactone) (PLACL), silk fibroin (SF) and Aloe Vera (AV) for fabricating biocomposite nanofibrous scaffolds for cardiac tissue engineering. SEM micrographs of fabricated electrospun PLACL, PLACL/SF and PLACL/SF/AV nanofibrous scaffolds are porous, beadless, uniform nanofibers with interconnected pores and obtained fibre diameter in the range of 459 ± 22 nm, 202 ± 12 nm and 188 ± 16 nm respectively. PLACL, PLACL/SF and PLACL/SF/AV electrospun mats obtained at room temperature with an elastic modulus of 14.1 ± 0.7, 9.96 ± 2.5 and 7.0 ± 0.9 MPa respectively. PLACL/SF/AV nanofibers have more desirable properties to act as flexible cell supporting scaffolds compared to PLACL for the repair of myocardial infarction (MI). The PLACL/SF and PLACL/SF/AV nanofibers had a contact angle of 51 ± 12° compared to that of 133 ± 15° of PLACL alone. Cardiac cell proliferation was increased by 21% in PLACL/SF/AV nanofibers compared to PLACL by day 6 and further increased to 42% by day 9. Confocal analysis for cardiac expression proteins myosin and connexin 43 was observed better by day 9 compared to all other nanofibrous scaffolds. The results proved that the fabricated PLACL/SF/AV nanofibrous scaffolds have good potentiality for the regeneration of infarcted myocardium in cardiac tissue engineering.

  19. Novel microRNA prosurvival cocktail for improving engraftment and function of cardiac progenitor cell transplantation.

    Science.gov (United States)

    Hu, Shijun; Huang, Mei; Nguyen, Patricia K; Gong, Yongquan; Li, Zongjin; Jia, Fangjun; Lan, Feng; Liu, Junwei; Nag, Divya; Robbins, Robert C; Wu, Joseph C

    2011-09-13

    Although stem cell therapy has provided a promising treatment for myocardial infarction, the low survival of the transplanted cells in the infarcted myocardium is possibly a primary reason for failure of long-term improvement. Therefore, the development of novel prosurvival strategies to boost stem cell survival will be of significant benefit to this field. Cardiac progenitor cells (CPCs) were isolated from transgenic mice, which constitutively express firefly luciferase and green fluorescent protein. The CPCs were transduced with individual lentivirus carrying the precursor of miR-21, miR-24, and miR-221, a cocktail of these 3 microRNA precursors, or green fluorescent protein as a control. After challenge in serum free medium, CPCs treated with the 3 microRNA cocktail showed significantly higher viability compared with untreated CPCs. After intramuscular and intramyocardial injections, in vivo bioluminescence imaging showed that microRNA cocktail-treated CPCs survived significantly longer after transplantation. After left anterior descending artery ligation, microRNA cocktail-treated CPCs boost the therapeutic efficacy in terms of functional recovery. Histological analysis confirmed increased myocardial wall thickness and CPC engraftment in the myocardium with the microRNA cocktail. Finally, we used bioinformatics analysis and experimental validation assays to show that Bim, a critical apoptotic activator, is an important target gene of the microRNA cocktail, which collectively can bind to the 3'UTR region of Bim and suppress its expression. We have demonstrated that a microRNA prosurvival cocktail (miR-21, miR-24, and miR-221) can improve the engraftment of transplanted cardiac progenitor cells and therapeutic efficacy for treatment of ischemic heart disease.

  20. Optimisation of atrioventricular delay during exercise improves cardiac output in patients stabilised with cardiac resynchronisation therapy.

    Science.gov (United States)

    Sun, Jing Ping; Lee, Alex Pui-Wai; Grimm, Richard A; Hung, Ming-Jui; Yang, Xing Sheng; Delurgio, David; Leon, Angel R; Merlino, John D; Yu, Cheuk-Man

    2012-01-01

    Atrioventricular (AV) delay in cardiac resynchronisation therapy (CRT) recipients are typically optimised at rest. However, there are limited data on the impact of exercise-induced changes in heart rate on the optimal AV delay and left ventricular function. The authors serially programmed AV delays in 41 CRT patients with intrinsic sinus rhythm at rest and during two stages of supine bicycle exercise with heart rates at 20 bpm (stage I) and 40 bpm (stage II) above baseline. The optimal AV delay during exercise was determined by the iterative method to maximise cardiac output using Doppler echocardiography. Results were compared to physiological change in PR intervals in 56 normal controls during treadmill exercise. The optimal AV delay was progressively shortened (pexercise level (baseline: 123±26 ms vs. stage I: 102±24 ms vs stage II: 70±22 ms, pexercise. A linear inverse relationship existed between optimal AV delays and heart rates in CRT patients (AV delay=241-1.61×heart rate, R2=0.639, pheart rate during exercise, which suggests the need for programming of rate-adaptive AV delay in CRT recipients.

  1. Sudden infant death syndrome caused by cardiac arrhythmias: only a matter of genes encoding ion channels?

    Science.gov (United States)

    Sarquella-Brugada, Georgia; Campuzano, Oscar; Cesar, Sergi; Iglesias, Anna; Fernandez, Anna; Brugada, Josep; Brugada, Ramon

    2016-03-01

    Sudden infant death syndrome is the unexpected demise of a child younger than 1 year of age which remains unexplained after a complete autopsy investigation. Usually, it occurs during sleep, in males, and during the first 12 weeks of life. The pathophysiological mechanism underlying the death is unknown, and the lethal episode is considered multifactorial. However, in cases without a conclusive post-mortem diagnosis, suspicious of cardiac arrhythmias may also be considered as a cause of death, especially in families suffering from any cardiac disease associated with sudden cardiac death. Here, we review current understanding of sudden infant death, focusing on genetic causes leading to lethal cardiac arrhythmias, considering both genes encoding ion channels as well as structural proteins due to recent association of channelopathies and desmosomal genes. We support a comprehensive analysis of all genes associated with sudden cardiac death in families suffering of infant death. It allows the identification of the most plausible cause of death but also of family members at risk, providing cardiologists with essential data to adopt therapeutic preventive measures in families affected with this lethal entity.

  2. Vascular endothelial growth factor is crucial for erythropoietin-induced improvement of cardiac function in heart failure

    NARCIS (Netherlands)

    Westenbrink, B. Daan; Ruifrok, Willem-Peter T.; Voors, Adriaan A.; Tilton, Ronald G.; van Veldhuisen, Dirk J.; Schoemaker, Regien G.; van Gilst, Wiek H.; de Boer, Rudolf A.

    2010-01-01

    We intended to delineate the mechanisms of erythropoietin (EPO)-induced cardiac vascular endothelial growth factor (VEGF) production and to establish if VEGF is crucial for EPO-induced improvement of cardiac performance. The effects of EPO on VEGF expression were studied in cultured cardiac cells an

  3. Vascular endothelial growth factor is crucial for erythropoietin-induced improvement of cardiac function in heart failure

    NARCIS (Netherlands)

    Westenbrink, B. Daan; Ruifrok, Willem-Peter T.; Voors, Adriaan A.; Tilton, Ronald G.; van Veldhuisen, Dirk J.; Schoemaker, Regien G.; van Gilst, Wiek H.; de Boer, Rudolf A.

    2010-01-01

    We intended to delineate the mechanisms of erythropoietin (EPO)-induced cardiac vascular endothelial growth factor (VEGF) production and to establish if VEGF is crucial for EPO-induced improvement of cardiac performance. The effects of EPO on VEGF expression were studied in cultured cardiac cells an

  4. Regular Football Practice Improves Autonomic Cardiac Function in Male Children

    Science.gov (United States)

    Fernandes, Luis; Oliveira, Jose; Soares-Miranda, Luisa; Rebelo, Antonio; Brito, Joao

    2015-01-01

    Background: The role of the autonomic nervous system (ANS) in the cardiovascular regulation is of primal importance. Since it has been associated with adverse conditions such as cardiac arrhythmias, sudden death, sleep disorders, hypertension and obesity. Objectives: The present study aimed to investigate the impact of recreational football practice on the autonomic cardiac function of male children, as measured by heart rate variability. Patients and Methods: Forty-seven male children aged 9 - 12 years were selected according to their engagement with football oriented practice outside school context. The children were divided into a football group (FG; n = 22) and a control group (CG; n = 25). The FG had regular football practices, with 2 weekly training sessions and occasional weekend matches. The CG was not engaged with any physical activity other than complementary school-based physical education classes. Data from physical activity, physical fitness, and heart rate variability measured in time and frequency domains were obtained. Results: The anthropometric and body composition characteristics were similar in both groups (P > 0.05). The groups were also similar in time spent daily on moderate-to-vigorous physical activities (FG vs. CG: 114 ± 64 vs. 87 ± 55 minutes; P > 0.05). However, the FG performed better (P football practice presented enhanced physical fitness and autonomic function, by increasing vagal tone at rest. PMID:26448848

  5. Mutations in the Kv1.5 channel gene KCNA5 in cardiac arrest patients

    DEFF Research Database (Denmark)

    Nielsen, Nathalie H; Winkel, Bo G; Kanters, Jørgen K

    2007-01-01

    identified the point mutations P91L and E33V in the KCNA5 gene encoding the Kv1.5 potassium channel that has not previously been associated with arrhythmia. We functionally characterized the mutations in HEK293 cells. The mutated channels behaved similarly to the wild-type with respect to biophysical......Mutations in one of the ion channels shaping the cardiac action potential can lead to action potential prolongation. However, only in a minority of cardiac arrest cases mutations in the known arrhythmia-related genes can be identified. In two patients with arrhythmia and cardiac arrest, we...... characteristics and drug sensitivity. Both patients also carried a D85N polymorphism in KCNE1, which was neither found to influence the Kv1.5 nor the Kv7.1 channel activity. We conclude that although the two N-terminal Kv1.5 mutations did not show any apparent electrophysiological phenotype, it is possible...

  6. Qiliqiangxin Enhances Cardiac Glucose Metabolism and Improves Diastolic Function in Spontaneously Hypertensive Rats

    Directory of Open Access Journals (Sweden)

    Jingfeng Wang

    2017-01-01

    Full Text Available Cardiac diastolic dysfunction has emerged as a growing type of heart failure. The present study aims to explore whether Qiliqiangxin (QL can benefit cardiac diastolic function in spontaneously hypertensive rat (SHR through enhancement of cardiac glucose metabolism. Fifteen 12-month-old male SHRs were randomly divided into QL-treated, olmesartan-treated, and saline-treated groups. Age-matched WKY rats served as normal controls. Echocardiography and histological analysis were performed. Myocardial glucose uptake was determined by 18F-FDG using small-animal PET imaging. Expressions of several crucial proteins and key enzymes related to glucose metabolism were also evaluated. As a result, QL improved cardiac diastolic function in SHRs, as evidenced by increased E′/A′and decreased E/E′ (P<0.01. Meanwhile, QL alleviated myocardial hypertrophy, collagen deposits, and apoptosis (P<0.01. An even higher myocardial glucose uptake was illustrated in QL-treated SHR group (P<0.01. Moreover, an increased CS activity and ATP production was observed in QL-treated SHRs (P<0.05. QL enhanced cardiac glucose utilization and oxidative phosphorylation in SHRs by upregulating AMPK/PGC-1α axis, promoting GLUT-4 expression, and regulating key enzymes related to glucose aerobic oxidation such as HK2, PDK4, and CS (P<0.01. Our data suggests that QL improves cardiac diastolic function in SHRs, which may be associated with enhancement of myocardial glucose metabolism.

  7. Phenotypical Manifestations of Mutations in the Genes Encoding Subunits of the Cardiac Sodium Channel

    NARCIS (Netherlands)

    Wilde, Arthur A. M.; Brugada, Ramon

    2011-01-01

    Variations in the gene encoding for the major sodium channel (Na(v)1.5) in the heart, SCN5A, has been shown to cause a number of arrhythmia syndromes (with or without structural changes in the myocardium), including the long-QT syndrome (type 3), Brugada syndrome, (progressive) cardiac conduction di

  8. Taurine depletion caused by knocking out the taurine transporter gene leads to cardiomyopathy with cardiac atrophy.

    Science.gov (United States)

    Ito, Takashi; Kimura, Yasushi; Uozumi, Yoriko; Takai, Mika; Muraoka, Satoko; Matsuda, Takahisa; Ueki, Kei; Yoshiyama, Minoru; Ikawa, Masahito; Okabe, Masaru; Schaffer, Stephen W; Fujio, Yasushi; Azuma, Junichi

    2008-05-01

    The sulfur-containing beta-amino acid, taurine, is the most abundant free amino acid in cardiac and skeletal muscle. Although its physiological function has not been established, it is thought to play an important role in ion movement, calcium handling, osmoregulation and cytoprotection. To begin examining the physiological function of taurine, we generated taurine transporter- (TauT-) knockout mice (TauTKO), which exhibited a deficiency in myocardial and skeletal muscle taurine content compared with their wild-type littermates. The TauTKO heart underwent ventricular remodeling, characterized by reductions in ventricular wall thickness and cardiac atrophy accompanied with the smaller cardiomyocytes. Associated with the structural changes in the heart was a reduction in cardiac output and increased expression of heart cardiac failure (fetal) marker genes, such as ANP, BNP and beta-MHC. Moreover, ultrastructural damage to the myofilaments and mitochondria was observed. Further, the skeletal muscle of the TauTKO mice also exhibited decreased cell volume, structural defects and a reduction of exercise endurance capacity. Importantly, the expression of Hsp70, ATA2 and S100A4, which are upregulated by osmotic stress, was elevated in both heart and skeletal muscle of the TauTKO mice. Taurine depletion causes cardiomyocyte atrophy, mitochondrial and myofiber damage and cardiac dysfunction, effects likely related to the actions of taurine. Our data suggest that multiple actions of taurine, including osmoregulation, regulation of mitochondrial protein expression and inhibition of apoptosis, collectively ensure proper maintenance of cardiac and skeletal muscular structure and function.

  9. Inhibition of Let-7 microRNA attenuates myocardial remodeling and improves cardiac function postinfarction in mice.

    Science.gov (United States)

    Tolonen, Anna-Maria; Magga, Johanna; Szabó, Zoltán; Viitala, Pirkko; Gao, Erhe; Moilanen, Anne-Mari; Ohukainen, Pauli; Vainio, Laura; Koch, Walter J; Kerkelä, Risto; Ruskoaho, Heikki; Serpi, Raisa

    2014-08-01

    The members of lethal-7 (Let-7) microRNA (miRNA) family are involved in regulation of cell differentiation and reprogramming of somatic cells into induced pluripotent stem cells. However, their function in the heart is not known. In this study, we examined the effect of inhibiting the function of Let-7c miRNA on the progression of postinfarction left ventricular (LV) remodeling in mice. Myocardial infarction was induced with permanent ligation of left anterior descending coronary artery with a 4-week follow-up period. Let-7c miRNA was inhibited with a specific antagomir administered intravenously. The inhibition of Let-7c miRNA downregulated the levels of mature Let-7c miRNA and its other closely related members of Let-7 family in the heart and resulted in increased expression of pluripotency-associated genes Oct4 and Sox2 in cardiac fibroblasts in vitro and in adult mouse heart in vivo. Importantly, Let-7c inhibitor prevented the deterioration of cardiac function postinfarction, as demonstrated by preserved LV ejection fraction and elevated cardiac output. Improvement in cardiac function by Let-7c inhibitor postinfarction was associated with decreased apoptosis, reduced fibrosis, and reduction in the number of discoidin domain receptor 2-positive fibroblasts, while the number of c-kit(+) cardiac stem cells and Ki-67(+) proliferating cells remained unaltered. In conclusion, inhibition of Let-7 miRNA may be beneficial for the prevention of postinfarction LV remodeling and progression of heart failure.

  10. Cardiac gene therapy: Recent advances and future directions.

    Science.gov (United States)

    Mason, Daniel; Chen, Yu-Zhe; Krishnan, Harini Venkata; Sant, Shilpa

    2015-10-10

    Gene therapy has the potential to serve as an adaptable platform technology for treating various diseases. Cardiovascular disease is a major cause of mortality in the developed world and genetic modification is steadily becoming a more plausible method to repair and regenerate heart tissue. Recently, new gene targets to treat cardiovascular disease have been identified and developed into therapies that have shown promise in animal models. Some of these therapies have advanced to clinical testing. Despite these recent successes, several barriers must be overcome for gene therapy to become a widely used treatment of cardiovascular diseases. In this review, we evaluate specific genetic targets that can be exploited to treat cardiovascular diseases, list the important delivery barriers for the gene carriers, assess the most promising methods of delivering the genetic information, and discuss the current status of clinical trials involving gene therapies targeted to the heart.

  11. Regular Football Practice Improves Autonomic Cardiac Function in Male Children

    Directory of Open Access Journals (Sweden)

    Fernandes

    2015-09-01

    Full Text Available Background The role of the autonomic nervous system (ANS in the cardiovascular regulation is of primal importance. Since it has been associated with adverse conditions such as cardiac arrhythmias, sudden death, sleep disorders, hypertension and obesity. Objectives The present study aimed to investigate the impact of recreational football practice on the autonomic cardiac function of male children, as measured by heart rate variability. Patients and Methods Forty-seven male children aged 9 - 12 years were selected according to their engagement with football oriented practice outside school context. The children were divided into a football group (FG; n = 22 and a control group (CG; n = 25. The FG had regular football practices, with 2 weekly training sessions and occasional weekend matches. The CG was not engaged with any physical activity other than complementary school-based physical education classes. Data from physical activity, physical fitness, and heart rate variability measured in time and frequency domains were obtained. Results The anthropometric and body composition characteristics were similar in both groups (P > 0.05. The groups were also similar in time spent daily on moderate-to-vigorous physical activities (FG vs. CG: 114 ± 64 vs. 87 ± 55 minutes; P > 0.05. However, the FG performed better (P < 0.05 in Yo-Yo intermittent endurance test (1394 ± 558 vs. 778 ± 408 m and 15-m sprint test (3.06 ± 0.17 vs. 3.20 ± 0.23 s. Also, the FG presented enhanced autonomic function. Significant differences were detected (P < 0.05 between groups for low frequency normalized units (38.0 ± 15.2 vs. 47.3 ± 14.2 n.u (normalized units, high frequency normalized units (62.1 ± 15.2 vs. 52.8 ± 14.2 n.u., and LF:HF ratio (0.7 ± 0.4 vs. 1.1 ± 0.6 ms2. Conclusions Children engaged with regular football practice presented enhanced physical fitness and autonomic function, by increasing vagal tone at rest.

  12. Hypoxic preconditioning improves survival of cardiac progenitor cells: role of stromal cell derived factor-1α-CXCR4 axis.

    Directory of Open Access Journals (Sweden)

    Fengdi Yan

    Full Text Available BACKGROUND: Cardiac progenitor cells (CPCs have been shown to be suitable in stem cell therapy for resurrecting damaged myocardium, but poor retention of transplanted cells in the ischemic myocardium causes ineffective cell therapy. Hypoxic preconditioning of cells can increase the expression of CXCR4 and pro-survival genes to promote better cell survival; however, it is unknown whether hypoxia preconditioning will influence the survival and retention of CPCs via the SDF-1α/CXCR4 axis. METHODS AND RESULTS: CPCs were isolated from adult mouse hearts and purified by magnetic activated cell sorting using c-kit magnetic beads. These cells were cultured at various times in either normoxic or hypoxic conditions, and cell survival was analyzed using flow cytometry and the expression of hypoxia-inducible factor-1α (HIF-1α, CXCR4, phosphorylated Akt and Bcl-2 were measured by Western blot. Results showed that the expression of pro-survival genes significantly increased after hypoxia treatment, especially in cells cultured in hypoxic conditions for six hours. Upon completion of hypoxia preconditioning from c-kit+ CPCs for six hours, the anti-apoptosis, migration and cardiac repair potential were evaluated. Results showed a significant enhancement in anti-apoptosis and migration in vitro, and better survival and cardiac function after being transplanted into acute myocardial infarction (MI mice in vivo. The beneficial effects induced by hypoxia preconditioning of c-kit+ CPCs could largely be blocked by the addition of CXCR4 selective antagonist AMD3100. CONCLUSIONS: Hypoxic preconditioning may improve the survival and retention of c-kit+ CPCs in the ischemic heart tissue through activating the SDF-1α/CXCR4 axis and the downstream anti-apoptosis pathway. Strategies targeting this aspect may enhance the effectiveness of cell-based cardiac regenerative therapy.

  13. Genetically engineered cardiac pacemaker: Stem cells transfected with HCN2 gene and myocytes-A model

    Energy Technology Data Exchange (ETDEWEB)

    Kanani, S. [Institut Genomique Fonctionelle, 141 Rue de la Cardonille, 34396 Montpellier (France); Institut Non Lineaire de Nice, CNRS and Universite de Nice, 1361 route des Lucioles, 06560 Valbonne (France); Pumir, A. [Institut Non Lineaire de Nice, CNRS and Universite de Nice, 1361 route des Lucioles, 06560 Valbonne (France); Laboratoire J.A. Dieudonne, CNRS and Universite de Nice, Parc Valrose, 06108 Nice (France)], E-mail: alain.pumir@unice.fr; Krinsky, V. [Institut Non Lineaire de Nice, CNRS and Universite de Nice, 1361 route des Lucioles, 06560 Valbonne (France)

    2008-01-07

    One of the successfully tested methods to design genetically engineered cardiac pacemaker cells consists in transfecting a human mesenchymal stem cell (hMSC) with a HCN2 gene and connecting it to a myocyte. We develop and study a mathematical model, describing a myocyte connected to a hMSC transfected with a HCN2 gene. The cardiac action potential is described both with the simple Beeler-Reuter model, as well as with the elaborate dynamic Luo-Rudy model. The HCN2 channel is described by fitting electrophysiological records, in the spirit of Hodgkin-Huxley. The model shows that oscillations can occur in a pair myocyte-stem cell, that was not observed in the experiments yet. The model predicted that: (1) HCN pacemaker channels can induce oscillations only if the number of expressed I{sub K1} channels is low enough. At too high an expression level of I{sub K1} channels, oscillations cannot be induced, no matter how many pacemaker channels are expressed. (2) At low expression levels of I{sub K1} channels, a large domain of values in the parameter space (n, N) exists, where oscillations should be observed. We denote N the number of expressed pacemaker channels in the stem cell, and n the number of gap junction channels coupling the stem cell and the myocyte. (3) The expression levels of I{sub K1} channels observed in ventricular myocytes, both in the Beeler-Reuter and in the dynamic Luo-Rudy models are too high to allow to observe oscillations. With expression levels below {approx}1/4 of the original value, oscillations can be observed. The main consequence of this work is that in order to obtain oscillations in an experiment with a myocyte-stem cell pair, increasing the values of n, N is unlikely to be helpful, unless the expression level of I{sub K1} has been reduced enough. The model also allows us to explore levels of gene expression not yet achieved in experiments, and could be useful to plan new experiments, aimed at improving the robustness of the oscillations.

  14. Genetically engineered cardiac pacemaker: Stem cells transfected with HCN2 gene and myocytes—A model

    Science.gov (United States)

    Kanani, S.; Pumir, A.; Krinsky, V.

    2008-01-01

    One of the successfully tested methods to design genetically engineered cardiac pacemaker cells consists in transfecting a human mesenchymal stem cell (hMSC) with a HCN2 gene and connecting it to a myocyte. We develop and study a mathematical model, describing a myocyte connected to a hMSC transfected with a HCN2 gene. The cardiac action potential is described both with the simple Beeler Reuter model, as well as with the elaborate dynamic Luo Rudy model. The HCN2 channel is described by fitting electrophysiological records, in the spirit of Hodgkin Huxley. The model shows that oscillations can occur in a pair myocyte-stem cell, that was not observed in the experiments yet. The model predicted that: (1) HCN pacemaker channels can induce oscillations only if the number of expressed I channels is low enough. At too high an expression level of I channels, oscillations cannot be induced, no matter how many pacemaker channels are expressed. (2) At low expression levels of I channels, a large domain of values in the parameter space (n, N) exists, where oscillations should be observed. We denote N the number of expressed pacemaker channels in the stem cell, and n the number of gap junction channels coupling the stem cell and the myocyte. (3) The expression levels of I channels observed in ventricular myocytes, both in the Beeler Reuter and in the dynamic Luo Rudy models are too high to allow to observe oscillations. With expression levels below ˜1/4 of the original value, oscillations can be observed. The main consequence of this work is that in order to obtain oscillations in an experiment with a myocyte-stem cell pair, increasing the values of n, N is unlikely to be helpful, unless the expression level of I has been reduced enough. The model also allows us to explore levels of gene expression not yet achieved in experiments, and could be useful to plan new experiments, aimed at improving the robustness of the oscillations.

  15. Activation of GATA4 gene expression at the early stage of cardiac specification

    Directory of Open Access Journals (Sweden)

    Ayse eYilbas

    2014-03-01

    Full Text Available Currently, there are no effective treatments to directly repair damaged heart tissue after cardiac injury since existing therapies focus on rescuing or preserving reversibly damaged tissue. Cell-based therapies using cardiomyocytes generated from stem cells present a promising therapeutic approach to directly replace damaged myocardium with new healthy tissue. However, the molecular mechanisms underlying the commitment of stem cells into cardiomyocytes are not fully understood and will be critical to guide this new technology into the clinic. Since GATA4 is a critical regulator of cardiac differentiation, we examined the molecular basis underlying the early activation of GATA4 gene expression during cardiac differentiation of pluripotent stem cells. Our studies demonstrate the direct involvement of histone acetylation and transcriptional coactivator p300 in the regulation of GATA4 gene expression. More importantly, we show that histone acetyltransferase (HAT activity is important for GATA4 gene expression with the use of curcumin, a HAT inhibitor. In addition, the widely used histone deacetylase inhibitor valproic acid enhances both histone acetylation and cardiac specification.

  16. Activation of GATA4 gene expression at the early stage of cardiac specification

    Science.gov (United States)

    Yilbas, Ayse; Hamilton, Alison; Wang, Yingjian; Mach, Hymn; Lacroix, Natascha; Davis, Darryl; Chen, Jihong; LI, Qiao

    2014-03-01

    Currently, there are no effective treatments to directly repair damaged heart tissue after cardiac injury since existing therapies focus on rescuing or preserving reversibly damaged tissue. Cell-based therapies using cardiomyocytes generated from stem cells present a promising therapeutic approach to directly replace damaged myocardium with new healthy tissue. However, the molecular mechanisms underlying the commitment of stem cells into cardiomyocytes are not fully understood and will be critical to guide this new technology into the clinic. Since GATA4 is a critical regulator of cardiac differentiation, we examined the molecular basis underlying the early activation of GATA4 gene expression during cardiac differentiation of pluripotent stem cells. Our studies demonstrate the direct involvement of histone acetylation and transcriptional coactivator p300 in the regulation of GATA4 gene expression. More importantly, we show that histone acetyltransferase (HAT) activity is important for GATA4 gene expression with the use of curcumin, a HAT inhibitor. In addition, the widely used histone deacetylase inhibitor valproic acid enhances both histone acetylation and cardiac specification.

  17. Simulation-guided cardiac auscultation improves medical students' clinical skills: the Pavia pilot experience.

    Science.gov (United States)

    Perlini, Stefano; Salinaro, Francesco; Santalucia, Paola; Musca, Francesco

    2014-03-01

    Clinical evaluation is the cornerstone of any cardiac diagnosis, although excessive over-specialisation often leads students to disregard the value of clinical skills, and to overemphasize the approach to instrumental cardiac diagnosis. Time restraints, low availability of "typical" cardiac patients on whom to perform effective bedside teaching, patients' respect and the underscoring of the value of clinical skills all lead to a progressive decay in teaching. Simulation-guided cardiac auscultation may improve clinical training in medical students and residents. Harvey(©) is a mannequin encompassing more than 50 cardiac diagnoses that was designed and developed at the University of Miami (Florida, USA). One of the advantages of Harvey(©) simulation resides in the possibility of listening, comparing and discussing "real" murmurs. To objectively assess its teaching performance, the capability to identify five different cardiac diagnoses (atrial septal defect, normal young subject, mitral stenosis with tricuspid regurgitation, chronic mitral regurgitation, and pericarditis) out of more than 50 diagnostic possibilities was assessed in 523 III-year medical students (i.e. at the very beginning of their clinical experience), in 92 VI-year students, and in 42 residents before and after a formal 10-h teaching session with Harvey(©). None of them had previously experienced simulation-based cardiac auscultation in addition to formal lecturing (all three groups) and bedside teaching (VI-year students and residents). In order to assess the "persistence" of the acquired knowledge over time, the test was repeated after 3 years in 85 students, who did not repeat the formal 10-h teaching session with Harvey(©) after the III year. As expected, the overall response was poor in the "beginners" who correctly identified 11.0 % of the administered cardiac murmurs. After simulation-guided training, the ability to recognise the correct cardiac diagnoses was much better (72.0 %; p

  18. A boolean model of the cardiac gene regulatory network determining first and second heart field identity.

    Directory of Open Access Journals (Sweden)

    Franziska Herrmann

    Full Text Available Two types of distinct cardiac progenitor cell populations can be identified during early heart development: the first heart field (FHF and second heart field (SHF lineage that later form the mature heart. They can be characterized by differential expression of transcription and signaling factors. These regulatory factors influence each other forming a gene regulatory network. Here, we present a core gene regulatory network for early cardiac development based on published temporal and spatial expression data of genes and their interactions. This gene regulatory network was implemented in a Boolean computational model. Simulations reveal stable states within the network model, which correspond to the regulatory states of the FHF and the SHF lineages. Furthermore, we are able to reproduce the expected temporal expression patterns of early cardiac factors mimicking developmental progression. Additionally, simulations of knock-down experiments within our model resemble published phenotypes of mutant mice. Consequently, this gene regulatory network retraces the early steps and requirements of cardiogenic mesoderm determination in a way appropriate to enhance the understanding of heart development.

  19. A Boolean Model of the Cardiac Gene Regulatory Network Determining First and Second Heart Field Identity

    Science.gov (United States)

    Zhou, Dao; Kestler, Hans A.; Kühl, Michael

    2012-01-01

    Two types of distinct cardiac progenitor cell populations can be identified during early heart development: the first heart field (FHF) and second heart field (SHF) lineage that later form the mature heart. They can be characterized by differential expression of transcription and signaling factors. These regulatory factors influence each other forming a gene regulatory network. Here, we present a core gene regulatory network for early cardiac development based on published temporal and spatial expression data of genes and their interactions. This gene regulatory network was implemented in a Boolean computational model. Simulations reveal stable states within the network model, which correspond to the regulatory states of the FHF and the SHF lineages. Furthermore, we are able to reproduce the expected temporal expression patterns of early cardiac factors mimicking developmental progression. Additionally, simulations of knock-down experiments within our model resemble published phenotypes of mutant mice. Consequently, this gene regulatory network retraces the early steps and requirements of cardiogenic mesoderm determination in a way appropriate to enhance the understanding of heart development. PMID:23056457

  20. Improved cardiac function and exercise capacity following correction of pectus excavatum: a review of current literature.

    Science.gov (United States)

    Maagaard, Marie; Heiberg, Johan

    2016-09-01

    Patients with pectus excavatum (PE) often describe improvements in exercise stamina following corrective surgery. Studies have investigated the surgical effect on physiological parameters; still, no consensus has yet been reached. Therefore, the aim of this literature review was to describe the cardiac outcome after surgical correction, both at rest and during exercise. In February 2016, a detailed search of the databases PubMed, Medline, and EMBASE was performed. We assessed clinical studies that described cardiac outcomes both before and after surgical correction of PE. We only included studies reporting either pre-defined echocardiographic or exercise test parameters. No exclusion criteria or statistical analyses were applied. Twenty-one full-text articles, published between 1972 and 2016, were selected, with cohort-ranges of 3-168 patients, mean age-ranges of 5-33 years, and mean follow-up-ranges from immediately to 4 years after surgery. Twelve studies described resting cardiac parameters. Four studies measured cardiac output, where one described 36% immediate increase after surgery, one reported 15% increase after Nuss-bar removal and two found no difference. Three studies demonstrated improvement in mean stroke volume ranges of 22-34% and two studies found no difference. Fifteen studies investigated exercise capacity, with 11 considering peak O2 pr. kg, where five studies demonstrated improvements with the mean ranging from 8% to 15% after surgery, five studies demonstrated no difference, and one saw a decrease of 19% 3 months after Nuss-bar implantation. A measurable increase in exercise capacity exists following surgery, which may be caused by multiple factors. This may be owed to the relief of compressed cardiac chambers with the increased anterior-posterior thoracic dimensions, which could facilitate an improved filling of the heart. With these results, the positive physiological impact of the surgery is emphasized and the potential gain in cardiac

  1. Cardiac conduction improvement in two heterozygotes for primary carnitine deficiency on L-carnitine supplementation.

    Science.gov (United States)

    Sarafoglou, K; Tridgell, A H C; Bentler, K; Redlinger-Grosse, K; Berry, S A; Schimmenti, L A

    2010-08-01

    Expanded newborn screening (NBS) for free carnitine levels has led to the identification of a larger number of heterozygous infants of undiagnosed mothers affected with systemic primary carnitine deficiency (PCD), which in turn leads to the identification of other undiagnosed heterozygous family members. There is an increasing recognition that individuals heterozygous for mutations of genes involved in fatty acid oxidation (FAO) may become symptomatic under environmental stress (fasting, prolonged exercise and illness). Considering the importance of carnitine in FAO, its role in heart and bowel function and in lipid metabolism, what is still little known is the phenotypic variability, biochemical parameters and clinical course of PCD heterozygotes with consistently low-to-normal levels to low levels of carnitine over a lifetime. We report on three generations of a family--an asymptomatic PCD heterozygous infant identified through NBS that led to the diagnosis of her asymptomatic PCD-affected mother and the heterozygous status of the maternal grandparents who report some cardiac symptoms that overlap with PCD that improved with L-carnitine supplementation.

  2. Stimulating endogenous cardiac regeneration

    Directory of Open Access Journals (Sweden)

    Amanda eFinan

    2015-09-01

    Full Text Available The healthy adult heart has a low turnover of cardiac myocytes. The renewal capacity, however, is augmented after cardiac injury. Participants in cardiac regeneration include cardiac myocytes themselves, cardiac progenitor cells, and peripheral stem cells, particularly from the bone marrow compartment. Cardiac progenitor cells and bone marrow stem cells are augmented after cardiac injury, migrate to the myocardium, and support regeneration. Depletion studies of these populations have demonstrated their necessary role in cardiac repair. However, the potential of these cells to completely regenerate the heart is limited. Efforts are now being focused on ways to augment these natural pathways to improve cardiac healing, primarily after ischemic injury but in other cardiac pathologies as well. Cell and gene therapy or pharmacological interventions are proposed mechanisms. Cell therapy has demonstrated modest results and has passed into clinical trials. However, the beneficial effects of cell therapy have primarily been their ability to produce paracrine effects on the cardiac tissue and recruit endogenous stem cell populations as opposed to direct cardiac regeneration. Gene therapy efforts have focused on prolonging or reactivating natural signaling pathways. Positive results have been demonstrated to activate the endogenous stem cell populations and are currently being tested in clinical trials. A potential new avenue may be to refine pharmacological treatments that are currently in place in the clinic. Evidence is mounting that drugs such as statins or beta blockers may alter endogenous stem cell activity. Understanding the effects of these drugs on stem cell repair while keeping in mind their primary function may strike a balance in myocardial healing. To maximize endogenous cardiac regeneration,a combination of these approaches couldameliorate the overall repair process to incorporate the participation ofmultiple cell players.

  3. An improved retractor for cardiac and thoracic operations.

    Science.gov (United States)

    McEnany, M T

    1980-10-01

    Several standard abdominal wall retractors have been modified to improve exposure at the extremes of thoracic and groin incisions and to enhance the efficiency and comfort of the assistant in supplying adequate visibility in these areas.

  4. Metformin improves cardiac function in a nondiabetic rat model of post-MI heart failure

    NARCIS (Netherlands)

    Yin, Meimei; van der Horst, Iwan C. C.; van Melle, Joost P.; Qian, Cheng; van Gilst, Wiek H.; Sillje, Herman H. W.; de Boer, Rudolf A.

    2011-01-01

    Yin M, van der Horst IC, van Melle JP, Qian C, van Gilst WH, Sillje HH, de Boer RA. Metformin improves cardiac function in a nondiabetic rat model of post-MI heart failure. Am J Physiol Heart Circ Physiol 301: H459-H468, 2011. First published May 13, 2011; doi:10.1152/ajpheart.00054.2011.-Metformin

  5. Erythropoietin improves cardiac function through endothelial progenitor cell and vascular endothelial growth factor mediated neovascularization

    NARCIS (Netherlands)

    Westenbrink, B. Daan; Lipsic, Erik; van der Meer, Peter; van der Harst, Pirn; Oeseburg, Hisko; Sarvaas, Gideon J. Du Marchie; Koster, Johan; Voors, Adriaan A.; van Veldhuisen, Dirk J.; van Gilst, Wiek H.; Schoemaker, Regien G.

    2007-01-01

    Aims Erythropoietin (EPO) improves cardiac function and induces neovascutarization in chronic heart failure (CHF), although the exact mechanism has not been elucidated. We studied the effects of EPO on homing and incorporation of endothelial progenitor cells (EPC) into the myocardial microvasculatur

  6. Identifying non-technical skills and barriers for improvement of teamwork in cardiac arrest teams

    DEFF Research Database (Denmark)

    Andersen, P.O.; Jensen, Michael Kammer; Lippert, A.

    2010-01-01

    2006 to November 2006. Interviews were focussed on barriers and recommendations for teamwork in the cardiac arrest team, optimal policy for improvement of resuscitation training and clinical practice, use of cognitive aids and adoption of European Resuscitation Council (ERC) Guidelines 2005. Interviews...

  7. Cardiac Rehabilitation Improves the QRS Fragmentation in Patients With ST Elevatıon Myocardial Infarction

    Directory of Open Access Journals (Sweden)

    Mustafa Bulut

    2015-09-01

    Conclusion: The existence of the fQRS decreases after CR in patients with STEMI especially in hypertensive individuals, which may be related to improved electrical stability in the myocardium as a predictor of increase in survival and decrease in major cardiac events.

  8. Cardiac autonomic function in patients with diabetes improves with practice of comprehensive yogic breathing program

    Directory of Open Access Journals (Sweden)

    Viveka P Jyotsna

    2013-01-01

    Full Text Available Background: The aim of this study was to observe the effect comprehensive yogic breathing (Sudarshan Kriya Yoga [SKY] and Pranayam had on cardiac autonomic functions in patients with diabetes. Materials and Methods: This is a prospective randomized controlled intervention trial. Cardiac autonomic functions were assessed in 64 diabetics. Patients were randomized into two groups, one group receiving standard therapy for diabetes and the other group receiving standard therapy for diabetes and comprehensive yogic breathing program. Standard therapy included dietary advice, brisk walking for 45 min daily, and administration of oral antidiabetic drugs. Comprehensive yogic breathing program was introduced to the participants through a course of 12 h spread over 3 days. It was an interactive session in which SKY, a rhythmic cyclical breathing, preceded by Pranayam is taught under the guidance of a certified teacher. Cardiac autonomic function tests were done before and after 6 months of intervention. Results: In the intervention group, after practicing the breathing techniques for 6 months, the improvement in sympathetic functions was statistically significant (P 0.04. The change in sympathetic functions in the standard therapy group was not significant (P 0.75.Parasympathetic functions did not show any significant change in either group. When both parasympathetic and sympathetic cardiac autonomic functions were considered, there was a trend toward improvement in patients following comprehensive yogic breathing program (P 0.06. In the standard therapy group, no change in cardiac autonomic functions was noted (P 0.99. Conclusion: Cardiac autonomic functions improved in patients with diabetes on standard treatment who followed the comprehensive yogic breathing program compared to patients who were on standard therapy alone.

  9. Improved cardiac function and exercise capacity following correction of pectus excavatum

    DEFF Research Database (Denmark)

    Sørensen, Marie Maagaard; Heiberg, Johan

    2016-01-01

    no difference, and one saw a decrease of 19% 3 months after Nuss-bar implantation. A measurable increase in exercise capacity exists following surgery, which may be caused by multiple factors. This may be owed to the relief of compressed cardiac chambers with the increased anterior-posterior thoracic dimensions......, which could facilitate an improved filling of the heart. With these results, the positive physiological impact of the surgery is emphasized and the potential gain in cardiac function should be integrated in the clinical assessment of patients with PE....

  10. Temporary epicardial left ventricular and biventricular pacing improves cardiac output after cardiopulmonary bypass

    Directory of Open Access Journals (Sweden)

    García-Bengochea Jose B

    2012-10-01

    Full Text Available Abstract Background To evaluate, with different pacing modes, acute changes in left ventricular systolic function, obtained by continuous cardiac output thermodilution in various subsets of patients undergoing cardiopulmonary bypass surgery. Increments of mean arterial pressure and cardiac output were considered the end point. Methods Fifty cases electively submitted to cardiac surgery were analyzed. Isolated valve surgery 62%, coronary revascularization 30% and 8% mixed disease. Left ventricular ejection fraction was preserved in 50%,36% had moderate depression,(EF 36%-50% whereas 14% had severe depression (EF  Results Right atrium-right ventricular pacing, decreased significantly mean arterial pressure and cardiac output (2.3% in the overall population and in the subgroups studied. Right atrium-left ventricle, increased mean arterial pressure and cardiac output in 79% of patients and yielded cardiac output increments of 7.5% (0.40 l/m in the low ejection fraction subgroup and 7.3% (0.43 l/m in the left bundle branch block subset. In atrial fibrillation patients, left ventricular and biventricular pacing produced a significant increase in cardiac output 8.5% (0.39 l/min and 11.6% (0.53 l/min respectively. The dP/dt max increased significantly with both modes (p = 0.021,p = 0.028. Conclusion Right atrial-right ventricular pacing generated adverse hemodynamic effects. Right atrium-left ventricular pacing produced significant CO improvement particularly in cases with depressed ventricular function and left bundle branch block. The greatest increments were observed with left ventricular or biventricular pacing in atrial fibrillation with depressed ejection fraction.

  11. Gene expression in cardiac tissues from infants with idiopathic conotruncal defects

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    Lofland Gary K

    2011-01-01

    Full Text Available Abstract Background Tetralogy of Fallot (TOF is the most commonly observed conotruncal congenital heart defect. Treatment of these patients has evolved dramatically in the last few decades, yet a genetic explanation is lacking for the failure of cardiac development for the majority of children with TOF. Our goal was to perform genome wide analyses and characterize expression patterns in cardiovascular tissue (right ventricle, pulmonary valve and pulmonary artery obtained at the time of reconstructive surgery from 19 children with tetralogy of Fallot. Methods We employed genome wide gene expression microarrays to characterize cardiovascular tissue (right ventricle, pulmonary valve and pulmonary artery obtained at the time of reconstructive surgery from 19 children with TOF (16 idiopathic and three with 22q11.2 deletions and compared gene expression patterns to normally developing subjects. Results We detected a signal from approximately 26,000 probes reflecting expression from about half of all genes, ranging from 35% to 49% of array probes in the three tissues. More than 1,000 genes had a 2-fold change in expression in the right ventricle (RV of children with TOF as compared to the RV from matched control infants. Most of these genes were involved in compensatory functions (e.g., hypertrophy, cardiac fibrosis and cardiac dilation. However, two canonical pathways involved in spatial and temporal cell differentiation (WNT, p = 0.017 and Notch, p = 0.003 appeared to be generally suppressed. Conclusions The suppression of developmental networks may represent a remnant of a broad malfunction of regulatory pathways leading to inaccurate boundary formation and improper structural development in the embryonic heart. We suggest that small tissue specific genomic and/or epigenetic fluctuations could be cumulative, leading to regulatory network disruption and failure of proper cardiac development.

  12. Optogenetics-enabled assessment of viral gene and cell therapy for restoration of cardiac excitability.

    Science.gov (United States)

    Ambrosi, Christina M; Boyle, Patrick M; Chen, Kay; Trayanova, Natalia A; Entcheva, Emilia

    2015-12-01

    Multiple cardiac pathologies are accompanied by loss of tissue excitability, which leads to a range of heart rhythm disorders (arrhythmias). In addition to electronic device therapy (i.e. implantable pacemakers and cardioverter/defibrillators), biological approaches have recently been explored to restore pacemaking ability and to correct conduction slowing in the heart by delivering excitatory ion channels or ion channel agonists. Using optogenetics as a tool to selectively interrogate only cells transduced to produce an exogenous excitatory ion current, we experimentally and computationally quantify the efficiency of such biological approaches in rescuing cardiac excitability as a function of the mode of application (viral gene delivery or cell delivery) and the geometry of the transduced region (focal or spatially-distributed). We demonstrate that for each configuration (delivery mode and spatial pattern), the optical energy needed to excite can be used to predict therapeutic efficiency of excitability restoration. Taken directly, these results can help guide optogenetic interventions for light-based control of cardiac excitation. More generally, our findings can help optimize gene therapy for restoration of cardiac excitability.

  13. Engineering the heart: Evaluation of conductive nanomaterials for improving implant integration and cardiac function

    Science.gov (United States)

    Zhou, Jin; Chen, Jun; Sun, Hongyu; Qiu, Xiaozhong; Mou, Yongchao; Liu, Zhiqiang; Zhao, Yuwei; Li, Xia; Han, Yao; Duan, Cuimi; Tang, Rongyu; Wang, Chunlan; Zhong, Wen; Liu, Jie; Luo, Ying; (Mengqiu) Xing, Malcolm; Wang, Changyong

    2014-01-01

    Recently, carbon nanotubes together with other types of conductive materials have been used to enhance the viability and function of cardiomyocytes in vitro. Here we demonstrated a paradigm to construct ECTs for cardiac repair using conductive nanomaterials. Single walled carbon nanotubes (SWNTs) were incorporated into gelatin hydrogel scaffolds to construct three-dimensional ECTs. We found that SWNTs could provide cellular microenvironment in vitro favorable for cardiac contraction and the expression of electrochemical associated proteins. Upon implantation into the infarct hearts in rats, ECTs structurally integrated with the host myocardium, with different types of cells observed to mutually invade into implants and host tissues. The functional measurements showed that SWNTs were essential to improve the performance of ECTs in inhibiting pathological deterioration of myocardium. This work suggested that conductive nanomaterials hold therapeutic potential in engineering cardiac tissues to repair myocardial infarction.

  14. Trichloroethylene effects on gene expression during cardiac development

    Energy Technology Data Exchange (ETDEWEB)

    Collier, John Michael; Selmin, Ornella; Johnson, Paula D.; Runyan, Raymond B.

    2003-05-09

    Background: Halogenated hydrocarbon exposure is associated with changes in gene expression in adult and embryonic tissue. The present study was undertaken to identify differentially expressed mRNA transcripts in embryonic hearts from Sprague-Dawley rats exposed to trichloroethylene (TCE) or potential bio-transformation products of TCE, Dichloroethylene (DCE) and Trichloroacetic acid (TCAA). Methods: cDNA subtractive hybridization was used to selectively amplify expressed mRNA in either control or day 11 embryonic rat hearts exposed to one of these halogenated hydrocarbons from day 0 to 11. The doses used were 1100 and 110 ppm (8300 and 830 mu M) TCE, 110 and 11 ppm (1100 and 110 mu M) DCE, 27.3 and 2.75 mg/ml (100 and 10 mM) TCAA. Control animals were given distilled drinking water throughout the period of experiments. Results: Sequencing of over 100 clones derived from halogenated hydrocarbon exposed groups=resulted in identification of numerous differentially regulate gene sequences. Up-regulated transcripts identified include genes associated with stress response (Hsp 70) and homeostasis (several ribosomal proteins). Down-regulated transcripts include extracellular matrix components (GPI-p137 and vimentin) and Ca2 + responsive proteins (Serca-2 Ca2+-ATPase and beta-catenin). Two possible markers for fetal TCE exposure were identified: Serca-2 and GPI-p137, a GPI-linked protein of unknown function. Both markers show a dose-related decrease in mRNA transcript levels associated with fetal exposure to TCE. Differential regulation of expression of both markers by TCE was confirmed by dot blot analysis and semi-quantitative RT-PCR. Levels of exposure between 100 and 250 ppb (0.76 and 1.9 mu M) TCE are sufficient to decrease expression of both the Ca2+-AT Pase and GPI-p137. Conclusion: Sequences down-regulated with TCE exposure appear to be those associated with cellular=housekeeping, cell adhesion and developmental processes, while TCE=exposure up-regulates expression

  15. Exercise improves cardiac function and attenuates insulin resistance in Dahl salt-sensitive rats.

    Science.gov (United States)

    Stevens, An L M; Ferferieva, Vesselina; Bito, Virginie; Wens, Inez; Verboven, Kenneth; Deluyker, Dorien; Voet, Annemie; Vanhoof, Joke; Dendale, Paul; Eijnde, Bert O

    2015-01-01

    The development of heart failure (HF) secondary to hypertension is a complex process related to a series of physiological and molecular factors including glucose dysregulation. The overall objective of this study was to investigate whether exercise training could improve cardiac function and insulin resistance in a rat model of hypertensive HF. Seven week old Dahl salt-sensitive rats received either 8% NaCl (n = 30) or 0.3% NaCl (n = 18) diet. After a 5-week diet, animals were randomly assigned to exercise training (treadmill running at 18 m/min, 5% inclination for 60 min, 5 days/week) or kept sedentary for 6 additional weeks. 2D echocardiography was used to calculate left ventricular (LV) dimensions, volumes and global functional parameters. LV global deformation parameters were measured with speckle tracking echocardiography. Insulin resistance was assessed using 1h oral glucose tolerance testing. High salt diet led to cardiac hypertrophy and HF, characterized by increased wall thicknesses and LV volumes as well as reduced deformation parameters. In addition, high salt diet was associated with the development of insulin resistance. Exercise training improved cardiac function, reduced the extent of interstitial fibrosis and reduced insulin levels 60 min post-glucose administration. Even if not fully reversed, exercise training in HF animals improved cardiac function and insulin resistance. Adjusted modalities of exercise training might offer new insights not only as a preventive strategy, but also as a treatment for HF patients. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

  16. Gene polymorphisms in APOE, NOS3, and LIPC genes may be risk factors for cardiac adverse events after primary CABG

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    Nollert Georg

    2009-08-01

    Full Text Available Abstract Introduction Coronary artery disease progression after primary coronary artery bypass grafting may, beside classical atherosclerosis risk factors, be depending on genetic predisposition. Methods We investigated 192 CABG patients (18% female, age: 60.9 ± 7.4 years. Clinically cardiac adverse events were defined as need for reoperation (n = 88; 46%, reintervention (n = 58; 30%, or angina (n = 89; 46%. Mean follow-up time measured 10.1 ± 5.1 years. Gene polymorphisms (ApoE, NOS3, LIPC, CETP, SERPINE-1, Prothrombin were investigated separately and combined (gene risk profile. Results Among classical risk factors, arterial hypertension and hypercholesterinemia significantly influenced CAD progression. Single ApoE, NOS3 and LIPC polymorphisms provided limited information. Patients missing the most common ApoE ε3 allele (5,2%, showed recurrent symptoms (p = 0,077 and had more frequently reintervention (p = 0,001. NOS3 a allele was associated with a significant increase for reintervention (p = 0,041 and recurrent symptoms (p = 0,042. Homozygous LIPC patients had a higher reoperation rate (p = 0.049. A gene risk profile enabled us to discriminate between faster and slower occurrence of cardiac adverse events (p = 0.0012. Conclusion Single APOE, LIPC and NOS3 polymorphisms permitted limited prognosis of cardiac adverse events in patients after CABG. Risk profile, in contrast, allowed for risk stratification.

  17. Beyond the Electrocardiogram: Mutations in Cardiac Ion Channel Genes Underlie Nonarrhythmic Phenotypes

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    Thomas M Roston

    2017-03-01

    Full Text Available Cardiac ion channelopathies are an important cause of sudden death in the young and include long QT syndrome, Brugada syndrome, catecholaminergic polymorphic ventricular tachycardia, idiopathic ventricular fibrillation, and short QT syndrome. Genes that encode ion channels have been implicated in all of these conditions, leading to the widespread implementation of genetic testing for suspected channelopathies. Over the past half-century, researchers have also identified systemic pathologies that extend beyond the arrhythmic phenotype in patients with ion channel gene mutations, including deafness, epilepsy, cardiomyopathy, periodic paralysis, and congenital heart disease. A coexisting phenotype, such as cardiomyopathy, can influence evaluation and management. However, prior to recent molecular advances, our understanding and recognition of these overlapping phenotypes were poor. This review highlights the systemic and structural heart manifestations of the cardiac ion channelopathies, including their phenotypic spectrum and molecular basis.

  18. Increased natriuretic peptide receptor A and C gene expression in rats with pressure-overload cardiac hypertrophy

    DEFF Research Database (Denmark)

    Christoffersen, Tue E.H.; Aplin, Mark; Strom, Claes C.

    2006-01-01

    Both atrial (ANP) and brain (BNP) natriuretic peptide affect development of cardiac hypertrophy and fibrosis via binding to natriuretic peptide receptor (NPR)-A in the heart. A putative clearance receptor, NPR-C, is believed to regulate cardiac levels of ANP and BNP. The renin-angiotensin system...... also affects cardiac hypertrophy and fibrosis. In this study we examined the expression of genes for the NPRs in rats with pressure-overload cardiac hypertrophy. The ANG II type 1 receptor was blocked with losartan (10 mg.kg(-1).day(-1)) to investigate a possible role of the renin-angiotensin system...

  19. Increased natriuretic peptide receptor A and C gene expression in rats with pressure-overload cardiac hypertrophy

    DEFF Research Database (Denmark)

    Christoffersen, Tue E.H.; Aplin, Mark; Strom, Claes C.

    2006-01-01

    Both atrial (ANP) and brain (BNP) natriuretic peptide affect development of cardiac hypertrophy and fibrosis via binding to natriuretic peptide receptor (NPR)-A in the heart. A putative clearance receptor, NPR-C, is believed to regulate cardiac levels of ANP and BNP. The renin-angiotensin system...... also affects cardiac hypertrophy and fibrosis. In this study we examined the expression of genes for the NPRs in rats with pressure-overload cardiac hypertrophy. The ANG II type 1 receptor was blocked with losartan (10 mg.kg(-1).day(-1)) to investigate a possible role of the renin-angiotensin system...

  20. INFLUENCE OF THE POLYMORPHISM OF THE RENIN-ANGIOTENSIN SYSTEM GENES ON THE CARDIAC ARRHYTHMIAS IN CHILDREN WITH HYPERTROPHIC CARDIOMYOPATHY

    Directory of Open Access Journals (Sweden)

    N. A. Berezneva

    2013-01-01

    Full Text Available Hypertrophic cardiomyopathy (HCMP is a genetically determined myocardial disease, characterized by massive hypertrophy of the myocardium of the left and/or (rarely the right ventricle, often associated with obstruction of the left ventricular outflow tract and diastolic dysfunction. The course of disease can be complicated by development of various cardiac arrhythmias.  It was reported that severity of HCMP course depends at certain degree on polymorphism of candidate genes, including genes of the renin angiotensin system (RAS. Influence of RAS genes polymorphism on the frequency and character of cardiac arrhythmias in childhood is almost not studied. Aim: to determine the influence of RAS genes polymorphism on the prevalence and structure of cardiac arrhythmias in children with HCMP. Patients and methods: analysis of influence of RAS genes polymorphism on the prevalence and structure of cardiac arrhythmias was performed in 32 children with HCMP. All the patients were carried out ECG, cardiac ultrasound and ECG Holter monitoring. Polymorphism of the RAS genes (renin gene (REN G83A, angiotensinogen gene (AGT M235T, angiotensin-converting enzyme gene (ACE I/D, angiotensin II receptor type 1 gene (AGTR1 A1166C. Results: in patients with HCMP was established a higher frequency of TT-genotype and T-alleles of angiotensinogen gene than in comparison group. In homozygous patients with T-allele of angiotensinogen gene ventricular arrhythmia was found reliably more often than in patients with MT- and MM-genotypes, which suggested that M235T polymorphism of angiotensinogen gene influenced on intensity of ventricular arrhythmias in children with HCMP. Conclusions: in children with HCMP and cardiac arrhythmias analysis of M235T polymorphism of angiotensinogen gene can be used as an additional criterion for revealing of patients with high risk of arrhythmic complications and for development of preventative measures.

  1. Is there any association between childhood cardiac septal defects and ROCK2 gene polymorphism?

    Science.gov (United States)

    Aksoy, M; Uygun, H; Baspinar, O; Demiryurek, S; Oztuzcu, S; Cengiz, B; Irdem, A; Araz, N C

    2014-03-17

    Rho/Rho-kinase pathway plays a critical role in the regulation of cellular functions such as proliferation and migration. One of the possible theories of the development of ventricular septal defects is cell migration disorder. The aim of this study was to analyze the genotype distributions and allele frequencies for the ROCK2 gene Thr431Asn polymorphisms in the development of cardiac septal defects in a Turkish population. In this case-control study, 300 patients with cardiac defects (150 patients with ventricular and 150 patients with atrial septal defects) and control group (150 healthy control subjects) were investigated. A single-nucleotide polymorphism in ROCK2 gene Thr431Asn was analyzed by real-time PCR using a Light-Cycler. Neither genotype distributions nor the allele frequencies for the Thr431Asn polymorphism showed a significant difference between the groups. These results suggest that there is no association of the ROCK2 gene Thr431Asn polymorphism with the development of cardiac septal defects in pediatric patients.

  2. Music Improves Subjective Feelings Leading to Cardiac Autonomic Nervous Modulation: A Pilot Study

    Science.gov (United States)

    Kume, Satoshi; Nishimura, Yukako; Mizuno, Kei; Sakimoto, Nae; Hori, Hiroshi; Tamura, Yasuhisa; Yamato, Masanori; Mitsuhashi, Rika; Akiba, Keigo; Koizumi, Jun-ichi; Watanabe, Yasuyoshi; Kataoka, Yosky

    2017-01-01

    It is widely accepted that listening to music improves subjective feelings and reduces fatigue sensations, and different kinds of music lead to different activations of these feelings. Recently, cardiac autonomic nervous modulation has been proposed as a useful objective indicator of fatigue. However, scientific considerations of the relation between feelings of fatigue and cardiac autonomic nervous modulation while listening to music are still lacking. In this study, we examined which subjective feelings of fatigue are related to participants' cardiac autonomic nervous function while they listen to music. We used an album of comfortable and relaxing environmental music, with blended sounds from a piano and violin as well as natural sound sources. We performed a crossover trial of environmental music and silent sessions for 20 healthy subjects, 12 females, and 8 males, after their daily work shift. We measured changes in eight types of subjective feelings, including healing, fatigue, sleepiness, relaxation, and refreshment, using the KOKORO scale, a subjective mood measurement system for self-reported feelings. Further, we obtained measures of cardiac autonomic nervous function on the basis of heart rate variability before and after the sessions. During the music session, subjective feelings significantly shifted toward healing and a secure/relaxed feeling and these changes were greater than those in the silent session. Heart rates (ΔHR) in the music session significantly decreased compared with those in the silent session. Other cardiac autonomic parameters such as high-frequency (HF) component and the ratio of low-frequency (LF) and HF components (LF/HF) were similar in the two sessions. In the linear regression analysis of the feelings with ΔHR and changes in LF/HF (ΔLF/HF), increases and decreases in ΔHR were correlated to the feeling axes of Fatigue-Healing and Anxiety/Tension–Security/Relaxation, whereas those in ΔLF/HF were related to the feeling axes

  3. Music Improves Subjective Feelings Leading to Cardiac Autonomic Nervous Modulation: A Pilot Study.

    Science.gov (United States)

    Kume, Satoshi; Nishimura, Yukako; Mizuno, Kei; Sakimoto, Nae; Hori, Hiroshi; Tamura, Yasuhisa; Yamato, Masanori; Mitsuhashi, Rika; Akiba, Keigo; Koizumi, Jun-Ichi; Watanabe, Yasuyoshi; Kataoka, Yosky

    2017-01-01

    It is widely accepted that listening to music improves subjective feelings and reduces fatigue sensations, and different kinds of music lead to different activations of these feelings. Recently, cardiac autonomic nervous modulation has been proposed as a useful objective indicator of fatigue. However, scientific considerations of the relation between feelings of fatigue and cardiac autonomic nervous modulation while listening to music are still lacking. In this study, we examined which subjective feelings of fatigue are related to participants' cardiac autonomic nervous function while they listen to music. We used an album of comfortable and relaxing environmental music, with blended sounds from a piano and violin as well as natural sound sources. We performed a crossover trial of environmental music and silent sessions for 20 healthy subjects, 12 females, and 8 males, after their daily work shift. We measured changes in eight types of subjective feelings, including healing, fatigue, sleepiness, relaxation, and refreshment, using the KOKORO scale, a subjective mood measurement system for self-reported feelings. Further, we obtained measures of cardiac autonomic nervous function on the basis of heart rate variability before and after the sessions. During the music session, subjective feelings significantly shifted toward healing and a secure/relaxed feeling and these changes were greater than those in the silent session. Heart rates (ΔHR) in the music session significantly decreased compared with those in the silent session. Other cardiac autonomic parameters such as high-frequency (HF) component and the ratio of low-frequency (LF) and HF components (LF/HF) were similar in the two sessions. In the linear regression analysis of the feelings with ΔHR and changes in LF/HF (ΔLF/HF), increases and decreases in ΔHR were correlated to the feeling axes of Fatigue-Healing and Anxiety/Tension-Security/Relaxation, whereas those in ΔLF/HF were related to the feeling axes

  4. Relationship of disease-associated gene expression to cardiac phenotype is buffered by genetic diversity and chromatin regulation.

    Science.gov (United States)

    Karbassi, Elaheh; Monte, Emma; Chapski, Douglas J; Lopez, Rachel; Rosa Garrido, Manuel; Kim, Joseph; Wisniewski, Nicholas; Rau, Christoph D; Wang, Jessica J; Weiss, James N; Wang, Yibin; Lusis, Aldons J; Vondriska, Thomas M

    2016-08-01

    Expression of a cohort of disease-associated genes, some of which are active in fetal myocardium, is considered a hallmark of transcriptional change in cardiac hypertrophy models. How this transcriptome remodeling is affected by the common genetic variation present in populations is unknown. We examined the role of genetics, as well as contributions of chromatin proteins, to regulate cardiac gene expression and heart failure susceptibility. We examined gene expression in 84 genetically distinct inbred strains of control and isoproterenol-treated mice, which exhibited varying degrees of disease. Unexpectedly, fetal gene expression was not correlated with hypertrophic phenotypes. Unbiased modeling identified 74 predictors of heart mass after isoproterenol-induced stress, but these predictors did not enrich for any cardiac pathways. However, expanded analysis of fetal genes and chromatin remodelers as groups correlated significantly with individual systemic phenotypes. Yet, cardiac transcription factors and genes shown by gain-/loss-of-function studies to contribute to hypertrophic signaling did not correlate with cardiac mass or function in disease. Because the relationship between gene expression and phenotype was strain specific, we examined genetic contribution to expression. Strikingly, strains with similar transcriptomes in the basal heart did not cluster together in the isoproterenol state, providing comprehensive evidence that there are different genetic contributors to physiological and pathological gene expression. Furthermore, the divergence in transcriptome similarity versus genetic similarity between strains is organ specific and genome-wide, suggesting chromatin is a critical buffer between genetics and gene expression.

  5. Lipid emulsion improves recovery from bupivacaine-induced cardiac arrest, but not from ropivacaine- or mepivacaine-induced cardiac arrest.

    Science.gov (United States)

    Zausig, York A; Zink, Wolfgang; Keil, Meike; Sinner, Barbara; Barwing, Juergen; Wiese, Christoph H R; Graf, Bernhard M

    2009-10-01

    Cardiac toxicity significantly correlates with the lipophilicity of local anesthetics (LAs). Recently, the infusion of lipid emulsions has been shown to be a promising approach to treat LA-induced cardiac arrest. As the postulated mechanism of action, the so-called "lipid sink" effect may depend on the lipophilicity of LAs. In this study, we investigated whether lipid effects differ with regard to the administered LAs. In the isolated rat heart, cardiac arrest was induced by administration of equipotent doses of bupivacaine, ropivacaine, and mepivacaine, respectively, followed by cardiac perfusion with or without lipid emulsion (0.25 mL x kg(-1) x min(-1)). Subsequently, the times from the start of perfusion to return of first heart activity and to recovery of heart rate and rate-pressure product (to 90% of baseline values) were assessed. In all groups, lipid infusion had no effects on the time to the return of any cardiac activity. However, recovery times of heart rate and rate-pressure product (to 90% of baseline values) were significantly shorter with the administration of lipids in bupivacaine-induced cardiac toxicity, but not in ropivacaine- or mepivacaine-induced cardiac toxicity. These data show that the effects of lipid infusion on LA-induced cardiac arrest are strongly dependent on the administered LAs itself. We conclude that lipophilicity of LAs has a marked impact on the efficacy of lipid infusions to treat cardiac arrest induced by these drugs.

  6. TBX1 Represses Vegfr2 Gene Expression and Enhances the Cardiac Fate of VEGFR2+ Cells

    Science.gov (United States)

    Lania, Gabriella; Ferrentino, Rosa; Baldini, Antonio

    2015-01-01

    The T-box transcription factor TBX1 has critical roles in maintaining proliferation and inhibiting differentiation of cardiac progenitor cells of the second heart field (SHF). Haploinsufficiency of the gene that encodes it is a cause of congenital heart disease. Here, we developed an embryonic stem (ES) cell-based model in which Tbx1 expression can be modulated by tetracycline. Using this model, we found that TBX1 down regulates the expression of VEGFR2, and we confirmed this finding in vivo during embryonic development. In addition, we found a Vegfr2 domain of expression, not previously described, in the posterior SHF and this expression is extended by loss of Tbx1. VEGFR2 has been previously described as a marker of a subpopulation of cardiac progenitors. Clonal analysis of ES-derived VEGFR2+ cells indicated that 12.5% of clones expressed three markers of cardiac lineage (cardiomyocyte, smooth muscle and endothelium). However, a pulse of Tbx1 expression was sufficient to increase the percentage to 20.8%. In addition, the percentage of clones expressing markers of multiple cardiac lineages increased from 41.6% to 79.1% after Tbx1 pulse. These results suggest that TBX1 plays a role in maintaining a progenitor state in VEGFR2+ cells. PMID:26382615

  7. 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...

  8. Improved hyponatremia after pericardial drainage in patients suffering from cardiac tamponade.

    Science.gov (United States)

    Jong, Bor-Hsin; Wei, Cheng-Chun; Shyu, Kou-Gi

    2016-06-11

    Some case reports showed unexplained hyponatremia in patients with cardiac tamponade. Reversible hyponatremia was observed in these patients who received pericardial drainage. The occurrence rate of hyponatremia in patients of cardiac tamponade is not clearly known. The objective of this study was to identify the relationship between hyponatremia, cardiac tamponade and their underlying diseases. We reviewed the clinical data of patients with cardiac tamponade and receiving pericardial drainage between January 2000 and January 2012 in our hospital. Cardiac tamponade was diagnosed by clinical presentation: hypotension, pulsus paradoxus, and increased jugular vein pressure. We used paired T test to compare the sodium change before and after pericardial drainage. Pearson's chi-square test was used to analyze the relationship of hyponatremia with malignancy and cardiac chamber compression proved by echocardiography. For the 48 patients, the mean pre-drainage sodium level was 129.1 ± 7.1 mEq/L and the mean post-drainage sodium level was 130.4 ± 5.6 mEq/L (p = 0.06). Among the 48 patients, 31 (65 %) had hyponatremia. For the 31 hyponatremia patients, the mean pre-drainage sodium level was 124.8 ± 4.9 mEq/L and the mean post drainage sodium level was 127.5 ± 4.5 mEq/L (p = 0.003). Hyponatremia was significantly associated with malignancy (p = 0.038). There was no significant change of pre-drainage and post-drainage sodium level in patients without malignancy. The post-drainage sodium level in the malignant patients significantly increased from 125.5 ± 8.0 to 129.1 ± 5.5 mEq/L (p = 0.017). The presence of hyponatremia was strongly associated with the cardiac tamponade sign (p tamponade especially for malignant pericardial effusion and for patients with cardiac chambers compression signs. Hyponatremia can be improved after pericardial effusion drainage.

  9. Cardiac lipid content is unresponsive to a physical activity training intervention in type 2 diabetic patients, despite improved ejection fraction

    Directory of Open Access Journals (Sweden)

    Leiner Tim

    2011-05-01

    Full Text Available Abstract Background Increased cardiac lipid content has been associated with diabetic cardiomyopathy. We recently showed that cardiac lipid content is reduced after 12 weeks of physical activity training in healthy overweight subjects. The beneficial effect of exercise training on cardiovascular risk is well established and the decrease in cardiac lipid content with exercise training in healthy overweight subjects was accompanied by improved ejection fraction. It is yet unclear whether diabetic patients respond similarly to physical activity training and whether a lowered lipid content in the heart is necessary for improvements in cardiac function. Here, we investigated whether exercise training is able to lower cardiac lipid content and improve cardiac function in type 2 diabetic patients. Methods Eleven overweight-to-obese male patients with type 2 diabetes mellitus (age: 58.4 ± 0.9 years, BMI: 29.9 ± 0.01 kg/m2 followed a 12-week training program (combination endurance/strength training, three sessions/week. Before and after training, maximal whole body oxygen uptake (VO2max and insulin sensitivity (by hyperinsulinemic, euglycemic clamp was determined. Systolic function was determined under resting conditions by CINE-MRI and cardiac lipid content in the septum of the heart by Proton Magnetic Resonance Spectroscopy. Results VO2max increased (from 27.1 ± 1.5 to 30.1 ± 1.6 ml/min/kg, p = 0.001 and insulin sensitivity improved upon training (insulin stimulated glucose disposal (delta Rd of glucose improved from 5.8 ± 1.9 to 10.3 ± 2.0 μmol/kg/min, p = 0.02. Left-ventricular ejection fraction improved after training (from 50.5 ± 2.0 to 55.6 ± 1.5%, p = 0.01 as well as cardiac index and cardiac output. Unexpectedly, cardiac lipid content in the septum remained unchanged (from 0.80 ± 0.22% to 0.95 ± 0.21%, p = 0.15. Conclusions Twelve weeks of progressive endurance/strength training was effective in improving VO2max, insulin sensitivity

  10. Cardiac Sarcoidosis or Giant Cell Myocarditis? On Treatment Improvement of Fulminant Myocarditis as Demonstrated by Cardiovascular Magnetic Resonance Imaging

    Directory of Open Access Journals (Sweden)

    Hari Bogabathina

    2012-01-01

    Full Text Available Giant cell myocarditis, but not cardiac sarcoidosis, is known to cause fulminant myocarditis resulting in severe heart failure. However, giant cell myocarditis and cardiac sarcoidosis are pathologically similar, and attempts at pathological differentiation between the two remain difficult. We are presenting a case of fulminant myocarditis that has pathological features suggestive of cardiac sarcoidosis, but clinically mimicking giant cell myocarditis. This patient was treated with cyclosporine and prednisone and recovered well. This case we believe challenges our current understanding of these intertwined conditions. By obtaining a sense of severity of cardiac involvement via delayed hyperenhancement of cardiac magnetic resonance imaging, we were more inclined to treat this patient as giant cell myocarditis with cyclosporine. This resulted in excellent improvement of patient’s cardiac function as shown by delayed hyperenhancement images, early perfusion images, and SSFP videos.

  11. Predicting Variabilities in Cardiac Gene Expression with a Boolean Network Incorporating Uncertainty.

    Science.gov (United States)

    Grieb, Melanie; Burkovski, Andre; Sträng, J Eric; Kraus, Johann M; Groß, Alexander; Palm, Günther; Kühl, Michael; Kestler, Hans A

    2015-01-01

    Gene interactions in cells can be represented by gene regulatory networks. A Boolean network models gene interactions according to rules where gene expression is represented by binary values (on / off or {1, 0}). In reality, however, the gene's state can have multiple values due to biological properties. Furthermore, the noisy nature of the experimental design results in uncertainty about a state of the gene. Here we present a new Boolean network paradigm to allow intermediate values on the interval [0, 1]. As in the Boolean network, fixed points or attractors of such a model correspond to biological phenotypes or states. We use our new extension of the Boolean network paradigm to model gene expression in first and second heart field lineages which are cardiac progenitor cell populations involved in early vertebrate heart development. By this we are able to predict additional biological phenotypes that the Boolean model alone is not able to identify without utilizing additional biological knowledge. The additional phenotypes predicted by the model were confirmed by published biological experiments. Furthermore, the new method predicts gene expression propensities for modelled but yet to be analyzed genes.

  12. Cell and gene therapy for arrhythmias: Repair of cardiac conduction damage

    Institute of Scientific and Technical Information of China (English)

    Yong-Fu Xiao

    2011-01-01

    Action potentials generated in the sinoatrial node(SAN)dominate the rhythm and rate of a healthy human heart.Subsequently,these action potentials propagate to the whole heart via its conduction system .Abnormalities of impulse generation and/or propagation in a heart can cause arrhythmias.For example,SAN dysfunction or conduction block of the atrioventricular node can lead to serious bradycardia which is currently treated with an implanted electronic pacemaker.On the other hand conduction damage may cause reentrant tachyarrhythmias which are primarily treated pharmacologically or by medical device-based therapies,including defibrillation and tissue ablation.However,drug therapies sometimes may not be effective or are associated with serious side effects.Device-based therapies for cardiac arrhythmias,even with well developed technology,still face inadequacies,limitations,hardware complications,and other challenges.Therefore,scientists are actively seeking other alternatives for antiarrhythmic therapy.In particular,cells and genes used for repairing cardiac conduction damage/defect have been investigated in various studies both in vitro and in vivo.Despite the complexities of the excitation and conduction systems of the heart,cell and gene-based strategies provide novel alternatives for treatment or cure of cardiac anhythmias.This review summarizes some highlights of recent research progress in this field.

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

    Directory of Open Access Journals (Sweden)

    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.

  14. Use of graphical statistical process control tools to monitor and improve outcomes in cardiac surgery.

    Science.gov (United States)

    Smith, Ian R; Garlick, Bruce; Gardner, Michael A; Brighouse, Russell D; Foster, Kelley A; Rivers, John T

    2013-02-01

    Graphical Statistical Process Control (SPC) tools have been shown to promptly identify significant variations in clinical outcomes in a range of health care settings. We explored the application of these techniques to qualitatively inform the routine cardiac surgical morbidity and mortality (M&M) review process at a single site. Baseline clinical and procedural data relating to 4774 consecutive cardiac surgical procedures, performed between the 1st January 2003 and the 30th April 2011, were retrospectively evaluated. A range of appropriate performance measures and benchmarks were developed and evaluated using a combination of CUmulative SUM (CUSUM) charts, Exponentially Weighted Moving Average (EWMA) charts and Funnel Plots. Charts have been discussed at the unit's routine M&M meetings. Risk adjustment (RA) based on EuroSCORE has been incorporated into the charts to improve performance. Discrete and aggregated measures, including Blood Product/Reoperation, major acute post-procedural complications and Length of Stay/Readmissiontools facilitate near "real-time" performance monitoring allowing early detection and intervention in altered performance. Careful interpretation of charts for group and individual operators has proven helpful in detecting and differentiating systemic vs. individual variation. Copyright © 2012 Australian and New Zealand Society of Cardiac and Thoracic Surgeons (ANZSCTS) and the Cardiac Society of Australia and New Zealand (CSANZ). Published by Elsevier B.V. All rights reserved.

  15. Exendin-4 improves cardiac function in mice overexpressing monocyte chemoattractant protein-1 in cardiomyocytes.

    Science.gov (United States)

    Younce, Craig W; Niu, Jianli; Ayala, Jennifer; Burmeister, Melissa A; Smith, Layton H; Kolattukudy, Pappachan; Ayala, Julio E

    2014-11-01

    The incretin hormone glucagon-like peptide-1 (Glp1) is cardioprotective in models of ischemia-reperfusion injury, myocardial infarction and gluco/lipotoxicity. Inflammation is a factor in these models, yet it is unknown whether Glp1 receptor (Glp1r) agonists are protective against cardiac inflammation. We tested the hypothesis that the Glp1r agonist Exendin-4 (Ex4) is cardioprotective in mice with cardiac-specific monocyte chemoattractant protein-1 overexpression. These MHC-MCP1 mice exhibit increased cardiac monocyte infiltration, endoplasmic reticulum (ER) stress, apoptosis, fibrosis and left ventricular dysfunction. Ex4 treatment for 8 weeks improved cardiac function and reduced monocyte infiltration, fibrosis and apoptosis in MHC-MCP1 mice. Ex4 enhanced expression of the ER chaperone glucose-regulated protein-78 (GRP78), decreased expression of the pro-apoptotic ER stress marker CCAAT/-enhancer-binding protein homologous protein (CHOP) and increased expression of the ER calcium regulator Sarco/Endoplasmic Reticulum Calcium ATPase-2a (SERCA2a). These findings suggest that the Glp1r is a viable target for treating cardiomyopathies associated with stimulation of pro-inflammatory factors.

  16. Chronic Intermittent Hypobaric Hypoxia Improves Cardiac Function through Inhibition of Endoplasmic Reticulum Stress.

    Science.gov (United States)

    Yuan, Fang; Zhang, Li; Li, Yan-Qing; Teng, Xu; Tian, Si-Yu; Wang, Xiao-Ran; Zhang, Yi

    2017-08-11

    We investigated the role of endoplasmic reticulum stress (ERS) in chronic intermittent hypobaric hypoxia (CIHH)-induced cardiac protection. Adult male Sprague-Dawley rats were exposed to CIHH treatment simulating 5000 m altitude for 28 days, 6 hours per day. The heart was isolated and perfused with Langendorff apparatus and subjected to 30-min ischemia followed by 60-min reperfusion. Cardiac function, infarct size, and lactate dehydrogenase (LDH) activity were assessed. Expression of ERS molecular chaperones (GRP78, CHOP and caspase-12) was assayed by western blot analysis. CIHH treatment improved the recovery of left ventricular function and decreased cardiac infarct size and activity of LDH after I/R compared to control rats. Furthermore, CIHH treatment inhibited over-expression of ERS-related factors including GRP78, CHOP and caspase-12. CIHH-induced cardioprotection and inhibition of ERS were eliminated by application of dithiothreitol, an ERS inducer, and chelerythrine, a protein kinase C (PKC) inhibitor. In conclusion CIHH treatment exerts cardiac protection against I/R injury through inhibition of ERS via PKC signaling pathway.

  17. Cardiomyocyte-specific expression of lamin a improves cardiac function in Lmna-/- mice.

    Directory of Open Access Journals (Sweden)

    Richard L Frock

    Full Text Available Lmna(-/- mice display multiple tissue defects and die by 6-8 weeks of age reportedly from dilated cardiomyopathy with associated conduction defects. We sought to determine whether restoration of lamin A in cardiomyocytes improves cardiac function and extends the survival of Lmna(-/- mice. We observed increased total desmin protein levels and disorganization of the cytoplasmic desmin network in ~20% of Lmna(-/- ventricular myocytes, rescued in a cell-autonomous manner in Lmna(-/- mice expressing a cardiac-specific lamin A transgene (Lmna(-/-; Tg. Lmna(-/-; Tg mice displayed significantly increased contractility and preservation of myocardial performance compared to Lmna(-/- mice. Lmna(-/-; Tg mice attenuated ERK1/2 phosphorylation relative to Lmna(-/- mice, potentially underlying the improved localization of connexin43 to the intercalated disc. Electrocardiographic recordings from Lmna(-/- mice revealed arrhythmic events and increased frequency of PR interval prolongation, which is partially rescued in Lmna(-/-; Tg mice. These findings support our observation that Lmna(-/-; Tg mice have a 12% median extension in lifespan compared to Lmna(-/- mice. While significant, Lmna(-/-; Tg mice only have modest improvement in cardiac function and survival likely stemming from the observation that only 40% of Lmna(-/-; Tg cardiomyocytes have detectable lamin A expression. Cardiomyocyte-specific restoration of lamin A in Lmna(-/- mice improves heart-specific pathology and extends lifespan, demonstrating that the cardiac pathology of Lmna(-/- mice limits survival. The expression of lamin A is sufficient to rescue certain cellular defects associated with loss of A-type lamins in cardiomyocytes in a cell-autonomous fashion.

  18. Does Glucagon Improve Survival in a Porcine (Sus Scrofa) of Adult Asphyxial Cardiac Arrest in Addition to Standard Epinephrine Therapy?

    Science.gov (United States)

    2012-01-17

    UDIIILI: oa. I..UN I ItA!.. I NUMDI:It Does Glucagon improve survival in a porcine (Sus Scrofa ) of adult asphyxial cardiac arrest in addition to...EXPIRATION DATE: 25 Mar 13 PROTOCOL TITLE: Does Glucagon Improve Survival in a Porcine (Sus scrofa ) Model of Adult Asphyxial Cardiac Arrest in Addition...Additions: Deletions: 2 Protocol No: A-2007-03 Protocol Title: Does Glucagon Improve Survival in a Porcine (Sus scrofa ) Model of Adult Asphyxial

  19. Evening primrose oil ameliorates platelet aggregation and improves cardiac recovery in myocardial-infarct hypercholesterolemic rats.

    Science.gov (United States)

    Abo-Gresha, Noha M; Abel-Aziz, Eman Z; Greish, Sahar M

    2014-01-01

    Omega-6 polyunsaturated fatty acids (n-6 PUFA) are well known for their role in cardiovascular disease (CVD). We proposed that Evening prime rose oil (EPO) can improve the outcome of a heart with myocardial infarction (MI) in the presence of diet-induced hyperaggregability. This study was designed to examine its cholesterol lowering, antithrombotic and anti-inflammatory effects. High fat diet was administered for 4 weeks then MI was induced by isoproterenol (85 mg/kg/s.c./24 h). Treatment with EPO (5 or 10 gm/kg/day) for 6 weeks improved the electrocardiographic pattern, serum lipid profile, cardiac biomarkers as well as Platelet aggregation percent. We reported decreased serum level of TNF-α, IL-6 and COX-2 with attenuation of TNF-α and TGF-β in the cardiac homogenate. Moreover, histopathology revealed marked amelioration. Finally, we provide evidence that EPO improve cardiac recovery in hypercholesterolemic myocardial infarct rats. These effects are attributed to direct hypocholesterolemic effect and indirect effect on the synthesis of eicosanoids (prostaglandins, cytokines).

  20. Anti-tachycardia therapy can improve altered cardiac adrenergic function in tachycardia-induced cardiomyopathy

    Energy Technology Data Exchange (ETDEWEB)

    Ohkusu, Yasuo; Takahashi, Nobukazu; Ishikawa, Toshiyuki [Yokohama City Univ. (Japan). School of Medicine] [and others

    2002-11-01

    We investigated whether anti-tachycardia therapy might improve the altered cardiac adrenergic and systolic function in tachycardia-induced cardiomyopathy (TC) in contrast to dilated cardiomyopathy (DCM). The subjects were 23 patients with heart failure, consisting of 8 patients with TC (43.6{+-}10.0 yrs) and 15 with DCM (45.3{+-}8.2 yrs). TC was determined as impairment of left ventricular function secondary to chronic or very frequent arrhythmia during more than 10% of the day. All patients were receiving anti-tachycardia treatment. Cardiac {sup 123}I-MIBG uptake was assessed as the heart/mediastinum activity ratio (H/M) before and after treatment. Left ventricular ejection fraction (LVEF) was also assessed. In the baseline study, H/M and LVEF showed no difference between TC and DCM (2.21{+-}0.44 vs. 2.10{+-}0.42, 35.3{+-}13.1 vs. 36.0{+-}10.9%, respectively). After treatment, the degree of change in H/M and LVEF differed significantly (0.41{+-}0.34 vs. 0.08{+-}0.20, 20.5{+-}14.4 vs. -2.1{+-}9.6%, p<0.01). In TC, heart failure improved after a shorter duration of treatment (p<0.05). In conclusion, anti-tachycardia therapy can improve altered cardiac adrenergic function and systolic function in patients with TC over a shorter period than in those with DCM. (author)

  1. Remote Postconditioning Alone and Combined with Hypothermia Improved Postresuscitation Cardiac and Neurological Outcomes in Swine.

    Science.gov (United States)

    Xu, Jiefeng; Huang, Zeng; Ye, Sen; Wang, Moli; Fang, Ya; Li, Zilong

    2016-01-01

    Objective. Previously, we demonstrated that remote ischemic postconditioning (RIpostC) improved postresuscitation myocardial and cerebral functions in rat. Here, we investigated the effects of RIpostC alone and combined with therapeutic hypothermia (TH) on cardiac and neurological outcomes after CPR in swine. Methods. Twenty-one pigs were subjected to 10 mins of VF and then 5 mins of CPR. The animals were randomized to receive RIpostC alone, or its combination with TH, or sham control. RIpostC was induced by 4 cycles of limb ischemia followed by reperfusion. TH was implemented by surface cooling to reach a temperature of 32-34°C. Results. During 72 hrs after resuscitation, lower level of cardiac troponin I and greater stroke volume and global ejection fraction were observed in animals that received RIpostC when compared to the control. RIpostC also decreased serum levels of neuron-specific enolase and S100B and increased neurologic alertness score after resuscitation. The combination of RIpostC and TH resulted in greater improvement in cardiac and neurological outcomes than RIpostC alone. Conclusion. RIpostC was conducive to improving postresuscitation myocardial and cerebral functions and reducing their organ injuries. Its combination with TH further enhanced its protective effects.

  2. Remote Postconditioning Alone and Combined with Hypothermia Improved Postresuscitation Cardiac and Neurological Outcomes in Swine

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    Jiefeng Xu

    2016-01-01

    Full Text Available Objective. Previously, we demonstrated that remote ischemic postconditioning (RIpostC improved postresuscitation myocardial and cerebral functions in rat. Here, we investigated the effects of RIpostC alone and combined with therapeutic hypothermia (TH on cardiac and neurological outcomes after CPR in swine. Methods. Twenty-one pigs were subjected to 10 mins of VF and then 5 mins of CPR. The animals were randomized to receive RIpostC alone, or its combination with TH, or sham control. RIpostC was induced by 4 cycles of limb ischemia followed by reperfusion. TH was implemented by surface cooling to reach a temperature of 32–34°C. Results. During 72 hrs after resuscitation, lower level of cardiac troponin I and greater stroke volume and global ejection fraction were observed in animals that received RIpostC when compared to the control. RIpostC also decreased serum levels of neuron-specific enolase and S100B and increased neurologic alertness score after resuscitation. The combination of RIpostC and TH resulted in greater improvement in cardiac and neurological outcomes than RIpostC alone. Conclusion. RIpostC was conducive to improving postresuscitation myocardial and cerebral functions and reducing their organ injuries. Its combination with TH further enhanced its protective effects.

  3. Hydroxocobalamin and epinephrine both improve survival in a swine model of cyanide-induced cardiac arrest.

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    Bebarta, Vikhyat S; Pitotti, Rebecca L; Dixon, Patricia S; Valtier, Sandra; Esquivel, Luis; Bush, Anneke; Little, Charles M

    2012-10-01

    To determine whether hydroxocobalamin will improve survival compared with epinephrine and saline solution controls in a model of cyanide-induced cardiac arrest. Forty-five swine (38 to 42 kg) were tracheally intubated, anesthetized, and central venous and arterial continuous cardiovascular monitoring catheters were inserted. Potassium cyanide was infused until cardiac arrest developed, defined as mean arterial pressure less than 30 mm Hg. Animals were treated with standardized mechanical chest compressions and were randomly assigned to receive one of 3 intravenous bolus therapies: hydroxocobalamin, epinephrine, or saline solution (control). All animals were monitored for 60 minutes after cardiac arrest. Additional epinephrine infusions were used in all arms of the study after return of spontaneous circulation for systolic blood pressure less than 90 mm Hg. A sample size of 15 animals per group was determined according to a power of 80%, a survival difference of 0.5, and an α of 0.05. Repeated-measure ANOVA was used to determine statistically significant changes between groups over time. Baseline weight, time to arrest, and cyanide dose at cardiac arrest were similar in the 3 groups. Coronary perfusion pressures with chest compressions were greater than 15 mm Hg in both treatment groups indicating sufficient compression depth. Zero of 15 (95% confidence interval [CI] 0% to 25%) animals in the control group, 11 of 15 (73%; 95% CI 48% to 90%) in the hydroxocobalamin group, and 11 of 15 (73%; 95% CI 48% to 90%) in the epinephrine group survived to the conclusion of the study (Pcyanide levels in the hydroxocobalamin group were also lower than that of the epinephrine group from cardiac arrest through the conclusion of the study. Intravenous hydroxocobalamin and epinephrine both independently improved survival compared with saline solution control in our swine model of cyanide-induced cardiac arrest. Hydroxocobalamin improved mean arterial pressure and pH, decreased

  4. Targeting the Innate Immune Response to Improve Cardiac Graft Recovery after Heart Transplantation: Implications for the Donation after Cardiac Death

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    Stefano Toldo

    2016-06-01

    Full Text Available Heart transplantation (HTx is the ultimate treatment for end-stage heart failure. The number of patients on waiting lists for heart transplants, however, is much higher than the number of available organs. The shortage of donor hearts is a serious concern since the population affected by heart failure is constantly increasing. Furthermore, the long-term success of HTx poses some challenges despite the improvement in the management of the short-term complications and in the methods to limit graft rejection. Myocardial injury occurs during transplantation. Injury initiated in the donor as result of brain or cardiac death is exacerbated by organ procurement and storage, and is ultimately amplified by reperfusion injury at the time of transplantation. The innate immune system is a mechanism of first-line defense against pathogens and cell injury. Innate immunity is activated during myocardial injury and produces deleterious effects on the heart structure and function. Here, we briefly discuss the role of the innate immunity in the initiation of myocardial injury, with particular focus on the Toll-like receptors and inflammasome, and how to potentially expand the donor population by targeting the innate immune response.

  5. Improved Cuff Technique for Establishing a Mouse-Rat Heterotopic Cardiac Xenotransplantation Model.

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    Li, C; Qi, F; Liu, T; Wang, H; Wang, P-Z

    2015-01-01

    The small animal model of cardiac transplantation is the most common model in organ transplantation studies. The cervical heterotopic transplantation is widely performed because this allows for direct observation of the graft heartbeat and contributes to early prediction of graft rejection. A mouse-rat cervical heterotopic cardiac xenotransplantation model was modified with respect to the anesthesia method, cardiac graft harvesting method, and perioperative treatment. These improvements ensure the stability and reliability of xenotransplantation models for in vivo studies of immune-mediated graft rejection. After establishing isoflurane inhalation anesthesia, the donors' hearts were harvested. The experimental method involved separate ligation of the left and right superior venae cavae; the other blood vessels were ligated in a cluster. Both the donor and recipient animals were placed on a heating pad intraoperatively to maintain a body temperature of 37-40 °C. The model establishment was divided into 3 stages: practice, stabilization, and stereotyping. The surgical success rate and operation time were recorded. Specimens were harvested at different time points for histopathological examination. The anesthetic effect of isoflurane was well maintained, and no animals died of adverse anesthetic events. Body temperature was maintained at 37-40 °C which effectively shortened the time to restoration. The modification of the cardiac graft harvesting method is conducive to rebeating of the donor heart. The success rates in the stabilization and stereotyping stages were significantly higher than that in the practice stage (P rat cervical heterotopic cardiac xenotransplantation model is the ideal animal model for studying xenograft rejection. Copyright © 2015 Elsevier Inc. All rights reserved.

  6. Cardiac gene activation analysis in mammalian non-myoblasic cells by Nkx2-5, Tbx5, Gata4 and Myocd.

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    Lei Zhou

    Full Text Available Cardiac transcription factors are master regulators during heart development. Some were shown to transdifferentiate tail tip and cardiac fibroblasts into cardiomyocytes. However, recent studies have showed that controversies exist. Potential difference in tail tip and cardiac fibroblast isolation may possibly confound the observations. Moreover, due to the use of a cardiac reporter (Myh6 selection strategy for induced cardiomyocyte enrichment, and the lack of tracking signals for each transcription factors, individual roles of each transcription factors in activating cardiac gene expression in mammalian non-myoblastic cells have never been elucidated. Answers to these questions are an important step toward cardiomyocyte regeneration. Because mouse 10T1/2 fibroblasts are non-myoblastic in nature and can be induced to express genes of all three types of muscle cells, they are an ideal model for the analysis of cardiac and non-cardiac gene activation after induction. We constructed bi-cistronic lentiviral vectors, capable of expressing cardiac transcription factors along with different fluorescent tracking signals. By infecting 10T1/2 fibroblasts with Nkx2-5, Tbx5, Gata4 or Myocd cardiac transcription factor lentivirus alone or different combinations, we found that only Tbx5+Myocd and Tbx5+Gata4+Myocd combinations induced Myh6 and Tnnt2 cardiac marker protein expression. Microarray-based gene ontology analysis revealed that Tbx5 alone activated genes involved in the Wnt receptor signaling pathway and inhibited genes involved in a number of cardiac-related processes. Myocd alone activated genes involved in a number of cardiac-related processes and inhibited genes involved in the Wnt receptor signaling pathway and non-cardiac processes. Gata4 alone inhibited genes involved in non-cardiac processes. Tbx5+Gata4+Myocd was the most effective activator of genes associated with cardiac-related processes. Unlike Tbx5, Gata4, Myocd alone or Tbx5+Myocd, Tbx5

  7. Effect of transverse aortic constriction on cardiac structure, function and gene expression in pregnant rats.

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    Nils Thomas Songstad

    Full Text Available BACKGROUND: There is an increased risk of heart failure and pulmonary edema in pregnancies complicated by hypertensive disorders. However, in a previous study we found that pregnancy protects against fibrosis and preserves angiogenesis in a rat model of angiotensin II induced cardiac hypertrophy. In this study we test the hypothesis that pregnancy protects against negative effects of increased afterload. METHODS: Pregnant (gestational day 5.5-8.5 and non-pregnant Wistar rats were randomized to transverse aortic constriction (TAC or sham surgery. After 14.2 ± 0.14 days echocardiography was performed. Aortic blood pressure and left ventricular (LV pressure-volume loops were obtained using a conductance catheter. LV collagen content and cardiomyocyte circumference were measured. Myocardial gene expression was assessed by real-time polymerase chain reaction. RESULTS: Heart weight was increased by TAC (p<0.001 but not by pregnancy. Cardiac myocyte circumference was larger in pregnant compared to non-pregnant rats independent of TAC (p = 0.01, however TAC per se did not affect this parameter. Collagen content in LV myocardium was not affected by pregnancy or TAC. TAC increased stroke work more in pregnant rats (34.1 ± 2.4 vs 17.5 ± 2.4 mmHg/mL, p<0.001 than in non-pregnant (28.2 ± 1.7 vs 20.9 ± 1.5 mmHg/mL, p = 0.06. However, it did not lead to overt heart failure in any group. In pregnant rats, α-MHC gene expression was reduced by TAC. Increased in the expression of β-MHC gene was higher in pregnant (5-fold compared to non-pregnant rats (2-fold after TAC (p = 0.001. Nine out of the 19 genes related to cardiac remodeling were affected by pregnancy independent of TAC. CONCLUSIONS: This study did not support the hypothesis that pregnancy is cardioprotective against the negative effects of increased afterload. Some differences in cardiac structure, function and gene expression between pregnant and non-pregnant rats following TAC indicated that

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

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    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.

  9. Treatment with hESC-Derived Myocardial Precursors Improves Cardiac Function after a Myocardial Infarction.

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    Jianqin Ye

    Full Text Available We previously reported the generation of a reporter line of human embryonic stem cells (hESCs with enhanced green fluorescent protein (eGFP expression driven by the α-myosin heavy chain (αMHC promoter. The GFP+/αMHC+ cells derived from this cell line behave as multipotent, human myocardial precursors (hMPs in vitro. In this study, we evaluated the therapeutic effects of GFP+/αMHC+ cells isolated from the reporter line in a mouse model of myocardial infarction (MI.MI was generated in immunodeficient mice. hMPs were injected into murine infarcted hearts under ultrasound guidance at 3 days post-MI. Human fetal skin fibroblasts (hFFs were injected as control. Cardiac function was evaluated by echocardiography. Infarct size, angiogenesis, apoptosis, cell fate, and teratoma formation were analyzed by immunohistochemical staining.Compared with control, hMPs resulted in improvement of cardiac function post-MI with smaller infarct size, induced endogenous angiogenesis, and reduced apoptosis of host cardiomyocytes at the peri-infarct zone at 28 days post-MI.Intramyocardial injection of hMPs improved cardiac function post-MI. The engraftment rate of these cells in the myocardium post-MI was low, suggesting that the majority of effect occurs via paracrine mechanisms.

  10. Localized Delivery of Mechano-Growth Factor E-domain Peptide via Polymeric Microstructures Improves Cardiac Function following Myocardial Infarction

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    Peña, James R.; Pinney, James; Ayala, Perla; Desai, Tejal; Goldspink, Paul H.

    2015-01-01

    The Insulin like growth factor-I isoform mechano-growth factor (MGF), is expressed in the heart following myocardial infarction and encodes a unique E-domain region. To examine E-domain function, we delivered a synthetic peptide corresponding to the unique E-domain region of the human MGF (IGF-1Ec) via peptide eluting polymeric microstructures to the heart. The microstructures were made of poly (ethylene glycol) dimethacrylate hydrogel and bioengineered to be the same size as an adult cardiac myocyte (100×15×15 μm) and with a stiffness of 20 kPa. Peptide eluting microrods and empty microrods were delivered via intramuscular injection following coronary artery ligation in mice. To examine the physiologic consequences, we assessed the impact of peptide delivery on cardiac function and cardiovascular hemodynamics using pressure-volume loops and gene expression by quantitative RT-PCR. A significant decline in both systolic and diastolic function accompanied by pathologic hypertrophy occurred by 2 weeks which decompensated further by 10 weeks post-infarct in the untreated groups. Delivery of the E-domain peptide eluting microrods decreased mortality, ameliorated the decline in hemodynamics, and delayed decompensation. This was associated with the inhibition of pathologic hypertrophy despite increasing vascular impedance. Delivery of the empty microrods had limited effects on hemodynamics and while pathologic hypertrophy persisted there was a decrease in ventricular stiffness. Our data show that cardiac restricted administration of the MGF E-domain peptide using polymeric microstructures may be used to prevent adverse remodeling of the heart and improve function following myocardial infarction. PMID:25678113

  11. Waon therapy improves quality of life as well as cardiac function and exercise capacity in patients with chronic heart failure.

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    Sobajima, Mitsuo; Nozawa, Takashi; Fukui, Yasutaka; Ihori, Hiroyuki; Ohori, Takashi; Fujii, Nozomu; Inoue, Hiroshi

    2015-01-01

    Waon therapy (WT), which in Japanese means soothing warmth, is a repeated sauna therapy that improves cardiac and vascular endothelial function in patients with chronic heart failure (CHF). We investigated whether WT could improve the quality of life (QOL) of CHF patients in addition to improving cardiac function and exercise capacity.A total of 49 CHF patients (69 ± 14 years old) were treated with a 60°C far infrared-ray dry sauna bath for 15 minutes and then kept in a bed covered with blankets for 30 minutes once a day for 3 weeks. At baseline and 3 weeks after starting WT, cardiac function, 6-minute walk distance (6MWD), flow mediated dilation (FMD) of the brachial artery, and SF36-QOL scores were determined.WT significantly improved left ventricular ejection fraction (LVEF), B-type natriuretic peptide (BNP), 6MWD, and FMD (3.6 ± 2.3 to 5.1 ± 2.8%, P improved not only the physical (PC) but also mental component (MC) of the QOL scores. WT-induced improvement of PC was negatively correlated with changes in BNP (r = -0.327, P improvement was not related directly to changes in BNP, LVEF, or 6MWD. WT-induced changes in MC were not parallel to PC improvement.WT improved QOL as well as cardiac function and exercise capacity in patients with CHF. Mental QOL improved independently of WT-induced improvement of cardiac function and exercise capacity.

  12. Altered activities of transcription factors and their related gene expression in cardiac tissues of diabetic rats.

    Science.gov (United States)

    Nishio, Y; Kashiwagi, A; Taki, H; Shinozaki, K; Maeno, Y; Kojima, H; Maegawa, H; Haneda, M; Hidaka, H; Yasuda, H; Horiike, K; Kikkawa, R

    1998-08-01

    Gene regulation in the cardiovascular tissues of diabetic subjects has been reported to be altered. To examine abnormal activities in transcription factors as a possible cause of this altered gene regulation, we studied the activity of two redox-sensitive transcription factors--nuclear factor-kappaB (NF-kappaB) and activating protein-1 (AP-1)--and the change in the mRNA content of heme oxygenase-1, which is regulated by these transcription factors in the cardiac tissues of rats with streptozotocin-induced diabetes. Increased activity of NF-kappaB and AP-1 but not nuclear transcription-activating factor, as determined by an electrophoretic mobility shift assay, was found in the hearts of 4-week diabetic rats. Glycemic control by a subcutaneous injection of insulin prevented these diabetes-induced changes in transcription factor activity. In accordance with these changes, the mRNA content of heme oxygenase-1 was increased fourfold in 4-week diabetic rats and threefold in 24-week diabetic rats as compared with control rats (P oxidative stress is involved in the activation of the transcription factors NF-kappaB and AP-1 in the cardiac tissues of diabetic rats, and that these abnormal activities of transcription factors could be associated with the altered gene regulation observed in the cardiovascular tissues of diabetic rats.

  13. Cardiac Characteristics of Transgenic Mice Overexpressing Refsum Disease Gene-Associated Protein within the Heart.

    Science.gov (United States)

    Koh, J T; Choi, H H; Ahn, K Y; Kim, J U; Kim, J H; Chun, J Y; Baik, Y H; Kim, K K

    2001-09-01

    Arrhythmia is a common cardiac symptom of Refsum disease. Recently, we identified a novel neuron-specific PAHX-associated protein (PAHX-AP1), which binds to the Refsum disease gene (PAHX). In this report, we developed heart-targeted transgenic (TG) mice under the control of alpha-myosin heavy chain promoter to determine whether cardiac overexpression of PAHX-AP1 provokes cardiac involvement symptoms. Northern and in situ hybridization analyses revealed PAHX-AP1 transcript was overexpressed in TG atrium, especially in the sinoatrial node. TG mice showed tachycardia, and tachyarrhythmia was observed in 20% of TG mice. Isolated TG atria showed higher frequency beating and were more sensitive to aconitine-induced tachyarrhythmia than the wild-type, and 40% of the TG atria showed irregular beating. Action potential duration in TG atrial fiber was shortened much more than the wild-type. Systemic administration of arrhythmogenic agents induced arrhythmia in TG mice, while no arrhythmia with the same dose in nonTG mice. Our results indicate that the chronic atrial tachycardia by overexpressed neuron-specific PAHX-AP1 transgene in atrium may be responsible for the increased susceptibility to arrhythmia.

  14. Toward improved myocardial maturity in an organ-on-chip platform with immature cardiac myocytes.

    Science.gov (United States)

    Sheehy, Sean P; Grosberg, Anna; Qin, Pu; Behm, David J; Ferrier, John P; Eagleson, Mackenzie A; Nesmith, Alexander P; Krull, David; Falls, James G; Campbell, Patrick H; McCain, Megan L; Willette, Robert N; Hu, Erding; Parker, Kevin K

    2017-01-01

    In vitro studies of cardiac physiology and drug response have traditionally been performed on individual isolated cardiomyocytes or isotropic monolayers of cells that may not mimic desired physiological traits of the laminar adult myocardium. Recent studies have reported a number of advances to Heart-on-a-Chip platforms for the fabrication of more sophisticated engineered myocardium, but cardiomyocyte immaturity remains a challenge. In the anisotropic musculature of the heart, interactions between cardiac myocytes, the extracellular matrix (ECM), and neighboring cells give rise to changes in cell shape and tissue architecture that have been implicated in both development and disease. We hypothesized that engineered myocardium fabricated from cardiac myocytes cultured in vitro could mimic the physiological characteristics and gene expression profile of adult heart muscle. To test this hypothesis, we fabricated engineered myocardium comprised of neonatal rat ventricular myocytes with laminar architectures reminiscent of that observed in the mature heart and compared their sarcomere organization, contractile performance characteristics, and cardiac gene expression profile to that of isolated adult rat ventricular muscle strips. We found that anisotropic engineered myocardium demonstrated a similar degree of global sarcomere alignment, contractile stress output, and inotropic concentration-response to the β-adrenergic agonist isoproterenol. Moreover, the anisotropic engineered myocardium exhibited comparable myofibril related gene expression to muscle strips isolated from adult rat ventricular tissue. These results suggest that tissue architecture serves an important developmental cue for building in vitro model systems of the myocardium that could potentially recapitulate the physiological characteristics of the adult heart. Impact statement With the recent focus on developing in vitro Organ-on-Chip platforms that recapitulate tissue and organ-level physiology

  15. Gene Regulation, Alternative Splicing, and Posttranslational Modification of Troponin Subunits in Cardiac Development and Adaptation: A Focused Review

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    Juan-Juan eSheng

    2014-04-01

    Full Text Available 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.

  16. 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.

  17. Investigation of the relationship between regression of hypertensive cardiac hypertrophy and improvement of cardiac sympathetic nervous dysfunction using iodine-123 metaiodobenzylguanidine myocardial imaging

    Energy Technology Data Exchange (ETDEWEB)

    Morimoto, Satoshi [Dept. of Internal Medicine, Murakami Memorial Hospital, Asahi Univ., Gifu (Japan); Terada, Koji [Dept. of Internal Medicine, Murakami Memorial Hospital, Asahi Univ., Gifu (Japan); Keira, Natsuya [Dept. of Internal Medicine, Murakami Memorial Hospital, Asahi Univ., Gifu (Japan); Satoda, Masahiko [Dept. of Internal Medicine, Murakami Memorial Hospital, Asahi Univ., Gifu (Japan); Inoue, Keiji [Dept. of Internal Medicine, Murakami Memorial Hospital, Asahi Univ., Gifu (Japan); Tatsukawa, Hirotaka [Dept. of Internal Medicine, Murakami Memorial Hospital, Asahi Univ., Gifu (Japan); Katoh, Shuji [Dept. of Internal Medicine, Murakami Memorial Hospital, Asahi Univ., Gifu (Japan); Ida, Kazunori [Dept. of Internal Medicine, Murakami Memorial Hospital, Asahi Univ., Gifu (Japan); Sugihara, Hiroki [Dept. of Radiology, Kyoto Prefectural Univ. of Medicine (Japan); Takeda, Kazuo [Second Dept. of Medicine, Kyoto Prefectural Univ. of Medicine (Japan); Nakagawa, Masao [Second Dept. of Medicine, Kyoto Prefectural Univ. of Medicine (Japan)

    1996-07-01

    Although many theories exist on the subject, the mechanisms responsible for a reduction of hypertensive cardiac hypertrophy in response to antihypertensive therapy are still unclear. In order to investigate the relationship between regression of hypertensive cardiac hypertrophy and cardiac nervous function, we studied ten patients with untreated essential hypertension (six men and four women, 62{+-}12 years old). Both echocardiography and iodine-123 metaiodobenzylguanidine (MIBG) myocardial imaging were performed before and after antihypertensive therapy. Left ventricular mass (LVM) was significantly reduced in conjunction with the reduction of blood pressure following treatment. MIBG myocardial images showed that the heart-to-mediastinum activity ratio (H/M) was significantly increased while the washout ratio was significantly decreased. Patients were divided into two groups according to the ratio of the LVM values before and after therapy (LVM ratio). Patients with an LVM ratio of less than 0.75 were classified as group A and those with values higher than 0.75 as group B. Neither the change in blood pressure nor the length of treatment was significantly different between these two groups. On the other hand, both the increase in H/M and the decrease in the washout ratio were significantly greater in group A than in group B. These results indicate that an improvement in cardiac sympathetic nervous function may be related to the regression of hypertensive cardiac hypertrophy. Increasing the subject base in these studies and a more precise analysis of the relevance of the data obtained from MIBG myocardial images are recommended to clarify how changes in cardiac sympathetic nervous function relate to the regression of hypertensive cardiac hypertrophy. (orig.)

  18. Cardiac function improved by sarcoplasmic reticulum Ca2+-ATPase overexpression in a heart failure model induced by chronic myocardial ischemia

    Directory of Open Access Journals (Sweden)

    Wei XIN

    2011-04-01

    Full Text Available Objective Chronic myocardial ischemia(CMI has become an important cause of heart failure(HF.The aim of present study was to examine the effects of Sarco-endoplasmic reticulum calcium ATPase(SERCA2a gene transfer in HF model in large animal induced by CMI.Methods HF was reproduced in minipigs by ligating the initial segment of proximal left anterior descending(LAD coronary artery with an ameroid constrictor to produce progressive vessel occlusion and ischemia.After confirmation of myocardial perfusion defect and cardiac function impairment by SPECT and echocardiography in the model,animals were divided into 4 groups: HF group;HF+enhanced green fluorescent protein(EGFP group;HF+SERCA2a group;and sham operation group as control.rAAV1-EGFP and rAAV1-SERCA2a(1×1012 vg for each animal were directly and intramyocardially injected to the animals of HF+EGFP and HF+SERCA2a groups.Sixty days after the gene transfer,the expression of SERCA2a at the protein level was examined by Western blotting and immunohistochemistry,the changes in cardiac function were determined by echocardiographic and hemodynamic analysis,and the changes in serum inflammatory and neuro-hormonal factors(including BNP,TNF-a,IL-6,ET-1 and Ang II were determined by radioimmunoassay.Results Sixty days after gene transfer,LVEF,Ev/Av and ±dp/dtmax increased significantly(P < 0.05,along with an increase of SERCA2a protein expression in the ischemic myocardium(PP < 0.05,accompanied by a significant decrease of inflammatory and neural-hormonal factors(PP < 0.05 in HF+SERCA2a group as compared with HF/HF+EGFP group.Conclusions Overexpression of SERCA2a may significantly improve the cardiac function of the ischemic myocardium of HF model induced by CMI and reverse the activation of neural-hormonal factors,implying that it has a potential therapeutic significance in CMI related heart failure.

  19. Influences of the G2350A polymorphism in the ACE Gene on cardiac structure and function of ball game players

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    Jang Yongwoo

    2012-01-01

    Full Text Available Abstract Background Except for the I/D polymorphism in the angiotensin I-converting enzyme (ACE gene, there were few reports about the relationship between other genetic polymorphisms in this gene and the changes in cardiac structure and function of athletes. Thus, we investigated whether the G2350A polymorphism in the ACE gene is associated with the changes in cardiac structure and function of ball game players. Total 85 healthy ball game players were recruited in this study, and they were composed of 35 controls and 50 ball game players, respectively. Cardiac structure and function were measured by 2-D echocardiography, and the G2350A polymorphism in the ACE gene analyzed by the SNaPshot method. Results There were significant differences in left ventricular mass index (LVmassI value among each sporting discipline studied. Especially in the athletes of basketball disciplines, indicated the highest LVmassI value than those of other sporting disciplines studied (p ACE gene in the both controls and ball game players. Conclusions Our data suggests that the G2350A polymorphism in the ACE gene may not significantly contribute to the changes in cardiac structure and function of ball game players, although sporting disciplines of ball game players may influence the changes in LVmassI value of these athletes. Further studies using a larger sample size and other genetic markers in the ACE gene will be needed.

  20. Modified criteria for the systemic inflammatory response syndrome improves their utility following cardiac surgery.

    Science.gov (United States)

    MacCallum, Niall S; Finney, Simon J; Gordon, Sarah E; Quinlan, Gregory J; Evans, Timothy W

    2014-06-01

    Debate remains regarding whether the systemic inflammatory response syndrome (SIRS) identifies patients with clinically important inflammation. Defining criteria may be disproportionately sensitive and lack specificity. We investigated the incidence and evolution of SIRS in a homogenous population (following cardiac surgery) over 7 days to establish the relationship between SIRS and outcome, modeling alternative permutations of the criteria to increase their discriminatory power for mortality, length of stay, and organ dysfunction. We conducted a retrospective analysis of prospectively collected data from a cardiothoracic ICU. Consecutive patients requiring ICU admission for the first time after cardiac surgery (N = 2,764) admitted over a 41-month period were studied. Concurrently, 96.2% of patients met the standard two criterion definition for SIRS within 24 h of ICU admission. Their mortality was 2.78%. By contrast, three or four criteria were more discriminatory of patients with higher mortality (4.21% and 10.2%, respectively). A test dataset suggested that meeting two criteria for at least 6 consecutive h may be the best model. This had a positive and negative predictive value of 7% and 99.5%, respectively, in a validation dataset. It performed well at predicting organ dysfunction and prolonged ICU admission. The concept of SIRS remains valid following cardiac surgery. With suitable modification, its specificity can be improved significantly. We propose that meeting two or more defining criteria for 6 h could be used to define better populations with more difficult clinical courses following cardiac surgery. This group may merit a different clinical approach.

  1. 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.

  2. Effects of insulin replacements, inhibitors of angiotensin, and PKCbeta's actions to normalize cardiac gene expression and fuel metabolism in diabetic rats.

    Science.gov (United States)

    Arikawa, Emi; Ma, Ronald C W; Isshiki, Keiji; Luptak, Ivan; He, Zhiheng; Yasuda, Yutaka; Maeno, Yasuhiro; Patti, Mary Elizabeth; Weir, Gordon C; Harris, Robert A; Zammit, Victor A; Tian, Rong; King, George L

    2007-05-01

    High-density oligonucleotide arrays were used to compare gene expression of rat hearts from control, untreated diabetic, and diabetic groups treated with islet cell transplantation (ICT), protein kinase C (PKC)beta inhibitor ruboxistaurin, or ACE inhibitor captopril. Among the 376 genes that were differentially expressed between untreated diabetic and control hearts included key metabolic enzymes that account for the decreased glucose and increased free fatty acid utilization in the diabetic heart. ICT or insulin replacements reversed these gene changes with normalization of hyperglycemia, dyslipidemia, and cardiac PKC activation in diabetic rats. Surprisingly, both ruboxistaurin and ACE inhibitors improved the metabolic gene profile (confirmed by real-time RT-PCR and protein analysis) and ameliorated PKC activity in diabetic hearts without altering circulating metabolites. Functional assessments using Langendorff preparations and (13)C nuclear magnetic resonance spectroscopy showed a 36% decrease in glucose utilization and an impairment in diastolic function in diabetic rat hearts, which were normalized by all three treatments. In cardiomyocytes, PKC inhibition attenuated fatty acid-induced increases in the metabolic genes PDK4 and UCP3 and also prevented fatty acid-mediated inhibition of basal and insulin-stimulated glucose oxidation. Thus, PKCbeta or ACE inhibitors may ameliorate cardiac metabolism and function in diabetes partly by normalization of fuel metabolic gene expression directly in the myocardium.

  3. Cardiac characterization of 16 patients with large NF1 gene deletions.

    Science.gov (United States)

    Nguyen, R; Mir, T S; Kluwe, L; Jett, K; Kentsch, M; Mueller, G; Kehrer-Sawatzki, H; Friedman, J M; Mautner, V-F

    2013-10-01

    The aim of this study was to characterize cardiac features of patients with neurofibromatosis 1 (NF1) and large deletions of the NF1 gene region. The study participants were 16 patients with large NF1 deletions and 16 age- and sex-matched NF1 patients without such deletions. All the patients were comprehensively characterized clinically and by echocardiography. Six of 16 NF1 deletion patients but none of 16 non-deletion NF1 patients have major cardiac abnormalities (p = 0.041). Congenital heart defects (CHDs) include mitral insufficiency in two patients and ventricular septal defect, aortic stenosis, and aortic insufficiency in one patient each. Three deletion patients have hypertrophic cardiomyopathy. Two patients have intracardiac tumors. NF1 patients without large deletions have increased left ventricular (LV) diastolic posterior wall thickness (p NF1, suggestive of eccentric LV hypertrophy. CHDs and other cardiovascular anomalies are more frequent among patients with large NF1 deletion and may cause serious clinical complications. Eccentric LV hypertrophy may occur in NF1 patients without whole gene deletions, but the clinical significance of this finding is uncertain. All patients with clinical suspicion for NF1 should be referred to a cardiologist for evaluation and surveillance.

  4. Transcriptome and Metabolite analysis reveal candidate genes of the cardiac glycoside biosynthetic pathway from Calotropis procera

    Science.gov (United States)

    Pandey, Akansha; Swarnkar, Vishakha; Pandey, Tushar; Srivastava, Piush; Kanojiya, Sanjeev; Mishra, Dipak Kumar; Tripathi, Vineeta

    2016-01-01

    Calotropis procera is a medicinal plant of immense importance due to its pharmaceutical active components, especially cardiac glycosides (CG). As genomic resources for this plant are limited, the genes involved in CG biosynthetic pathway remain largely unknown till date. Our study on stage and tissue specific metabolite accumulation showed that CG’s were maximally accumulated in stems of 3 month old seedlings. De novo transcriptome sequencing of same was done using high throughput Illumina HiSeq platform generating 44074 unigenes with average mean length of 1785 base pair. Around 66.6% of unigenes were annotated by using various public databases and 5324 unigenes showed significant match in the KEGG database involved in 133 different pathways of plant metabolism. Further KEGG analysis resulted in identification of 336 unigenes involved in cardenolide biosynthesis. Tissue specific expression analysis of 30 putative transcripts involved in terpenoid, steroid and cardenolide pathways showed a positive correlation between metabolite and transcript accumulation. Wound stress elevated CG levels as well the levels of the putative transcripts involved in its biosynthetic pathways. This result further validated the involvement of identified transcripts in CGs biosynthesis. The identified transcripts will lay a substantial foundation for further research on metabolic engineering and regulation of cardiac glycosides biosynthesis pathway genes. PMID:27703261

  5. Ginsenoside Rg3 improves cardiac mitochondrial population quality: Mimetic exercise training

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    Sun, Mengwei [Key Laboratory of State General Administration of Sport, Shanghai Research Institute of Sports Science, Shanghai 200031 (China); Huang, Chenglin [Shanghai Key Laboratory of Vascular Biology, Department of Hypertension and Pharmacology, Ruijin Hospital, Shanghai Jiaotong University, School of Medicine, Shanghai 200025 (China); Wang, Cheng; Zheng, Jianheng; Zhang, Peng; Xu, Yangshu [Key Laboratory of State General Administration of Sport, Shanghai Research Institute of Sports Science, Shanghai 200031 (China); Chen, Hong, E-mail: hchen100@hotmail.com [Shanghai Key Laboratory of Vascular Biology, Department of Hypertension and Pharmacology, Ruijin Hospital, Shanghai Jiaotong University, School of Medicine, Shanghai 200025 (China); Shen, Weili, E-mail: weili_shen@hotmail.com [Shanghai Key Laboratory of Vascular Biology, Department of Hypertension and Pharmacology, Ruijin Hospital, Shanghai Jiaotong University, School of Medicine, Shanghai 200025 (China)

    2013-11-08

    Highlights: •Rg3 is an ergogenic aid. •Rg3 improves mitochondrial antioxidant capacity. •Rg3 regulates mitochondria dynamic remodeling. •Rg3 alone matches some the benefits of aerobic exercise. -- Abstract: Emerging evidence indicates exercise training could mediate mitochondrial quality control through the improvement of mitochondrial dynamics. Ginsenoside Rg3 (Rg3), one of the active ingredients in Panax ginseng, is well known in herbal medicine as a tonic and restorative agent. However, the molecular mechanism underlying the beneficial effects of Rg3 has been elusive. In the present study, we compared the effects of Rg3 administration with aerobic exercise on mitochondrial adaptation in cardiac muscle tissue of Sprague–Dawley (SD) rats. Three groups of SD rats were studied: (1) sedentary control, (2) Rg3-treated and (3) aerobic exercise trained. Both aerobic exercise training and Rg3 supplementation enhanced peroxisome proliferator-activated receptor coactivator 1 alpha (PGC-1α) and nuclear factor-E2-related factor 2 (Nrf2) protein levels in cardiac muscle. The activation of PGC-1α led to increased mRNA levels of mitochondrial transcription factor A (Tfam) and nuclear related factor 1(Nrf1), these changes were accompanied by increases in mitochondrial DNA copy number and complex protein levels, while activation of Nrf2 increased levels of phase II detoxifying enzymes, including nicotinamide adenine dinucleotide phosphate:quinone oxidoreductase 1(NQO1), superoxide dismutase (MnSOD) and catalase. Aerobic exercise also enhanced mitochondrial autophagy pathway activity, including increased conversion of LC3-I to LC3-II and greater expression of beclin1 and autophagy-related protein 7 (ATG7), these effects of aerobic exercise are comparable to that of Rg3. These results demonstrate that Rg3 mimics improved cardiac adaptations to exercise by regulating mitochondria dynamic remodeling and enhancing the quantity and quality of mitochondria.

  6. Search for cardiac calcium cycling gene mutations in familial ventricular arrhythmias resembling catecholaminergic polymorphic ventricular tachycardia

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    Toivonen Lauri

    2009-02-01

    Full Text Available Abstract Background Catecholaminergic polymorphic ventricular tachycardia (CPVT is a severe inherited cardiac disorder caused by mutations predominantly in the ryanodine receptor (RyR2 gene. We sought to identify mutations in genes affecting cardiac calcium cycling in patients with CPVT and in less typical familial exercise-related ventricular arrhythmias. Methods and Results We recruited 33 consecutive patients with frequent ventricular premature complexes (VPCs without structural heart disease and often history of syncope or sudden death in family. Sixteen of the patients featured a phenotype typical of CPVT. In 17 patients, VPCs emerged also at rest. Exercise stress test and echocardiography were performed to each patient and 232 family members. Familial background was evident in 42% of cases (n = 14. We sequenced all the coding exons of the RyR2, FKBP1B, ATP2A2 and SLC8A1 genes from the index patients. Single channel recordings of a mutant RyR2 were performed in planar lipid bilayers. Two novel RyR2 missense mutations (R1051P and S616L and two RyR2 exon 3 deletions were identified, explaining 25% of the CPVT phenotypes. A rare variant (N3308S with open probabilities similar to the wild type channels in vitro, was evident in a patient with resting VPCs. No disease-causing variants were detectable in the FKBP1B, ATP2A2 or SLC8A1 genes. Conclusion We report two novel CPVT-causing RyR2 mutations and a novel RyR2 variant of uncertain clinical significance in a patient with abundant resting VPCs. Our data also strengthen the previous assumption that exon 3 deletions of RyR2 should screened for in CPVT and related phenotypes.

  7. Methamphetamine and HIV-Tat Alter Murine Cardiac DNA Methylation and Gene Expression

    Science.gov (United States)

    Koczor, Christopher A.; Fields, Earl; Jedrzejczak, Mark J.; Jiao, Zhe; Ludaway, Tomika; Russ, Rodney; Shang, Joan; Torres, Rebecca A.; Lewis, William

    2015-01-01

    This study addresses the individual and combined effects of HIV-1 and methamphetamine (N-methyl-1-phenylpropan-2-amine, METH) on cardiac dysfunction in a transgenic mouse model of HIV/AIDS. METH is abused epidemically and is frequently associated with acquisition of HIV-1 infection or AIDS. We employed microarrays to identify mRNA differences in cardiac left ventricle (LV) gene expression following METH administration (10d, 3mg/kg/d, subcutaneously) in C57Bl/6 wild-type littermates (WT) and Tat-expressing transgenic (TG) mice. Arrays identified 880 differentially expressed genes (expression fold change>1.5, p<0.05) following METH exposure, Tat expression, or both. Using pathway enrichment analysis, mRNAs encoding polypeptides for calcium signaling and contractility were altered in the LV samples. Correlative DNA methylation analysis revealed significant LV DNA methylation changes following METH exposure and Tat expression. By combining these data sets, 38 gene promoters (27 related to METH, 11 related to Tat) exhibited differences by both methods of analysis. Among those, only the promoter for CACNA1C that encodes L-type calcium channel Cav1.2 displayed DNA methylation changes concordant with its gene expression change. Quantitative PCR verified that Cav1.2 LV mRNA abundance doubled following METH. Correlative immunoblots specific for Cav1.2 revealed a 3.5-fold increase in protein abundance in METH LVs. Data implicate Cav1.2 in calcium dysregulation and hypercontractility in the murine LV exposed to METH. They suggest a pathogenetic role for METH exposure to promote LV dysfunction that outweighs Tat-induced effects. PMID:26307267

  8. Transcriptional regulation of cardiac genes balance pro- and anti-hypertrophic mechanisms in hypertrophic cardiomyopathy

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    Nina Gennebäck

    2012-06-01

    Full Text Available Hypertrophic cardiomyopathy (HCM is characterized by unexplained left ventricular hypertrophy. HCM is often hereditary, but our knowledge of the mechanisms leading from mutation to phenotype is incomplete. The transcriptional expression patterns in the myocar - dium of HCM patients may contribute to understanding the mechanisms that drive and stabilize the hypertrophy. Cardiac myectomies/biopsies from 8 patients with hypertrophic obstructive cardiomyopathy (HOCM and 5 controls were studied with whole genome Illumina microarray gene expression (detecting 18 189 mRNA. When comparing HOCM myocardium to controls, there was significant transcriptional down-regulation of the MYH6, EGR1, APOB and FOS genes, and significant transcriptional up-regulation of the ACE2, JAK2, NPPA (ANP, APOA1 and HDAC5 genes. The transcriptional regulation revealed both pro- and anti-hypertrophic mechanisms. The pro-hypertrophic response was explained by the transcriptional down-regulation of MYH6, indicating that the switch to the fetal gene program is maintained, and the transcriptional up-regulation of JAK2 in the JAK-STAT pathway. The anti-hypertrophic response was seen as a transcriptional down-regulation of the immediate early genes (IEGs, FOS and EGR1, and a transcriptional up-regulation of ACE2 and HDAC5. This can be interpreted as a transcriptional endogenous protection system in the heart of the HOCM patients, neither growing nor suppressing the already hypertrophic myocardium.

  9. Development of a Comprehensive Sequencing Assay for Inherited Cardiac Condition Genes.

    Science.gov (United States)

    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 ).

  10. New intronic splicing mutation in the LMNA gene causing progressive cardiac conduction defects and variable myopathy.

    Science.gov (United States)

    Rogozhina, Y; Mironovich, S; Shestak, A; Adyan, T; Polyakov, A; Podolyak, D; Bakulina, A; Dzemeshkevich, S; Zaklyazminskaya, E

    2016-12-31

    Most of mutations in the LMNA gene are unique and have been found in only a few unrelated families. The clinical interpretation of new genetic variants, especially beyond the coding area and canonical splice sites, is proving to be difficult and requires advanced investigation. This study included patients with progressive cardiac conduction defects with neuromuscular involvement. The clinical evaluation included medical history and 24-h Holter monitoring. The genetic evaluation included mutation screening in the LMNA gene by the Sanger sequence. Sanger sequencing was followed by RT-PCR of the target fragment of cDNA. In silico modeling was performed with CCBulder and Modeller software. The diagnosis of limb-girdle muscular dystrophy type 1B (LGMD1B) was established. The new intronic variant c.513+45T>G was found in the LMNA gene in the proband and affected daughter. The insertion of 45bp was confirmed in the proband's cDNA. The structural and possible functional effects of the aberrant protein were predicted. Variant c.513+45T>G in the LMNA gene likely translates into the longer lamin A/C proteins with additional 15 amino acids. This variant is thought to be pathogenic. Intronic variants in the LMNA gene located beside canonic splice sites may be responsible for some genotype-negative cases with clinical phenotype of laminopathies. Copyright © 2016 Elsevier B.V. All rights reserved.

  11. 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

  12. Preoperative education interventions to reduce anxiety and improve recovery among cardiac surgery patients: a review of randomised controlled trials.

    Science.gov (United States)

    Guo, Ping

    2015-01-01

    To update evidence of the effectiveness of preoperative education among cardiac surgery patients. Patients awaiting cardiac surgery may experience high levels of anxiety and depression, which can adversely affect their existing disease and surgery and result in prolonged recovery. There is evidence that preoperative education interventions can lead to improved patient experiences and positive postoperative outcomes among a mix of general surgical patients. However, a previous review suggested limited evidence to support the positive impact of preoperative education on patients' recovery from cardiac surgery. Comprehensive review of the literature. The Cochrane Central Register of Controlled Trials from the Cochrane Library, MEDLINE, CINAHL, PsycINFO, EMBASE and Web of Science were searched for English-language articles published between 2000-2011. Original articles were included reporting randomised controlled trials of cardiac preoperative education interventions. Six trials were identified and have produced conflicting findings. Some trials have demonstrated the effects of preoperative education on improving physical and psychosocial recovery of cardiac patients, while others found no evidence that patients' anxiety is reduced or of any effect on pain or hospital stay. Evidence of the effectiveness of preoperative education interventions among cardiac surgery patients remains inconclusive. Further research is needed to evaluate cardiac preoperative education interventions for sustained effect and in non-Western countries. A nurse-coordinated multidisciplinary preoperative education approach may offer a way forward to provide a more effective and efficient service. Staff training in developing and delivering such interventions is a priority. © 2014 John Wiley & Sons Ltd.

  13. Traditional Chinese Medicine Tongxinluo Improves Cardiac Function of Rats with Dilated Cardiomyopathy

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    Fang-Fang Shen

    2014-01-01

    Full Text Available The study aimed at testing the hypothesis that tongxinluo capsule might exert its cardioprotective effect by preventing ventricular remodeling and improving coronary microvascular function in a rat model of doxorubicin-induced dilated cardiomyopathy (DCM. Rats that survived DCM induction were randomly divided into three groups to be given 1.5 g·kg−1·day−1 (TXL-H, n=9 or 0.15 g·kg−1·day−1 (TXL-L, n=10 of tongxinluo, or normal saline at the same volume (DCM-C, n=10 intragastrically. Age matched normal rats treated with normal saline were used as normal controls (NOR-C, n=9. After four weeks of treatment, the DCM-C, TXL-H, and TXL-L groups exhibited significant cardiac dysfunction, left ventricular remodeling, and coronary microvascular dysfunction, compared with the NOR-C rats. However, myocardial functional parameters were significantly improved and microvascular density (MVD increased in the TXL-H group compared with the DCM-C group (all P<0.01. Left ventricular remodeling was prevented. There were close linear relationships between CVF and LVEF (r=-0.683, P<0.05, MVD and LVEF (r=0.895, P<0.05, and MVD and CVF (r=-0.798, P<0.05. It was indicated that high-dose tongxinluo effectively improved cardiac function in rat model of DCM.

  14. Ablation of the cardiac-specific gene leucine-rich repeat containing 10 (Lrrc10 results in dilated cardiomyopathy.

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    Matthew J Brody

    Full Text Available Leucine-rich repeat containing 10 (LRRC10 is a cardiac-specific protein exclusively expressed in embryonic and adult cardiomyocytes. However, the role of LRRC10 in mammalian cardiac physiology remains unknown. To determine if LRRC10 is critical for cardiac function, Lrrc10-null (Lrrc10(-/- mice were analyzed. Lrrc10(- (/- mice exhibit prenatal systolic dysfunction and dilated cardiomyopathy in postnatal life. Importantly, Lrrc10(-/- mice have diminished cardiac performance in utero, prior to ventricular dilation observed in young adults. We demonstrate that LRRC10 endogenously interacts with α-actinin and α-actin in the heart and all actin isoforms in vitro. Gene expression profiling of embryonic Lrrc10(-/- hearts identified pathways and transcripts involved in regulation of the actin cytoskeleton to be significantly upregulated, implicating dysregulation of the actin cytoskeleton as an early defective molecular signal in the absence of LRRC10. In contrast, microarray analyses of adult Lrrc10(-/- hearts identified upregulation of oxidative phosphorylation and cardiac muscle contraction pathways during the progression of dilated cardiomyopathy. Analyses of hypertrophic signal transduction pathways indicate increased active forms of Akt and PKCε in adult Lrrc10(-/- hearts. Taken together, our data demonstrate that LRRC10 is essential for proper mammalian cardiac function. We identify Lrrc10 as a novel dilated cardiomyopathy candidate gene and the Lrrc10(-/- mouse model as a unique system to investigate pediatric cardiomyopathy.

  15. Acute improvement of cardiac function with intravenous L-propionylcarnitine in humans.

    Science.gov (United States)

    Bartels, G L; Remme, W J; Pillay, M; Schönfeld, D H; Cox, P H; Kruijssen, H A; Knufman, N M

    1992-07-01

    As the myocardial carnitine content, a key control factor in myocardial oxidative metabolism and energy transfer, is reduced in heart failure, administration of L-propionylcarnitine (LPC), a potent analogue of L-carnitine, potentially may improve cardiac function, possibly through a positive inotropic effect. As its hemodynamic profile is unknown in humans, 32 fasting normotensive patients with coronary artery disease received either 15 mg/kg of LPC (n = 16) or vehicle (mannitol/acetate, n = 16) infused over 5 min. Hemodynamic, radionuclide [peak ejection and filling rates (PER and PFR, respectively)], and metabolic variables (myocardial O2, lactate, and carnitine uptake) were studied at baseline and 1, 3, 5, 10, 15, and 45 min postdrug. The baseline ejection fraction was depressed in LPC patients (40 +/- 3% vs. 48 +/- 4% in the vehicle group, p less than 0.05) as a result of a significant high incidence of previous infarctions. Immediately following LPC, the cardiac total carnitine uptake changed from 102 +/- 181 to 5,335 +/- 1,761 mumol/L (p less than 0.05). In both groups, left ventricular systolic and end-diastolic pressures increased significantly by 5 and 20%, respectively, during the first 5 min. In the vehicle group, contractility decreased by 5%, accompanied by a significant 11% fall in the stroke volume. In contrast, following LPC, isovolumetric contractility indices remained unaltered. Instead, both the PER and PFR improved by 16% at 45 min. Moreover, the cardiac output increased by 8%. LPC did not affect systemic or coronary hemodynamics. Lactate uptake increased by 42%, but myocardial O2 consumption did not change.(ABSTRACT TRUNCATED AT 250 WORDS)

  16. Improved myocardial strain measured by strain-encoded magnetic resonance imaging in a patient with cardiac sarcoidosis.

    Science.gov (United States)

    Nakano, Shintaro; Kimura, Fumiko; Osman, Nael; Sugi, Keiki; Tanno, Jun; Uchida, Yoshitaka; Shiono, Ayako; Senbonmatsu, Takaaki; Nishimura, Shigeyuki

    2013-11-01

    A woman aged 64 years with cardiac sarcoidosis responded favourably to corticosteroid therapy in terms of recovered longitudinal myocardial strain, as evaluated by strain-encoded magnetic resonance imaging (SENC-MRI). In contrast, circumferential myocardial strain and late gadolinium enhancement demonstrated minimal improvement, suggesting relatively advanced pathology of the myocardial middle layer. We propose SENC-MRI as a marker of disease at an early stage of cardiac sarcoidosis.

  17. Amlodipine and Atorvastatin Improved Hypertensive Cardiac Remodeling through Regulation of MMPs/TIMPs in SHR Rats

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    Jingchao Lu

    2016-06-01

    Full Text Available Background: MMPs/TIMPs system is well known to play important roles in pressure overload-induced cardiac remodeling, and Amlodipine and Atorvastatin have been showed to exert favourable protective effects on cardiovascular disease, however, it is not clear whether Amlodipine and Atorvastatin can improve hypertensive cardiac remodeling and whether the MMPs/TIMPs system is involved. The present study aims to answer these questions. Methods: 36 weeks old male spontaneous hypertension (SHR rats were randomly divided into four groups: 1. SHR control group, 2. Amlodipine alone (10 mg/kg/d group, 3. Atorvastatin alone (10 mg/kg/d group, 4.Combination of Amlodipine and Atorvastatin (10 mg/kg/d for each group. Same gender, weight and age of Wistar-Kyoto (WKY rats with normal blood pressure were used as normal control. Drugs were administered by oral gavage over 12 weeks. The blood pressure and left ventricle mass index were measured. Enzyme activity of MMP-2 and MMP-9 was assessed with Gelatin zymography. MMP-2, MMP-9, TIMP-1 and TIMP-2 mRNA and protein expression was studied by RT-PCR and Western blot. Single factor ANOVA and LSD-t test were used in statistical analysis. Results: Treatment with Amlodipine alone or combination with atorvastatin significantly decreased blood pressure, left ventricle mass index in SHR rats (P Conclusion: Amlodipine and Atorvastatin could improve ventricular remodeling in SHR rats through intervention with the imbalance of MMP-2/TIMP-2 and MMP-9/TIMP-1 system.

  18. Foxf genes integrate tbx5 and hedgehog pathways in the second heart field for cardiac septation.

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    Andrew D Hoffmann

    2014-10-01

    Full Text Available The Second Heart Field (SHF has been implicated in several forms of congenital heart disease (CHD, including atrioventricular septal defects (AVSDs. Identifying the SHF gene regulatory networks required for atrioventricular septation is therefore an essential goal for understanding the molecular basis of AVSDs. We defined a SHF Hedgehog-dependent gene regulatory network using whole genome transcriptional profiling and GLI-chromatin interaction studies. The Forkhead box transcription factors Foxf1a and Foxf2 were identified as SHF Hedgehog targets. Compound haploinsufficiency for Foxf1a and Foxf2 caused atrioventricular septal defects, demonstrating the biological relevance of this regulatory network. We identified a Foxf1a cis-regulatory element that bound the Hedgehog transcriptional regulators GLI1 and GLI3 and the T-box transcription factor TBX5 in vivo. GLI1 and TBX5 synergistically activated transcription from this cis-regulatory element in vitro. This enhancer drove reproducible expression in vivo in the posterior SHF, the only region where Gli1 and Tbx5 expression overlaps. Our findings implicate Foxf genes in atrioventricular septation, describe the molecular underpinnings of the genetic interaction between Hedgehog signaling and Tbx5, and establish a molecular model for the selection of the SHF gene regulatory network for cardiac septation.

  19. Foxf genes integrate tbx5 and hedgehog pathways in the second heart field for cardiac septation.

    Science.gov (United States)

    Hoffmann, Andrew D; Yang, Xinan Holly; Burnicka-Turek, Ozanna; Bosman, Joshua D; Ren, Xiaomeng; Steimle, Jeffrey D; Vokes, Steven A; McMahon, Andrew P; Kalinichenko, Vladimir V; Moskowitz, Ivan P

    2014-10-01

    The Second Heart Field (SHF) has been implicated in several forms of congenital heart disease (CHD), including atrioventricular septal defects (AVSDs). Identifying the SHF gene regulatory networks required for atrioventricular septation is therefore an essential goal for understanding the molecular basis of AVSDs. We defined a SHF Hedgehog-dependent gene regulatory network using whole genome transcriptional profiling and GLI-chromatin interaction studies. The Forkhead box transcription factors Foxf1a and Foxf2 were identified as SHF Hedgehog targets. Compound haploinsufficiency for Foxf1a and Foxf2 caused atrioventricular septal defects, demonstrating the biological relevance of this regulatory network. We identified a Foxf1a cis-regulatory element that bound the Hedgehog transcriptional regulators GLI1 and GLI3 and the T-box transcription factor TBX5 in vivo. GLI1 and TBX5 synergistically activated transcription from this cis-regulatory element in vitro. This enhancer drove reproducible expression in vivo in the posterior SHF, the only region where Gli1 and Tbx5 expression overlaps. Our findings implicate Foxf genes in atrioventricular septation, describe the molecular underpinnings of the genetic interaction between Hedgehog signaling and Tbx5, and establish a molecular model for the selection of the SHF gene regulatory network for cardiac septation.

  20. Regular physical exercise improves cardiac autonomic and muscle vasodilatory responses to isometric exercise in healthy elderly

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    Sarmento AO

    2017-06-01

    sympathetic activity compared to physically active older adult subjects at baseline (63.13±3.31 vs 50.45±3.55 nu, P=0.02. The variance (heart rate variability index was increased in active older adults (1,438.64±448.90 vs 1,402.92±385.14 ms, P=0.02, and cardiac sympathetic activity (symbolic analysis was increased in sedentary older adults (5,660.91±1,626.72 vs 4,381.35±1,852.87, P=0.03 during isometric handgrip exercise. Sedentary older adults showed higher cardiac sympathetic activity (spectral analysis (71.29±4.40 vs 58.30±3.50 nu, P=0.03 and lower parasympathetic modulation (28.79±4.37 vs 41.77±3.47 nu, P=0.03 compared to physically active older adult subjects during isometric handgrip exercise. Regarding muscle vasodilation response, there was an increase in the skeletal muscle blood flow in the second (4.1±0.5 vs 3.7±0.4 mL/min per 100 mL, P=0.01 and third minute (4.4±0.4 vs 3.9±0.3 mL/min per 100 mL, P=0.03 of handgrip exercise in active older adults. The results indicate that regular physical activity improves neurovascular control of muscle blood flow and cardiac autonomic response during isometric handgrip exercise in healthy older adult subjects. Keywords: forearm blood flow, handgrip exercise, heart rate variability, sympathetic, parasympathetic, aging

  1. X indening oral liquid improves cardiac function of rats with chronic cardiac failure via TGF-ß1/Smad3 and p38 MAPK pathway.

    Science.gov (United States)

    Wei, Yunliang; Guo, Changsheng; Zhao, Jingsheng; Yang, Jun; Yi, Weiguo; Liu, Hong; Lin, Xinwei; Zhang, Zhengchen

    2017-05-01

    Xindening oral liquid (Xin) is a widely used traditional Chinese medicine for the treatment of chronic heart failure (CHF). However, the exact mechanisms related to its therapeutic effects against CHF remain unclear. In the present study, we investigate the effects of Xin on cardiac function in CHF rats and the possible mechanisms involved. Transverse aortic constriction (TAC) was conducted to induce a CHF rat model in this study. Sixty male Wistar rats were randomly assigned to six groups 28 days after TAC: sham; CHF model; Xin at concentrations of 5 ml/kg, 10 mL/kg, and 20 mL/kg; and QiLi 0.6 g/kg. After four weeks, the rats were treated with Xin (5, 10, or 20 mL/kg/d) for six weeks consecutively. At the end of the study, the cardiac function, heart weight index (HWI) and left ventricular mass index (LVMI), serum level of LDH, B-type natriuretic peptide (BNP), cTnI and CK-MB, and collagen volume fraction were studied. The expression of transforming growth factor-ß1 (TGF-ß1), drosophila mothers against decapentaplegic protein 3 (Smad3), and p38 mitogen activated protein kinase (p38 MAPK) were detected. The results showed that Xin treatment significantly improved cardiac function but decreased the serum level of LDH, BNP, cTnI, and CKMB of CHF rats. In addition, it reduced the HWI, LVMI, and collagen volume fraction compared with the model group. Xin treatment significantly improved cardiac function and attenuated cardiac fibrosis by suppressing the p38 MAPK and TGF-ß1/Smad3 signaling pathway in CHF rats. These results suggested that Xin might be a promising complementary treatment for CHF. More detailed experimental studies will be carried out in our subsequent research.

  2. Lrrc10 is a novel cardiac-specific target gene of Nkx2-5 and GATA4

    Science.gov (United States)

    Brody, Matthew J.; Cho, Eunjin; Mysliwiec, Matthew R.; Kim, Tae-gyun; Carlson, Clayton D.; Lee, Kyu-Ho; Lee, Youngsook

    2013-01-01

    Cardiac gene expression is precisely regulated and its perturbation causes developmental defects and heart disease. Leucine-rich repeat containing 10 (Lrrc10) is a cardiac-specific factor that is crucial for proper cardiac development and deletion of Lrrc10 in mice results in dilated cardiomyopathy. However, the mechanisms regulating Lrrc10 expression in cardiomyocytes remain unknown. Therefore, we set out to determine trans-acting factors and cis-elements critical for mediating Lrrc10 expression. We identify Lrrc10 as a transcriptional target of Nkx2-5 and GATA4. The Lrrc10 promoter region contains two highly conserved cardiac regulatory elements, which are functional in cardiomyocytes but not in fibroblasts. In vivo, Nkx2-5 and GATA4 endogenously occupy the proximal and distal cardiac regulatory elements of Lrrc10 in the heart. Moreover, embryonic hearts of Nkx2-5 knockout mice have dramatically reduced expression of Lrrc10. These data demonstrate the importance of Nkx2-5 and GATA4 in regulation of Lrrc10 expression in vivo. The proximal cardiac regulatory element located at around −200 bp is synergistically activated by Nkx2-5 and GATA4 while the distal cardiac regulatory element present around −3 Kb requires SRF in addition to Nkx2-5 and GATA4 for synergistic activation. Mutational analyses identify a pair of adjacent Nkx2-5 and GATA binding sites within the proximal cardiac regulatory element that are necessary to induce expression of Lrrc10. In contrast, only the GATA site is functional in the distal regulatory element. Taken together, our data demonstrate that the transcription factors Nkx2-5 and GATA4 cooperatively regulate cardiac-specific expression of Lrrc10. PMID:23751912

  3. Heme oxygenase-1 induction improves cardiac function following myocardial ischemia by reducing oxidative stress.

    Directory of Open Access Journals (Sweden)

    Yossi Issan

    Full Text Available BACKGROUND: Oxidative stress plays a key role in exacerbating diabetes and cardiovascular disease. Heme oxygenase-1 (HO-1, a stress response protein, is cytoprotective, but its role in post myocardial infarction (MI and diabetes is not fully characterized. We aimed to investigate the protection and the mechanisms of HO-1 induction in cardiomyocytes subjected to hypoxia and in diabetic mice subjected to LAD ligation. METHODS: In vitro: cultured cardiomyocytes were treated with cobalt-protoporphyrin (CoPP and tin protoporphyrin (SnPP prior to hypoxic stress. In vivo: CoPP treated streptozotocin-induced diabetic mice were subjected to LAD ligation for 2/24 h. Cardiac function, histology, biochemical damage markers and signaling pathways were measured. RESULTS: HO-1 induction lowered release of lactate dehydrogenase (LDH and creatine phospho kinase (CK, decreased propidium iodide staining, improved cell morphology and preserved mitochondrial membrane potential in cardiomyocytes. In diabetic mice, Fractional Shortening (FS was lower than non-diabetic mice (35±1%vs.41±2, respectively p<0.05. CoPP-treated diabetic animals improved cardiac function (43±2% p<0.01, reduced CK, Troponin T levels and infarct size compared to non-treated diabetic mice (P<0.01, P<0.001, P<0.01 respectively. CoPP-enhanced HO-1 protein levels and reduced oxidative stress in diabetic animals, as indicated by the decrease in superoxide levels in cardiac tissues and plasma TNFα levels (p<0.05. The increased levels of HO-1 by CoPP treatment after LAD ligation led to a shift of the Bcl-2/bax ratio towards the antiapoptotic process (p<0.05. CoPP significantly increased the expression levels of pAKT and pGSK3β (p<0.05 in cardiomyocytes and in diabetic mice with MI. SnPP abolished CoPP's cardioprotective effects. CONCLUSIONS: HO-1 induction plays a role in cardioprotection against hypoxic damage in cardiomyocytes and in reducing post ischemic cardiac damage in the diabetic heart

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

    Science.gov (United States)

    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.

  5. Improved survival after an out-of-hospital cardiac arrest using new guidelines

    DEFF Research Database (Denmark)

    Steinmetz, Jacob; Barnung, S.; Nielsen, S.L.

    2008-01-01

    BACKGROUND: An out-of-hospital cardiac arrest (OHCA) is associated with a poor prognosis. We hypothesized that the implementations of 2005 European Resuscitation Council resuscitation guidelines were associated with improved 30-day survival after OHCA. METHODS: We prospectively recorded data on all...... that 30-day survival increased after the implementation from 31/372 (8.3%) to 67/419 (16%), P=0.001. ROSC at hospital admission, as well as survival to hospital discharge, were obtained in a significantly higher proportion from 23.4% to 39.1%, P.... Treatment after implementation was confirmed as a significant predictor of better 30-day survival in a logistic regression analysis. CONCLUSION: The implementation of new resuscitation guidelines was associated with improved 30-day survival after OHCA Udgivelsesdato: 2008/8...

  6. Cardiac rehabilitation programs improve metabolic parameters in patients with the metabolic syndrome and coronary heart disease.

    Science.gov (United States)

    Pérez, Ignacio P; Zapata, Maria A; Cervantes, Carlos E; Jarabo, Rosario M; Grande, Cristina; Plaza, Rose; Garcia, Sara; Rodriguez, Miriam L; Crespo, Silvia; Perea, Jesús

    2010-05-01

    This study was performed to determine the effectiveness of a cardiac rehabilitation and exercise training program on metabolic parameters and coronary risk factors in patients with the metabolic syndrome and coronary heart disease. The study involved 642 patients with coronary heart disease. Of them, 171 (26.7%) fulfilled criteria for the metabolic syndrome. Clinical data, laboratory tests, and exercise testing were performed before and after the program, which lasted 2 to 3 months. Except for waist circumference, there were no significant differences between groups; blood pressure, high-density lipoprotein cholesterol, triglycerides, and fasting glucose improvements during the follow-up were higher in patients with the metabolic syndrome (all Pmetabolic syndrome, functional capacity increased by 26.45% ( Pmetabolic equivalents, with a slight increase of 1.25% ( P=not significant) in the double product. Patients with the metabolic syndrome who took part in this secondary prevention program reported improvements in cardiovascular risk profile and functional capacity.

  7. Ecstasy (MDMA) Alters Cardiac Gene Expression and DNA Methylation: Implications for Circadian Rhythm Dysfunction in the Heart.

    Science.gov (United States)

    Koczor, Christopher A; Ludlow, Ivan; Hight, Robert S; Jiao, Zhe; Fields, Earl; Ludaway, Tomika; Russ, Rodney; Torres, Rebecca A; Lewis, William

    2015-11-01

    MDMA (ecstasy) is an illicit drug that stimulates monoamine neurotransmitter release and inhibits reuptake. MDMA's acute cardiotoxicity includes tachycardia and arrhythmia which are associated with cardiomyopathy. MDMA acute cardiotoxicity has been explored, but neither long-term MDMA cardiac pathological changes nor epigenetic changes have been evaluated. Microarray analyses were employed to identify cardiac gene expression changes and epigenetic DNA methylation changes. To identify permanent MDMA-induced pathogenetic changes, mice received daily 10- or 35-day MDMA, or daily 10-day MDMA followed by 25-day saline washout (10 + 25 days). MDMA treatment caused differential gene expression (p 1.5) in 752 genes following 10 days, 558 genes following 35 days, and 113 genes following 10-day MDMA + 25-day saline washout. Changes in MAPK and circadian rhythm gene expression were identified as early as 10 days. After 35 days, circadian rhythm genes (Per3, CLOCK, ARNTL, and NPAS2) persisted to be differentially expressed. MDMA caused DNA hypermethylation and hypomethylation that was independent of gene expression; hypermethylation of genes was found to be 71% at 10 days, 68% at 35 days, and 91% at 10 + 25 days washout. Differential gene expression paralleled DNA methylation in 22% of genes at 10-day treatment, 17% at 35 days, and 48% at 10 + 25 days washout. We show here that MDMA induced cardiac epigenetic changes in DNA methylation where hypermethylation predominated. Moreover, MDMA induced gene expression of key elements of circadian rhythm regulatory genes. This suggests a fundamental organism-level event to explain some of the etiologies of MDMA dysfunction in the heart.

  8. Hemodynamic improvement in cardiac resynchronization does not require improvement in left ventricular rotation mechanics: three-dimensional tagged MRI analysis.

    Science.gov (United States)

    Ashikaga, Hiroshi; Leclercq, Christophe; Wang, Jiangxia; Kass, David A; McVeigh, Elliot R

    2010-07-01

    Earlier studies have yielded conflicting evidence on whether or not cardiac resynchronization therapy (CRT) improves left ventricular (LV) rotation mechanics. In dogs with left bundle branch block and pacing-induced heart failure (n=7), we studied the effects of CRT on LV rotation mechanics in vivo by 3-dimensional tagged magnetic resonance imaging with a temporal resolution of 14 ms. CRT significantly improved hemodynamic parameters but did not significantly change the LV rotation or rotation rate. LV torsion, defined as LV rotation of each slice with respect to that of the most basal slice, was not significantly changed by CRT. CRT did not significantly change the LV torsion rate. There was no significant circumferential regional heterogeneity (anterior, lateral, inferior, and septal) in LV rotation mechanics in either left bundle branch block with pacing-induced heart failure or CRT, but there was significant apex-to-base regional heterogeneity. CRT acutely improves hemodynamic parameters without improving LV rotation mechanics. There is no significant circumferential regional heterogeneity of LV rotation mechanics in the mechanically dyssynchronous heart. These results suggest that LV rotation mechanics is an index of global LV function, which requires coordination of all regions of the left ventricle, and improvement in LV rotation mechanics appears to be a specific but insensitive index of acute hemodynamic response to CRT.

  9. GenePRIMP: A GENE PRediction IMprovement Pipeline for Prokaryotic genomes

    Energy Technology Data Exchange (ETDEWEB)

    Pati, Amrita; Ivanova, Natalia N.; Mikhailova, Natalia; Ovchinnikova, Galina; Hooper, Sean D.; Lykidis, Athanasios; Kyrpides, Nikos C.

    2010-04-01

    We present 'gene prediction improvement pipeline' (GenePRIMP; http://geneprimp.jgi-psf.org/), a computational process that performs evidence-based evaluation of gene models in prokaryotic genomes and reports anomalies including inconsistent start sites, missed genes and split genes. We found that manual curation of gene models using the anomaly reports generated by GenePRIMP improved their quality, and demonstrate the applicability of GenePRIMP in improving finishing quality and comparing different genome-sequencing and annotation technologies.

  10. A novel lamin A/C gene mutation causing spinal muscular atrophy phenotype with cardiac involvement: report of one case.

    Science.gov (United States)

    Iwahara, Naotoshi; Hisahara, Shin; Hayashi, Takashi; Kawamata, Jun; Shimohama, Shun

    2015-02-20

    Mutations of the lamin A/C gene have been associated with several diseases such as Emery-Dreifuss muscular dystrophy, dilated cardiomyopathy and Charcot-Marie-Tooth disease, referred to as laminopathies. Only one report of spinal muscular atrophy and cardiomyopathy phenotype with lamin A/C gene mutations has been published. The concept that lamin A/C gene mutations cause spinal muscular atrophy has not been established. We report a man aged 65 years who presented with amyotrophy of lower limbs, arrhythmia and cardiac hypofunction. He showed gait disturbance since childhood, and his family showed similar symptoms. Neurological and electrophysiological findings suggested spinal muscular atrophy type 3. Gene analysis of lamin A/C gene showed a novel nonsense mutation p.Q353X (c.1057C > T). Further investigations revealed that he and his family members had cardiac diseases including atrioventricular block. We report the first Japanese case of spinal muscular atrophy phenotype associated with lamin A/C mutation. When a patient presents a spinal muscular atrophy phenotype and unexplained cardiac disease, especially when the family history is positive, gene analysis of lamin A/C gene should be considered.

  11. Prospective randomized controlled intervention trial: Comprehensive Yogic Breathing Improves Cardiac autonomic functions and Quality of life in Diabetes

    Directory of Open Access Journals (Sweden)

    V P Jyotsna

    2012-01-01

    Full Text Available Aims and Objectives: To assess the effect of Comprehensive Yogic Breathing Program on glycemic control, quality of life, and cardiac autonomic functions in diabetes. Material and Methods: This is a prospective randomized controlled intervention trial. Cardiac autonomic functions were assessed in 120 diabetics. Patients were randomized into two groups, one group receiving standard therapy for diabetes (n = 56 and the other group receiving standard therapy for diabetes and comprehensive yogic breathing program (n = 64. Standard therapy included advice on diet, walk, and oral antidiabetic drugs. Comprehensive yogic breathing program was an interactive session in which Sudarshan kriya yoga, a rhythmic cyclical breathing, preceded by Pranayam was taught under guidance of a certified teacher. Change in fasting, post prandial blood sugars, glycated hemoglobin, and quality of life were assessed. Cardiac autonomic function tests were done before and six months after intervention. Results: There was significant improvement in psychological (P = 0.006 and social domains (P = 0.04 and total quality of life (P = 0.02 in the group practicing comprehensive yogic breathing program as compared to the group following standard therapy alone. In the group following breathing program, the improvement in sympathetic cardiac autonomic functions was statistically significant (P = 0.01, while the change in the standard group was not significant (P = 0.17. When both parasympathetic and sympathetic cardiac autonomic functions were considered, there was a trend toward improvement in patients following comprehensive yogic breathing program (P = 0.07. In the standard therapy group, no change in cardiac autonomic functions was noted (P = 0.76. The parameters of glycemic control were comparable in both groups. Conclusion: There was significant improvement in quality of life and cardiac autonomic functions in the diabetes patients practicing comprehensive yogic breathing

  12. Sca-1+ cardiosphere-derived cells are enriched for Isl1-expressing cardiac precursors and improve cardiac function after myocardial injury.

    Directory of Open Access Journals (Sweden)

    Jianqin Ye

    Full Text Available BACKGROUND: Endogenous cardiac progenitor cells are a promising option for cell-therapy for myocardial infarction (MI. However, obtaining adequate numbers of cardiac progenitors after MI remains a challenge. Cardiospheres (CSs have been proposed to have cardiac regenerative properties; however, their cellular composition and how they may be influenced by the tissue milieu remains unclear. METHODOLOGY/PRINCIPAL FINDING: Using "middle aged" mice as CSs donors, we found that acute MI induced a dramatic increase in the number of CSs in a mouse model of MI, and this increase was attenuated back to baseline over time. We also observed that CSs from post-MI hearts engrafted in ischemic myocardium induced angiogenesis and restored cardiac function. To determine the role of Sca-1(+CD45(- cells within CSs, we cloned these from single cell isolates. Expression of Islet-1 (Isl1 in Sca-1(+CD45(- cells from CSs was 3-fold higher than in whole CSs. Cloned Sca-1(+CD45(- cells had the ability to differentiate into cardiomyocytes, endothelial cells and smooth muscle cells in vitro. We also observed that cloned cells engrafted in ischemic myocardium induced angiogenesis, differentiated into endothelial and smooth muscle cells and improved cardiac function in post-MI hearts. CONCLUSIONS/SIGNIFICANCE: These studies demonstrate that cloned Sca-1(+CD45(- cells derived from CSs from infarcted "middle aged" hearts are enriched for second heart field (i.e., Isl-1(+ precursors that give rise to both myocardial and vascular tissues, and may be an appropriate source of progenitor cells for autologous cell-therapy post-MI.

  13. Cardiac sympathetic activity in chronic heart failure: cardiac (123)I-mIBG scintigraphy to improve patient selection for ICD implantation.

    Science.gov (United States)

    Verschure, D O; van Eck-Smit, B L F; Somsen, G A; Knol, R J J; Verberne, H J

    2016-12-01

    Heart failure is a life-threatening disease with a growing incidence in the Netherlands. This growing incidence is related to increased life expectancy, improvement of survival after myocardial infarction and better treatment options for heart failure. As a consequence, the costs related to heart failure care will increase. Despite huge improvements in treatment, the prognosis remains unfavourable with high one-year mortality rates. The introduction of implantable devices such as implantable cardioverter defibrillators (ICD) and cardiac resynchronisation therapy (CRT) has improved the overall survival of patients with chronic heart failure. However, after ICD implantation for primary prevention in heart failure a high percentage of patients never have appropriate ICD discharges. In addition 25-50 % of CRT patients have no therapeutic effect. Moreover, both ICDs and CRTs are associated with malfunction and complications (e. g. inappropriate shocks, infection). Last but not least is the relatively high cost of these devices. Therefore, it is essential, not only from a clinical but also from a socioeconomic point of view, to optimise the current selection criteria for ICD and CRT. This review focusses on the role of cardiac sympathetic hyperactivity in optimising ICD selection criteria. Cardiac sympathetic hyperactivity is related to fatal arrhythmias and can be non-invasively assessed with (123)I-meta-iodobenzylguanide ((123)I-mIBG) scintigraphy. We conclude that cardiac sympathetic activity assessed with (123)I-mIBG scintigraphy is a promising tool to better identify patients who will benefit from ICD implantation.

  14. Improved discretisation and linearisation of active tension in strongly coupled cardiac electro-mechanics simulations.

    Science.gov (United States)

    Sundnes, J; Wall, S; Osnes, H; Thorvaldsen, T; McCulloch, A D

    2014-01-01

    Mathematical models of cardiac electro-mechanics typically consist of three tightly coupled parts: systems of ordinary differential equations describing electro-chemical reactions and cross-bridge dynamics in the muscle cells, a system of partial differential equations modelling the propagation of the electrical activation through the tissue and a nonlinear elasticity problem describing the mechanical deformations of the heart muscle. The complexity of the mathematical model motivates numerical methods based on operator splitting, but simple explicit splitting schemes have been shown to give severe stability problems for realistic models of cardiac electro-mechanical coupling. The stability may be improved by adopting semi-implicit schemes, but these give rise to challenges in updating and linearising the active tension. In this paper we present an operator splitting framework for strongly coupled electro-mechanical simulations and discuss alternative strategies for updating and linearising the active stress component. Numerical experiments demonstrate considerable performance increases from an update method based on a generalised Rush-Larsen scheme and a consistent linearisation of active stress based on the first elasticity tensor.

  15. Improving Low-dose Cardiac CT Images based on 3D Sparse Representation

    Science.gov (United States)

    Shi, Luyao; Hu, Yining; Chen, Yang; Yin, Xindao; Shu, Huazhong; Luo, Limin; Coatrieux, Jean-Louis

    2016-03-01

    Cardiac computed tomography (CCT) is a reliable and accurate tool for diagnosis of coronary artery diseases and is also frequently used in surgery guidance. Low-dose scans should be considered in order to alleviate the harm to patients caused by X-ray radiation. However, low dose CT (LDCT) images tend to be degraded by quantum noise and streak artifacts. In order to improve the cardiac LDCT image quality, a 3D sparse representation-based processing (3D SR) is proposed by exploiting the sparsity and regularity of 3D anatomical features in CCT. The proposed method was evaluated by a clinical study of 14 patients. The performance of the proposed method was compared to the 2D spares representation-based processing (2D SR) and the state-of-the-art noise reduction algorithm BM4D. The visual assessment, quantitative assessment and qualitative assessment results show that the proposed approach can lead to effective noise/artifact suppression and detail preservation. Compared to the other two tested methods, 3D SR method can obtain results with image quality most close to the reference standard dose CT (SDCT) images.

  16. Combination of principal component analysis and optical-flow motion compensation for improved cardiac MR thermometry

    Science.gov (United States)

    Toupin, S.; de Senneville, B. Denis; Ozenne, V.; Bour, P.; Lepetit-Coiffe, M.; Boissenin, M.; Jais, P.; Quesson, B.

    2017-02-01

    The use of magnetic resonance (MR) thermometry for the monitoring of thermal ablation is rapidly expanding. However, this technique remains challenging for the monitoring of the treatment of cardiac arrhythmia by radiofrequency ablation due to the heart displacement with respiration and contraction. Recent studies have addressed this problem by compensating in-plane motion in real-time with optical-flow based tracking technique. However, these algorithms are sensitive to local variation of signal intensity on magnitude images associated with tissue heating. In this study, an optical-flow algorithm was combined with a principal component analysis method to reduce the impact of such effects. The proposed method was integrated to a fully automatic cardiac MR thermometry pipeline, compatible with a future clinical workflow. It was evaluated on nine healthy volunteers under free breathing conditions, on a phantom and in vivo on the left ventricle of a sheep. The results showed that local intensity changes in magnitude images had lower impact on motion estimation with the proposed method. Using this strategy, the temperature mapping accuracy was significantly improved.

  17. Improvements in logistics could increase survival after out-of-hospital cardiac arrest in Sweden.

    Science.gov (United States)

    Strömsöe, A; Afzelius, S; Axelsson, C; Södersved Källestedt, M L; Enlund, M; Svensson, L; Herlitz, J

    2013-06-01

    In a review based on estimations and assumptions, to report the estimated number of survivors after out-of-hospital cardiac arrest (OHCA) in whom cardiopulmonary resuscitation (CPR) was started and to speculate about possible future improvements in Sweden. An observational study. All ambulance organisations in Sweden. Patients included in the Swedish Cardiac Arrest Registry who suffered an OHCA between January 1, 2008 and December 31, 2010. Approximately 80% of OHCA cases in Sweden in which CPR was started are included. None In 11 005 patients, the 1-month survival rate was 9.4%. There are approximately 5000 OHCA cases annually in which CPR is started and 30-day survival is achieved in up to 500 patients yearly (6 per 100 000 inhabitants). Based on findings on survival in relation to the time to calling for the Emergency Medical Service (EMS) and the start of CPR and defibrillation, it was estimated that, if the delay from collapse to (i) calling EMS, (ii) the start of CPR, and (iii) the time to defibrillation were reduced to <2 min, <2 min, and <8 min, respectively, 300-400 additional lives could be saved. Based on findings relating to the delay to calling for the EMS and the start of CPR and defibrillation, we speculate that 300-400 additional OHCA patients yearly (4 per 100 000 inhabitants) could be saved in Sweden. © 2013 The Association for the Publication of the Journal of Internal Medicine.

  18. Sustained delivery of VEGF from designer self-assembling peptides improves cardiac function after myocardial infarction

    Energy Technology Data Exchange (ETDEWEB)

    Guo, Hai-dong [Department of Anatomy, School of Basic Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 201203 (China); Cui, Guo-hong; Yang, Jia-jun [Department of Neurology, Shanghai No. 6 People' s Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200233 (China); Wang, Cun [Institutes of Biomedical Sciences, Fudan University, Shanghai 200032 (China); Zhu, Jing; Zhang, Li-sheng; Jiang, Jun [Department of Anatomy, School of Basic Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 201203 (China); Shao, Shui-jin, E-mail: shaoshuijin@163.com [Department of Anatomy, School of Basic Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 201203 (China)

    2012-07-20

    Highlights: Black-Right-Pointing-Pointer The designer peptide LRKKLGKA could self-assemble into nanofibers. Black-Right-Pointing-Pointer Injection of LRKKLGKA peptides could promote the sustained delivery of VEGF. Black-Right-Pointing-Pointer Injection of VEGF with LRKKLGKA peptides lead to sufficient angiogenesis. Black-Right-Pointing-Pointer Injection of VEGF with LRKKLGKA peptides improves heart function. -- Abstract: Poor vascularization and insufficient oxygen supply are detrimental to the survival of residual cardiomyocytes or transplanted stem cells after myocardial infarction. To prolong and slow the release of angiogenic factors, which stimulate both angiogenesis and vasculogenesis, we constructed a novel self-assembling peptide by attaching the heparin-binding domain sequence LRKKLGKA to the self-assembling peptide RADA16. This designer self-assembling peptide self-assembled into nanofiber scaffolds under physiological conditions, as observed by atomic force microscopy. The injection of designer self-assembling peptides can efficiently provide the sustained delivery of VEGF for at least 1 month. At 4 weeks after transplantation, cardiac function was improved, and scar size and collagen deposition were markedly reduced in the group receiving VEGF with the LRKKLGKA scaffolds compared with groups receiving VEGF alone, LRKKLGKA scaffolds alone or VEGF with RADA16 scaffolds. The microvessel density in the VEGF with LRKKLGKA group was higher than that in the VEGF with RADA16 group. TUNEL and cleaved caspase-3 expression assays showed that the transplantation of VEGF with LRKKLGKA enhanced cell survival in the infarcted heart. These results present the tailor-made peptide scaffolds as a new generation of sustained-release biomimetic biomaterials and suggest that the use of angiogenic factors along with designer self-assembling peptides can lead to myocardial protection, sufficient angiogenesis, and improvement in cardiac function.

  19. SYSTEMIC IMBALANCE OF ESSENTIAL METALS AND CARDIAC GENE EXPRESSION IN RATS FOLLOWING ACUTE PULMONARY ZINC EXPOSURE

    Science.gov (United States)

    We have recently demonstrated that PM containing water-soluble zinc may cause cardiac injury following pulmonary exposure. To investigate if pulmonary zinc exposure causes systemic metal imbalance and direct cardiac effects, we intratracheally (IT) instilled male Wistar Kyoto (WK...

  20. Adaptive servo ventilation improves cardiac dysfunction and prognosis in chronic heart failure patients with Cheyne-Stokes respiration.

    Science.gov (United States)

    Yoshihisa, Akiomi; Shimizu, Takeshi; Owada, Takashi; Nakamura, Yuichi; Iwaya, Shoji; Yamauchi, Hiroyuki; Miyata, Makiko; Hoshino, Yasuto; Sato, Takamasa; Suzuki, Satoshi; Sugimoto, Koichi; Yamaki, Takayoshi; Kunii, Hiroyuki; Nakazato, Kazuhiko; Suzuki, Hitoshi; Saitoh, Shu-ichi; Takeishi, Yasuchika

    2011-01-01

    Cheyne-Stokes respiration (CSR) is often observed in patients with chronic heart failure (CHF). Although adaptive servo ventilation (ASV) is effective for CSR, it remains unclear whether ASV improves the cardiac function and prognosis of patients with CHF and CSR.Sixty patients with CHF and CSR (mean left ventricular ejection fraction 38.7%, mean apnea hypopnea index 36.8 times/hour, mean central apnea index 19.1 times/hour) were enrolled in this study. Patients were divided into two groups: 23 patients treated with ASV (ASV group) and 37 patients treated without ASV (Non-ASV group). Measurement of plasma B-type natriuretic peptide (BNP) levels and echocardiography were performed before, 3 and 6 months after treatments in each group. Patients were followed-up for cardiac events (cardiac death and re-hospitalization) after discharge. In the ASV group, NYHA functional class, BNP levels, cardiac systolic and diastolic function were significantly improved with ASV treatment for 6 months. In contrast, none of these parameters changed in the Non-ASV group. Importantly, Kaplan-Meier analysis clearly demonstrated that the event-free rate was significantly higher in the ASV group than in the Non-ASV group.Adaptive servo ventilation improves cardiac function and prognosis in patients with chronic heart failure and Cheyne-Stokes respiration.

  1. Identifying non-technical skills and barriers for improvement of teamwork in cardiac arrest teams

    DEFF Research Database (Denmark)

    Andersen, P.O.; Jensen, Michael Kammer; Lippert, A.

    2010-01-01

    Background: The application of non-technical skills (NTSs) in health care has previously been described in other health-care educational programmes. NTSs are behavioural principles such as leadership, task distribution and communication. The aim of this study was to identify NTSs suitable...... and data analysis were supported by a template describing 25 NTSs derived from other educational programmes in health care. Results: A framework with five categories relating to NTSs was identified: leadership, communication, mutual performance monitoring, maintenance of standards and guidelines and task...... management. Important barriers that were identified were inexperienced team leaders, task overload and hierarchic structure in the teams' inability to maintain focus on chest compressions. Conclusion: Interview participants pointed out that NTSs of teams could improve the treatment of cardiac arrest...

  2. The patient education - Learning and Coping Strategies - improves adherence in cardiac rehabilitation (LC-REHAB)

    DEFF Research Database (Denmark)

    Lynggaard, Vibeke; Nielsen, Claus Vinther; Zwisler, Ann-Dorthe

    2017-01-01

    BACKGROUND: Despite proven benefits of cardiac rehabilitation (CR), adherence to CR remains suboptimal. This trial aimed to assess the impact of the patient education 'Learning and Coping Strategies' (LC) on patient adherence to an eight-week CR program. METHODS: 825 patients with ischaemic heart...... patients as co-educators, situational, reflective and inductive teaching. The control arm received structured deductive teaching. The primary outcomes were patient adherence to at least 75% of the exercise training or education sessions. We tested for subgroup effects on the primary outcomes using...... (79% versus 70%, adjusted OR:1.61, 1.17 to 2.22, P=0.003). Some evidence of larger effects of LC on adherence was seen for patients with heart failure, low education and household income. CONCLUSIONS: Addition of LC strategies improved adherence in rehabilitation both in terms of exercise training...

  3. Role of the clinical nurse specialist in improving patient outcomes after cardiac surgery.

    Science.gov (United States)

    Soltis, Lisa M

    2015-01-01

    Health care reform continues to focus on improving patient outcomes while reducing costs. Clinical nurse specialists (CNSs) should facilitate this process to ensure that best practice standards are used and patient safety is enhanced. One example of ensuring best practices and patient safety is early extubation after open heart surgery, which is a critical component of fast track protocols that reduces may reduce the development of pulmonary complications in the postoperative period while decreasing overall length of stay in the hospital. This project was an interdisciplinary endeavor, led by the CNS and nurse manager, which combined early extubation protocols with enhanced rounding initiatives to help decrease overall length of ventilation time as well as reduce pulmonary complications in patients in the cardiac surgery intensive care unit. The project resulted in a significant decrease in length of stay and a decrease in pulmonary complications in the postoperative period.

  4. A novel urotensin II receptor antagonist, KR-36996, improved cardiac function and attenuated cardiac hypertrophy in experimental heart failure.

    Science.gov (United States)

    Oh, Kwang-Seok; Lee, Jeong Hyun; Yi, Kyu Yang; Lim, Chae Jo; Park, Byung Kil; Seo, Ho Won; Lee, Byung Ho

    2017-03-15

    Urotensin II and its receptor are thought to be involved in various cardiovascular diseases such as heart failure, pulmonary hypertension and atherosclerosis. Since the regulation of the urotensin II/urotensin II receptor offers a great potential for therapeutic strategies related to the treatment of cardiovascular diseases, the study of selective and potent antagonists for urotensin II receptor is more fascinating. This study was designed to determine the potential therapeutic effects of a newly developed novel urotensin II receptor antagonist, N-(1-(3-bromo-4-(piperidin-4-yloxy)benzyl)piperidin-4-yl)benzo[b]thiophene-3-carboxamide (KR-36996), in experimental models of heart failure. KR-36996 displayed a high binding affinity (Ki=4.44±0.67nM) and selectivity for urotensin II receptor. In cell-based study, KR-36996 significantly inhibited urotensin II-induced stress fiber formation and cellular hypertrophy in H9c2UT cells. In transverse aortic constriction-induced cardiac hypertrophy model in mice, the daily oral administration of KR-36996 (30mg/kg) for 14 days significantly decreased left ventricular weight by 40% (Preceptor antagonist could efficiently attenuate both cardiac hypertrophy and dysfunction in experimental heart failure. KR-36996 may be useful as an effective urotensin II receptor antagonist for pharmaceutical or clinical applications.

  5. Dexmedetomidine Versus Propofol Sedation Improves Sublingual Microcirculation After Cardiac Surgery: A Randomized Controlled Trial.

    Science.gov (United States)

    Liu, Xu; Zhang, Kai; Wang, Wei; Xie, Guohao; Cheng, Baoli; Wang, Yan; Hu, Yaoqin; Fang, Xiangming

    2016-12-01

    To compare the effects of dexmedetomidine and propofol on sublingual microcirculation in patients after cardiac surgery. A prospective, randomized, single-blind study. University hospital. Adult patients undergoing elective valve surgery with cardiopulmonary bypass. On arrival in the intensive care unit (ICU), patients were assigned randomly to receive either dexmedetomidine (0.2-1.5 μg/kg/h) or propofol (5-50 μg/kg/min) with open-label titration to a target Richmond Agitation-Sedation Scale of 0 to -3. Sublingual microcirculation was recorded using sidestream dark-field imaging at ICU admission (baseline [T1]) and 4 hours (T2) and 24 hours after ICU admission (T3). At T2, median changes in perfused small-vessel density and the De Backer score from baseline were significantly greater in the dexmedetomidine group (n = 29) than in the propofol group (n = 32) (1.3 v 0 mm/mm(2), p = 0.025; 0.9 v -0.1/mm, p = 0.005, respectively); median changes in small-vessel density and the proportion of perfused small vessels from baseline also tended to be higher in the dexmedetomidine group compared with the propofol group (1.0 v -0.1 mm/mm(2), p = 0.050; 2.1% v 0.5%, p = 0.062, respectively). At T3, there still was a trend toward greater improvements in the small-vessel density, proportion of perfused small-vessels, perfused small-vessel density, and De Backer score from baseline in the dexmedetomidine group than in the propofol group. This trial demonstrated that dexmedetomidine sedation may be better able to improve microcirculation in cardiac surgery patients during the early postoperative period compared with propofol. Copyright © 2016. Published by Elsevier Inc.

  6. PAI-1 gene: pharmacogenetic association of 4G/4G genotype with bleeding after cardiac surgery--pilot study.

    Science.gov (United States)

    Sirgo, Gonzalo; Morales, Pablo; Rello, Jordi

    2009-05-01

    To investigate whether the 4G/4G genotype of the PAI-1 gene is associated with bleeding after cardiac surgery and whether it may influence the use of antifibrinolytic drugs. After a case-control association study to compare the distribution of genotypes of the 4G/5G polymorphism of the PAI-1 gene (4G/4G, 4G/5G and 5G/5G) between cardiac surgery patients (n = 260) and nonhospitalized age-matched controls (n = 111), we have evaluated the possible association of genotype homozygous 4G/4G (considered procoagulant) in two cohorts of cardiac surgery patients (treated with aprotinin or tranexamic acid) with postoperative bleeding and transfusion requirements. Chest tube output was measured at 6 h and 24 h and then total blood output. Genotypes were typed using restriction fragment length polymorphism analysis. The PAI-1 4G/4G genotype was not associated with bleeding except in the subgroup of patients treated with aprotinin in whom blood loss was significantly lower than in nonhomozygous 4G/4G patients at 6 h and 24 h [mean 135.9 ml (SD 101.8 ml) vs. mean 227.6 ml (SD 218.2 ml), P bleeding in the general patient population. The 4G/4G genotype of the PAI-1 gene was associated with less bleeding after cardiac surgery only in the subgroup of patients treated with aprotinin.

  7. Intramyocardial implantation of differentiated rat bone marrow mesenchymal stem cells enhanced by TGF-β1 improves cardiac function in heart failure rats

    Energy Technology Data Exchange (ETDEWEB)

    Lv, Y. [Department of Histology and Embryology, Hebei Medical University, Shijiazhuang, Hebei (China); Liu, B. [Department of Pathology, the First Affiliated Hospital of Hebei North University, Zhangjiakou, Hebei (China); Wang, H.P. [Department of Histology and Embryology, Hebei North University, Zhangjiakou, Hebei (China); Zhang, L. [Department of Histology and Embryology, Hebei Medical University, Shijiazhuang, Hebei (China)

    2016-05-31

    The present study tested the hypotheses that i) transforming growth factor beta 1 (TGF-β1) enhances differentiation of rat bone marrow mesenchymal stem cells (MSCs) towards the cardiomyogenic phenotype and ii) intramyocardial implantation of the TGF-β1-treated MSCs improves cardiac function in heart failure rats. MSCs were treated with different concentrations of TGF-β1 for 72 h, and then morphological characteristics, surface antigens and mRNA expression of several transcription factors were assessed. Intramyocardial implantation of these TGF-β1-treated MSCs to infarcted heart was also investigated. MSCs were initially spindle-shaped with irregular processes. On day 28 after TGF-β1 treatment, MSCs showed fusiform shape, orientating parallel with one another, and were connected with adjoining cells forming myotube-like structures. Immunofluorescence revealed the expression of cardiomyocyte-specific proteins, α-sarcomeric actin and troponin T, in these cells. The mRNA expression of GATA4 and Nkx2.5 genes was slightly increased on day 7, enhanced on day 14 and decreased on day 28 while α-MHC gene was not expressed on day 7, but expressed slightly on day 14 and enhanced on day 28. Transmission electron microscopy showed that the induced cells had myofilaments, z line-like substances, desmosomes, and gap junctions, in contrast with control cells. Furthermore, intramyocardial implantation of TGF-β1-treated MSCs to infarcted heart reduced scar area and increased the number of muscle cells. This structure regeneration was concomitant with the improvement of cardiac function, evidenced by decreased left ventricular end-diastolic pressure, increased left ventricular systolic pressure and increased maximal positive pressure development rate. Taken together, these results indicate that intramyocardial implantation of differentiated MSCs enhanced by TGF-β1 improved cardiac function in heart failure rats.

  8. Impact of lean six sigma process improvement methodology on cardiac catheterization laboratory efficiency.

    Science.gov (United States)

    Agarwal, Shikhar; Gallo, Justin J; Parashar, Akhil; Agarwal, Kanika K; Ellis, Stephen G; Khot, Umesh N; Spooner, Robin; Murat Tuzcu, Emin; Kapadia, Samir R

    2016-03-01

    Operational inefficiencies are ubiquitous in several healthcare processes. To improve the operational efficiency of our catheterization laboratory (Cath Lab), we implemented a lean six sigma process improvement initiative, starting in June 2010. We aimed to study the impact of lean six sigma implementation on improving the efficiency and the patient throughput in our Cath Lab. All elective and urgent cardiac catheterization procedures including diagnostic coronary angiography, percutaneous coronary interventions, structural interventions and peripheral interventions performed between June 2009 and December 2012 were included in the study. Performance metrics utilized for analysis included turn-time, physician downtime, on-time patient arrival, on-time physician arrival, on-time start and manual sheath-pulls inside the Cath Lab. After implementation of lean six sigma in the Cath Lab, we observed a significant improvement in turn-time, physician downtime, on-time patient arrival, on-time physician arrival, on-time start as well as sheath-pulls inside the Cath Lab. The percentage of cases with optimal turn-time increased from 43.6% in 2009 to 56.6% in 2012 (p-trendsix sigma, on improving and sustaining efficiency of our Cath Lab operation. After the successful implementation of this continuous quality improvement initiative, there was a significant improvement in the selected performance metrics namely turn-time, physician downtime, on-time patient arrival, on-time physician arrival, on-time start as well as sheath-pulls inside the Cath Lab. Copyright © 2016 Elsevier Inc. All rights reserved.

  9. Improved Outcome of Cardiac Extracorporeal Membrane Oxygenation in Infants and Children Using Magnetic Levitation Centrifugal Pumps.

    Science.gov (United States)

    Luciani, Giovanni Battista; Hoxha, Stiljan; Torre, Salvatore; Rungatscher, Alessio; Menon, Tiziano; Barozzi, Luca; Faggian, Giuseppe

    2016-01-01

    repair (P = 0.03). During a median follow-up of 34 months (range 4-62 months), there were three (23%) late deaths and two late survivors with neurological sequelae. Weaning rate (5/7 vs. 21/26, P = NS) and prevalence of renal failure requiring dialysis (4/7 vs. 13/26, P = NS) were comparable between SP and ML ECMO groups. Patients supported with ML had a trend toward higher hospital survival (1/7 vs. 12/26, P = 0.07) and significantly higher late survival (0/7 vs. 10/26, P = 0.05). The present experience shows that V-A ECMO for cardiac indications using centrifugal pumps in infants and children yields outcomes absolutely comparable to international registry (ELSO) data using mostly roller pumps. Although changes in practice may have contributed to these results, use of ML centrifugal pumps appears to further improve end-organ recovery and hospital and late survival. Copyright © 2015 International Center for Artificial Organs and Transplantation and Wiley Periodicals Inc.

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

    Institute of Scientific and Technical Information of China (English)

    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.

  11. 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.

  12. Cardiac rehabilitation: a good measure to improve quality of life in peri- and postmenopausal women with microvascular angina

    Directory of Open Access Journals (Sweden)

    Wojciech Szot

    2015-05-01

    Full Text Available Cardiac Syndrome X (CSX was considered a stable coronary syndrome, yet due to its nature, CSX symptoms often have a great impact on patients’ Quality of Life (QoL. According to ESC 2013 stable coronary artery disease criteria, CSX was replaced by Microvascular Angina (MA.Unfortunately, most CSX or MA patients, after classical angina (involving main coronary vessels has been ruled out, often do not receive proper treatment. Indications for pharmacological treatment of MA patients were introduced only recently. Another problematic issue is that scientists describing the pathophysiology of both CSX and MA stress a lack of a deeper insight into the multifactorial etiology of the source of pain associated with this disease. In the presented article we have attempted to study the influence of cardiac rehabilitation (3 months programme on the QoL of patients recognized as suffering from MA, as well as to check if changes in myocardial perfusion in these patients at baseline and after completion of cardiac rehabilitation match changes in their QoL. Therefore, after screening 436 women for MA, we studied 55 of them who were confirmed as having MA and who agreed to participate in the study. Exercise tests, Myocardial Perfusion Imaging, and QoL questionnaires were studied at baseline and after completing 3 months period of cardiac rehabilitation. Results were subsequently compared, which showed a link between improved perfusion score in SPECT study and improved overall physical capacity, on one hand, and improved QoL score on the other. These results confirm that cardiac rehabilitation is a very useful treatment option for MA patients. It seems that training during cardiac rehabilitation is a very important factor (improved physical efficiency –> increase in self-belief, and that taking into consideration the multifactor pathophysiology of pain, it is connected with a better quality of life for MA patients.

  13. Cardiac Paraganglioma Arising From the Right Atrioventricular Groove in a Paraganglioma-Pheochromocytoma Family Syndrome With Evidence of SDHB Gene Mutation: An Unusual Presentation.

    Science.gov (United States)

    Del Forno, Benedetto; Zingaro, Carlo; Di Palma, Enza; Capestro, Filippo; Rescigno, Giuseppe; Torracca, Lucia

    2016-09-01

    Primary cardiac paragangliomas are extremely rare. Recently this neoplasm has been associated with a familiar syndrome as a result of mutation of genes that encode proteins in the mitochondrial complex II. We report a case of a 46-year-old woman having cases of vertebral paraganglioma in her family showing an unusual anatomic and clinical presentation of cardiac paraganglioma and expressing a genetic mutation never associated before with cardiac localization of this neoplasm.

  14. Whether noninvasive optimization of AV and VV delays improves the response to cardiac resynchronization therapy.

    Science.gov (United States)

    Urbanek, Bożena; Chudzik, Michał; Klimczak, Artur; Rosiak, Marcin; Lewek, Joanna; Wranicz, Jerzy Krzysztof

    2013-01-01

    Device optimization is not routinely performed in patients who underwent cardiac resynchronization therapy (CRT) device implantation. Noninvasive optimization of CRT devices by measurement of cardiac output (CO) can be used as a simple method to assess ventricular systolic performance. The aim of this study was to assess whether optimization of atrioventricular (AV) and interventricular (VV) delay can improve hemodynamic response to CRT and whether this optimization should be performed for each patient individually. Twenty patients with advanced heart failure New York Heart Association (NYHA) class III/IV, left ventricular ejection fraction ≤ 35% and left bundle branch block (QRS ≥ 120 ms) in sinus rhythm were evaluated from 24 h to 48 h after implantation of a CRT device by means of impedance cardiography (ICG). CO was first measured at each patient's intrinsic rhythm. Patients then underwent adjustments of AV and VV delay from 80 ms to 140 ms and from -60 ms to +60 ms, respectively in 20 ms increment steps and CO at each setting was measured by ICG. Both AV and VV delays were programmed according to the greatest improvement in CO compared to intrinsic rhythm. There was a statistically signifi cant increase in CO measured at the intrinsic rhythm compared to different AV delay by mean of 21% (3.8 ± 1.0 vs. 4.6 ± 0.1 L/min, p AV/VV delays with left ventricle-preexcitation or simultaneous biventricular pacing caused additional increased CO from intrinsic rhythm by mean of 32.6% (3.8 ± 1.0 vs. 5.04 ± ± 1.0 L/min, p AV/VV setting delays also resulted in improved hemodynamic responses compared to VV factory setting delay. Both AV and VV delay optimization should be performed in clinical practice. Optimal AV delay improved outcome. However, combination of optimized AV/VV delays provided the best hemodynamic response. Optimized AV/VV delays with left ventricle-preexcitation or simultaneous biventricular pacing increased hemodynamic output compared to intrinsic

  15. Granulocyte-macrophage colony stimulating factor improves cardiac function in rabbits following myocardial infarction

    Institute of Scientific and Technical Information of China (English)

    董安平; 马爱群; 韩克; 杨春; 蔡平; 蒋文慧

    2003-01-01

    Objective: To investigate the therapeutic potency of recombinant human Granulocyte-Macrophage Colony-Stimulating Factor (GM-CSF) in a rabbit myocardial infarction model. Methods: A myocardial infarction was created by the ligation of the major ventricular branch of the left coronary artery in rabbits. After myocardial infarction, the animals were randomly assigned to GM-CSF treatment group, untreated groups and sham-operated group. The rabbits of the treated group were injected into GM-CSF by subcutaneous administration, 10 μg/kg/day, once a day for 5 days. The untreated and sham-operated group received a equal saline in the same manner as treated group. Six weeks later echocardiography and haemodynamic assessment were undertaken to assesse cardiac function. The size of the infarct region of the heart were also studied. Results: The untreated group exhibited significant higher left ventricle end-diastolic pressure, higher central venous pressure, and with significant lower mean blood pressure, lower peak first derivative of left ventricle pressure (dP/dt) than the sham group. Also, Rabbits in untreated group display significant systolic dysfunction shown by the decreased ejection fraction, diastolic dysfunction shown by increasing in the ratio of E wave to A wave (E/A), and display left ventricle enlargement. However, GS-CSF singnificantly prevented heart dysfunction, left ventricle enlargement, and reduced infarct size in treatment group. Conclusion: Administration GM-CSF after cardiac infarction can improve heart function. These findings indicate the technique may be a novel and simple therapeutic method for ischemic myocardium.

  16. Cardiac Rehabilitation Improves the QRS Fragmentation in Patients With ST Elevatıon Myocardial Infarction

    Science.gov (United States)

    Bulut, Mustafa; Deniz Acar, Rezzan; Ergün, Sunay; Geçmen, Çetin; Akçakoyun, Mustafa

    2015-01-01

    Introduction: We aimed to evaluate the effect of exercise-based cardiac rehabilitation (CR) on the fragmented QRS (fQRS) in patients with ST elevation myocardial infarction (STEMI). Methods: Ninety-seven patients with STEMI participated CR and 81 patients as a control group were included to the study. The trained patients were grouped according to the presence and persistence of QRS fragmentation on the electrocardiogram (ECG) before and after CR. If the fragmentation was present on the ECG at the beginning of the CR but not on the ECG at the end of CR; the transient group, if the fQRS persists after CR; the persistent fQRS group. ECGs obtained from the control group were grouped according to the presence of a fQRS on ECG. Results: Among the trained patients, 45 (46%) did not have a fQRS before CR, whereas 52 (54%) presented a fQRS before CR, which was persistent in 35 patients (the persistent fQRS group) and transient in 17 patients (the transient fQRS group). Among 81 patients included in the control group, fQRS was persistent in 41 patients. Presence of fQRS on the ECG was significantly decreased with CR and it is better in trained group than the control group (P = .034). There were not significant correlations with other characteristics, except hypertension. Conclusion: The existence of the fQRS decreases after CR in patients with STEMI especially in hypertensive individuals, which may be related to improved electrical stability in the myocardium as a predictor of increase in survival and decrease in major cardiac events. PMID:26430496

  17. Heparin and protamine titration do not improve haemostasis in cardiac surgical patients.

    Science.gov (United States)

    Shore-Lesserson, L; Reich, D L; DePerio, M

    1998-01-01

    Weight-based heparin and protamine dosing strategies for cardiopulmonary bypass (CPB) do not take into account interpatient variability in drug sensitivity and may result in bleeding complications. We compared the Hemochron RxDx heparin and protamine titration system with standard weight based management with regard to heparin dose, protamine dose, and perioperative bleeding. One hundred and thirty-five cardiac surgical patients were randomised into four groups. Group 1 received standard heparin and protamine management: Group 2 received heparin and protamine by in vitro titration. Group 3 had the heparin dose titrated, and group 4 had the protamine dose titrated. Coagulation tests, bleeding, and transfusion requirements were measured. The initial heparin bolus predicted by the titration was < 300 U.kg-1 in all patients. Group 2 received a lower heparin bolus for the initiation of bypass but total heparin doses were not different among groups (group 1 = 365 +/- 43, group 2 = 348 +/- 73 U.kg-1, group 3 = 394 +/- 86 U.kg-1, group 4 = 376 +/- 60; P = 0.06). Groups 2 and 4 received a lower initial and a lower total protamine dose (total dose group 1 = 4.03 +/- 0.65 mg.kg-1, group 2 = 3.56 +/- 1.11 mg.kg-1, group 3 = 4.22 +/- 0.90 mg.kg-1, group 4 = 3.38 +/- 0.98 mg.kg-1, P = 0.001). The incidences of incomplete heparin neutralisation (P = 0.14) and heparin rebound (P = 0.1) were not different among groups. Postoperative bleeding and transfusion requirements did not differ. In cardiac surgical patients, heparin and protamine titration did predict a lower protamine dose but did not result in a measurable improvement in haemostasis during the perioperative period.

  18. [Mutation screening for the causative gene in a four-generation Chinese pedigree with progressive cardiac conduction defect].

    Science.gov (United States)

    Tan, X J; Huang, H; He, F; Zhu, L; Li, H; Jiang, Y S; Li, H; Huang, X H; Sun, Z S; Li, Z H

    2016-05-24

    To define the potential causative gene mutation in a Chinese pedigree with progressive cardiac conduction defect (PCCD). Sanger sequencing was performed to define potential causative gene mutation in a four-generation family with 68 members including seven PCCD patients (5 male) from 2010 to 2015.No causative gene was detected by screening known candidate genes related to PCCD including SCN5A, NKX2.5 and LMNA.High-throughput sequencing technology on exon-enriched DNA was then used to search the causative genes in 2 patients and one normal family member. Eight new non-synonymous single nucleotide variants including AQP7 gene (exon5: c.T343C: p.Y115H), CACNA1B gene (NM_001243812: exon19: c.A2986G: p.T996A), CATSPERB gene (exon27: c.C3254G: p.P1085R), CLCA2 gene (exon11: c.G1725T: p.W575C), CLCA3P gene (ncRNA_intronic), MYLK-AS1 gene (ncRNA_intronic), TTN gene (ncRNA_UTR3), LMNA gene (LMNA: NM_170708: exon5: c.C922T: p.Q308X) were identified by comparing and filtering the results with known public databases.Then, more detailed biological analysis on these 8 genes was conducted.Traditional Sanger sequencing validated the exome sequencing results, and found that the mutation c. 1725G﹥T in gene CLCA2 segregated with the phenotype of this PCCD pedigree.The mutation c. 1725G﹥T in gene CLCA2 was thus be considered as the causative PCCD gene in this pedigree from the perspective of genetics and genomics. The heterozygote mutation c. 1725G﹥T in gene CLCA2 might be causative gene in this PCCD pedigree.This finding adds new gene mutation variant responsible for PCCD.

  19. 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.

  20. Cardiac resynchronization therapy improves psycho-cognitive performance in patients with heart failure.

    Science.gov (United States)

    Duncker, David; Friedel, Katrin; König, Thorben; Schreyer, Hendrik; Lüsebrink, Ulrich; Duncker, Mareke; Oswald, Hanno; Klein, Gunnar; Gardiwal, Ajmal

    2015-09-01

    Reduced cognitive performance and high prevalence of depression have been reported in patients with congestive heart failure (CHF) and severe left ventricular dysfunction. However, effects of contemporary device therapy on cognitive performance and depression symptoms have not been studied thoroughly. Seventy-four consecutive CHF patients-45 receiving a biventricular defibrillator (CRT-D) and 29 receiving an implantable single or dual-chamber defibrillator (ICD) as a control group-were enrolled in this investigator-initiated, prospective, controlled, and investigator-blinded study. A set of neuropsychological tests (mini-mental state examination, DemTect, age-concentration test, and Beck depression inventory) was performed before, at 3 and at 6 months after device implantation. DemTect-score improved significantly (F = 7.8; P = 0.007) after CRT-D-implantation compared with ICD. Age-concentration test revealed better concentration ability after CRT-D-implantation (F = 8.3; P = 0.005) compared with ICD. Under CRT-D mini-mental state examination showed a significant improvement (F = 4.2; P = 0.043). CRT with defibrillator therapy also improved depression revealed by beck depression inventory (F = 14.7; Pcognitive improvement by resynchronization therapy in CHF patients with severe left ventricular dysfunction. In contrast to ICD therapy, the beneficial effect of CRT-D on psycho-cognitive performance might be attributed to improved cardiac function and haemodynamics. Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2015. For permissions please email: journals.permissions@oup.com.

  1. Chip/Ldb1 interacts with Tailup/islet1 to regulate cardiac gene expression in Drosophila.

    Science.gov (United States)

    Werner, Kathrin; Donow, Cornelia; Pandur, Petra

    2017-04-01

    The LIM-homeodomain transcription factor Tailup (Tup) is a component of the complex cardiac transcriptional network governing specification and differentiation of cardiac cells in Drosophila. LIM-domain containing factors are known to interact with the adaptor molecule Chip/Ldb1 to form higher order protein complexes to regulate gene expression thereby determining a cell's developmental fate. However, with respect to Drosophila heart development, it has not been investigated yet, whether Chip and tup interact to regulate the generation of different cardiac cell types. Here we show that Chip is required for normal heart development and that it interacts with tup in this context. Particularly the number of Odd skipped-expressing pericardial cells depends on balanced amounts of Chip and Tup. Data from luciferase assays using Hand- and even-skipped reporter constructs in Drosophila S2 cells indicate that Chip and Tup act as a tetrameric complex on the regulatory regions of Hand and even-skipped (eve). Finally we have identified and verified five Tup binding sites in the eve mesodermal enhancer, which adds Tup as novel factor to directly regulate eve expression. Taken together this study provides novel findings regarding cardiac gene expression regulation in Drosophila. © 2017 Wiley Periodicals, Inc.

  2. Usefulness of case reports to improve medical knowledge regarding trigemino-cardiac reflex in skull base surgery

    Directory of Open Access Journals (Sweden)

    Sadr-Eshkevari Pooan

    2011-04-01

    Full Text Available Abstract We describe the discovery of the trigemino-cardiac reflex by Schaller in 1999 and the continued improvement of the knowledge about the trigemino-cardiac reflex involved in neurosurgery, especially in skull base surgery, during the past several years. The achieved medical progress could be gained only by the practical experience described by different case reports and later case series that have been published in several principal scientific journals. Additionally, we explain the scientific as well as clinical importance of the communication of the case reports on TCR. Special reference has been given to the validity of the case reports for new phenomena in clinical medicine.

  3. Usefulness of case reports to improve medical knowledge regarding trigemino-cardiac reflex in skull base surgery.

    Science.gov (United States)

    Sandu, Nora; Sadr-Eshkevari, Pooan; Schaller, Bernhard J

    2011-04-15

    We describe the discovery of the trigemino-cardiac reflex by Schaller in 1999 and the continued improvement of the knowledge about the trigemino-cardiac reflex involved in neurosurgery, especially in skull base surgery, during the past several years. The achieved medical progress could be gained only by the practical experience described by different case reports and later case series that have been published in several principal scientific journals. Additionally, we explain the scientific as well as clinical importance of the communication of the case reports on TCR. Special reference has been given to the validity of the case reports for new phenomena in clinical medicine.

  4. Role of prophylactic coronary revascularisation in improving cardiovascular outcomes during non-cardiac surgery: A narrative review.

    Science.gov (United States)

    Rahat, T; Nguyen, T; Latif, F

    2016-10-01

    Coronary revascularisation has been a topic of debate for over three decades in patients undergoing high-risk non-cardiac surgery. The paradigm shifted from routine coronary angiography toward stress test guided decision-making based on larger randomised trials. However, this paradigm is challenged by relatively newer data where routine coronary angiography and revascularisation is shown to improve perioperative cardiovascular outcomes. We review major studies performed over a long period including more contemporary data with regard to the 2014 American College of Cardiology/American Heart Association as well as 2014 European Society of Cardiology guideline on perioperative cardiovascular evaluation of patients undergoing non-cardiac surgery.

  5. Early Regulation of Profibrotic Genes in Primary Human Cardiac Myocytes by Trypanosoma cruzi.

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    Aniekanabassi N Udoko

    2016-01-01

    Full Text Available The molecular mechanisms of Trypanosoma cruzi induced cardiac fibrosis remains to be elucidated. Primary human cardiomyoctes (PHCM exposed to invasive T. cruzi trypomastigotes were used for transcriptome profiling and downstream bioinformatic analysis to determine fibrotic-associated genes regulated early during infection process (0 to 120 minutes. The identification of early molecular host responses to T. cruzi infection can be exploited to delineate important molecular signatures that can be used for the classification of Chagasic patients at risk of developing heart disease. Our results show distinct gene network architecture with multiple gene networks modulated by the parasite with an incline towards progression to a fibrogenic phenotype. Early during infection, T. cruzi significantly upregulated transcription factors including activator protein 1 (AP1 transcription factor network components (including FOSB, FOS and JUNB, early growth response proteins 1 and 3 (EGR1, EGR3, and cytokines/chemokines (IL5, IL6, IL13, CCL11, which have all been implicated in the onset of fibrosis. The changes in our selected genes of interest did not all start at the same time point. The transcriptome microarray data, validated by quantitative Real-Time PCR, was also confirmed by immunoblotting and customized Enzyme Linked Immunosorbent Assays (ELISA array showing significant increases in the protein expression levels of fibrogenic EGR1, SNAI1 and IL 6. Furthermore, phosphorylated SMAD2/3 which induces a fibrogenic phenotype is also upregulated accompanied by an increased nuclear translocation of JunB. Pathway analysis of the validated genes and phospho-proteins regulated by the parasite provides the very early fibrotic interactome operating when T. cruzi comes in contact with PHCM. The interactome architecture shows that the parasite induces both TGF-β dependent and independent fibrotic pathways, providing an early molecular foundation for Chagasic

  6. Gene mutations in cardiac arrhythmias: a review of recent evidence in ion channelopathies

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    Hsiao PY

    2013-01-01

    Full Text Available Pi-Yin Hsiao,1 Hui-Chun Tien,2 Chu-Pin Lo,2 Jyh-Ming Jimmy Juang,3 Yi-Hsin Wang,2 Ruey J Sung41Institute of Life Sciences, National Central University, Taoyuan, Taiwan; 2Department of Financial and Computational Mathematics, Providence University, Taichung, Taiwan; 3Cardiovascular Center and Department of Cardiology, National Taiwan University, Taipei, Taiwan; 4Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, CA, USAAbstract: Over the past 15 years, molecular genetic studies have linked gene mutations to many inherited arrhythmogenic disorders, in particular, "ion channelopathies", in which mutations in genes encode functional units of ion channels and/or their transporter-associated proteins in patients without primary cardiac structural abnormalities. These disorders are exemplified by congenital long QT syndrome (LQTS, short QT syndrome, Brugada syndrome (BrS and catecholaminergic polymorphic ventricular tachycardia (CPVT. Functional and pathophysiological studies have led to better understanding of the clinical spectrum, ion channel structures and cellular electrophysiology involving dynamics of intracellular calcium cycling in many subtypes of these disorders and more importantly, development of potentially more effective pharmacological agents and even curative gene therapy. In this review, we have summarized (1 the significance of unveiling mutations in genes encoding transporter-associated proteins as the cause of congenital LQTS, (2 the technique of catheter ablation applied at the right ventricular outflow tract may be curative for severely symptomatic BrS, (3 mutations with channel function modulated by protein Kinase A-dependent phosphorylation can be the culprit of CPVT mimicry in Andersen-Tawil syndrome (LQT7, (4 ablation of the ion channel anchoring protein may prevent arrhythmogenesis in Timothy syndrome (LQT8, (5 altered intracellular Ca2+ cycling can be the basis of effective targeted

  7. Social media in paediatric heart disease: professional use and opportunities to improve cardiac care.

    Science.gov (United States)

    Schumacher, Kurt R; Lee, Joyce M; Pasquali, Sara K

    2015-12-01

    Social media is any type of communication utilising electronic technology that follows two guiding principles: free publishing or sharing of content and ideas and group collaboration and inter-connectedness. Over the last 10 years, social media technology has made tremendous inroads into all facets of communication. Modalities such as Facebook, YouTube, and Twitter are no longer viewed as new communication technologies. Owing to their tremendous usage, they are now common ways to conduct a dialogue with individuals and groups. Greater than 91% of teenagers and 89% of young adults routinely use social media. Further, 24% of teenagers reported being online "almost constantly". These forms of communication are readily used by individuals cared for in the field of paediatric cardiology; thus, they should carry significant interest for cardiology care providers; however, social media's influence on medicine extends beyond use by patients. It directly affects all medical providers, both users and non-users. Further, social media has the ability to improve care for patients with paediatric heart disease. This article details social media's current influence on paediatric cardiology, including considerations for professional use of social media and potential opportunities to improve cardiac care.

  8. Thymosin beta 4 prevents oxidative stress by targeting antioxidant and anti-apoptotic genes in cardiac fibroblasts.

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    Sandeep Kumar

    Full Text Available RATIONALE: Thymosin beta-4 (Tβ4 is a ubiquitous protein with diverse functions relating to cell proliferation and differentiation that promotes wound healing and modulates inflammatory responses. The effecter molecules targeted by Tβ4 for cardiac protection remains unknown. The purpose of this study is to determine the molecules targeted by Tβ4 that mediate cardio-protection under oxidative stress. METHODS: Rat neonatal fibroblasts cells were exposed to hydrogen peroxide (H(2O(2 in presence and absence of Tβ4 and expression of antioxidant, apoptotic and pro-fibrotic genes was evaluated by quantitative real-time PCR and western blotting. Reactive oxygen species (ROS levels were estimated by DCF-DA using fluorescent microscopy and fluorimetry. Selected antioxidant and antiapoptotic genes were silenced by siRNA transfections in cardiac fibroblasts and the effect of Tβ4 on H(2O(2-induced profibrotic events was evaluated. RESULTS: Pre-treatment with Tβ4 resulted in reduction of the intracellular ROS levels induced by H(2O(2 in the cardiac fibroblasts. This was associated with an increased expression of antioxidant enzymes Cu/Zn superoxide dismutase (SOD and catalase and reduction of Bax/Bcl(2 ratio. Tβ4 treatment reduced the expression of pro-fibrotic genes [connective tissue growth factor (CTGF, collagen type-1 (Col-I and collagen type-3 (Col-III] in the cardiac fibroblasts. Silencing of Cu/Zn-SOD and catalase gene triggered apoptotic cell death in the cardiac fibroblasts, which was prevented by treatment with Tβ4. CONCLUSION: This is the first report that exhibits the targeted molecules modulated by Tβ4 under oxidative stress utilizing the cardiac fibroblasts. Tβ4 treatment prevented the profibrotic gene expression in the in vitro settings. Our findings indicate that Tβ4 selectively targets and upregulates catalase, Cu/Zn-SOD and Bcl(2, thereby, preventing H(2O(2-induced profibrotic changes in the myocardium. Further studies are

  9. 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

  10. ASSUMED OXYGEN-CONSUMPTION BASED ON CALCULATION FROM DYE DILUTION CARDIAC-OUTPUT - AN IMPROVED FORMULA

    NARCIS (Netherlands)

    BERGSTRA, A; VANDIJK, RB; HILLEGE, HL; LIE, KI; MOOK, GA

    1995-01-01

    This study was performed because of observed differences between dye dilution cardiac output and the Fick cardiac output, calculated from estimated oxygen consumption according to LaFarge and Miettinen, and to find a better formula for assumed oxygen consumption. In 250 patients who underwent left a

  11. Trpm4 Gene Invalidation Leads to Cardiac Hypertrophy and Electrophysiological Alterations

    Science.gov (United States)

    Gueffier, Mélanie; Finan, Amanda; Khoueiry, Ziad; Cassan, Cécile; Serafini, Nicolas; Aimond, Franck; Granier, Mathieu; Pasquié, Jean-Luc; Launay, Pierre; Richard, Sylvain

    2014-01-01

    Rationale TRPM4 is a non-selective Ca2+-activated cation channel expressed in the heart, particularly in the atria or conduction tissue. Mutations in the Trpm4 gene were recently associated with several human conduction disorders such as Brugada syndrome. TRPM4 channel has also been implicated at the ventricular level, in inotropism or in arrhythmia genesis due to stresses such as ß-adrenergic stimulation, ischemia-reperfusion, and hypoxia re-oxygenation. However, the physiological role of the TRPM4 channel in the healthy heart remains unclear. Objectives We aimed to investigate the role of the TRPM4 channel on whole cardiac function with a Trpm4 gene knock-out mouse (Trpm4-/-) model. Methods and Results Morpho-functional analysis revealed left ventricular (LV) eccentric hypertrophy in Trpm4-/- mice, with an increase in both wall thickness and chamber size in the adult mouse (aged 32 weeks) when compared to Trpm4+/+ littermate controls. Immunofluorescence on frozen heart cryosections and qPCR analysis showed no fibrosis or cellular hypertrophy. Instead, cardiomyocytes in Trpm4-/- mice were smaller than Trpm4+/+with a higher density. Immunofluorescent labeling for phospho-histone H3, a mitosis marker, showed that the number of mitotic myocytes was increased 3-fold in the Trpm4-/-neonatal stage, suggesting hyperplasia. Adult Trpm4-/- mice presented multilevel conduction blocks, as attested by PR and QRS lengthening in surface ECGs and confirmed by intracardiac exploration. Trpm4-/-mice also exhibited Luciani-Wenckebach atrioventricular blocks, which were reduced following atropine infusion, suggesting paroxysmal parasympathetic overdrive. In addition, Trpm4-/- mice exhibited shorter action potentials in atrial cells. This shortening was unrelated to modifications of the voltage-gated Ca2+ or K+ currents involved in the repolarizing phase. Conclusions TRPM4 has pleiotropic roles in the heart, including the regulation of conduction and cellular electrical activity

  12. Osteopenia and male-specific sudden cardiac death in mice lacking a zinc transporter gene, Znt5.

    Science.gov (United States)

    Inoue, Koichi; Matsuda, Koichi; Itoh, Makoto; Kawaguchi, Hiroshi; Tomoike, Hitonobu; Aoyagi, Teruhiko; Nagai, Ryozo; Hori, Masatsugu; Nakamura, Yusuke; Tanaka, Toshihiro

    2002-07-15

    We isolated a mammalian gene whose expression transiently increased in response to intimal denudation of rabbit aorta. It was identical to a gene encoding a zinc transporter, ZNT5, reported very recently by others. Mice deficient for this gene showed poor growth and a decrease in bone density due to impairment of osteoblast maturation to osteocyte. More than 60% of male null mice died suddenly because of the bradyarrhythmias. Analysis of gene-expression profiles in murine hearts by means of an oligonucleotide microarray disclosed that a subset of genes encoding immediate-early response factors (IEGs) and heat shock proteins (HSPs) were down-regulated in Znt5-null mice. These results indicate that Znt5 protein plays an important role in maturation of osteoblasts and in maintenance of the cells involved in the cardiac conduction system, partly owing to dysregulated expression of IEGs and HSPs.

  13. Improved cardiac management with a disease management program incorporating comprehensive lipid profiling.

    Science.gov (United States)

    McAna, John F; Goldfarb, Neil I; Couto, Joseph; Henry, Michelle A; Piefer, Gary; Rapier, George M

    2012-02-01

    The objective of this study was to evaluate the improved effectiveness of a disease management treatment protocol incorporating comprehensive lipid profiling and targeted lipid care based on lipid profile findings in patients with ischemic heart disease (IHD) or congestive heart failure (CHF) enrolled in a managed care plan. This retrospective cohort study, conducted over a 2-year period, compared outcomes between patients with a standard lipid profile to those evaluated with a comprehensive lipid profile. All adult members of the WellMed Medical Management, Inc. managed care health plan diagnosed with IHD or CHF, and continuously enrolled between July 1, 2006 and June 30, 2008, were included in the study. Cases were defined as those who had at least 1 comprehensive lipid test (the VAP [vertical auto profile] ultracentrifuge test) during this period (n=1767); they were compared to those who had no lipid testing or traditional standard lipid testing only (controls, n=289). Univariate statistics were analyzed to describe the groups, and bivariate t tests or chi-squares examined differences between the 2 cohorts. Multivariate regression analyses were performed to control for potential confounders. The results show that the case group had lower total costs ($4852.62 vs. $7413.18; P=0.0255), fewer inpatient stays (13.1% vs. 18.3% of controls; P=0.0175) and emergency department visits (11.9% vs. 15.6% of controls; P=0.0832). Prescription use and frequency of lipid measurement suggested improved control resulting from a targeted approach to managing specific dyslipidemias. A treatment protocol incorporating a comprehensive lipid profile appears to improve care and reduce utilization and costs in a disease management program for cardiac patients.

  14. Phosphomimetic modulation of eNOS improves myocardial reperfusion and mimics cardiac postconditioning in mice.

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    Terrence Pong

    Full Text Available OBJECTIVE: Myocardial infarction resulting from ischemia-reperfusion injury can be reduced by cardiac postconditioning, in which blood flow is restored intermittently prior to full reperfusion. Although key molecular mechanisms and prosurvival pathways involved in postconditioning have been identified, a direct role for eNOS-derived NO in improving regional myocardial perfusion has not been shown. The objective of this study is to measure, with high temporal and spatial resolution, regional myocardial perfusion during ischemia-reperfusion and postconditioning, in order to determine the contribution of regional blood flow effects of NO to infarct size and protection. METHODS AND RESULTS: We used myocardial contrast echocardiography to measure regional myocardial blood flow in mice over time. Reperfusion after myocardial ischemia-reperfusion injury is improved by postconditioning, as well as by phosphomimetic eNOS modulation. Knock-in mice expressing a phosphomimetic S1176D form of eNOS showed improved myocardial reperfusion and significantly reduced infarct size. eNOS knock-out mice failed to show cardioprotection from postconditioning. The size of the no-reflow zone following ischemia-reperfusion is substantially reduced by postconditioning and by the phosphomimetic eNOS mutation. CONCLUSIONS AND SIGNIFICANCE: Using myocardial contrast echocardiography, we show that temporal dynamics of regional myocardial perfusion restoration contribute to reduced infarct size after postconditioning. eNOS has direct effects on myocardial blood flow following ischemia-reperfusion, with reduction in the size of the no-reflow zone. These results have important implications for ongoing clinical trials on cardioprotection, because the degree of protective benefit may be significantly influenced by the regional hemodynamic effects of eNOS-derived NO.

  15. Cardiac C-type natriuretic peptide gene expression and plasma concentrations in neonatal piglets

    DEFF Research Database (Denmark)

    Hansen, Lasse H; Smith, Julie; Goetze, Jens Peter

    2014-01-01

    and cardiac tissue extracts were quantified by a porcine-specific radioimmunoassay. RESULTS: Cardiac CNP mRNA contents (n=24) were low compared to sites of known expression, where porcine seminal vesicle CNP mRNA contents were 200-fold higher. In addition, plasma proCNP concentrations in the newborn piglets...

  16. Cardiac C-type natriuretic peptide gene expression and plasma concentrations in neonatal piglets

    DEFF Research Database (Denmark)

    Hansen, Lasse; Smith, Julie; Goetze, Jens P

    2014-01-01

    in plasma and cardiac tissue extracts were quantified by a porcine-specific radioimmunoassay. RESULTS: Cardiac CNP mRNA contents (n=24) were low compared to sites of known expression, where porcine seminal vesicle CNP mRNA contents were 200-fold higher. In addition, plasma proCNP concentrations...

  17. Human Mesenchymal Stromal Cells Improve Cardiac Perfusion in an Ovine Immunocompetent Animal Model.

    Science.gov (United States)

    Dayan, Victor; Sotelo, Veronica; Delfina, Valentina; Delgado, Natalia; Rodriguez, Carlos; Suanes, Carol; Langhain, María; Ferrando, Rodolfo; Keating, Armand; Benech, Alejandro; Touriño, Cristina

    2016-08-01

    Mesenchymal stromal cells (MSCs) hold considerable promise in the treatment of ischemic heart disease. Most preclinical studies of MSCs for acute myocardial infarction (AMI) have been performed either in syngeneic animal models or with human cells in xenogeneic immunodeficient animals. A preferable pre-clinical model, however, would involve human MSCs in an immunocompetent animal. AMI was generated in adult sheep by inducing ischemia reperfusion of the second diagonal branch. Sheep (n = 10) were randomized to receive an intravenous injection of human MSCs (1 × 10(6) cells/kg) or phosphate buffered saline. Cardiac function and remodeling were evaluated with echocardiography. Perfusion scintigraphy was used to identify sustained myocardial ischemia. Interaction between human MSCs and ovine lymphocytes was assessed by a mixed lymphocyte response (MLR). Sheep receiving human MSCs showed significant improvement in myocardial perfusion at 1 month compared with baseline measurements. There was no change in ventricular dimensions in either group after 1 month of AMI. No adverse events or symptoms were observed in the sheep receiving human MSCs. The MLR was negative. The immunocompetent ovine AMI model demonstrates the clinical safety and efficacy of human MSCs. The human cells do not appear to be immunogenic, further suggesting that immunocompetent sheep may serve as a suitable pre-clinical large animal model for testing human MSCs.

  18. Glucose oxidation positively regulates glucose uptake and improves cardiac function recovery after myocardial reperfusion.

    Science.gov (United States)

    Li, Tingting; Xu, Jie; Qin, Xinghua; Hou, Zuoxu; Guo, Yongzheng; Liu, Zhenhua; Wu, Jianjiang; Zheng, Hong; Zhang, Xing; Gao, Feng

    2017-03-21

    Myocardial reperfusion decreases glucose oxidation and uncouples glucose oxidation from glycolysis. Therapies that increase glucose oxidation lessen myocardial ischemia/reperfusion injury. However, the regulation of glucose uptake during reperfusion remains poorly understood. Here we found that glucose uptake was remarkably diminished in myocardium following reperfusion in Sprague-Dawley rats as detected by 18F-labeled and fluorescent-labeled glucose analogs, even though GLUT1 was upregulated by 3 folds and GLUT4 translocation remained unchanged compared with those of sham rats. The decreased glucose uptake was accompanied by suppressed glucose oxidation. Interestingly, stimulating glucose oxidation by inhibition of pyruvate dehydrogenase kinase 4 (PDK4), a rate-limiting enzyme for glucose oxidation, increased glucose uptake and alleviated ischemia/reperfusion injury. In vitro data in neonatal myocytes showed that PDK4 overexpression decreased glucose uptake, while its knockdown increased glucose uptake, suggesting a role of PDK4 in regulating glucose uptake. Moreover, inhibition of PDK4 increased myocardial glucose uptake with concomitant enhancement of cardiac insulin sensitivity following myocardial ischemia/reperfusion. These results showed that the suppressed glucose oxidation mediated by PDK4 contributes to the reduced glucose uptake in myocardium following reperfusion, and enhancement of glucose uptake exerts cardioprotection. The findings suggest that stimulating glucose oxidation via PDK4 could be an efficient approach to improve recovery from myocardial ischemia/reperfusion injury. Copyright © 2017, American Journal of Physiology-Endocrinology and Metabolism.

  19. Gene control of acupuncture and moxibustion preconditioning on apoptosis in ischemic cardiac muscle of rats with re-perfusion

    Institute of Scientific and Technical Information of China (English)

    SUN Zhong-ren; LI Xiao-ning; ZHAO Yu-hui; TIAN Yan-yan; XU Li

    2008-01-01

    In order to explore the effect of acupuncture preconditioning on rats' cell apoptosis with cardiac muscle re-perfusion damage and bcl-2mRNA genes, we used differentiating acupuncture and moxibustion preconditioning among groups, then compared acupuncture and moxibustion preconditioning with ischemic preconditioning. The experimental results show that acupuncture and moxibustion preconditioning makes more bcl-2mRNA genes expressed and produces less cell apeptosis, furthermore, groups of acupuncture and moxibustion preconditioning for twice a day are more effective than those of ischemic preconditioning.

  20. Genetic Background Influences Adaptation To Cardiac Hypertrophy and Ca2+ Handling Gene Expression

    Directory of Open Access Journals (Sweden)

    Steve B Waters

    2013-03-01

    Full Text Available Genetic variability has a profound effect on the development of cardiac hypertrophy in response to stress. Consequently, using a variety of inbred mouse strains with known genetic profiles may be powerful models for studying the response to cardiovascular stress. To explore this approach we looked at male C57BL/6J and 129/SvJ mice. Hemodynamic analyses of left ventricular pressures indicated significant differences in 129/SvJ and C57BL/6J mice that implied altered Ca2+ handling. Specifically, 129/SvJ mice demonstrated reduced rates of relaxation and insensitivity to dobutamine(Db. We hypothesized that altered expression of genes controlling the influx and efflux of Ca2+ from the sarcoplasmic reticulum was responsible and investigated the expression of several genes involved in maintaining the intracellular and sarcoluminal Ca2+ concentration using quantitative real-time PCR analyses (qRT-PCR. We observed significant differences in baseline gene expression as well as different responses in expression to isoproterenol (ISO challenge. In untreated control animals, 129/SvJ mice expressed 1.68x more ryanodine recptor 2(Ryr2 mRNA than C57BL/6J mice but only 0.37x as much calsequestrin 2(Casq2. After treatment with ISO, sarco(endoplasmic reticulum Ca2+-ATPase(Serca2 expression was reduced nearly two-fold in 129/SvJ while expression in C57BL/6J was stable. Interestingly, β(1 adrenergic receptor(Adrb1 expression was lower in 129/SvJ compared to C57BL/6J at baseline and lower in both strains after treatment. Metabolically, the brain isoform of creatine kinase(Ckb was up-regulated in response to ISO in C57BL/6J but not in 129/SvJ. These data suggest that the two strains of mice regulate Ca2+ homeostasis via different mechanisms and may be useful in developing personalized therapies in human patients.

  1. Genetic background influences adaptation to cardiac hypertrophy and Ca(2+) handling gene expression.

    Science.gov (United States)

    Waters, Steve B; Diak, Douglass M; Zuckermann, Matthew; Goldspink, Paul H; Leoni, Lara; Roman, Brian B

    2013-01-01

    Genetic variability has a profound effect on the development of cardiac hypertrophy in response to stress. Consequently, using a variety of inbred mouse strains with known genetic profiles may be powerful models for studying the response to cardiovascular stress. To explore this approach we looked at male C57BL/6J and 129/SvJ mice. Hemodynamic analyses of left ventricular pressures (LVPs) indicated significant differences in 129/SvJ and C57BL/6J mice that implied altered Ca(2+) handling. Specifically, 129/SvJ mice demonstrated reduced rates of relaxation and insensitivity to dobutamine (Db). We hypothesized that altered expression of genes controlling the influx and efflux of Ca(2+) from the sarcoplasmic reticulum (SR) was responsible and investigated the expression of several genes involved in maintaining the intracellular and sarcoluminal Ca(2+) concentration using quantitative real-time PCR analyses (qRT-PCR). We observed significant differences in baseline gene expression as well as different responses in expression to isoproterenol (ISO) challenge. In untreated control animals, 129/SvJ mice expressed 1.68× more ryanodine receptor 2(Ryr2) mRNA than C57BL/6J mice but only 0.37× as much calsequestrin 2 (Casq2). After treatment with ISO, sarco(endo)plasmic reticulum Ca(2+)-ATPase(Serca2) expression was reduced nearly two-fold in 129/SvJ while expression in C57BL/6J was stable. Interestingly, β (1) adrenergic receptor(Adrb1) expression was lower in 129/SvJ compared to C57BL/6J at baseline and lower in both strains after treatment. Metabolically, the brain isoform of creatine kinase (Ckb) was up-regulated in response to ISO in C57BL/6J but not in 129/SvJ. These data suggest that the two strains of mice regulate Ca(2+) homeostasis via different mechanisms and may be useful in developing personalized therapies in human patients.

  2. Plant improvement by known-function genes

    Directory of Open Access Journals (Sweden)

    Jesús Quiroz Chávez

    2012-09-01

    Full Text Available Plant molecular improvement by recombinant DNA technology represents an advantage to obtain new varieties or traits. This technique is promised for genetic improvement of crop plants. Lines with increased yield, quality, disease resistance, or tolerant to abiotic stress have been obtained, with clear advantages for producers, marketers and consumers. However, they have several limitations in its application to agriculture because of its risk and hazards. The aim of the document is to show the advantages and disadvantages of GM crop plant, to develop represent an opportunity to have new exotic traits.

  3. Translation of Cardiac Myosin Activation With 2-Deoxy-ATP to Treat Heart Failure Via an Experimental Ribonucleotide Reductase-Based Gene Therapy

    Directory of Open Access Journals (Sweden)

    Kassandra S. Thomson, PhD

    2016-12-01

    Full Text Available Despite recent advances, chronic heart failure remains a significant and growing unmet medical need, reaching epidemic proportions carrying substantial morbidity, mortality, and costs. A safe and convenient therapeutic agent that produces sustained inotropic effects could ameliorate symptoms and improve functional capacity and quality of life. The authors discovered that small amounts of 2-deoxy-ATP (dATP activate cardiac myosin leading to enhanced contractility in normal and failing heart muscle. Cardiac myosin activation triggers faster myosin cross-bridge cycling with greater force generation during each contraction. They describe the rationale and results of a translational medicine effort to increase dATP levels using a gene therapy strategy that up-regulates ribonucleotide reductase, the rate-limiting enzyme for dATP synthesis, selectively in cardiomyocytes. In small and large animal models of heart failure, a single dose of this gene therapy has led to sustained inotropic effects with no toxicity or safety concerns identified to date. Further animal studies are being conducted with the goal of testing this agent in patients with heart failure.

  4. Dedicated pediatric cardiac intensive care unit in a developing country: Does it improve the outcome?

    Directory of Open Access Journals (Sweden)

    Rakhi Balachandran

    2011-01-01

    Conclusions : Establishment of a dedicated pediatric cardiac intensive care unit has shown better outcomes in terms of earlier extubation, de-intensification, and discharge from the ICU. Blood stream infections were also reduced.

  5. Improvements in determination of cardiac output with a Swan-Ganz catheter.

    Science.gov (United States)

    Sakagami, M; Kuwana, K; Nakanishi, H; Sakai, K

    1990-01-01

    The time constant for heat transfer may affect exact determination of cardiac output with Swan-Ganz catheters. Commercially available Swan-Ganz catheters are provided with thermistors with varying time constants. Current monitoring of cardiac output is not corrected for these time constants, so the conventional method of determining cardiac output using the equation of Stewart-Hamilton produces marked errors. The authors propose a new method of determining cardiac output with Swan-Ganz catheters with varying time constants from thermal dilution curve data based on Newton's cooling law. Values for blood flow rate determined by the new method using a completely stirred tank of original design, mimicking the natural heart and using bovine blood, are almost the same as values observed at varying saline infusion volumes, saline temperatures, and saline infusion times.

  6. Coiled fiber scaffolds embedded with gold nanoparticles improve the performance of engineered cardiac tissues

    Science.gov (United States)

    Fleischer, Sharon; Shevach, Michal; Feiner, Ron; Dvir, Tal

    2014-07-01

    Coiled perimysial fibers within the heart muscle provide it with the ability to contract and relax efficiently. Here, we report on a new nanocomposite scaffold for cardiac tissue engineering, integrating coiled electrospun fibers with gold nanoparticles. Cultivation of cardiac cells within the hybrid scaffolds promoted cell organization into elongated and aligned tissues generating a strong contraction force, high contraction rate and low excitation threshold.Coiled perimysial fibers within the heart muscle provide it with the ability to contract and relax efficiently. Here, we report on a new nanocomposite scaffold for cardiac tissue engineering, integrating coiled electrospun fibers with gold nanoparticles. Cultivation of cardiac cells within the hybrid scaffolds promoted cell organization into elongated and aligned tissues generating a strong contraction force, high contraction rate and low excitation threshold. Electronic supplementary information (ESI) available. See DOI: 10.1039/c4nr00300d

  7. Dietary salt restriction improves cardiac and adipose tissue pathology independently of obesity in a rat model of metabolic syndrome.

    Science.gov (United States)

    Hattori, Takuya; Murase, Tamayo; Takatsu, Miwa; Nagasawa, Kai; Matsuura, Natsumi; Watanabe, Shogo; Murohara, Toyoaki; Nagata, Kohzo

    2014-12-02

    Metabolic syndrome (MetS) enhances salt sensitivity of blood pressure and is an important risk factor for cardiovascular disease. The effects of dietary salt restriction on cardiac pathology associated with metabolic syndrome remain unclear. We investigated whether dietary salt restriction might ameliorate cardiac injury in DahlS.Z-Lepr(fa)/Lepr(fa) (DS/obese) rats, which are derived from a cross between Dahl salt-sensitive and Zucker rats and represent a model of metabolic syndrome. DS/obese rats were fed a normal-salt (0.36% NaCl in chow) or low-salt (0.0466% NaCl in chow) diet from 9 weeks of age and were compared with similarly treated homozygous lean littermates (DahlS.Z-Lepr(+)/Lepr(+), or DS/lean rats). DS/obese rats fed the normal-salt diet progressively developed hypertension and showed left ventricular hypertrophy, fibrosis, and diastolic dysfunction at 15 weeks. Dietary salt restriction attenuated all of these changes in DS/obese rats. The levels of cardiac oxidative stress and inflammation and the expression of cardiac renin-angiotensin-aldosterone system genes were increased in DS/obese rats fed the normal-salt diet, and dietary salt restriction downregulated these parameters in both DS/obese and DS/lean rats. In addition, dietary salt restriction attenuated the increase in visceral adipose tissue inflammation and the decrease in insulin signaling apparent in DS/obese rats without reducing body weight or visceral adipocyte size. Dietary salt restriction did not alter fasting serum glucose levels but it markedly decreased the fasting serum insulin concentration in DS/obese rats. Dietary salt restriction not only prevents hypertension and cardiac injury but also ameliorates insulin resistance, without reducing obesity, in this model of metabolic syndrome. © 2014 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell.

  8. Association of National Initiatives to Improve Cardiac Arrest Management With Rates of Bystander Intervention and Patient Survival After Out-of-Hospital Cardiac Arrest

    DEFF Research Database (Denmark)

    Wissenberg, Mads; Lippert, Freddy K; Folke, Fredrik

    2013-01-01

    resuscitation was attempted were identified between 2001 and 2010 in the nationwide Danish Cardiac Arrest Registry. Of 29 111 patients with cardiac arrest, we excluded those with presumed noncardiac cause of arrest (n = 7390) and those with cardiac arrests witnessed by emergency medical services personnel (n...

  9. Oxidant-NO dependent gene regulation in dogs with type I diabetes: impact on cardiac function and metabolism

    Directory of Open Access Journals (Sweden)

    Ojaimi Caroline

    2010-08-01

    Full Text Available Abstract Background The mechanisms responsible for the cardiovascular mortality in type I diabetes (DM have not been defined completely. We have shown in conscious dogs with DM that: 1 baseline coronary blood flow (CBF was significantly decreased, 2 endothelium-dependent (ACh coronary vasodilation was impaired, and 3 reflex cholinergic NO-dependent coronary vasodilation was selectively depressed. The most likely mechanism responsible for the depressed reflex cholinergic NO-dependent coronary vasodilation was the decreased bioactivity of NO from the vascular endothelium. The goal of this study was to investigate changes in cardiac gene expression in a canine model of alloxan-induced type 1 diabetes. Methods Mongrel dogs were chronically instrumented and the dogs were divided into two groups: one normal and the other diabetic. In the diabetic group, the dogs were injected with alloxan monohydrate (40-60 mg/kg iv over 1 min. The global changes in cardiac gene expression in dogs with alloxan-induced diabetes were studied using Affymetrix Canine Array. Cardiac RNA was extracted from the control and DM (n = 4. Results The array data revealed that 797 genes were differentially expressed (P 2+ cycling genes (ryanodine receptor; SERCA2 Calcium ATPase, structural proteins (actin alpha. Of particular interests are genes involved in glutathione metabolism (glutathione peroxidase 1, glutathione reductase and glutathione S-transferase, which were markedly down regulated. Conclusion our findings suggest that type I diabetes might have a direct effect on the heart by impairing NO bioavailability through oxidative stress and perhaps lipid peroxidases.

  10. Analysis of the stability of housekeeping gene expression in the left cardiac ventricle of rats submitted to chronic intermittent hypoxia

    Directory of Open Access Journals (Sweden)

    Guilherme Silva Julian

    Full Text Available ABSTRACT Obstructive sleep apnea (OSA has been associated with oxidative stress and various cardiovascular consequences, such as increased cardiovascular disease risk. Quantitative real-time PCR is frequently employed to assess changes in gene expression in experimental models. In this study, we analyzed the effects of chronic intermittent hypoxia (an experimental model of OSA on housekeeping gene expression in the left cardiac ventricle of rats. Analyses via four different approaches-use of the geNorm, BestKeeper, and NormFinder algorithms; and 2−ΔCt (threshold cycle data analysis-produced similar results: all genes were found to be suitable for use, glyceraldehyde-3-phosphate dehydrogenase and 18S being classified as the most and the least stable, respectively. The use of more than one housekeeping gene is strongly advised.

  11. Methotrexate carried in lipid core nanoparticles reduces myocardial infarction size and improves cardiac function in rats.

    Science.gov (United States)

    Maranhão, Raul C; Guido, Maria C; de Lima, Aline D; Tavares, Elaine R; Marques, Alyne F; Tavares de Melo, Marcelo D; Nicolau, Jose C; Salemi, Vera Mc; Kalil-Filho, Roberto

    2017-01-01

    Acute myocardial infarction (MI) is accompanied by myocardial inflammation, fibrosis, and ventricular remodeling that, when excessive or not properly regulated, may lead to heart failure. Previously, lipid core nanoparticles (LDE) used as carriers of the anti-inflammatory drug methotrexate (MTX) produced an 80-fold increase in the cell uptake of MTX. LDE-MTX treatment reduced vessel inflammation and atheromatous lesions induced in rabbits by cholesterol feeding. The aim of the study was to investigate the effects of LDE-MTX on rats with MI, compared with commercial MTX treatment. Thirty-eight Wistar rats underwent left coronary artery ligation and were treated with LDE-MTX, or with MTX (1 mg/kg intraperitoneally, once/week, starting 24 hours after surgery) or with LDE without drug (MI-controls). A sham-surgery group (n=12) was also included. Echocardiography was performed 24 hours and 6 weeks after surgery. The animals were euthanized and their hearts were analyzed for morphometry, protein expression, and confocal microscopy. LDE-MTX treatment achieved a 40% improvement in left ventricular (LV) systolic function and reduced cardiac dilation and LV mass, as shown by echocardiography. LDE-MTX reduced the infarction size, myocyte hypertrophy and necrosis, number of inflammatory cells, and myocardial fibrosis, as shown by morphometric analysis. LDE-MTX increased antioxidant enzymes; decreased apoptosis, macrophages, reactive oxygen species production; and tissue hypoxia in non-infarcted myocardium. LDE-MTX increased adenosine bioavailability in the LV by increasing adenosine receptors and modulating adenosine catabolic enzymes. LDE-MTX increased the expression of myocardial vascular endothelium growth factor (VEGF) associated with adenosine release; this correlated not only with an increase in angiogenesis, but also with other parameters improved by LDE-MTX, suggesting that VEGF increase played an important role in the beneficial effects of LDE-MTX. Overall effects of

  12. Ginsenoside Rh2 Improves Cardiac Fibrosis via PPARδ–STAT3 Signaling in Type 1-Like Diabetic Rats

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    Shih-Hsiang Lo

    2017-06-01

    Full Text Available Ginsenoside Rh2 (Rh2 is an active principal ingredient contained in ginseng (Panax ginseng Meyer, a medicinal herb used to enhance health worldwide. The present study is designed to investigate the effect of Rh2 on myocardial fibrosis in diabetic rats. In a streptozotocin-induced model of type-1 diabetic rats (STZ-diabetic rats, the increased fasting blood glucose levels and heart weight/body weight (HW/BW ratio were substantially alleviated by Rh2. Moreover, Rh2 improved cardiac performance in STZ-diabetic rats. Histological results from Masson staining showed that Rh2 attenuated cardiac fibrosis in STZ-diabetic rats. The effects of Rh2 were reversed by GSK0660 at a dose sufficient to inhibit peroxisome proliferator-activated receptor δ (PPARδ in STZ-diabetic rats. The role of PPARδ was subsequently investigated in vitro. Rh2 restored the decreased PPARδ expression level in high glucose-cultured cardiomyocytes. Moreover, increased protein levels of fibrotic signals, including signal transducer and activator of transcription 3 (STAT3, connective tissue growth factor (CCN2 and fibronectin, were reduced by Rh2 in high glucose-cultured cardiomyocytes. These effects of Rh2 were reversed by GSK0660 or siRNA specific for PPARδ Taken together, PPARδ activation may inhibit STAT3 activation to reduce CCN2 and fibronectin expression in diabetic rats with cardiac fibrosis. Moreover, Rh2 improves cardiac function and fibrosis by increasing PPARδ signaling. Therefore, Rh2 is suitable to develop as an alternative remedy for cardiac fibrosis.

  13. Mechanism of ghrelin in improving cardiac function by inhibiting endoplasmic reticulum stress in rats with acute myocardial infarctio

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    Min CAI

    2012-11-01

    Full Text Available Objective  To establish the rat model of acute myocardial infarction (AMI, and to explore the mechanism of ghrelin in improving cardiac function through inhibiting endoplasmic reticulum stress (ERS. Methods  AMI model was reproduced in 18 adult male Sprague-Dawley rats (220±20g by ligation of the left anterior descending coronary artery. Four days after the reproduction of the model, 14 survived rats with AMI were randomly divided into two groups (7 each: model group, animals were subcutaneously (sc injected with normal saline only; treatment group, animals were given ghrelin (100μg/kg twice a day (12h interval for two weeks. In addition, a sham-operated group was set up (Sham operation+saline, n=8. Two weeks later, the cardiac function was examined by echocardiography (UCG, the morphological changes in myocardial tissue were observed with hematoxylin-eosin (HE staining, the levels of LDH and CK-MB were determined by ELISA, and the expressions of glucose-regulated protein 78 (GRP-78 and C/EBP homologous protein (CHOP were assessed by Western blotting. Results  AMI model was successfully reproduced in SD rats. Compared with the rats in sham group, those in model group showed poor cardiac function (P < 0.05, HE staining revealed loosening of tissue and edema, ELISA revealed elevation of serum LDH and CK-MB levels (P < 0.05, and up regulation of expressions of GRP-78 and CHOP protein (P < 0.05. While compared with model group, rats in treatment group showed better cardiac function (P < 0.05, tissue loosening and edema were alleviated, the levels of serum LDH and CK-MB lowered (P < 0.05, and inhibition of the expressions of GRP-78 and CHOP protein (P < 0.05. Conclusion  Ghrelin may improve the cardiac function by in hibiting ERS, thus ameliorating the myocardial damage caused by AMI.

  14. Improving Islet Engraftment by Gene Therapy

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    Xiaojie Wang

    2011-01-01

    Full Text Available Islet cell transplantation is currently the only feasible long-term treatment option for patients with type 1 diabetes. However, the majority of transplanted islets experience damage and apoptosis during the isolation process, a blood-mediated inflammatory microenvironment in the portal vein upon islet infusion, hypoxia induced by the low oxygenated milieu, and poor-revascularization-mediated lack of nutrients, and impaired hormone modulation in the local transplanted site. Strategies using genetic modification methods through overexpression or silencing of those proteins involved in promoting new formation of blood vessels or inhibition of apoptosis may overcome these hurdles and improve islet engraftment outcomes.

  15. Reranking candidate gene models with cross-species comparison for improved gene prediction

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    Pereira Fernando CN

    2008-10-01

    Full Text Available Abstract Background Most gene finders score candidate gene models with state-based methods, typically HMMs, by combining local properties (coding potential, splice donor and acceptor patterns, etc. Competing models with similar state-based scores may be distinguishable with additional information. In particular, functional and comparative genomics datasets may help to select among competing models of comparable probability by exploiting features likely to be associated with the correct gene models, such as conserved exon/intron structure or protein sequence features. Results We have investigated the utility of a simple post-processing step for selecting among a set of alternative gene models, using global scoring rules to rerank competing models for more accurate prediction. For each gene locus, we first generate the K best candidate gene models using the gene finder Evigan, and then rerank these models using comparisons with putative orthologous genes from closely-related species. Candidate gene models with lower scores in the original gene finder may be selected if they exhibit strong similarity to probable orthologs in coding sequence, splice site location, or signal peptide occurrence. Experiments on Drosophila melanogaster demonstrate that reranking based on cross-species comparison outperforms the best gene models identified by Evigan alone, and also outperforms the comparative gene finders GeneWise and Augustus+. Conclusion Reranking gene models with cross-species comparison improves gene prediction accuracy. This straightforward method can be readily adapted to incorporate additional lines of evidence, as it requires only a ranked source of candidate gene models.

  16. High-sensitivity cardiac troponin assays: From improved analytical performance to enhanced risk stratification.

    Science.gov (United States)

    Kozinski, Marek; Krintus, Magdalena; Kubica, Jacek; Sypniewska, Grazyna

    2017-05-01

    Implementation of cardiac troponin (cTn) assays has revolutionized the diagnosis, risk stratification, triage and management of patients with suspected myocardial infarction (MI). The Universal Definition of MI brought about a shift in the diagnostics of MI, from an approach primarily based on electrocardiography (ECG) to one primarily based on biomarkers. Currently, detection of a rise and/or fall in concentration or activity of myocardial necrosis biomarkers, preferentially cTns, with at least one value above the 99th percentile upper reference limit (URL), is the essential component for the diagnosis of MI. High-sensitivity cardiac troponin (hs-cTn) assays with their superior analytical performance were designed to further facilitate clinical decision making. The ability of hs-cTn assays to detect measurable cTn concentrations in at least 50% of healthy individuals, along with their improved precision (expressed as coefficient of variation ≤10% at the 99th percentile URL) associated with increased recognition of changing values, leads to enhanced risk stratification of patients with suspected MI, and also enables them to be used as prognostic tools potentially useful in other patient subsets. In this comprehensive review, we aim to integrate updated laboratory and clinical knowledge regarding hs-cTn assays in order to promote their optimal use in daily practice. We primarily focus on the role of hs-cTn assays in patients with suspected MI, discussing recommended diagnostic algorithms and result interpretation. Emphasis is also placed on the release of cTns following myocardial injury, the characteristics of antibodies used in available cTn immunoassays, and analytical performance of hs-cTn assays. In this paper, we also review potential challenges related to the selection of a healthy reference population in determining 99th percentile values, biological variation of hs-cTns, inequality between hs-cTn assays, and outline the current status of c

  17. Cardiac Gene Expression Knockdown Using Small Inhibitory RNA-Loaded Microbubbles and Ultrasound

    OpenAIRE

    2016-01-01

    RNA interference has potential therapeutic value for cardiac disease, but targeted delivery of interfering RNA is a challenge. Custom designed microbubbles, in conjunction with ultrasound, can deliver small inhibitory RNA to target tissues in vivo. The efficacy of cardiac RNA interference using a microbubble-ultrasound theranostic platform has not been demonstrated in vivo. Therefore, our objective was to test the hypothesis that custom designed microbubbles and ultrasound can mediate effecti...

  18. New mutation of the desmin gene identified in an extended Indian pedigree presenting with distal myopathy and cardiac disease

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    Atchayaram Nalini

    2013-01-01

    Full Text Available In this report, we describe a new mutation located in the coiled 1B domain of desmin and associated with a predominant cardiac involvement and a high degree of cardiac sudden death in a large Indian pedigree with 12 affected members. The index cases was 38-year-old man who presented with progressive difficulty in gripping footwear of 5 years duration with the onset in the left lower limb followed by right lower limb in 6 months. 3 years from onset, he developed lower limb proximal and truncal muscle weakness. There was mild atrophy of the shoulder girdle muscles with grade 3 weakness, moderate wasting of thigh and anterior leg muscles with proximal muscle weakness and foot drop. At 40 years, he had a pacemaker implanted. The 9 exons and intronic boundaries of the desmin gene were sequenced and a heterozygous nucleotide change c. 734A > G in exon 3 was identified.

  19. Improved cardiac protection with Sabax cardioplegia in Langendorff isolated rat hearts

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    Perian M.

    2014-12-01

    Full Text Available Objective: Cardioplegia is an important step to facilitate cardiac surgery while limiting intraoperative myocardial injury. Although recent advances in cardioplegic arrest methods have significantly contributed to better postoperative outcomes, there is still controversy regarding the optimal composition and temperature of the cardioplegic solution. Accordingly, we aimed to assess whether cold or lukewarm Sabax cardioplegia offer improved myocardial protection compared with the classical Krebs-Henseleit solution. Methods: The hearts of 40 male Wistar rats were isolated and submitted to constant-flow retrograde perfusion using a Langendorff perfusion apparatus. The hearts were randomly assigned to cold Krebs-Henseleit (K-H, cold Sabax, or lukewarm Sabax cardioplegia. The ECG, heart rates, and left ventricular systolic pressures (LVSP were recorded pre- and post-cardioplegia. The time needed for cardioplegia induction and post-cardioplegia recovery were also noted. Results: Both cold and lukewarm Sabax cardioplegia insured faster induction and faster recovery following isothermic reperfusion compared to the standard K-H solution (both p< 0.01. With K-H cardioplegia, the hearts presented a 21.7% force loss after reperfusion (p< 0.001, whilst Sabax cardioplegia was associated with a slight increase in ventricular mechanical activity (3% LVSP increase with lukewarm Sabax cardioplegia, p< 0.001 and 2% LVSP increase with cold Sabax cardioplegia, p = 0.02. With Sabax cardioplegia the hearts displayed considerably less major arrhythmic events and presented less significant bradycardia. Conclusions: The present data suggest that Sabax cardioplegia may be superior to the classical cold crystalloid K-H solution in preserving mechanical activity of the heart and may provide superior protection against major arrhythmias.

  20. Isolation of rat cardiac sarcoplasmic reticulum with improved Ca2+ uptake and ryanodine binding.

    Science.gov (United States)

    Feher, J J; Davis, M D

    1991-03-01

    The instability of the oxalate-supported Ca2+ uptake activity of rat cardiac sarcoplasmic reticulum (CSR) in ventricular homogenates most likely accounts for the low specific activity of the rate of oxalate-supported Ca2+ uptake in previously reported fractions of isolated rat CSR. We have found that CSR vesicles with improved Ca2+ transport capabilities can be isolated if 1 M KCl is used to stabilize the CSR activity and to allow the extraction of the CSR from the cellular debris. The average rate of Ca2+ uptake by the isolated rat CSR in the presence of 10 mM oxalate at 37 degrees C was 0.45 mumols/min-mg in the absence of CSR Ca2+ channel blockers and 0.87 mumols/min-mg in the presence of 10 microM ruthenium red. The Ca(2+)-dependent ATPase activity under the conditions of oxlate-supported uptake was 1.25 mumols/min-mg and 0.84 mumols/min-mg in the absence and presence of 10 microM ruthenium red, respectively. The rat CSR vesicles bound 3H-ryanodine with a Kd of 1.45 nM and a Bmax of 3.7 pmol mg. The level of phosphorylated intermediate was 0.30 nmol/mg. The values Bmax, EP and Ca(2+)-ATPase activity are from one-third to one-half of those previously reported for isolated canine CSR vesicles. These results suggest that the isolated rat CSR may be quite similar to dog CSR.

  1. Insulin improves cardiac myocytes contractile function recovery in simulated ischemia-reperfusion: Key role of Akt

    Institute of Scientific and Technical Information of China (English)

    ZHANG Bo; ZHANG Haifeng; FAN Qian; MA Xinliang; GAO Feng

    2003-01-01

    The present study examined cardiac myocyte contractile and Ca2+ transient responses to insulin during simulated ischemia/reperfusion (I/R) and furtherinvestigated the role of protein kinase B (Akt) in the insulin- induced inotropic effect. Ventricular myocytes were enzymatically isolated from adult Sprague-Dawley rats and perfused with Tyrode solution while electrically field-stimulated. Simulated I/R was induced by perfusing the cells with chemical anoxic solution including sodium cyanide-sodium lactate for 15 min followed by reperfusion with normal oxygenated Tyrode solution with or without insulin. It is found that insulin only at concentration as high as 10 IU/L could increase cell shortening (16±5%, P < 0.05) in normal myocytes, whereas it concentration-dependently (0.01-10 IU/L) increased the contraction,the velocity of shortening/releng- theningand Ca2+ transient in I/R myocytes. In addition, insulin treatment (1 IU/L) increased Akt phosphorylation of I/R cardiomyocytes by 2.4-fold compared with that of the control (P < 0.01). Most importantly, pretreatment with LY 294002, a specific inhibitor of phosphatidylinositol 3′-kinase (PI3-kinase), significantly inhibited both Akt phosphorylation and the positive inotropic response to insulin in the I/R cardiomyocytes. These results suggest that insulin exerts direct positive inotropic effect by increasing Ca2+ transient of cardiomyocytes, which is enhanced in the pathological condition of I/R. Akt activation plays an important role in the insulin-induced improvement of myocyte contractile function following I/R.

  2. Propofol improves cardiac functional recovery after ischemia-reperfusion by upregulating nitric oxide synthase activity in the isolated rat hearts

    Institute of Scientific and Technical Information of China (English)

    SUN Hai-yan; XUE Fu-shan; XU Ya-chao; LI Cheng-wen; XIONG Jun; LIAO Xu; ZHANG Yan-ming

    2009-01-01

    Background There are few studies to assess whether propofol attenuates myocardial ischemia-reperfusion injury via a mechanism related to nitric oxide (NO) route, so we designed this randomized blinded experiment to observe the changes of NO contents, nitric oxide synthase (NOS) activity, NOS contents in the myocardium, and cardiac function in ischemic reperfused isolated rat hearts, and to assess the relation between myocardial NO system and cardioprotection of propofol.Methods The hearts of 30 Sprague-Dawley male rats were removed, mounted on a Langendorff apparatus, and randomly assigned to one of three groups (n=10 each group) to be treated with the following treatments in a blinded manner: Group 1, control group, after perfusion with pure Krebs Henseleit bicarbonate (K-HBB) buffer solution for 15 minutes, hearts were subjected to 20 minutes global ischemia followed by 60 minutes reperfusion with pure K-HBB buffer; Group 2, after perfusion with K-HBB buffer solution containing propofol (10 μg/ml) for 15 minutes, the hearts underwent 20 minutes global ischemia followed by 60 minutes reperfusion with the same K-HBB buffer solution; Group 3, after perfusion with K-HBB buffer solution containing propofol (10 μg/ml) and L-NAME (100 μmol/L) for 15 minutes, the hearts underwent 20 minutes global ischemia followed by 60 minutes reperfusion with the same K-HBB buffer solution. The cardiac function was continuously monitored throughout the experiment.The coronary flow was also measured. An ISO-NO electrode was placed into the right atrium close to the coronary sinus to continuously measure NO concentration in the coronary effluent. The tissue samples from apex of hearts in Groups 1 and 2 were obtained to measure the NOS activity by spectrophotometry and the NOS contents by immunohistochemistry, respectively.Results The cardiac function was significantly inhibited after ischemia and then gradually improved with reperfusion in all three groups. As compared with Group 1

  3. Enhanced Cardiac Akt/Protein Kinase B Signaling Contributes to Pathological Cardiac Hypertrophy in Part by Impairing Mitochondrial Function via Transcriptional Repression of Mitochondrion-Targeted Nuclear Genes

    Science.gov (United States)

    Wende, Adam R.; O'Neill, Brian T.; Bugger, Heiko; Riehle, Christian; Tuinei, Joseph; Buchanan, Jonathan; Tsushima, Kensuke; Wang, Li; Caro, Pilar; Guo, Aili; Sloan, Crystal; Kim, Bum Jun; Wang, Xiaohui; Pereira, Renata O.; McCrory, Mark A.; Nye, Brenna G.; Benavides, Gloria A.; Darley-Usmar, Victor M.; Shioi, Tetsuo; Weimer, Bart C.

    2014-01-01

    Sustained Akt activation induces cardiac hypertrophy (LVH), which may lead to heart failure. This study tested the hypothesis that Akt activation contributes to mitochondrial dysfunction in pathological LVH. Akt activation induced LVH and progressive repression of mitochondrial fatty acid oxidation (FAO) pathways. Preventing LVH by inhibiting mTOR failed to prevent the decline in mitochondrial function, but glucose utilization was maintained. Akt activation represses expression of mitochondrial regulatory, FAO, and oxidative phosphorylation genes in vivo that correlate with the duration of Akt activation in part by reducing FOXO-mediated transcriptional activation of mitochondrion-targeted nuclear genes in concert with reduced signaling via peroxisome proliferator-activated receptor α (PPARα)/PGC-1α and other transcriptional regulators. In cultured myocytes, Akt activation disrupted mitochondrial bioenergetics, which could be partially reversed by maintaining nuclear FOXO but not by increasing PGC-1α. Thus, although short-term Akt activation may be cardioprotective during ischemia by reducing mitochondrial metabolism and increasing glycolysis, long-term Akt activation in the adult heart contributes to pathological LVH in part by reducing mitochondrial oxidative capacity. PMID:25535334

  4. Telmisartan improves cardiac fibrosis in diabetes through peroxisome proliferator activated receptor δ (PPARδ): from bedside to bench.

    Science.gov (United States)

    Chang, Wei-Ting; Cheng, Juei-Tang; Chen, Zhih-Cherng

    2016-08-12

    Despite the known risk of diabetes-induced cardiac fibrosis, less is known about whether diabetes causes an altered cardiac phenotype independent of coronary atherosclerosis. Peroxisome proliferator-activated receptor δ (PPARδ), a versatile regulator of metabolic homeostasis, may be a potential therapeutic target. Herein we investigated the effectiveness of telmisartan, a unique angiotensin receptor blocker that increases PPARδ expression, in improving left ventricular remodeling in diabetic humans and rats. In this longitudinal, prospective study, we enrolled 15 diabetic patients receiving telmisartan (20 mg/day) for 12 weeks. After treatment, strain was measured and compared with the baseline value. Using streptozotocin to induce type 1 diabetes rat model, we measured PPARδ expression and downstream targets. After treatment with telmisartan, both longitudinal and circumferential strains improved in diabetic patients. Compared with that of controls, the diabetic rat heart developed significant fibrosis, which markedly decreased after treatment with telmisartan (30 mg/kg/day, orally) for 7 days. After incubation with 30 mM glucose, rat cardiomyocytes showed a significant down-regulation of PPARδ. Interestingly, the increased expression of fibrosis-associated proteins, including signal transducer and activator of transcription 3 (STAT3) was attenuated by the co-incubation of GW0742, a PPARδ agonist. By knockdown or inhibition of STAT3, the hyperglycemia related high expression of fibrosis associated targets was reversed. Independent from the hyperglycemic incubation, STAT3 over-expression led to similar results. Conversely, in the presence of GSK0660, a PPARδ inhibitor, the protective effects of telmisartan were diminished. Telmisartan improved the hyperglycemia-induced cardiac fibrosis through the PPARδ/STAT3 pathway. Graphical abstract Summary of the mechanism of telmisartan's effect on the suppression of hyperglycemia-induced cardiac fibrosis through

  5. Absence of mutation at the 5'-upstream promoter region of the TPM4 gene from cardiac mutant axolotl (Ambystoma mexicanum).

    Science.gov (United States)

    Denz, Christopher R; Zhang, Chi; Jia, Pingping; Du, Jianfeng; Huang, Xupei; Dube, Syamalima; Thomas, Anish; Poiesz, Bernard J; Dube, Dipak K

    2011-09-01

    Tropomyosins are a family of actin-binding proteins that show cell-specific diversity by a combination of multiple genes and alternative RNA splicing. Of the 4 different tropomyosin genes, TPM4 plays a pivotal role in myofibrillogenesis as well as cardiac contractility in amphibians. In this study, we amplified and sequenced the upstream regulatory region of the TPM4 gene from both normal and mutant axolotl hearts. To identify the cis-elements that are essential for the expression of the TPM4, we created various deletion mutants of the TPM4 promoter DNA, inserted the deleted segments into PGL3 vector, and performed promoter-reporter assay using luciferase as the reporter gene. Comparison of sequences of the promoter region of the TPM4 gene from normal and mutant axolotl revealed no mutations in the promoter sequence of the mutant TPM4 gene. CArG box elements that are generally involved in controlling the expression of several other muscle-specific gene promoters were not found in the upstream regulatory region of the TPM4 gene. In deletion experiments, loss of activity of the reporter gene was noted upon deletion which was then restored upon further deletion suggesting the presence of both positive and negative cis-elements in the upstream regulatory region of the TPM4 gene. We believe that this is the first axolotl promoter that has ever been cloned and studied with clear evidence that it functions in mammalian cell lines. Although striated muscle-specific cis-acting elements are absent from the promoter region of TPM4 gene, our results suggest the presence of positive and negative cis-elements in the promoter region, which in conjunction with positive and negative trans-elements may be involved in regulating the expression of TPM4 gene in a tissue-specific manner.

  6. Comprehensive cardiac rehabilitation improves outcome for patients with implantable cardioverter defibrillator

    DEFF Research Database (Denmark)

    Berg, Selina Kikkenborg; Pedersen, Preben Ulrich; Zwisler, Ann-Dorthe

    2015-01-01

    Aims:The aim of this randomised clinical trial was to assess a comprehensive cardiac rehabilitation intervention including exercise training and psycho-education vs 'treatment as usual' in patients treated with an implantable cardioverter defibrillator (ICD).Methods:In this study 196 patients...... with first time ICD implantation (mean age 57.2 (standard deviation (SD)=13.2); 79% men) were randomised (1:1) to comprehensive cardiac rehabilitation vs 'treatment as usual'. Altogether 144 participants completed the 12 month follow-up. The intervention consisted of twelve weeks of exercise training and one...... year of psycho-educational follow-up focusing on modifiable factors associated with poor outcomes. Two primary outcomes, general health score (Short Form-36 (SF-36)) and peak oxygen uptake (VO2), were used. Post-hoc analyses included SF-36 and ICD therapy history.Results:Comprehensive cardiac...

  7. Simvastatin-induced cardiac autonomic control improvement in fructose-fed female rats.

    Science.gov (United States)

    Silva, Renata Juliana da; Bernardes, Nathalia; Brito, Janaina de O; Sanches, Iris Callado; Irigoyen, Maria Cláudia; De Angelis, Kátia

    2011-01-01

    Because autonomic dysfunction has been found to lead to cardiometabolic disorders and because studies have reported that simvastatin treatment has neuroprotective effects, the objective of the present study was to investigate the effects of simvastatin treatment on cardiovascular and autonomic changes in fructose-fed female rats. Female Wistar rats were divided into three groups: controls (n = 8), fructose (n = 8), and fructose+ simvastatin (n = 8). Fructose overload was induced by supplementing the drinking water with fructose (100 mg/L, 18 wks). Simvastatin treatment (5 mg/kg/day for 2 wks) was performed by gavage. The arterial pressure was recorded using a data acquisition system. Autonomic control was evaluated by pharmacological blockade. Fructose overload induced an increase in the fasting blood glucose and triglyceride levels and insulin resistance. The constant rate of glucose disappearance during the insulin intolerance test was reduced in the fructose group (3.4 ± 0.32%/min) relative to that in the control group (4.4 ± 0.29%/min). Fructose + simvastatin rats exhibited increased insulin sensitivity (5.4 ± 0.66%/min). The fructose and fructose + simvastatin groups demonstrated an increase in the mean arterial pressure compared with controls rats (fructose: 124 ± 2 mmHg and fructose+simvastatin: 126 ± 3 mmHg vs. controls: 112 ± 2 mmHg). The sympathetic effect was enhanced in the fructose group (73 ± 7 bpm) compared with that in the control (48 ± 7 bpm) and fructose+simvastatin groups (31 ± 8 bpm). The vagal effect was increased in fructose + simvastatin animals (84 ± 7 bpm) compared with that in control (49 ± 9 bpm) and fructose animals (46 ± 5 bpm). Simvastatin treatment improved insulin sensitivity and cardiac autonomic control in an experimental model of metabolic syndrome in female rats. These effects were independent of the improvements in the classical plasma lipid profile and of reductions in arterial pressure. These results support the

  8. Simvastatin-induced cardiac autonomic control improvement in fructose-fed female rats

    Directory of Open Access Journals (Sweden)

    Renata Juliana da Silva

    2011-01-01

    Full Text Available OBJECTIVE: Because autonomic dysfunction has been found to lead to cardiometabolic disorders and because studies have reported that simvastatin treatment has neuroprotective effects, the objective of the present study was to investigate the effects of simvastatin treatment on cardiovascular and autonomic changes in fructose-fed female rats. METHODS: Female Wistar rats were divided into three groups: controls (n=8, fructose (n=8, and fructose+ simvastatin (n=8. Fructose overload was induced by supplementing the drinking water with fructose (100 mg/L, 18 wks. Simvastatin treatment (5 mg/kg/day for 2 wks was performed by gavage. The arterial pressure was recorded using a data acquisition system. Autonomic control was evaluated by pharmacological blockade. RESULTS: Fructose overload induced an increase in the fasting blood glucose and triglyceride levels and insulin resistance. The constant rate of glucose disappearance during the insulin intolerance test was reduced in the fructose group (3.4+ 0.32%/min relative to that in the control group (4.4+ 0.29%/min. Fructose+simvastatin rats exhibited increased insulin sensitivity (5.4+0.66%/min. The fructose and fructose+simvastatin groups demonstrated an increase in the mean arterial pressure compared with controls rats (fructose: 124+2 mmHg and fructose+simvastatin: 126 + 3 mmHg vs. controls: 112 + 2 mmHg. The sympathetic effect was enhanced in the fructose group (73 + 7 bpm compared with that in the control (48 + 7 bpm and fructose+simvastatin groups (31+8 bpm. The vagal effect was increased in fructose+simvastatin animals (84 + 7 bpm compared with that in control (49 + 9 bpm and fructose animals (46+5 bpm. CONCLUSION: Simvastatin treatment improved insulin sensitivity and cardiac autonomic control in an experimental model of metabolic syndrome in female rats. These effects were independent of the improvements in the classical plasma lipid profile and of reductions in arterial pressure. These results

  9. Improved virtual cardiac phantom with variable diastolic filling rates and coronary artery velocities

    Science.gov (United States)

    Sturgeon, Gregory M.; Richards, Taylor W.; Samei, E.; Segars, W. P.

    2017-03-01

    To facilitate studies of measurement uncertainty in computed tomography angiography (CTA), we investigated the cardiac motion profile and resulting coronary artery motion utilizing innovative dynamic virtual and physical phantoms. The four-chamber cardiac finite element (FE) model developed in the Living Heart Project (LHP) served as the computational basis for our virtual cardiac phantom. This model provides deformation or strain information at high temporal and spatial resolution, exceeding that of speckle tracking echocardiography or tagged MRI. This model was extended by fitting its motion profile to left ventricular (LV) volume-time curves obtained from patient echocardiography data. By combining the dynamic patient variability from echo with the local strain information from the FE model, a series of virtual 4D cardiac phantoms were developed. Using the computational phantoms, we characterized the coronary motion and its effect on plaque imaging under a range of heart rates subject to variable diastolic function. The coronary artery motion was sampled at 248 spatial locations over 500 consecutive time frames. The coronary artery velocities were calculated as their average velocity during an acquisition window centered at each time frame, which minimized the discretization error. For the initial set of twelve patients, the diastatic coronary artery velocity ranged from 36.5 mm/s to 2.0 mm/s with a mean of 21.4 mm/s assuming an acquisition time of 75 ms. The developed phantoms have great potential in modeling cardiac imaging, providing a known truth and multiple realistic cardiac motion profiles to evaluate different image acquisition or reconstruction methods.

  10. Controlled Release of Collagen-Binding SDF-1α Improves Cardiac Function after Myocardial Infarction by Recruiting Endogenous Stem Cells.

    Science.gov (United States)

    Sun, Jie; Zhao, Yannan; Li, Qingguo; Chen, Bing; Hou, Xianglin; Xiao, Zhifeng; Dai, Jianwu

    2016-05-26

    Stromal cell-derived factor-1α (SDF-1α) is a well-characterized chemokine that mobilizes stem cells homing to the ischemic heart, which is beneficial for cardiac regeneration. However, clinically administered native SDF-1α diffuses quickly, thus decreasing its local concentration, and results in side effects. Thus, a controlled release system for SDF-1α is required to produce an effective local concentration in the ischemic heart. In this study, we developed a recombinant chemokine, consisting of SDF-1α and a collagen-binding domain, which retains both the SDF-1α and collagen-binding activity (CBD-SDF-1α). In an in vitro assay, CBD-SDF-1α could specifically bind to a collagen gel and achieve sustained release. An intramyocardial injection of CBD-SDF-1α after acute myocardial infarction demonstrated that the protein was largely tethered in the ischemic area and that controlled release had been achieved. Furthermore, CBD-SDF-1α enhanced the recruitment of c-kit positive (c-kit(+)) stem cells, increased capillary density and improved cardiac function, whereas NAT-SDF-1α had no such beneficial effects. Our findings demonstrate that CBD-SDF-1α can specifically bind to collagen and achieve controlled release both in vitro and in vivo. Local delivery of this protein could mobilize endogenous stem cells homing to the ischemic heart and improve cardiac function after myocardial infarction.

  11. Intra coronary freshly isolated bone marrow cells transplantation improve cardiac function in patients with ischemic heart disease

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    Bozdag-Turan Ilkay

    2012-04-01

    Full Text Available Abstract Background Autologous bone marrow cell transplantation (BMCs-Tx is a promising novel option for treatment of cardiovascular disease. In this study we analyzed whether intracoronary autologous freshly isolated BMCs-Tx have beneficial effects on cardiac function in patients with ischemic heart disease (IHD. Results In this prospective nonrandomized study we treated 12 patients with IHD by freshly isolated BMCs-Tx by use of point of care system and compared them with a representative 12 control group without cell therapy. Global ejection fraction (EF and infarct size area were determined by left ventriculography. Intracoronary transplantation of autologous freshly isolated BMCs led to a significant reduction of infarct size (p  Conclusions These results demonstrate that intracoronary transplantation of autologous freshly isolated BMCs by use of point of care system is safe and may lead to improvement of cardiac function in patients with IHD. Trial registration Registration number: ISRCTN54510226

  12. Myocardial injection of apelin-overexpressing bone marrow cells improves cardiac repair via upregulation of Sirt3 after myocardial infarction.

    Directory of Open Access Journals (Sweden)

    Lanfang Li

    Full Text Available Our previous study shows that treatment with apelin increases bone marrow cells (BMCs recruitment and promotes cardiac repair after myocardial infarction (MI. The objective of this study was to investigate whether overexpression of apelin in BMCs improved cell therapy and accelerated cardiac repair and functional recovery in post-MI mice. Mouse myocardial infarction was achieved by coronary artery ligation and BMCs overexpressing apelin (apelin-BMCs or GFP (GFP-BMCs were injected into ischemic area immediately after surgery. In vitro, exposure of cultured BMCs to apelin led to a gradual increase in SDF-1á and CXCR4 expression. Intramyocardial delivery of apelin-BMCs in post-MI mice resulted in a significant increase number of APJ⁺/c-kit⁺/Sca1⁺ cells in the injected area compared to GFP-BMCs treated post-MI mice. Treatment with apelin-BMCs increased expression of VEGF, Ang-1 and Tie-2 in post-MI mice. Apelin-BMCs treatment also significantly increased angiogenesis and attenuated cardiac fibrosis formation in post-MI mice. Most importantly, treatment with apelin-BMCs significantly improved left ventricular (LV systolic function in post-MI mice. Mechanistically, Apelin-BMCs treatment led to a significant increase in Sirtuin3 (Sirt3 expression and reduction of reactive oxygen species (ROS formation. Treatment of cultured BMCs with apelin also increased Notch3 expression and Akt phosphorylation. Apelin treatment further attenuated stress-induced apoptosis whereas knockout of Sirt3 abolished anti-apoptotic effect of apelin in cultured BMCs. Moreover, knockout of Sirt3 significantly attenuated apelin-BMCs-induced VEGF expression and angiogenesis in post-MI mice. Knockout of Sirt3 further blunted apelin-BMCs-mediated improvement of cardiac repair and systolic functional recovery in post-MI mice. These data suggest that apelin improves BMCs therapy on cardiac repair and systolic function in post-MI mice. Upregulation of Sirt3 may contribute to the

  13. Early upregulation of myocardial CXCR4 expression is critical for dimethyloxalylglycine-induced cardiac improvement in acute myocardial infarction.

    Science.gov (United States)

    Mayorga, Mari; Kiedrowski, Matthew; Shamhart, Patricia; Forudi, Farhad; Weber, Kristal; Chilian, William M; Penn, Marc S; Dong, Feng

    2016-01-01

    The stromal cell-derived factor-1 (SDF-1):CXCR4 is important in myocardial repair. In this study we tested the hypothesis that early upregulation of cardiomyocyte CXCR4 (CM-CXCR4) at a time of high myocardial SDF-1 expression could be a strategy to engage the SDF-1:CXCR4 axis and improve cardiac repair. The effects of the hypoxia inducible factor (HIF) hydroxylase inhibitor dimethyloxalylglycine (DMOG) on CXCR4 expression was tested on H9c2 cells. In mice a myocardial infarction (MI) was produced in CM-CXCR4 null and wild-type controls. Mice were randomized to receive injection of DMOG (DMOG group) or saline (Saline group) into the border zone after MI. Protein and mRNA expression of CM-CXCR4 were quantified. Echocardiography was used to assess cardiac function. During hypoxia, DMOG treatment increased CXCR4 expression of H9c2 cells by 29 and 42% at 15 and 24 h, respectively. In vivo DMOG treatment increased CM-CXCR4 expression at 15 h post-MI in control mice but not in CM-CXCR4 null mice. DMOG resulted in increased ejection fraction in control mice but not in CM-CXCR4 null mice 21 days after MI. Consistent with greater cardiomyocyte survival with DMOG treatment, we observed a significant increase in cardiac myosin-positive area within the infarct zone after DMOG treatment in control mice, but no increase in CM-CXCR4 null mice. Inhibition of cardiomyocyte death in MI through the stabilization of HIF-1α requires downstream CM-CXCR4 expression. These data suggest that engagement of the SDF-1:CXCR4 axis through the early upregulation of CM-CXCR4 is a strategy for improving cardiac repair after MI.

  14. Extended cardiac rehabilitation for socially vulnerable patients improves attendance and outcome

    DEFF Research Database (Denmark)

    Nielsen, Kirsten Melgaard; Meillier, Lucette Kirsten; Larsen, Mogens Lytken

    2013-01-01

    Patients living alone or having a low socioeconomic status are likely to quit cardiac rehabilitation. We aimed to compare patients being offered extended rehabilitation (ERP) with those being offered standard rehabilitation (SRP) as concerns 1) attendance rates and 2) achievement of treatment goals...

  15. IMPROVING AGREEMENT BETWEEN THORACIC BIOIMPEDANCE AND DYE DILUTION CARDIAC-OUTPUT ESTIMATION IN CHILDREN

    NARCIS (Netherlands)

    OCONNELL, AJ; TIBBALLS, J; COULTHARD, M

    1991-01-01

    The measurement of thoracic electrical bioimpedance (TEB) offers a continuous, non-invasive method for monitoring cardiac output (CO). For clinical use, agreement with a current standard should be demonstrated. We describe a modification to the manufacturer's suggested data entry into the NCCOM3-R6

  16. Deletion of JAM-C, a candidate gene for heart defects in Jacobsen syndrome, results in a normal cardiac phenotype in mice.

    Science.gov (United States)

    Ye, Maoqing; Hamzeh, Rabih; Geddis, Amy; Varki, Nissi; Perryman, M Benjamin; Grossfeld, Paul

    2009-07-01

    The 11q terminal deletion disorder (11q-) is a rare chromosomal disorder caused by a deletion in distal 11q. Fifty-six percent of patients have clinically significant congenital heart defects. A cardiac "critical region" has been identified in distal 11q that contains over 40 annotated genes. In this study, we identify the distal breakpoint of a patient with a paracentric inversion in distal 11q who had hypoplastic left heart and congenital thrombocytopenia. The distal breakpoint mapped to JAM-3, a gene previously identified as a candidate gene for causing HLHS in 11q-. To determine the role of JAM-3 in cardiac development, we performed a comprehensive cardiac phenotypic assessment in which the mouse homolog for JAM-3, JAM-C, has been deleted. These mice have normal cardiac structure and function, indicating that haplo-insufficiency of JAM-3 is unlikely to cause the congenital heart defects that occur in 11q- patients. Notably, we identified a previously undescribed phenotype, jitteriness, in most of the sick or dying adult JAM-C knockout mice. These data provide further insights into the identification of the putative disease-causing cardiac gene(s) in distal 11q, as well as the functions of JAM-C in normal organ development.

  17. Improving Prediction of Postoperative Myocardial Infarction With High-Sensitivity Cardiac Troponin T and NT-proBNP.

    Science.gov (United States)

    Kopec, Michael; Duma, Andreas; Helwani, Mohammad A; Brown, Jamie; Brown, Frank; Gage, Brian F; Gibson, David W; Miller, J Philip; Novak, Eric; Jaffe, Allan S; Apple, Fred S; Scott, Mitchell G; Nagele, Peter

    2017-02-01

    This study sought to determine whether preoperatively measured high-sensitivity cardiac troponin T (hs-cTnT) and N-terminal pro-brain natriuretic peptide (NT-proBNP) improve cardiac risk prediction in patients undergoing major noncardiac surgery compared with the standard risk indices. In this ancillary study to the Vitamins in Nitrous Oxide trial, patients were included who had preoperative hs-cTnT and NT-proBNP measured (n = 572). Study outcome was the incidence of postoperative myocardial infarction (MI) within the first 3 postoperative days. hs-cTnT was considered elevated if >14 ng/L and NT-proBNP if >300 ng/L. Additional cutoff values were investigated on the basis of receiver operating characteristic statistics. Biomarker risk prediction was compared with Lee's Revised Cardiac Risk Index (RCRI) with the use of standard methods and net reclassification index. The addition of hs-cTnT (>14 ng/L) and NT-proBNP (>300 ng/L) to RCRI significantly improved the prediction of postoperative MI (event rate 30/572 [5.2%], Area under the receiver operating characteristic curve increased from 0.590 to 0.716 with a 0.66 net reclassification index [95% confidence interval 0.32-0.99], P sensitivity compared with 300 ng/L (0.87 vs 0.53). Sensitivity, specificity, positive, and negative predictive value for hs-cTnT were 0.70, 0.60, 0.09, and 0.97 and for NT-proBNP were 0.53, 0.68, 0.08, and 0.96. The addition of cardiac biomarkers hs-cTnT and NT-proBNP to RCRI improves the prediction of adverse cardiac events in the immediate postoperative period after major noncardiac surgery. The high negative predictive value of preoperative hs-cTnT and NT-proBNP suggest usefulness as a "rule-out" test to confirm low risk of postoperative MI.

  18. Diagnosis of Coronary Heart Diseases Using Gene Expression Profiling; Stable Coronary Artery Disease, Cardiac Ischemia with and without Myocardial Necrosis.

    Science.gov (United States)

    Kazmi, Nabila; Gaunt, Tom R

    2016-01-01

    Cardiovascular disease (including coronary artery disease and myocardial infarction) is one of the leading causes of death in Europe, and is influenced by both environmental and genetic factors. With the recent advances in genomic tools and technologies there is potential to predict and diagnose heart disease using molecular data from analysis of blood cells. We analyzed gene expression data from blood samples taken from normal people (n = 21), non-significant coronary artery disease (n = 93), patients with unstable angina (n = 16), stable coronary artery disease (n = 14) and myocardial infarction (MI; n = 207). We used a feature selection approach to identify a set of gene expression variables which successfully differentiate different cardiovascular diseases. The initial features were discovered by fitting a linear model for each probe set across all arrays of normal individuals and patients with myocardial infarction. Three different feature optimisation algorithms were devised which identified two discriminating sets of genes, one using MI and normal controls (total genes = 6) and another one using MI and unstable angina patients (total genes = 7). In all our classification approaches we used a non-parametric k-nearest neighbour (KNN) classification method (k = 3). The results proved the diagnostic robustness of the final feature sets in discriminating patients with myocardial infarction from healthy controls. Interestingly it also showed efficacy in discriminating myocardial infarction patients from patients with clinical symptoms of cardiac ischemia but no myocardial necrosis or stable coronary artery disease, despite the influence of batch effects and different microarray gene chips and platforms.

  19. Exosomes derived from dendritic cells improve cardiac function via activation of CD4(+) T lymphocytes after myocardial infarction.

    Science.gov (United States)

    Liu, Haibo; Gao, Wei; Yuan, Jie; Wu, Chaoneng; Yao, Kang; Zhang, Li; Ma, Leilei; Zhu, Jianbing; Zou, Yunzeng; Ge, Junbo

    2016-02-01

    CD4(+) T cell activation plays a key role in facilitating wound healing after myocardial infarction (MI). Exosomes (EXs) secreted from dendritic cells (DCs) can activate T cells in tumor models; however, whether DEXs (DC-EXs) can mediate CD4(+) T cell activation and improve wound healing post-MI remains unknown. This study sought to determine whether DEXs mediate CD4(+) T cell activation and improve cardiac function post-MI in mice. We used supernatants of hypoxic primary or necrotic HL-1 cardiomyocytes to simulate the post-MI cardiomyocyte microenvironment in vitro. Cultured bone marrow-derived DCs (BMDCs) from mice were stimulated with the supernatants of normal (Control group), hypoxic primary or necrotic HL-1 cardiomyocytes (MI group); a subset of BMDCs remained unstimulated (Negative group). DEXs were then isolated from the BMDC supernatants and either incubated with CD4(+) T cells or injected into mice via the tail vein. In this study, we found that the supernatants of both hypoxic primary and necrotic HL-1 cardiomyocytes upregulate DC maturation markers. After the injection of DEXs, a greater number of MI-DEXs are recruited by the mouse spleen and with greater rapidity than control- or negative-DEXs. Confocal imaging and flow cytometry revealed that MI-DEXs exhibited higher uptake by splenic CD4(+) T cells than the control- and negative-DEXs, and this increase was correlated with significantly greater increases in the expression of chemokines and the inflammatory cytokines IFN-γ and TNF by the CD4(+) T cells in vitro and in vivo. In addition, the injection of MI-DEXs improved cardiac function in mice post-MI. These results suggest that DEXs could mediate the activation of CD4(+) T cells through an endocrine mechanism and improve cardiac function post-MI. Our findings provide the basis for a novel strategy for the treatment of MI through the systemic delivery of DEXs.

  20. Changes in cardiac phenotype in hypertrophy and failure: From receptor to gene

    NARCIS (Netherlands)

    H.A. van Heugten (Han); J.M.J. Lamers (Jos)

    1997-01-01

    textabstractThe terminally differentiated adult cardiac myocyte cannot undergo cellular division. Growth of the heart in response to chronic hemodynamic overload therefore occurs through hypertrophy of the myocytes. The adaptation of the myocyte during hypertrophy not only involves an increase in ce

  1. PULMONARY AND CARDIAC GENE EXPRESSION FOLLOWING ACUTE ULTRAFINE CARBON PARTICLE INHALATION IN HYPERTENSIVE RATS

    Science.gov (United States)

    Inhalation of ultrafine carbon particles (ufCP) causes cardiac physiological changes without marked pulmonary injury or inflammation. We hypothesized that acute ufCP exposure of 13 months old Spontaneously Hypertensive (SH) rats will cause differential effects on the lung and hea...

  2. Human embryonic stem cells as a model for cardiac gene discovery : from chip to chap

    NARCIS (Netherlands)

    Beqqali, A.

    2008-01-01

    Here we described the use of human embryonic stem cells (hESCs) as a model to obtain insights into commitment to the mesoderm and endoderm lineages and the early steps in human cardiac cell differentiation by means of whole-genome temporal expression profiling. Furthermore, we used it as an approach

  3. Polymorphisms in the GNAS Gene as Predictors of Ventricular Tachyarrhythmias and Sudden Cardiac Death

    DEFF Research Database (Denmark)

    Wieneke, Heinrich; Svendsen, Jesper Hastrup; Lande, Jeffrey

    2016-01-01

    BACKGROUND: Population-based studies suggest that genetic factors contribute to sudden cardiac death (SCD). METHODS AND RESULTS: In the first part of the present study (Diagnostic Data Influence on Disease Management and Relation of Genetic Polymorphisms to Ventricular Tachy-arrhythmia in ICD Pat...

  4. Sequential mechanical ventilation improves hemodynamics, cardiac function and neurohumoral status in elderly patients with acute left heart failure

    Institute of Scientific and Technical Information of China (English)

    Xing-Hong Zeng; Ming Chen; Qi Cao; Yan-Xia Chen

    2016-01-01

    Objective:To analyze the effect of sequential mechanical ventilation on improving hemodynamics, cardiac function and neurohumoral status in elderly patients with acute left heart failure.Methods:A total of 90 cases of elderly patients with acute left heart failure were randomly divided into observation group and control group, control group received conventional mechanical ventilation therapy, observation group received sequential mechanical ventilation, and then differences in hemodynamics, cardiac function and neurohumoral status were compared between two groups after treatment.Results:24 h after treatment, mPAP, PCWP and RAP levels of observation group after treatment were lower than those of control group, and CO level was higher than that of control group; LVEF value was higher than that of control group, and SVR, LVEDV and LVESV values were lower than those of control group; 12 h and 24 h after treatment, plasma Nt-proBNP, ANP, R, AngⅡ and ALD levels of observation group were significantly lower than those of control group.Conclusion:Sequential mechanical ventilation can optimize the illness in elderly patients with acute left heart failure, and plays a positive role in promoting patients' cardiac function recovery, restoring homeostasis and other aspects.

  5. Cardiac rehabilitation improves the ischemic burden in patients with ischemic heart disease who are not suitable for revascularization

    Energy Technology Data Exchange (ETDEWEB)

    El Demerdash, Salah [Department of Cardiology, Ain Shams University Hospital, Cairo (Egypt); Khorshid, Hazem, E-mail: hazemkhorshid@yahoo.com [Department of Cardiology, Ain Shams University Hospital, Cairo (Egypt); Salah, Iman; Abdel-Rahman, Mohamed A. [Department of Cardiology, Ain Shams University Hospital, Cairo (Egypt); Salem, Alaa M. [Department of Internal Medicine, Medical Division, National Research Centre, Cairo (Egypt)

    2015-07-15

    Background: Ischemic heart diseases including stable angina & acute events, represent a huge burden on both the individual & the society and represent an important source of disability. Aim: We aimed to identify the effect of cardiac rehabilitation program (CRP) on the ischemic burden in patients with ischemic heart disease (IHD) unsuitable for coronary revascularization. Methods: The study included 40 patients with IHD who were not suitable for coronary revascularization either by PCI or CABG (due to unsuitable coronary anatomy, co morbidities, high surgical/procedural risk or patient preference). All patients were subjected to sophisticated CRP protocols, including patient education, nutritional, medical, psychological and sexual counseling and group smoking cessation. All patients participated in low intensity exercise program twice weekly. The patient’s symptoms, vitals and medications were evaluated at each visit and clinical and laboratory data, echocardiography and stress myocardial perfusion imaging (SPECT) were evaluated before and 3 months after the end of the study. Results: The mean age was 56.8 ± 3.1 years and only 2 patients (5%) were females. 22 (55%) patients were diabetic, 21 (53%) were hypertensive and 30 (75%) were smokers. It was found that 3 months after completion of CRP, there was a significant decrease in BMI (30.3 ± 2.9 vs. 31.2 ± 1.9, p < 0.001), and mean blood pressure (93.4 ± 11 vs. 105 ± 10.6 mmHg, p < 0.001). There was also a favorable effect on lipid profile and a significant improvement of the functional capacity in terms of NYHA functional class (2.1 ± 0.62 vs. 1.4 ± 0.6, p < 0.001). Despite that wall motion score index did not significantly change after CRP, there was a strong trend toward a better ejection fraction (53.7 ± 7.8 vs. 54.5 ± 6.3 %, p = 0.06) and significant improvement of Canadian cardiovascular class (1.42 ± 0.6 vs. 1.95 ± 0.5, p < 0.001) post CRP. Importantly, the difference between the SPECT

  6. Interleukin-18 gene deletion protects against sepsis-induced cardiac dysfunction by inhibiting PP2A activity.

    Science.gov (United States)

    Okuhara, Yoshitaka; Yokoe, Shunichi; Iwasaku, Toshihiro; Eguchi, Akiyo; Nishimura, Koichi; Li, Wen; Oboshi, Makiko; Naito, Yoshiro; Mano, Toshiaki; Asahi, Michio; Okamura, Haruki; Masuyama, Tohru; Hirotani, Shinichi

    2017-09-15

    Interleukin-18 (IL-18) neutralization protects against lipopolysaccharide (LPS)-induced injuries, including myocardial dysfunction. However, the mechanism is yet to be fully elucidated. The aim of the present study was to determine whether IL-18 gene deletion prevents sepsis-induced cardiac dysfunction and to elucidate the potential mechanisms underlying IL-18-mediated cardiotoxicity by LPS. Ten-week-old male wild-type (WT) and IL-18 knockout (IL-18 KO) mice were intraperitoneally administered LPS. Serial echocardiography showed better systolic pump function and less left ventricular (LV) dilatation in LPS-treated IL-18 KO mice compared with those in LPS-treated WT mice. LPS treatment significantly decreased the levels of phospholamban (PLN) and Akt phosphorylation in WT mice compared with those in saline-treated WT mice, while the LPS-induced decrease in the phosphorylation levels was attenuated in IL-18 KO mice compared with that in WT mice. IL-18 gene deletion also attenuated an LPS-induced increase of type 2 protein phosphatase 2A (PP2A) activity, a molecule that dephosphorylates PLN and Akt. There was no difference in type 1 protein phosphatase (PP1) activity. To address whether IL-18 affects PLN and Akt phosphorylation via PP2A activation in cardiomyocytes, rat neonatal cardiac myocytes were cultured and stimulated using 100ng/ml of recombinant rat IL-18. Exogenous IL-18 decreased the level of PLN and Akt phosphorylation in cardiomyocytes. PP2A activity but not PP1 activity was increased by IL-18 stimulation in cardiomyocytes. IL-18 plays a pivotal role in advancing sepsis-induced cardiac dysfunction, and the mechanisms underlying IL-18-mediated cardiotoxicity potentially involve the regulation of PLN and Akt phosphorylation through PP2A activity. Copyright © 2017 Elsevier B.V. All rights reserved.

  7. Ad-HGF improves the cardiac remodeling of rat following myocardial infarction by upregulating autophagy and necroptosis and inhibiting apoptosis

    Science.gov (United States)

    Liu, Jiabao; Wu, Peng; Wang, Yunle; Du, Yingqiang; A, Nan; Liu, Shuiyuan; Zhang, Yiming; Zhou, Ningtian; Xu, Zhihui; Yang, Zhijian

    2016-01-01

    Cell death in MI is the most critical determinant of subsequent left ventricular remodeling and heart failure. Besides apoptosis, autophagy and necroptosis have been recently found to be another two regulated cell death styles. HGF has been reported to have a protective role in MI, but its impact on the three death styles remains unclear. Thus, our study was performed to investigate the distribution of autophagy, apoptosis and necroptosis in cardiac tissues after MI and explore the role and mechanism of Ad-HGF on cardiac remodeling by regulating the three death styles. We firstly showed the distribution of autophagy, apoptosis and necroptosis differs in temporal and spatial context after MI using immunofluorescence. Notably, Ad-HGF treatment improves the cardiac remodeling of SD rats following MI by preserving the heart function, reducing the scar size and aggresomes. Further mechanism study reveals Ad-HGF promotes autophagy and necroptosis and inhibits apoptosis in vivo and in vitro. Co-immunoprecipitation assays showed Ad-HGF treatment significantly decreased the binding of Bcl-2 to Beclin1 but enhanced Bcl-2 binding to Bax in H9c2 cells under hypoxia. Moreover, HGF-induced sequestration of Bax by Bcl-2 allows Bax to become inactive, thereby inhibiting apoptosis. In addition, Ad-HGF markedly increased the formation of Beclin1-Vps34-Atg14L complex, which accounted for promoting autophagy. Both the western blot and activity assay showed Ad-HGF significantly decreased the caspase 8 protein and activity levels, which obligated the cell to undergo necroptosis under hypoxia and block apoptosis. Thus, our findings offer new evidence and strategies for the treatment of MI and post-MI cardiac remodeling. PMID:27904666

  8. Cardiac CaM Kinase II Genes δ and γ Contribute to Adverse Remodeling but Redundantly Inhibit Calcineurin-Induced Myocardial Hypertrophy

    Science.gov (United States)

    Kreusser, Michael M.; Lehmann, Lorenz H.; Keranov, Stanislav; Hoting, Marc-Oscar; Oehl, Ulrike; Kohlhaas, Michael; Reil, Jan-Christian; Neumann, Kay; Schneider, Michael D.; Hill, Joseph A.; Dobrev, Dobromir; Maack, Christoph; Maier, Lars S.; Gröne, Hermann-Josef; Katus, Hugo A.; Olson, Eric N.; Backs, Johannes

    2014-01-01

    Background Ca2+-dependent signaling through CaM Kinase II (CaMKII) and calcineurin was suggested to contribute to adverse cardiac remodeling. However, the relative importance of CaMKII versus calcineurin for adverse cardiac remodeling remained unclear. Methods and Results We generated double-knockout mice (DKO) lacking the 2 cardiac CaMKII genes δ and γ specifically in cardiomyocytes. We show that both CaMKII isoforms contribute redundantly to phosphorylation not only of phospholamban, ryanodine receptor 2, and histone deacetylase 4, but also calcineurin. Under baseline conditions, DKO mice are viable and display neither abnormal Ca2+ handling nor functional and structural changes. On pathological pressure overload and β-adrenergic stimulation, DKO mice are protected against cardiac dysfunction and interstitial fibrosis. But surprisingly and paradoxically, DKO mice develop cardiac hypertrophy driven by excessive activation of endogenous calcineurin, which is associated with a lack of phosphorylation at the auto-inhibitory calcineurin A site Ser411. Likewise, calcineurin inhibition prevents cardiac hypertrophy in DKO. On exercise performance, DKO mice show an exaggeration of cardiac hypertrophy with increased expression of the calcineurin target gene RCAN1-4 but no signs of adverse cardiac remodeling. Conclusions We established a mouse model in which CaMKII’s activity is specifically and completely abolished. By the use of this model we show that CaMKII induces maladaptive cardiac remodeling while it inhibits calcineurin-dependent hypertrophy. These data suggest inhibition of CaMKII but not calcineurin as a promising approach to attenuate the progression of heart failure. PMID:25124496

  9. Statin treatment increases lifespan and improves cardiac health in Drosophila by decreasing specific protein prenylation.

    Directory of Open Access Journals (Sweden)

    Stephen R Spindler

    Full Text Available Statins such as simvastatin are 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA reductase inhibitors and standard therapy for the prevention and treatment of cardiovascular diseases in mammals. Here we show that simvastatin significantly increased the mean and maximum lifespan of Drosophila melanogaster (Drosophila and enhanced cardiac function in aging flies by significantly reducing heart arrhythmias and increasing the contraction proportion of the contraction/relaxation cycle. These results appeared independent of internal changes in ubiquinone or juvenile hormone levels. Rather, they appeared to involve decreased protein prenylation. Simvastatin decreased the membrane association (prenylation of specific small Ras GTPases in mice. Both farnesyl (L744832 and type 1 geranylgeranyl transferase (GGTI-298 inhibitors increased Drosophila lifespan. These data are the most direct evidence to date that decreased protein prenylation can increase cardiac health and lifespan in any metazoan species, and may explain the pleiotropic (non-cholesterol related health effects of statins.

  10. Goal-directed therapy improves the outcome of high-risk cardiac patients undergoing off-pump coronary artery bypass

    Directory of Open Access Journals (Sweden)

    Poonam Malhotra Kapoor

    2017-01-01

    Full Text Available Background: There has been a constant emphasis on developing management strategies to improve the outcome of high-risk cardiac patients undergoing surgical revascularization. The performance of coronary artery bypass surgery on an off-pump coronary artery bypass (OPCAB avoids the risks associated with extra-corporeal circulation. The preliminary results of goal-directed therapy (GDT for hemodynamic management of high-risk cardiac surgical patients are encouraging. The present study was conducted to study the outcome benefits with the combined use of GDT with OPCAB as compared to the conventional hemodynamic management. Material and Method: Patients with the European System for Cardiac Operative Risk Evaluation ≥3 scheduled for OPCAB were randomly divided into two groups; the control and GDT groups. The GDT group included the monitoring and optimization of advanced parameters, including cardiac index (CI, systemic vascular resistance index, oxygen delivery index, stroke volume variation; continuous central venous oxygen saturation (ScVO 2 , global end-diastolic volume, and extravascular lung water (EVLW, using FloTrac™ , PreSep™ , and EV-1000 ® monitoring panels, in addition to the conventional hemodynamic management in the control group. The hemodynamic parameters were continuously monitored for 48 h in Intensive Care Unit (ICU and corrected according to GDT protocol. A total of 163 patients consented for the study. Result: Seventy-five patients were assigned to the GDT group and 88 patients were in the control group. In view of 9 exclusions from the GDT group and 12 exclusions from control group, 66 patients in the GDT group and 76 patients in control group completed the study. Conclusion: The length of stay in hospital (LOS-H (7.42 ± 1.48 vs. 5.61 ± 1.11 days, P < 0.001 and ICU stay (4.2 ± 0.82 vs. 2.53 ± 0.56 days, P < 0.001 were significantly lower in the GDT group as compared to control group. The duration of inotropes (3.24 ± 0

  11. Genetic polymorphisms of the TYMS gene are not associated with congenital cardiac septal defects in a Han Chinese population.

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    Jian-Yuan Zhao

    Full Text Available BACKGROUND: Clinical research indicates that periconceptional administration of folic acid can reduce the occurrence of congenital cardiac septal defects (CCSDs. The vital roles of folate exhibits in three ways: the unique methyl donor for DNA expression regulation, the de novo biosynthesis of purine and pyrimidine for DNA construction, and the serum homocysteine removal. Thymidylate synthase (TYMS is the solo catalysis enzyme for the de novo synthesis of dTMP, which is the essential precursor of DNA biosynthesis and repair process. To examine the role of TYMS in Congenital Cardiac Septal Defects (CCSDs risk, we investigated whether genetic polymorphisms in the TYMS gene associated with the CCSDs in a Han Chinese population. METHOD: Polymorphisms in the noncoding region of TYMS were identified via direct sequencing in 32 unrelated individuals composed of half CCSDs and half control subjects. Nine SNPs and two insertion/deletion polymorphisms were genotyped from two independent case-control studies involving a total of 529 CCSDs patients and 876 healthy control participants. The associations were examined by both single polymorphism and haplotype tests using logistic regression. RESULT: We found that TYMS polymorphisms were not related to the altered CCSDs risk, and even to the changed risk of VSDs subgroup, when tested in both studied groups separately or in combination. In the haplotype analysis, there were no haplotypes significantly associated with risks for CCSDs either. CONCLUSION: Our results show no association between common genetic polymorphisms of the regulatory region of the TYMS gene and CCSDs in the Han Chinese population.

  12. Improved Cardiac Contractility of Human Recombinant Growth Hormone on the Congestive Heart Failure of Pig

    Institute of Scientific and Technical Information of China (English)

    Yang Ping; He Yu-quan; Zeng Hong; Ni Jin-song; Yun Qing-jun; Huang Xiao-ping; Li Shu-mei

    2005-01-01

    The enhanced cardiac contractility effect of human recombinant growth hormone (hr-GH) on the congestive heart failure (CHF) was studied on the pig. To build a pig model of congestive heart failure, a temporary artificial cardiac pacemaker was implanted in the pig's body and paced at 220 beats to 240 beats per minute for 1 week. After the model of congestive heart failure was successfully set up, the frequency of the pacemaker was changed to 150 beats to 180 beats per minute to maintain the CHF model stable. Pigs were divided into three groups: The hr-GH group in which 0.5 mg/kg per day of hr-GH was administrated intramuscularly for 15 days, the injection control group in which an equal amount of physiological saline was injected intramuscularly, and a normal control group. The left ventricular diastolic end pressure was (10.60±2.41 ) mmHg in the hr-GH group, but (19.00±3.81) mmHg in the saline control group (P<0.01); Cardiac output was (1.86±0.13) L/min in the hr-GH group, but (1.56 ±0.18) L/min in the saline control group (P<0.05); Peripheral min) -1 in the saline control group (P<0.05); ± dp/dtmax was (2900 ±316.23) and (2280 ±286.36) in the hr-HG group and the saline control group respectively (P<0.05). The results show that hr-GH enhances myocardial contractility of CHF, and the CHF model built by a temporary artificial cardiac pacemaker at a high rate of stimulation is reasonable and applicable.

  13. Doxorubicin Cardiotoxicity and Cardiac Function Improvement After Stem Cell Therapy Diagnosed by Strain Echocardiography

    OpenAIRE

    Oliveira, Maira S.; Melo, Marcos B; Carvalho, Juliana L; Melo, Isabela M; Lavor, Mario SL; Gomes, Dawidson A.; Goes, Alfredo M.; Melo, Marilia M

    2013-01-01

    Doxorubicin (Dox) is one of the most effective chemotherapeutic agents; however, it causes dose-dependent cardiotoxicity. Evaluation of left ventricular function relies on measurements based on M-mode echocardiography. A new technique based on quantification of myocardial motion and deformation, strain echocardiography, has been showed promising profile for early detection of cardiac dysfunction. Different therapy strategies, such as flavonoid plant extracts and stem cells, have been investig...

  14. Influence of nitrous oxide anesthesia, B-vitamins, and MTHFR gene polymorphisms on perioperative cardiac events: the vitamins in nitrous oxide (VINO) randomized trial.

    Science.gov (United States)

    Nagele, Peter; Brown, Frank; Francis, Amber; Scott, Mitchell G; Gage, Brian F; Miller, J Philip

    2013-07-01

    Nitrous oxide causes an acute increase in plasma homocysteine that is more pronounced in patients with the methylenetetrahydrofolate reductase (MTHFR) C677T or A1298C gene variant. In this randomized controlled trial, the authors sought to determine whether patients carrying the MTHFR C677T or A1298C variant had a higher risk for perioperative cardiac events after nitrous oxide anesthesia and whether this risk could be mitigated by B-vitamins. The authors randomized adult patients with cardiac risk factors undergoing noncardiac surgery, to receive nitrous oxide plus intravenous B-vitamins before and after surgery, or to nitrous oxide and placebo. Serial cardiac biomarkers and 12-lead electrocardiograms were obtained. The primary study endpoint was the incidence of myocardial injury, as defined by cardiac troponin I increase within the first 72 h after surgery. A total of 500 patients completed the trial. Patients who were homozygous for either MTHFR C677T, or A1298C gene variant (n=98; 19.6%) had no increased rate of postoperative cardiac troponin I increase compared with wild-type and heterozygous patients (11.2 vs. 14.0%; relative risk 0.96; 95% CI, 0.85-1.07; P=0.48). B-vitamins blunted the rise in homocysteine, but had no effect on cardiac troponin I increase compared with patients receiving placebo (13.2 vs. 13.6%; relative risk 1.02; 95% CI 0.78 to 1.32; P=0.91). Neither MTHFR C677T and A1298C gene variant, nor acute homocysteine increase are associated with perioperative cardiac troponin increase after nitrous oxide anesthesia. B-vitamins blunt nitrous oxide-induced homocysteine increase but have no effect on cardiac troponin I increase.

  15. Improved cardiac filling facilitates the postprandial elevation of stroke volume in Python regius.

    Science.gov (United States)

    Enok, Sanne; Leite, Gabriella S P C; Leite, Cléo A C; Gesser, Hans; Hedrick, Michael S; Wang, Tobias

    2016-10-01

    To accommodate the pronounced metabolic response to digestion, pythons increase heart rate and elevate stroke volume, where the latter has been ascribed to a massive and fast cardiac hypertrophy. However, numerous recent studies show that heart mass rarely increases, even upon ingestion of large meals, and we therefore explored the possibility that a rise in mean circulatory filling pressure (MCFP) serves to elevate venous pressure and cardiac filling during digestion. To this end, we measured blood flows and pressures in anaesthetized Python regius The anaesthetized snakes exhibited the archetypal tachycardia as well as a rise in both venous pressure and MCFP that fully account for the approximate doubling of stroke volume. There was no rise in blood volume and the elevated MCFP must therefore stem from increased vascular tone, possibly by means of increased sympathetic tone on the veins. Furthermore, although both venous pressure and MCFP increased during volume loading, there was no evidence that postprandial hearts were endowed with an additional capacity to elevate stroke volume. In vitro measurements of force development of paced ventricular strips also failed to reveal signs of increased contractility, but the postprandial hearts had higher activities of cytochrome oxidase and pyruvate kinase, which probably serves to sustain the rise in cardiac work during digestion. © 2016. Published by The Company of Biologists Ltd.

  16. Same day admission for elective cardiac surgery: how to improve outcome with satisfaction and decrease expenses.

    Science.gov (United States)

    Silvay, George; Goldberg, Andrew; Gutsche, Jacob T; T Augoustides, John G

    2016-06-01

    Admission on the day of surgery for elective cardiac and non-cardiac surgery has been established as a prevalent, critical practice. This approach realizes medical, logistical, psychological and fiscal benefits, and its success is predicated on an effective outpatient pre-operative evaluation. The establishment of a highly functional pre-operative clinic with a comprehensive set-up and efficient logistical pathways is invaluable. This notion has been expanded in recent years to include the entire peri-operative period and the concept of a 'peri-operative anesthesia/surgical home' is gaining popularity and support. Evaluating patients prior to admission for surgery, anesthesiologists can place themselves at the forefront of reducing unnecessary pre-operative hospital admissions, excess lab tests, unneeded consultations, and ultimately decrease the cancellations on the day of surgery. Furthermore, by taking a leadership role in the pre-operative clinic, anesthesiologists place themselves squarely at the forefront of the burgeoning movement for the peri-operative surgical home and continue to cement the indispensability of the anesthesiologist during the entire peri-operative course. The authors present this review as a follow-up describing the successful implementation of a pre-operative same-day cardiac surgery clinic and offer these experiences over the last 8 years as a guide to helping other anesthesiologists do the same.

  17. [The value of an intervention for improving secondary prevention in patients undergoing cardiac surgery].

    Science.gov (United States)

    Reyes, Guillermo; Rodríguez-Abella, Hugo; Cuerpo, Gregorio; López, José; Montalvo, Elena; Duarte, Juan; Vallejo, José L; Bueno, Héctor

    2008-07-01

    Given that treatment for secondary prevention in patients undergoing cardiac surgery is underused, we devised a hospital intervention to increase its implementation. The intervention involved all physicians in the department of cardiac surgery agreeing to complete a report on each patient before hospital discharge. The document recorded the indications for the recommended treatments, and prompted for details of the drugs prescribed, the doses used, the reasons for not prescribing the recommended drugs, if that was the case, and the use of alternative medicines. The efficacy of the intervention was evaluated by comparing the rate of drug use in the year in which it was introduced (2003, n=341) with retrospective data on the rate in the previous year (n=369). The rates of use of aspirin, statins, angiotensin-converting enzyme inhibitors, and beta-blockers by patients who required them all showed an absolute increase, of 13.4%, 38.3%, 21.8%, and 21.5%, respectively. In conclusion, the introduction of a simple and inexpensive intervention was able to significantly increase the use of drugs for secondary prevention in patients undergoing cardiac surgery.

  18. Gene cloning: exploring cotton functional genomics and genetic improvement

    Institute of Scientific and Technical Information of China (English)

    Diqiu LIU; Xianlong ZHANG

    2008-01-01

    Cotton is the most important natural fiber plant in the world. The genetic improvement of the quality of the cotton fiber and agricultural productivity is imperative under the situation of increasing consumption and rapid development of textile technology. Recently, the study of cotton molecular biology has progressed greatly. A lot of specifically or preferentially expressed cotton fiber genes were cloned and analyzed. On the other hand, identification of stress response genes expressed in cotton was performed by other research groups. The major stress factors were studied including the wilt pathogens Verticillium dahliae, Fusarium oxy-sporum f. sp. vasinfectum, bacterial blight, root-knot nematode, drought, and salt stress. What is more, a few genes related to the biosynthesis of gossypol, other sesquiterpene phytoalexins and the major seed oil fatty acids were isolated from cotton. In the present review, we focused on the major advances in cotton gene cloning and expression profiling in the recent years.

  19. Grouping Gene Ontology terms to improve the assessment of gene set enrichment in microarray data.

    Science.gov (United States)

    Lewin, Alex; Grieve, Ian C

    2006-10-03

    Gene Ontology (GO) terms are often used to assess the results of microarray experiments. The most common way to do this is to perform Fisher's exact tests to find GO terms which are over-represented amongst the genes declared to be differentially expressed in the analysis of the microarray experiment. However, due to the high degree of dependence between GO terms, statistical testing is conservative, and interpretation is difficult. We propose testing groups of GO terms rather than individual terms, to increase statistical power, reduce dependence between tests and improve the interpretation of results. We use the publicly available package POSOC to group the terms. Our method finds groups of GO terms significantly over-represented amongst differentially expressed genes which are not found by Fisher's tests on individual GO terms. Grouping Gene Ontology terms improves the interpretation of gene set enrichment for microarray data.

  20. Grouping Gene Ontology terms to improve the assessment of gene set enrichment in microarray data

    Directory of Open Access Journals (Sweden)

    Grieve Ian C

    2006-10-01

    Full Text Available Abstract Background Gene Ontology (GO terms are often used to assess the results of microarray experiments. The most common way to do this is to perform Fisher's exact tests to find GO terms which are over-represented amongst the genes declared to be differentially expressed in the analysis of the microarray experiment. However, due to the high degree of dependence between GO terms, statistical testing is conservative, and interpretation is difficult. Results We propose testing groups of GO terms rather than individual terms, to increase statistical power, reduce dependence between tests and improve the interpretation of results. We use the publicly available package POSOC to group the terms. Our method finds groups of GO terms significantly over-represented amongst differentially expressed genes which are not found by Fisher's tests on individual GO terms. Conclusion Grouping Gene Ontology terms improves the interpretation of gene set enrichment for microarray data.

  1. Identification of direct serum-response factor gene targets during Me2SO-induced P19 cardiac cell differentiation.

    Science.gov (United States)

    Zhang, Shu Xing; Garcia-Gras, Eduardo; Wycuff, Diane R; Marriot, Suzanne J; Kadeer, Nijiati; Yu, Wei; Olson, Eric N; Garry, Daniel J; Parmacek, Michael S; Schwartz, Robert J

    2005-05-13

    Serum-response factor (SRF) is an obligatory transcription factor, required for the formation of vertebrate mesoderm leading to the origin of the cardiovascular system. Protein A-TEV-tagged chromatin immunoprecipitation technology was used to collect direct SRF-bound gene targets from pluripotent P19 cells, induced by Me2SO treatment into an enriched cardiac cell population. From 242 sequenced DNA fragments, we identified 188 genomic DNA fragments as potential direct SRF targets that contain CArG boxes and CArG-like boxes. Of the 92 contiguous genes that were identified, a subgroup of 43 SRF targets was then further validated by co-transfection assays with SRF. Expression patterns of representative candidate genes were compared with the LacZ reporter expression activity of the endogenous SRF gene. According to the Unigene data base, 84% of the SRF target candidates were expressed, at least, in the heart. In SRF null embryonic stem cells, 81% of these SRF target candidates were greatly affected by the absence of SRF. Among these SRF-regulated genes, Raf1, Map4k4, and Bicc1 have essential roles in mesoderm formation. The 12 regulated SRF target genes, Mapk10 (JNK3), Txnl2, Azi2, Tera, Sema3a, Lrp4, Actc1, Myl3, Hspg2, Pgm2, Hif3a, and Asb5, have been implicated in cardiovascular formation, and the Ski and Hes6 genes have roles in muscle differentiation. SRF target genes related to cell mitosis and cycle, E2f5, Npm1, Cenpb, Rbbp6, and Scyl1, expressed in the heart tissue were differentially regulated in SRF null ES cells.

  2. Executive functions improvement following a 5-month aquaerobics program in older adults: Role of cardiac vagal control in inhibition performance.

    Science.gov (United States)

    Albinet, Cédric T; Abou-Dest, Amira; André, Nathalie; Audiffren, Michel

    2016-03-01

    The aims of this study were to examine the effects of aerobic exercise on measures of executive performance and their relationships with changes in cardiorespiratory fitness, cardiac vagal control (heart rate variability) and psychological variables. Thirty-six sedentary seniors aged 60-75 years were randomly assigned to a swimming and aquaerobics program or a stretching program two times a week for 21 weeks. Executive functions (inhibition, updating of working memory and cognitive flexibility) and cardiorespiratory fitness (estimated VO2max) were assessed at the start, after 10 weeks of program and at the end of the program. Resting HRV and measures of psychological outcomes (depression, self-efficacy, decisional balance) were obtained at the start and at the end of the program. Participants of both groups significantly improved their VO2max level, their psychological state and their performance for the 2-back task. Only the participants in the aquaerobics group significantly improved their vagally-mediated HRV and their performance for the Stroop test and the verbal running-span test at the end of the program. Only improvements in cardiac vagal control and in inhibition were shown to be functionally related. These results are discussed in line with the model of neurovisceral integration.

  3. An Improved Method for Discriminating ECG Signals using Typical Nonlinear Dynamic Parameters and Recurrence Quantification Analysis in Cardiac Disease Therapy.

    Science.gov (United States)

    Tang, M; Chang, C Q; Fung, P C W; Chau, K T; Chan, F H Y

    2005-01-01

    The discrimination of ECG signals using nonlinear dynamic parameters is of crucial importance in the cardiac disease therapy and chaos control for arrhythmia defibrillation in the cardiac system. However, the discrimination results of previous studies using features such as maximal Lyapunov exponent (λmax) and correlation dimension (D2) alone are somewhat limited in recognition rate. In this paper, improved methods for computing λmaxand D2are purposed. Another parameter from recurrence quantification analysis is incorporated to the new multi-feature Bayesian classifier with λmaxand D2so as to improve the discrimination power. Experimental results have verified the prediction using Fisher discriminant that the maximal vertical line length (Vmax) from recurrence quantification analysis is the best to distinguish different ECG classes. Experimental results using the MIT-BIH Arrhythmia Database show improved and excellent overall accuracy (96.3%), average sensitivity (96.3%) and average specificity (98.15%) for discriminating sinus, premature ventricular contraction and ventricular flutter signals.

  4. Sumoylation in gene regulation and cardiac disease: potential for drug discovery

    Directory of Open Access Journals (Sweden)

    Beketaev I

    2014-11-01

    Full Text Available Ilimbek Beketaev, Jun Wang Center for Stem Cell Engineering, Department of Basic Research Laboratories, Texas Heart Institute at St Luke’s Episcopal Hospital, Houston, TX, USA Abstract: Small ubiquitin-related modifier (SUMO proteins are members of ubiquitin-like super-family proteins that can be covalently conjugated to their targets through multistep enzymatic reactions. Sumoylation has caught much attention due to its versatility, wide involvement in cellular events, and disease association. Sumoylation has been well studied at cellular and molecular levels. A newly emerging role that SUMO conjugation plays is in cardiac pathophysiology. In this review we will update new advances in the study of implications of the sumoylation pathway in the pathogenesis of cardiac diseases, discuss promise of the SUMO pathway as a potential therapeutic target, and conclude with future directions for SUMO research in the heart field. Keywords: posttranslational modification, SUMO, SENP, heart

  5. Improved hepatic arterial fraction estimation using cardiac output correction of arterial input functions for liver DCE MRI

    Science.gov (United States)

    Chouhan, Manil D.; Bainbridge, Alan; Atkinson, David; Punwani, Shonit; Mookerjee, Rajeshwar P.; Lythgoe, Mark F.; Taylor, Stuart A.

    2017-02-01

    Liver dynamic contrast enhanced (DCE) MRI pharmacokinetic modelling could be useful in the assessment of diffuse liver disease and focal liver lesions, but is compromised by errors in arterial input function (AIF) sampling. In this study, we apply cardiac output correction to arterial input functions (AIFs) for liver DCE MRI and investigate the effect on dual-input single compartment hepatic perfusion parameter estimation and reproducibility. Thirteen healthy volunteers (28.7  ±  1.94 years, seven males) underwent liver DCE MRI and cardiac output measurement using aortic root phase contrast MRI (PCMRI), with reproducibility (n  =  9) measured at 7 d. Cardiac output AIF correction was undertaken by constraining the first pass AIF enhancement curve using the indicator-dilution principle. Hepatic perfusion parameters with and without cardiac output AIF correction were compared and 7 d reproducibility assessed. Differences between cardiac output corrected and uncorrected liver DCE MRI portal venous (PV) perfusion (p  =  0.066), total liver blood flow (TLBF) (p  =  0.101), hepatic arterial (HA) fraction (p  =  0.895), mean transit time (MTT) (p  =  0.646), distribution volume (DV) (p  =  0.890) were not significantly different. Seven day corrected HA fraction reproducibility was improved (mean difference 0.3%, Bland–Altman 95% limits-of-agreement (BA95%LoA)  ±27.9%, coefficient of variation (CoV) 61.4% versus 9.3%, ±35.5%, 81.7% respectively without correction). Seven day uncorrected PV perfusion was also improved (mean difference 9.3 ml min‑1/100 g, BA95%LoA  ±506.1 ml min‑1/100 g, CoV 64.1% versus 0.9 ml min‑1/100 g, ±562.8 ml min‑1/100 g, 65.1% respectively with correction) as was uncorrected TLBF (mean difference 43.8 ml min‑1/100 g, BA95%LoA  ±586.7 ml min‑1/ 100 g, CoV 58.3% versus 13.3 ml min‑1/100 g, ±661.5 ml min‑1/100 g, 60

  6. Paracrine action of HO-1-modified mesenchymal stem cells mediates cardiac protection and functional improvement.

    Science.gov (United States)

    Zeng, Bin; Ren, Xiaofeng; Lin, Guosheng; Zhu, Chengang; Chen, Honglei; Yin, Jiechao; Jiang, Hong; Yang, Bo; Ding, Danhua

    2008-10-01

    The aim has been to determine whether the supernatants of mesenchymal stem cells (MSCs) transfected with adenovirus carrying human heme oxygenase-1 (hHO-1) gene protect cardiomyocytes from ischemic injury. We have found that hHO-1 infected MSCs (hHO-1-MSCs) increased expression of hHO-1 protein. Apoptosis of cultured hHO-1-MSCs exposed to hypoxia was suppressed. Several cytokines, including HGF, bFGF, TGF-beta, VEGF and IL-1beta, were produced by hHO-1-MSCs, some being significantly enhanced under hypoxia stimulation. Meanwhile, those cytokines reduced caspase-3 level and activity in cultured adult rat ventricular cardiomyocytes (ARVCs) exposed to hypoxia. Supernatants obtained from hHO-1-MSCs improved left ventricular function, limited myocardial infarct size, increased microvessel density, and inhibited apoptosis of cardiomyocytes in rat myocardial infarction. It can be concluded hHO-1-modified MSCs prevent myocardial cell injury via secretion of paracrine-acting mediators.

  7. A model-based time-reversal of left ventricular motion improves cardiac motion analysis using tagged MRI data

    Directory of Open Access Journals (Sweden)

    Cook Larry T

    2008-05-01

    Full Text Available Abstract Background Myocardial motion is an important observable for the assessment of heart condition. Accurate estimates of ventricular (LV wall motion are required for quantifying myocardial deformation and assessing local tissue function and viability. Harmonic Phase (HARP analysis was developed for measuring regional LV motion using tagged magnetic resonance imaging (tMRI data. With current computer-aided postprocessing tools including HARP analysis, large motions experienced by myocardial tissue are, however, often intractable to measure. This paper addresses this issue and provides a solution to make such measurements possible. Methods To improve the estimation performance of large cardiac motions while analyzing tMRI data sets, we propose a two-step solution. The first step involves constructing a model to describe average systolic motion of the LV wall within a subject group. The second step involves time-reversal of the model applied as a spatial coordinate transformation to digitally relax the contracted LV wall in the experimental data of a single subject to the beginning of systole. Cardiac tMRI scans were performed on four healthy rats and used for developing the forward LV model. Algorithms were implemented for preprocessing the tMRI data, optimizing the model parameters and performing the HARP analysis. Slices from the midventricular level were then analyzed for all systolic phases. Results The time-reversal operation derived from the LV model accounted for the bulk portion of the myocardial motion, which was the average motion experienced within the overall subject population. In analyzing the individual tMRI data sets, removing this average with the time-reversal operation left small magnitude residual motion unique to the case. This remaining residual portion of the motion was estimated robustly using the HARP analysis. Conclusion Utilizing a combination of the forward LV model and its time reversal improves the performance of

  8. Analysis of the stability of housekeeping gene expression in the left cardiac ventricle of rats submitted to chronic intermittent hypoxia.

    Science.gov (United States)

    Julian, Guilherme Silva; Oliveira, Renato Watanabe de; Tufik, Sergio; Chagas, Jair Ribeiro

    2016-01-01

    Obstructive sleep apnea (OSA) has been associated with oxidative stress and various cardiovascular consequences, such as increased cardiovascular disease risk. Quantitative real-time PCR is frequently employed to assess changes in gene expression in experimental models. In this study, we analyzed the effects of chronic intermittent hypoxia (an experimental model of OSA) on housekeeping gene expression in the left cardiac ventricle of rats. Analyses via four different approaches-use of the geNorm, BestKeeper, and NormFinder algorithms; and 2-ΔCt (threshold cycle) data analysis-produced similar results: all genes were found to be suitable for use, glyceraldehyde-3-phosphate dehydrogenase and 18S being classified as the most and the least stable, respectively. The use of more than one housekeeping gene is strongly advised. RESUMO A apneia obstrutiva do sono (AOS) tem sido associada ao estresse oxidativo e a várias consequências cardiovasculares, tais como risco aumentado de doença cardiovascular. A PCR quantitativa em tempo real é frequentemente empregada para avaliar alterações na expressão gênica em modelos experimentais. Neste estudo, analisamos os efeitos da hipóxia intermitente crônica (um modelo experimental de AOS) na expressão de genes de referência no ventrículo cardíaco esquerdo de ratos. Análises a partir de quatro abordagens - uso dos algoritmos geNorm, BestKeeper e NormFinder e análise de dados 2-ΔCt (ciclo limiar) - produziram resultados semelhantes: todos os genes mostraram-se adequados para uso, sendo que gliceraldeído-3-fosfato desidrogenase e 18S foram classificados como o mais e o menos estável, respectivamente. A utilização de mais de um gene de referência é altamente recomendada.

  9. Whole blood transcriptomics in cardiac surgery identifies a gene regulatory network connecting ischemia reperfusion with systemic inflammation.

    Directory of Open Access Journals (Sweden)

    Orfeas Liangos

    Full Text Available BACKGROUND: Cardiac surgery with cardiopulmonary bypass (CS/CPB is associated with increased risk for postoperative complications causing substantial morbidity and mortality. To identify the molecular mechanisms underlying CS/CPB-induced pathophysiology we employed an integrative systems biology approach using the whole blood transcriptome as the sentinel organ. METHODOLOGY/PRINCIPAL FINDINGS: Total RNA was isolated and globin mRNA depleted from whole blood samples prospectively collected from 10 patients at time points prior (0, 2 and 24 hours following CS/CPB. Genome-wide transcriptional analysis revealed differential expression of 610 genes after CS/CPB (p<0.01. Among the 375 CS/CPB-upregulated genes, we found a gene-regulatory network consisting of 50 genes, reminiscent of activation of a coordinated genetic program triggered by CS/CPB. Intriguingly, the highly connected hub nodes of the identified network included key sensors of ischemia-reperfusion (HIF-1alpha and C/EBPbeta. Activation of this network initiated a concerted inflammatory response via upregulation of TLR-4/5, IL1R2/IL1RAP, IL6, IL18/IL18R1/IL18RAP, MMP9, HGF/HGFR, CalgranulinA/B, and coagulation factors F5/F12 among others. Differential regulation of 13 candidate genes including novel, not hitherto CS/CBP-associated genes, such as PTX3, PGK1 and Resistin, was confirmed using real-time quantitative RT-PCR. In support of the mRNA data, differential expression of MMP9, MIP1alpha and MIP1beta plasma proteins was further confirmed in 34 additional patients. CONCLUSIONS: Analysis of blood transcriptome uncovered critical signaling pathways governing the CS/CPB-induced pathophysiology. The molecular signaling underlying ischemia reperfusion and inflammatory response is highly intertwined and includes pro-inflammatory as well as cardioprotective elements. The herein identified candidate genes and pathways may provide promising prognostic biomarker and therapeutic targets.

  10. Doxycycline attenuates protein aggregation in cardiomyocytes and improves survival of a mouse model of cardiac proteinopathy.

    Science.gov (United States)

    Zheng, Hanqiao; Tang, Mingxin; Zheng, Qingwen; Kumarapeli, Asangi R K; Horak, Kathleen M; Tian, Zongwen; Wang, Xuejun

    2010-10-19

    The goal of this pre-clinical study was to assess the therapeutic efficacy of doxycycline (Doxy) for desmin-related cardiomyopathy (DRC) and to elucidate the potential mechanisms involved. DRC, exemplifying cardiac proteinopathy, is characterized by intrasarcoplasmic protein aggregation and cardiac insufficiency. No effective treatment for DRC is available presently. Doxy was shown to attenuate aberrant intranuclear aggregation and toxicity of misfolded proteins in noncardiac cells and animal models of other proteinopathies. Mice and cultured neonatal rat cardiomyocytes with transgenic (TG) expression of a human DRC-linked missense mutation R120G of αB-crystallin (CryAB(R120G)) were used for testing the effect of Doxy. Doxy was administered via drinking water (6 mg/ml) initiated at 8 or 16 weeks of age. Doxy treatment initiated at 16 weeks of age significantly delayed the premature death of CryAB(R120G) TG mice, with a median lifespan of 30.4 weeks (placebo group, 25 weeks; p Doxy treatment initiated at 8 weeks of age significantly attenuated cardiac hypertrophy in 1 month. Further investigation revealed that Doxy significantly reduced the abundance of CryAB-positive microscopic aggregates, detergent-resistant CryAB oligomers, and total ubiquitinated proteins in CryAB(R120G) TG hearts. In cell culture, Doxy treatment dose-dependently suppressed the formation of both microscopic protein aggregates and detergent-resistant soluble CryAB(R120G) oligomers and reversed the up-regulation of p62 protein induced by adenovirus-mediated CryAB(R120G) expression. Doxy suppresses CryAB(R120G)-induced aberrant protein aggregation in cardiomyocytes and prolongs CryAB(R120G)-based DRC mouse survival. Copyright © 2010 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

  11. Epac-Rap1-activated mesenchymal stem cells improve cardiac function in rat model of myocardial infarction.

    Science.gov (United States)

    Khan, Irfan; Ali, Anwar; Akhter, Muhammad Aleem; Naeem, Nadia; Chotani, Maqsood Ahmed; Iqbal, Hana'a; Kabir, Nurul; Atiq, Mehnaz; Salim, Asmat

    2017-04-01

    Rap1, a member of Ras superfamily of small GTP-binding proteins, is involved in cardiovascular biology in numerous ways. It is an evolutionary conserved regulator of adhesion, polarity, differentiation and growth. Our aim was to analyze Rap1-activated rat bone marrow mesenchymal stem cells (MSCs) for their potential role in adhesion and cardiac differentiation. Myocardial infarction (MI) was produced in Sprague Dawley (SD) rats through occlusion of the left anterior descending coronary artery. MSCs were treated with 8-pCPT-2'-O-Me-cAMP (CPT) to activate Rap1. Normal (untreated) and CPT-treated MSCs were transplanted through intramyocardial injection in respective groups. Cardiac function was assessed by echocardiography at 2 and 4 weeks after cell transplantation. Histological analysis was performed to observe changes at tissue level. Homing of CPT-treated MSCs was significantly (***Pinfarcted hearts. This may be due to increase in the gene expression of some of the cell adhesion molecules as evident by qRT-PCR analysis. Significant (***Pinfarct area restored functional myocardium. © 2016 John Wiley & Sons Ltd.

  12. Improvement of cardiac function by hepatocyte growth factor via intracoronary transfection in the swine myocardial infarction model

    Institute of Scientific and Technical Information of China (English)

    Wei Wang; Wenzhu Ma; Zhijian Yang; Dongchao Ma; Shunlin Xu; Yourong Zhang; Yuqing Zhang; Liansheng Wang; Bo Chen; Kejiang Cao

    2006-01-01

    Objective: To study the amelioration effect of Adenovirus5-mediated human hepatocyte growth factor (Ad5-HGF) on postinfarction heart failure in the swine myocardial infarction model. Methods: Twelve SuZhong young swine were randomly divided into 2 groups with 6 swine in each group: Ad5-HGF-treated group and null-Ad5 group. Four weeks after ligation at left anterior descending coronary artery in swine hearts, Ad5-HGF was transferred to the swine myocardium. Simultaneously,Gated myocardial perfusion imaging was performed to evaluate cardiac perfusion and heart function. After three weeks, Gated myocardial perfusion imaging was performed again, then the hearts were harvested and sectioned to examine the expression of HGF through ELISA. Results: High expression of human HGF was observed in the myocardium of Ad5-HGF-treated group. From 4 weeks to 7 weeks after operation, Left ventricular ejection fraction was increased in Ad5-HGF-treated group. The improvement in LVEF was greater in Ad5-HGF-treated group than that in null-Ad5 group at 7 weeks after operation. Cardiac perfusion was significantly improved in the Ad5-HGF-treated group. Conclusion: High expression of human HGF was observed in the myocardium through intracoronary transfection, which suggests that HGF can ameliorate heart function in swine with postinfarction heart failure.

  13. Improvement of left ventricular function under cardiac resynchronization therapy goes along with a reduced incidence of ventricular arrhythmia.

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    Christian Eickholt

    Full Text Available OBJECTIVES: The beneficial effects of cardiac resynchronization therapy (CRT are thought to result from favorable left ventricular (LV reverse remodeling, however CRT is only successful in about 70% of patients. Whether response to CRT is associated with a decrease in ventricular arrhythmias (VA is still discussed controversially. Therefore, we investigated the incidence of VA in CRT responders in comparison with non-responders. METHODS: In this nonrandomized, two-center, observational study patients with moderate-to-severe heart failure, LV ejection fraction (LVEF ≤35%, and QRS duration >120 ms undergoing CRT were included. After 6 months patients were classified as CRT responders or non-responders. Incidence of VA was compared between both groups by Kaplan-Meier analysis and Cox regression analysis. ROC analysis was performed to determine the aptitude of LVEF cut-off values to predict VA. RESULTS: In total 126 consecutive patients (64±11 years; 67%male were included, 74 were classified as responders and 52 as non-responders. While the mean LVEF at baseline was comparable in both groups (25±7% vs. 24±8%; P = 0.4583 only the responder group showed an improvement of LVEF (36±6% vs. 24±7; p7% was found to be a predictor of a significantly lower incidence of VA (AUC = 0.606. CONCLUSIONS: Improvement of left ventricular function under cardiac resynchronization therapy goes along with a reduced incidence of ventricular arrhythmia.

  14. Improving full-cardiac cycle strain estimation from tagged CMR by accurate modeling of 3D image appearance characteristics

    Directory of Open Access Journals (Sweden)

    Matt Nitzken

    2016-03-01

    Full Text Available To improve the tagged cardiac magnetic resonance (CMR image analysis, we propose a 3D (2D space + 1D time energy minimization framework, based on learning first- and second-order visual appearance models from voxel intensities. The former model approximates the marginal empirical distribution of intensities with two linear combinations of discrete Gaussians (LCDG. The second-order model considers an image of a sample from a translation–rotation invariant 3D Markov–Gibbs random field (MGRF with multiple pairwise spatiotemporal interactions within and between adjacent temporal frames. Abilities of the framework to accurately recover noise-corrupted strain slopes were experimentally evaluated and validated on 3D geometric phantoms and independently on in vivo data. In multiple noise and motion conditions, the proposed method outperformed comparative image filtering in restoring strain curves and reliably improved HARP strain tracking during the entirety of the cardiac cycle. According to these results, our framework can augment popular spectral domain techniques, such as HARP, by optimizing the spectral domain characteristics and thereby providing more reliable estimates of strain parameters.

  15. Combining gene signatures improves prediction of breast cancer survival.

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    Xi Zhao

    Full Text Available BACKGROUND: Several gene sets for prediction of breast cancer survival have been derived from whole-genome mRNA expression profiles. Here, we develop a statistical framework to explore whether combination of the information from such sets may improve prediction of recurrence and breast cancer specific death in early-stage breast cancers. Microarray data from two clinically similar cohorts of breast cancer patients are used as training (n = 123 and test set (n = 81, respectively. Gene sets from eleven previously published gene signatures are included in the study. PRINCIPAL FINDINGS: To investigate the relationship between breast cancer survival and gene expression on a particular gene set, a Cox proportional hazards model is applied using partial likelihood regression with an L2 penalty to avoid overfitting and using cross-validation to determine the penalty weight. The fitted models are applied to an independent test set to obtain a predicted risk for each individual and each gene set. Hierarchical clustering of the test individuals on the basis of the vector of predicted risks results in two clusters with distinct clinical characteristics in terms of the distribution of molecular subtypes, ER, PR status, TP53 mutation status and histological grade category, and associated with significantly different survival probabilities (recurrence: p = 0.005; breast cancer death: p = 0.014. Finally, principal components analysis of the gene signatures is used to derive combined predictors used to fit a new Cox model. This model classifies test individuals into two risk groups with distinct survival characteristics (recurrence: p = 0.003; breast cancer death: p = 0.001. The latter classifier outperforms all the individual gene signatures, as well as Cox models based on traditional clinical parameters and the Adjuvant! Online for survival prediction. CONCLUSION: Combining the predictive strength of multiple gene signatures improves

  16. Improved oxygen uptake efficiency slope in acute myocardial infarction patients after early phase I cardiac rehabilitation.

    Science.gov (United States)

    Tsai, Yun-Jeng; Li, Min-Hui; Chen, Chia-Hsin; Tuan, Sheng-Hui; Chen, Yi-Jen; Lin, Ko-Long

    2017-09-01

    A predischarge submaximal exercise test is often recommended after acute myocardial infarction (AMI) as part of phase I cardiac rehabilitation. In this study, a submaximal exercise parameter, oxygen uptake efficiency slope (OUES), was used to monitor the benefit of early mobilization within 48 h after AMI. An early mobilization protocol within 48 h after AMI has been initiated since 1 September 2012 in our center. Patients with onset time of AMI within 1 year before and 1 year after initiation of the early mobilization protocol were recruited for comparisons. Sixty patients were analyzed on the basis of this criterion, and were subjected to predischarge submaximal exercise tests. The OUES calculated with 100% exercise duration (OUES100) and calculated with the first 50% of exercise duration (OUES50) were obtained and analyzed. Both OUES100 and OUES50 of the AMI patients with early mobilization were significantly higher than those without early mobilization (P=0.025 and 0.007, respectively). The OUES100 and OUES50 were also highly correlated (r=0.891, P<0.001). The subgroup analysis using patients within 3 months before and 3 months after initiation of the protocol also showed a significant difference. OUES could be used to measure the exercise capacity and monitor the effect of phase I cardiac rehabilitation in patients soon after AMI. Early mobilization within 48 h following AMI significantly enhanced the patient's exercise capacity.

  17. Reduction of Leukocyte Counts by Hydroxyurea Improves Cardiac Function in Rats with Acute Myocardial Infarction.

    Science.gov (United States)

    Zhu, Guiyue; Yao, Yucai; Pan, Lingyun; Zhu, Wei; Yan, Suhua

    2015-12-17

    BACKGROUND This study aimed to decrease leukocytes counts by hydroxyurea (Hu) in an acute myocardial infarction (AMI) rat model and examine its effect on the inflammatory response of myocardial infarction and cardiac functions. MATERIAL AND METHODS AMI was successfully caused in 36 rats, and 12 control rats received sham operation. Rats in the AMI group were then randomly divided into Hu and vehicle group with 18 rats each. Rats in the Hu AMI group received Hu (200 mg/kg) intragastrically while vehicle AMI group received saline. Leukocytes counts, cardiac functions, myocardial tissue morphology, and levels of soluble intercellular adhesion molecule-1 (sICAM), P-selectin and platelet activating factor (PAF) were measured and compared among the three groups four weeks after AMI induction. RESULTS Leukocytes, neutrophils, and leukomonocyte counts in vehicle AMI rats were significantly higher than that of the normal control group (pEchocardiography analysis showed that Hu treatment increased left ventricular ejection fraction (LVEF) and left ventricular fractional shortening (LVFS) compared to that of vehicle AMI group (prats.

  18. Cardiac expression of microsomal triglyceride transfer protein is increased in obesity and serves to attenuate cardiac triglyceride accumulation.

    Directory of Open Access Journals (Sweden)

    Emil D Bartels

    Full Text Available Obesity causes lipid accumulation in the heart and may lead to lipotoxic heart disease. Traditionally, the size of the cardiac triglyceride pool is thought to reflect the balance between uptake and beta-oxidation of fatty acids. However, triglycerides can also be exported from cardiomyocytes via secretion of apolipoproteinB-containing (apoB lipoproteins. Lipoprotein formation depends on expression of microsomal triglyceride transfer protein (MTP; the mouse expresses two isoforms of MTP, A and B. Since many aspects of the link between obesity-induced cardiac disease and cardiac lipid metabolism remain unknown, we investigated how cardiac lipoprotein synthesis affects cardiac expression of triglyceride metabolism-controlling genes, insulin sensitivity, and function in obese mice. Heart-specific ablation of MTP-A in mice using Cre-loxP technology impaired upregulation of MTP expression in response to increased fatty acid availability during fasting and fat feeding. This resulted in cardiac triglyceride accumulation but unaffected cardiac insulin-stimulated glucose uptake. Long-term fat-feeding of male C57Bl/6 mice increased cardiac triglycerides, induced cardiac expression of triglyceride metabolism-controlling genes and attenuated heart function. Abolishing cardiac triglyceride accumulation in fat-fed mice by overexpression of an apoB transgene in the heart prevented the induction of triglyceride metabolism-controlling genes and improved heart function. The results suggest that in obesity, the physiological increase of cardiac MTP expression serves to attenuate cardiac triglyceride accumulation albeit without major effects on cardiac insulin sensitivity. Nevertheless, the data suggest that genetically increased lipoprotein secretion prevents development of obesity-induced lipotoxic heart disease.

  19. Cardiac Expression of Microsomal Triglyceride Transfer Protein Is Increased in Obesity and Serves to Attenuate Cardiac Triglyceride Accumulation

    Science.gov (United States)

    Bartels, Emil D.; Nielsen, Jan M.; Hellgren, Lars I.; Ploug, Thorkil; Nielsen, Lars B.

    2009-01-01

    Obesity causes lipid accumulation in the heart and may lead to lipotoxic heart disease. Traditionally, the size of the cardiac triglyceride pool is thought to reflect the balance between uptake and β-oxidation of fatty acids. However, triglycerides can also be exported from cardiomyocytes via secretion of apolipoproteinB-containing (apoB) lipoproteins. Lipoprotein formation depends on expression of microsomal triglyceride transfer protein (MTP); the mouse expresses two isoforms of MTP, A and B. Since many aspects of the link between obesity-induced cardiac disease and cardiac lipid metabolism remain unknown, we investigated how cardiac lipoprotein synthesis affects cardiac expression of triglyceride metabolism-controlling genes, insulin sensitivity, and function in obese mice. Heart-specific ablation of MTP-A in mice using Cre-loxP technology impaired upregulation of MTP expression in response to increased fatty acid availability during fasting and fat feeding. This resulted in cardiac triglyceride accumulation but unaffected cardiac insulin-stimulated glucose uptake. Long-term fat-feeding of male C57Bl/6 mice increased cardiac triglycerides, induced cardiac expression of triglyceride metabolism-controlling genes and attenuated heart function. Abolishing cardiac triglyceride accumulation in fat-fed mice by overexpression of an apoB transgene in the heart prevented the induction of triglyceride metabolism-controlling genes and improved heart function. The results suggest that in obesity, the physiological increase of cardiac MTP expression serves to attenuate cardiac triglyceride accumulation albeit without major effects on cardiac insulin sensitivity. Nevertheless, the data suggest that genetically increased lipoprotein secretion prevents development of obesity-induced lipotoxic heart disease. PMID:19390571

  20. Green tea polyphenols improve cardiac muscle mRNA, and protein levels of signal pathways related to insulin and lipid metabolism and inflammation in insulin-resistant rats

    Science.gov (United States)

    Epidemiologic studies indicate that the consumption of green tea polyphenols (GTP) may reduce the risk of coronary artery disease. To explore the underlying mechanisms of action at the molecular level, we examined the effects of GTP on cardiac mRNA and protein levels of genes involved in insulin an...

  1. Cardiac Rehabilitation

    Science.gov (United States)

    ... your risk of future heart problems, and to improve your health and quality of life. Cardiac rehabilitation programs increase ... exercise routine at home or at a local gym. You may also continue to ... health concerns. Education about nutrition, lifestyle and weight loss ...

  2. Improved heterologous gene expression in Trichoderma reesei by cellobiohydrolase I gene (cbh1) promoter optimization

    Institute of Scientific and Technical Information of China (English)

    Ti Liu; Tianhong Wang; Xian Li; Xuan Liu

    2008-01-01

    To improve heterologous gene expression in Trichoderma reesei, a set of optimal artificial cellobiohydrolase I gene (cbh1) promoters was obtained. The region from-677 to -724 with three potential glucose repressor binding sites was deleted. Then the region from-620 to-820 of the modified cbh1 promoter, including the CCAAT box and the Ace2 binding site, was repeatedly inserted into the modified cbh1 promoter, obtaining promoters with copy numbers 2, 4,and 6. The results showed that the glucose repression effects were abolished and the expression level of the glucuronidase (gus) reporter gene regulated by these multi-copy promoters was markedly enhanced as the copy number increased simultaneously. The data showed the great promise of using the promoter artificial modification strategy to increase heterologous gene expression in filamentous fungi and provided a set of optional high-expression vectors for gene function investigation and strain modification.

  3. Improvement of cardiac contractile function by peptide-based inhibition of NF-κB in the utrophin/dystrophin-deficient murine model of muscular dystrophy

    Directory of Open Access Journals (Sweden)

    Guttridge Denis C

    2011-05-01

    Full Text Available Abstract Background Duchenne muscular dystrophy (DMD is an inherited and progressive disease causing striated muscle deterioration. Patients in their twenties generally die from either respiratory or cardiac failure. In order to improve the lifespan and quality of life of DMD patients, it is important to prevent or reverse the progressive loss of contractile function of the heart. Recent studies by our labs have shown that the peptide NBD (Nemo Binding Domain, targeted at blunting Nuclear Factor κB (NF-κB signaling, reduces inflammation, enhances myofiber regeneration, and improves contractile deficits in the diaphragm in dystrophin-deficient mdx mice. Methods To assess whether cardiac function in addition to diaphragm function can be improved, we investigated physiological and histological parameters of cardiac muscle in mice deficient for both dystrophin and its homolog utrophin (double knockout = dko mice treated with NBD peptide. These dko mice show classic pathophysiological hallmarks of heart failure, including myocyte degeneration, an impaired force-frequency response and a severely blunted β-adrenergic response. Cardiac contractile function at baseline and frequencies and pre-loads throughout the in vivo range as well as β-adrenergic reserve was measured in isolated cardiac muscle preparations. In addition, we studied histopathological and inflammatory markers in these mice. Results At baseline conditions, active force development in cardiac muscles from NBD treated dko mice was more than double that of vehicle-treated dko mice. NBD treatment also significantly improved frequency-dependent behavior of the muscles. The increase in force in NBD-treated dko muscles to β-adrenergic stimulation was robustly restored compared to vehicle-treated mice. However, histological features, including collagen content and inflammatory markers were not significantly different between NBD-treated and vehicle-treated dko mice. Conclusions We conclude

  4. Improved bioresorbable microporous intravascular stents for gene therapy.

    Science.gov (United States)

    Ye, Y W; Landau, C; Meidell, R S; Willard, J E; Moskowitz, A; Aziz, S; Carlisle, E; Nelson, K; Eberhart, R C

    1996-01-01

    Drug imbibing microporous stents are under development at a number of centers to enhance healing of the arterial wall after balloon coronary angioplasty procedures. The authors improved the mechanical strength and reservoir properties of a biodegradable microporous stent reported to this Society in 1994. A combined tubular/helical coil stent is readily fabricated by flotation/precipitation and casting/ winding techniques. A two stage solvent swelling technique allows precise adjustment of the surface hydrophilic/hydrophobic balance. These developments permit seven-fold improvement in drug capacity without significantly altering mechanical properties. Stents modified in this manner retain tensile and compressive strength and are suitable for remote deployment. Elution kinetics of these modified stents suggest they are suitable for gene delivery. Successful gene transfer and transmural expression have been demonstrated after implantation of stents impregnated with a recombinant adenovirus carrying a nuclear localizing beta-galactosidase reporter gene into rabbit carotid arteries. These studies suggest that surface modified, bioresorbable polymer stents ultimately may be useful adjunctive devices for gene transfer during percutaneous transluminal revascularization.

  5. Icariin-mediated expression of cardiac genes and modulation of nitric oxide signaling pathway during differentiation of mouse embryonic stem cells into cardiomyocytes in vitro

    Institute of Scientific and Technical Information of China (English)

    Dan-yan ZHU; Yi-jia LOU

    2006-01-01

    Aim:To investigate effects of icariin on cardiac gene expression and the modulation of nitric oxide (NO)signal transduction during the differentiation of embryonic stem(ES)cells into cardiomyocytes in vitro.Methods:The expression levels of cardiac developmental-dependent genes were measured using reverse transcription-polymerase chain reaction(RT-PCR).The chronotropic responses of cardiomyocytes to β-adrenoceptor stimulation were determined.The levels of cAMP and cGMP in ES cells were measured using radioimmunoassay.Endogenous NO levels were measured by using the Griess reaction.Aminoguanidine (AG) was used to confirm the influence of icariin on the endogenous NO signal pathway.Results:Icariin significantly elevated mRNA levels of cardiac transcription factors GATA4 and Nkx2.5,and cardiac-specific α-MHC,MLC-2ν and β-AR genes in a concentration-and time-dependent manner (P<0.05).Cardiomyocytes derived from embryoid body (EB)treated with icariin were more sensitive to isoprenaline (P<0.01).Treatment of ES cells with icariin resulted in a continued elevation in the cAMP/cGMP ratio before a shift to the cardiomyocyte phenotype (P<0.05).AG decreased the NO level,and delayed and decreased the incidence of contracting EB to only approximately 35% on d 5+11,an effect that could be rescued by icariin.When cells were cocultured with icariin and AG,the percentage of beating EB reached a peak level of 73% on d 5+11(P<0.05).Conclusion:The inducible effects of icariin were partly related to increase in the expression of cardiac developmental-dependent genes,and elevation of the cAMP/cGMP ratio in ES cells,as well as upregulation of endogenous NO generation during the early stages of cardiac development.

  6. Gene pool conservation and tree improvement in Serbia

    Directory of Open Access Journals (Sweden)

    Isajev Vasilije

    2009-01-01

    Full Text Available This paper presents the concepts applied in the gene pool conservation and tree improvement in Serbia. Gene pool conservation of tree species in Serbia includes a series of activities aiming at the sustainability and protection of genetic and species variability. This implies the investigation of genetic resources and their identification through the research of the genetic structure and the breeding system of individual species. Paper also includes the study of intra- and inter-population variability in experiments - provenance tests, progeny tests, half- and full-sib lines, etc. The increased use of the genetic potential in tree improvement in Serbia should be intensified by the following activities: improvement of production of normal forest seed, application of the concept of new selections directed primarily to the improvement of only one character, because in that case the result would be certain, establishment and management of seed orchards as specialized plantations for long-term production of genetically good-quality forest seeds, and the shortening of the improvement process by introducing new techniques and methods (molecular markers, somaclonal variation, genetic engineering, protoplast fusion, micropropagation, etc..

  7. Bromocriptine for an acromegalic patient. Improvement in cardiac function and carpal tunnel syndrome.

    Science.gov (United States)

    Luboshitzky, R; Barzilai, D

    1980-10-17

    A 64-year-old woman with active acromegaly of 33 years' duration, severe carpal tunnel syndrome, and subclinical heart disease was treated with bromocriptine mesylate. Within eight months of therapy, basal growth hormone (GH) levels decreased from 90.0 to 7.0 ng/mL, and hand volume was reduced from 375 to 295 mL. Concomitantly, echocardiographic studies showed normal left ventricular size and function. Electromyographic studies demonstrated normal function in both median nerves. Bromocriptine may correct cardiac dysfunction and carpal tunnel syndrome in acromegaly either by reduction of GH oversecretion or by a direct effect of bromocriptine on dopamine receptors in the heart and peripheral nerve endings.

  8. Ultrastructural changes, increased oxidative stress, inflammation, and altered cardiac hypertrophic gene expressions in heart tissues of rats exposed to incense smoke.

    Science.gov (United States)

    Al-Attas, Omar S; Hussain, Tajamul; Ahmed, Mukhtar; Al-Daghri, Nasser; Mohammed, Arif A; De Rosas, Edgard; Gambhir, Dikshit; Sumague, Terrance S

    2015-07-01

    Incense smoke exposure has recently been linked to cardiovascular disease risk, heart rate variability, and endothelial dysfunction. To test the possible underlying mechanisms, oxidative stress, and inflammatory markers, gene expressions of cardiac hypertrophic and xenobiotic-metabolizing enzymes and ultrastructural changes were measured, respectively, using standard, ELISA-based, real-time PCR, and transmission electron microscope procedures in heart tissues of Wistar rats after chronically exposing to Arabian incense. Malondialdehyde, tumor necrosis alpha (TNF)-α, and IL-4 levels were significantly increased, while catalase and glutathione levels were significantly declined in incense smoke-exposed rats. Incense smoke exposure also resulted in a significant increase in atrial natriuretic peptide, brain natriuretic peptide, β-myosin heavy chain, CYP1A1 and CYP1A2 messenger RNAs (mRNAs). Rats exposed to incense smoke displayed marked ultrastructural changes in heart muscle with distinct cardiac hypertrophy, which correlated with the augmented hypertrophic gene expression as well as markers of cardiac damage including creatine kinase-myocardial bound (CK-MB) and lactate dehydrogenase (LDH). Increased oxidative stress, inflammation, altered cardiac hypertrophic gene expression, tissue damage, and architectural changes in the heart may collectively contribute to increased cardiovascular disease risk in individuals exposed to incense smoke. Increased gene expressions of CYP1A1 and CYP1A2 may be instrumental in the incense smoke-induced oxidative stress and inflammation. Thus, incense smoke can be considered as a potential environmental pollutant and its long-term exposure may negatively impact human health.

  9. Peroxisome proliferator-activated receptor (PPAR) alpha and PPAR beta/delta, but not PPAR gamma, modulate the expression of genes involved in cardiac lipid metabolism

    NARCIS (Netherlands)

    Gilde, AJ; van der Lee, KAJM; Willemsen, PHM; Chinetti, G; van der Leij, FR; van der Vusse, GJ; Staels, B; van Bilsen, M

    2003-01-01

    Long-chain fatty acids ( FA) coordinately induce the expression of a panel of genes involved in cellular FA metabolism in cardiac muscle cells, thereby promoting their own metabolism. These effects are likely to be mediated by peroxisome proliferator-activated receptors (PPARs). Whereas the

  10. Mutations in Genes Encoding Cardiac Ion Channels Previously Associated With Sudden Infant Death Syndrome (SIDS) Are Present With High Frequency in New Exome Data

    DEFF Research Database (Denmark)

    Andreasen, Charlotte Hartig; Refsgaard, Lena; Nielsen, Jonas B

    2013-01-01

    Sudden infant death syndrome (SIDS) is the leading cause of death in the first 6 months after birth in the industrialized world. The genetic contribution to SIDS has been investigated intensively and to date, 14 cardiac channelopathy genes have been associated with SIDS. Newly published data from...

  11. Vigna unguiculata modulates cholesterol induced cardiac markers, genotoxicity and gene expressions profile in an experimental rabbit model.

    Science.gov (United States)

    Janeesh, P A; Abraham, Annie

    2013-04-25

    Vigna unguiculata (VU) leaves are edible and used as a leafy vegetable in cuisine from traditional times in India. This study was designed to investigate the cardioprotective effect of VU in cholesterol fed rabbits. The animals were randomly divided into 4 groups of 6 animals each and the experimental period was 3 months. Group I-ND [normal diet 40 g feed], Group II-ND + FVU [flavanoid fraction of Vigna unguiculata (150 mg kg (-1) per body weight)], Group III-ND + CH [cholesterol (400 mg)] and Group IV-ND + CH (400 mg) +FVU (150 mg kg(-1) per body weight). After the experimental period, animals were sacrificed and the various parameters, such as cardiac markers, toxicity parameters, genotoxicity and gene expression, were investigated. Cholesterol feeding causes a significant increase in the levels of cardiac marker enzymes, namely lactate dehydrogenase (LDH) and creatine phospokinase (CPK), atherogenic index, toxicity parameters like serum glutamate oxaloacetate transaminase (SGOT) and serum glutamate pyruvate transaminase (SGPT) were elevated. Antioxidant enzyme levels were decreased, lipid peroxidation products in heart tissue and inflammatory markers, namely cyclooxygenase (COX2) and lipooxygenase (LOX15) in peripheral blood monocytes (PBMCs), were significantly increased. A genotoxicity study using a Comet assay and gene expression by reverse transcriptase-polymerase chain reaction (RT-PCR) of transforming growth factor-b1 (TGF-b1) and heme oxygenase-1 (HO-1) from heart tissue showed an altered expression in the disease group. The supplementation of the flavonoid fraction of Vigna unguiculata leaves (FVU) in the CH + FVU group caused the reversal of the above parameters and cardiotoxicity to near normal when compared with the CH group and FVU. This study revealed the cardioprotective nature of Vigna unguiculata in preventing cardiovascular diseases and this effect is attributed to the presence of antioxidants and the antihyperlipidemic properties of the

  12. Oxygen therapy improves cardiac index and pulmonary vascular resistance in patients with pulmonary hypertension.

    Science.gov (United States)

    Roberts, D H; Lepore, J J; Maroo, A; Semigran, M J; Ginns, L C

    2001-11-01

    We tested the hypothesis that breathing 100% oxygen could result in selective pulmonary vasodilatation in patients with pulmonary hypertension, including those patients who would not meet current Health Care Finance Administration guidelines for long-term oxygen therapy. From 1996 to 1999, 23 adult patients (mean +/- SEM age, 51 +/- 4 years) with pulmonary arterial hypertension without left-heart failure underwent cardiac catheterization in a university teaching hospital while breathing air and then 100% oxygen. Treatment with 100% oxygen increased arterial oxygen saturation (91 +/- 1% to 99 +/- 0.1%, p < 0.05) and PaO(2) (64 +/- 3 to 309 +/- 28 mm Hg, p < 0.05). Treatment with 100% oxygen also decreased mean pulmonary artery pressure (56 +/- 3 to 53 +/- 2 mm Hg, p < 0.05) and increased cardiac index (2.1 +/- 0.1 to 2.5 +/- 0.2 L/min/m(2), p < 0.05). Calculated mean pulmonary vascular resistance (PVR) decreased from 14.1 +/- 1.4 to 10.6 +/- 1.0 Wood units (p < 0.05). Vasodilatation with 100% oxygen occurred preferentially in the pulmonary circulation (PVR/systemic vascular resistance, 0.53 +/- 0.04 to 0.48 +/- 0.03; p < 0.05). The magnitude of the PVR response to oxygen therapy was correlated only with decreasing patient age (r = 0.45, p < 0.05). Treatment with 100% oxygen is a selective pulmonary vasodilator in patients with pulmonary hypertension, regardless of primary diagnosis, baseline oxygenation, or right ventricular function. Development of disease-specific oxygen prescription guidelines warrants consideration.

  13. Combined treatment with erythropoietin and granulocyte colony-stimulating factor enhances neovascularization and improves cardiac function after myocardial infarction

    Institute of Scientific and Technical Information of China (English)

    Xue Jingyi; Du Guoqing; Shi Jing; Li Yue; Masahiro Yasutake; Liu Lei; Li Jianqiang

    2014-01-01

    Background Erythropoietin (EPO) and granulocyte colony-stimulating factor (G-CSF) are both potential novel therapeutics for use after myocardial infarction (MI).However,their underlying mechanisms remain unclear and the efficacy of monotherapy with EPO or G-CSF is also controversial.Therefore,we investigated the effects of combined treatment with EPO and G-CSF on neovascularization and cardiac function in post-infarction rats and explored the potential mechanisms.Methods Four groups of rats were used:control (saline injection after MI,i.h.),EPO (a single dose of 5 000 IU/kg after MI,i.h.),G-CSF (a dose of 50 μg· kg-1· d-1 for 5 days after MI,i.h.),and both EPO and G-CSF (EPO+G-CSF,using the same regiment as above).Cardiac function was assessed by echocardiography before and 1 day,7 days,14 days and 21 days after MI.CD34+/Flk-1+ cells in the peripheral blood were evaluated by flow cytometry before and 3 days,5 days and 7 days after MI.The infarct area and angiogenesis in the peri-infarct area were analyzed.The mRNA and protein expression of vascular endothelial growth factor (VEGF) and stromal-derived factor-1α (SDF-1α) in the peri-infarct area were detected by real-time quantitative RT-PCR and Western blotting.Results Compared with the control and monotherapy groups,the EPO+G-CSF group had significantly increased CD34+/ Flk-1+ endothelial progenitor calls (EPCs)in the peripheral blood (P <0.05),up-regulated VEGF and SDF-1α levels in the peri-infarct region (P <0.05),enhanced capillary density (P <0.05),reduced infarct size (P <0.05) and improved cardiac structure and function (P <0.05).G-CSF alone did not dramatically increase EPCs in the peripheral blood,enhance capillary density in the peri-infarct area or reduce infarct size compared with the control group.Conclusions Combined treatment with EPO and G-CSF increased EPCs mobilization,up-regulated VEGF and SDF-1α levels in the post-infarction microenvironment,subsequently enhanced

  14. The Effect of a High-Protein Diet and Exercise on Cardiac AQP7 and GLUT4 Gene Expression.

    Science.gov (United States)

    Palabiyik, Orkide; Karaca, Aziz; Taştekin, Ebru; Yamasan, Bilge Eren; Tokuç, Burcu; Sipahi, Tammam; Vardar, Selma Arzu

    2016-10-01

    High-protein (HP) diets are commonly consumed by athletes despite their potential health hazard, which is postulated to enforce a negative effect on bone and renal health. However, its effects on heart have not been known yet. Aquaporin-7 (AQP7) is an aquaglyceroporin that facilitates glycerol and water transport. Glycerol is an important cardiac energy production substrate, especially during exercise, in conjunction with fatty acids and glucose. Glucose transporter 4 (GLUT4) is an insulin-sensitive glucose transporter in heart. We aimed to investigate the effect of HPD on AQP7 and GLUT4 levels in the rat heart subjected to exercise. Male Sprague-Dawley rats were divided into control (n = 12), exercise (E) training (n = 10), HPD (n = 12), and HPD-E training (n = 9) groups. The HPD groups were fed a 45 % protein-containing diet 5 weeks. The HPD-E and E groups were performed the treadmill exercise during the 5-week study period. Real-time polymerase chain reaction and immunohistochemistry techniques were used to determine the gene expression and localization of AQP7 and GLUT4 in heart tissue. Results of relative gene expression were calculated by the 'Pfaffl' mathematical method using the REST program. Differences in AQP7 and GLUT4 gene expression were expressed as fold change compared to the control group. Heart weight/tibia ratio and ventricular wall thickness were evaluated as markers of cardiac hypertrophy. Further, serum glucose, glycerol, and insulin levels were also measured. AQP7 gene expression was found to be increased in the E (3.47-fold, p GLUT4 showed a significant increase in the E (2.16-fold, p GLUT4 protein expression was significantly increased in the E, HPD, and HPD-E groups compared to the control group (p = 0.024, p GLUT4 expression in rat heart.

  15. Exploring and Mobilizing the Gene Bank Biodiversity for Wheat Improvement

    Science.gov (United States)

    Sehgal, Deepmala; Vikram, Prashant; Sansaloni, Carolina Paola; Ortiz, Cynthia; Pierre, Carolina Saint; Payne, Thomas; Ellis, Marc; Amri, Ahmed; Petroli, César Daniel; Wenzl, Peter; Singh, Sukhwinder

    2015-01-01

    Identifying and mobilizing useful genetic variation from germplasm banks to breeding programs is an important strategy for sustaining crop genetic improvement. The molecular diversity of 1,423 spring bread wheat accessions representing major global production environments was investigated using high quality genotyping-by-sequencing (GBS) loci, and gene-based markers for various adaptive and quality traits. Mean diversity index (DI) estimates revealed synthetic hexaploids to be genetically more diverse (DI= 0.284) than elites (DI = 0.267) and landraces (DI = 0.245). GBS markers discovered thousands of new SNP variations in the landraces which were well known to be adapted to drought (1273 novel GBS SNPs) and heat (4473 novel GBS SNPs) stress environments. This may open new avenues for pre-breeding by enriching the elite germplasm with novel alleles for drought and heat tolerance. Furthermore, new allelic variation for vernalization and glutenin genes was also identified from 47 landraces originating from Iraq, Iran, India, Afghanistan, Pakistan, Uzbekistan and Turkmenistan. The information generated in the study has been utilized to select 200 diverse gene bank accessions to harness their potential in pre-breeding and for allele mining of candidate genes for drought and heat stress tolerance, thus channeling novel variation into breeding pipelines. This research is part of CIMMYT’s ongoing ‘Seeds of Discovery’ project visioning towards the development of high yielding wheat varieties that address future challenges from climate change. PMID:26176697

  16. Exploring and Mobilizing the Gene Bank Biodiversity for Wheat Improvement.

    Science.gov (United States)

    Sehgal, Deepmala; Vikram, Prashant; Sansaloni, Carolina Paola; Ortiz, Cynthia; Pierre, Carolina Saint; Payne, Thomas; Ellis, Marc; Amri, Ahmed; Petroli, César Daniel; Wenzl, Peter; Singh, Sukhwinder

    2015-01-01

    Identifying and mobilizing useful genetic variation from germplasm banks to breeding programs is an important strategy for sustaining crop genetic improvement. The molecular diversity of 1,423 spring bread wheat accessions representing major global production environments was investigated using high quality genotyping-by-sequencing (GBS) loci, and gene-based markers for various adaptive and quality traits. Mean diversity index (DI) estimates revealed synthetic hexaploids to be genetically more diverse (DI= 0.284) than elites (DI = 0.267) and landraces (DI = 0.245). GBS markers discovered thousands of new SNP variations in the landraces which were well known to be adapted to drought (1273 novel GBS SNPs) and heat (4473 novel GBS SNPs) stress environments. This may open new avenues for pre-breeding by enriching the elite germplasm with novel alleles for drought and heat tolerance. Furthermore, new allelic variation for vernalization and glutenin genes was also identified from 47 landraces originating from Iraq, Iran, India, Afghanistan, Pakistan, Uzbekistan and Turkmenistan. The information generated in the study has been utilized to select 200 diverse gene bank accessions to harness their potential in pre-breeding and for allele mining of candidate genes for drought and heat stress tolerance, thus channeling novel variation into breeding pipelines. This research is part of CIMMYT's ongoing 'Seeds of Discovery' project visioning towards the development of high yielding wheat varieties that address future challenges from climate change.

  17. Exploring and Mobilizing the Gene Bank Biodiversity for Wheat Improvement.

    Directory of Open Access Journals (Sweden)

    Deepmala Sehgal

    Full Text Available Identifying and mobilizing useful genetic variation from germplasm banks to breeding programs is an important strategy for sustaining crop genetic improvement. The molecular diversity of 1,423 spring bread wheat accessions representing major global production environments was investigated using high quality genotyping-by-sequencing (GBS loci, and gene-based markers for various adaptive and quality traits. Mean diversity index (DI estimates revealed synthetic hexaploids to be genetically more diverse (DI= 0.284 than elites (DI = 0.267 and landraces (DI = 0.245. GBS markers discovered thousands of new SNP variations in the landraces which were well known to be adapted to drought (1273 novel GBS SNPs and heat (4473 novel GBS SNPs stress environments. This may open new avenues for pre-breeding by enriching the elite germplasm with novel alleles for drought and heat tolerance. Furthermore, new allelic variation for vernalization and glutenin genes was also identified from 47 landraces originating from Iraq, Iran, India, Afghanistan, Pakistan, Uzbekistan and Turkmenistan. The information generated in the study has been utilized to select 200 diverse gene bank accessions to harness their potential in pre-breeding and for allele mining of candidate genes for drought and heat stress tolerance, thus channeling novel variation into breeding pipelines. This research is part of CIMMYT's ongoing 'Seeds of Discovery' project visioning towards the development of high yielding wheat varieties that address future challenges from climate change.

  18. Lowering body weight in obese mice with diastolic heart failure improves cardiac insulin sensitivity and function: implications for the obesity paradox.

    Science.gov (United States)

    Sankaralingam, Sowndramalingam; Abo Alrob, Osama; Zhang, Liyan; Jaswal, Jagdip S; Wagg, Cory S; Fukushima, Arata; Padwal, Raj S; Johnstone, David E; Sharma, Arya M; Lopaschuk, Gary D

    2015-05-01

    Recent studies suggest improved outcomes and survival in obese heart failure patients (i.e., the obesity paradox), although obesity and heart failure unfavorably alter cardiac function and metabolism. We investigated the effects of weight loss on cardiac function and metabolism in obese heart failure mice. Obesity and heart failure were induced by feeding mice a high-fat (HF) diet (60% kcal from fat) for 4 weeks, following which an abdominal aortic constriction (AAC) was produced. Four weeks post-AAC, mice were switched to a low-fat (LF) diet (12% kcal from fat; HF AAC LF) or maintained on an HF (HF AAC HF) for a further 10 weeks. After 18 weeks, HF AAC LF mice weighed less than HF AAC HF mice. Diastolic function was improved in HF AAC LF mice, while cardiac hypertrophy was decreased and accompanied by decreased SIRT1 expression, increased FOXO1 acetylation, and increased atrogin-1 expression compared with HF AAC HF mice. Insulin-stimulated glucose oxidation was increased in hearts from HF AAC LF mice, compared with HF AAC HF mice. Thus lowering body weight by switching to LF diet in obese mice with heart failure is associated with decreased cardiac hypertrophy and improvements in both cardiac insulin sensitivity and diastolic function, suggesting that weight loss does not negatively impact heart function in the setting of obesity.

  19. Next-generation sequencing of 100 candidate genes in young victims of suspected sudden cardiac death with structural abnormalities of the heart

    DEFF Research Database (Denmark)

    Hertz, C L; Christiansen, S L; Ferrero-Miliani, Laura;

    2016-01-01

    BACKGROUND: In sudden, unexpected, non-traumatic death in young individuals, structural abnormalities of the heart are frequently identified at autopsy. However, the findings may be unspecific and cause of death may remain unclear. A significant proportion of these cases are most likely caused...... by inherited cardiac diseases, and the cases are categorized as sudden cardiac death (SCD). The purpose of this study was to explore the added diagnostic value of genetic testing by next-generation sequencing (NGS) of a broad gene panel, as a supplement to the traditional forensic investigation in cases...... with non-diagnostic structural abnormalities of the heart. METHODS AND RESULTS: We screened 72 suspected SCD cases (

  20. Adrenomedullin gene delivery attenuates renal damage and cardiac hypertrophy in Goldblatt hypertensive rats

    National Research Council Canada - National Science Library

    Cindy Wang; Eric Dobrzynski; Julie Chao; Lee Chao

    2001-01-01

    .... A single tail vein injection of adenovirus harboring the human AM gene significantly blunted a blood pressure increase that lasted for more than 3 wk in two-kidney one-clip (2K1C) hypertensive rats...

  1. Impact of animal strain on gene expression in a rat model of acute cardiac rejection

    Directory of Open Access Journals (Sweden)

    Norsworthy Kelly J

    2009-06-01

    Full Text Available Abstract Background The expression levels of many genes show wide natural variation among strains or populations. This study investigated the potential for animal strain-related genotypic differences to confound gene expression profiles in acute cellular rejection (ACR. Using a rat heart transplant model and 2 different rat strains (Dark Agouti, and Brown Norway, microarrays were performed on native hearts, transplanted hearts, and peripheral blood mononuclear cells (PBMC. Results In heart tissue, strain alone affected the expression of only 33 probesets while rejection affected the expression of 1368 probesets (FDR 10% and FC ≥ 3. Only 13 genes were affected by both strain and rejection, which was Conclusion In ACR, genetic background has a large impact on the transcriptome of immune cells, but not heart tissue. Gene expression studies of ACR should avoid study designs that require cross strain comparisons between leukocytes.

  2. N-ethylmaleimide-sensitive factor siRNA improves cardiac function following myocardial infarction in rats.

    Science.gov (United States)

    Zhou, Y; Liu, Y; Yang, S X; Wang, Z

    2015-08-14

    This study examined the effects of N-ethylmaleimide-sensitive factor (NSF) small interfering RNA (siRNA) on cardiac function following myocardial infarction (MI) in rats. Thirty-six adult Sprague Dawley rats were randomly divided into three equivalent groups. An acute MI model was established by ligating the anterior descending branch of the left coronary artery and confirmed by electrocardiogram. Recombinant NSF-siRNA adenovirus (experimental), negative adenovirus (control), and normal saline were injected near the infarcted area of the left ventricle in each respective group. The left ventricular ejection fraction (LVEF) was measured with a noninvasive ultrasonic cardiogram. Left ventricular end-diastolic pressure (LVEDP) and the maximum rate of rise in left ventricular pressure (+dp/dt max) were measured using the BL-420 Biological Functional Experimental System. Hearts were sectioned and stained with 2,3,5,-triphenyl tetrazolium chloride (TTC) to observe the MI area. Two weeks after surgery, LVEF in the experimental group (46.0 ± 7.5%) was higher than control (34.0 ± 6.0%) and saline (37.5 ± 4.5%) group LVEFs (P function two weeks after MI, but had no impact on the MI area.

  3. Exercise training improves cardiac autonomic nervous system activity in type 1 diabetic children.

    Science.gov (United States)

    Shin, Ki Ok; Moritani, Toshio; Woo, Jinhee; Jang, Ki Soeng; Bae, Ju Yong; Yoo, Jaeho; Kang, Sunghwun

    2014-01-01

    [Purpose] We investigated the effect exercise training has on cardiac autonomic nervous system (ANS) and cardiovascular risk profiles in children with type 1 diabetes mellitus (DM). [Subjects] Fifteen type 1 DM children (all boys; 13.0±1.0 years of age) were enrolled in the study. [Methods] The subjects received exercise training three times a week in a 12-week program. Each child was asked to walk on a treadmill to achieve an exercise intensity of VO2max 60%. ANS activity was measured by power spectral analysis of the electrocardiogram (ECG). Blood samples were obtained for serum lipid profiles. To evaluate Doppler-shifted Fourier pulsatility index (PI) analysis, a 5-MHz continuous wave Doppler (VASCULAB D10) set was used to measure forward blood flow velocity (FLOW) in the radial artery. [Results] Total and low-frequency (LF) power of heart rate variability increased significantly after exercise intervention. Total cholesterol (TC) levels were significant lower after exercise intervention. Total and high-frequency (HF) power were significantly correlated with higher TC levels, but diastolic blood pressure and HF was significantly correlated with lower TC levels. [Conclusion] Regular exercise intervention should be prescribed for children with type 1 DM.

  4. Aliskiren improves blood pressure control and prevents cardiac damage in high-risk hypertensive subjects.

    Science.gov (United States)

    Mazza, A; Montemurro, D; Zuin, M; Schiavon, L; Zorzan, S; Chondrogiannis, S; Ferretti, A; Ramazzina, E; Rubello, D

    2013-08-01

    Longitudinal study aimed to evaluate the antihypertensive efficacy, safety and the effect on cardiac damage of Aliskiren, administered to a group of high-risk hypertensive patients with mild impairment of renal function and uncontrolled blood pressure (BP) despite a two-drug antihypertensive treatment. One hundred and six patients (56 men and 50 females) aged 61.9±12.7 years, were assigned to receive Aliskiren 150-300 mg once-daily for 12 months. Clinic BP measurements were taken at every follow-up visit (1st, 6th and 12th month), while biochemical tests, estimated glomerular filtration rate (eGFR), 24-hours ambulatory BP measurements (ABMP) and echocardiography were evaluated at baseline and at the end of follow-up. Analysis of variance for repeated measures compared BP, left ventricular mass index (LVMI) and eGFR values changes. A significant reduction (all P0.05). Putative adverse events caused withdrawal of 7 subjects (6 for gastrointestinal disturbances, 1 for alopecia). Aliskiren was effective in decreasing both clinical and ABPM values and in reducing LVMI in both genders without any influence on eGFR. The treatment resulted safe, even in combination with ACE-inhibitors and angiotensin II receptor blockers. A significant reduction in the use of concomitant antihypertensive drugs was observed.

  5. [Intensity of cardiac free-radicals processes and expression of glutathione peroxidase and glutathione reductase genes in rats with adrenaline].

    Science.gov (United States)

    Iskusnykh, I Iu; Popova, T N; Musharova, O S

    2012-01-01

    The correlation between changes in activities of glutathione peroxidase and glutathione reductase in heart of rats during development of adrenaline myocarditis and intensity of free radical processes estimated by biochemiluminesce parameters and the content of lipoperoxidation products was demonstrated. The maximal increase of glutathione peroxidase and glutathione reductase activities (in 1.8 and 1.4 times accordingly) was observed t 24 h after the development of the pathological process; this coincided with the maximum intensity of prosesses of free radical oxidation. Using combination of reverse transcriptions with real-time polymerase chain reaction the cardiac mRNA levels of glutathione peroxidase and glutathione reductase genes were determined during the development of adrenaline myocarditis in rats. Analysis of expression of glutathione peroxidase and glutathione reductase genes showed, that the level of this transcripts demonstrated 2,8- and 7,3- increase in rats with adrenaline myocarditis, respectively. Obviously, overexpression of these enzymes can increase the resistance of cardiomyocites to oxidative stress.

  6. Selection of reference genes is critical for miRNA expression analysis in human cardiac tissue. A focus on atrial fibrillation

    Science.gov (United States)

    Masè, Michela; Grasso, Margherita; Avogaro, Laura; D’Amato, Elvira; Tessarolo, Francesco; Graffigna, Angelo; Denti, Michela Alessandra; Ravelli, Flavia

    2017-01-01

    MicroRNAs (miRNAs) are emerging as key regulators of complex biological processes in several cardiovascular diseases, including atrial fibrillation (AF). Reverse transcription-quantitative polymerase chain reaction is a powerful technique to quantitatively assess miRNA expression profile, but reliable results depend on proper data normalization by suitable reference genes. Despite the increasing number of studies assessing miRNAs in cardiac disease, no consensus on the best reference genes has been reached. This work aims to assess reference genes stability in human cardiac tissue with a focus on AF investigation. We evaluated the stability of five reference genes (U6, SNORD48, SNORD44, miR-16, and 5S) in atrial tissue samples from eighteen cardiac-surgery patients in sinus rhythm and AF. Stability was quantified by combining BestKeeper, delta-Cq, GeNorm, and NormFinder statistical tools. All methods assessed SNORD48 as the best and U6 as the worst reference gene. Applications of different normalization strategies significantly impacted miRNA expression profiles in the study population. Our results point out the necessity of a consensus on data normalization in AF studies to avoid the emergence of divergent biological conclusions. PMID:28117343

  7. Effectiveness of public report cards for improving the quality of cardiac care: the EFFECT study: a randomized trial.

    Science.gov (United States)

    Tu, Jack V; Donovan, Linda R; Lee, Douglas S; Wang, Julie T; Austin, Peter C; Alter, David A; Ko, Dennis T

    2009-12-02

    Publicly released report cards on hospital performance are increasingly common, but whether they are an effective method for improving quality of care remains uncertain. To evaluate whether the public release of data on cardiac quality indicators effectively stimulates hospitals to undertake quality improvement activities that improve health care processes and patient outcomes. Population-based cluster randomized trial (Enhanced Feedback for Effective Cardiac Treatment [EFFECT]) of 86 hospital corporations in Ontario, Canada, with patients admitted for acute myocardial infarction (AMI) or congestive heart failure (CHF). Participating hospital corporations were randomized to early (January 2004) or delayed (September 2005) feedback of a public report card on their baseline performance (between April 1999 and March 2001) on a set of 12 process-of-care indicators for AMI and 6 for CHF. Follow-up performance data (between April 2004 and March 2005) also were collected. The coprimary outcomes were composite AMI and CHF indicators based on 12 AMI and 6 CHF process-of-care indicators. Secondary outcomes were the individual process-of-care indicators, a hospital report card impact survey, and all-cause AMI and CHF mortality. The publication of the early feedback hospital report card did not result in a significant systemwide improvement in the early feedback group in either the composite AMI process-of-care indicator (absolute change, 1.5%; 95% confidence interval [CI], -2.2% to 5.1%; P = .43) or the composite CHF process-of-care indicator (absolute change, 0.6%; 95% CI, -4.5% to 5.7%; P = .81). During the follow-up period, the mean 30-day AMI mortality rates were 2.5% lower (95% CI, 0.1% to 4.9%; P = .045) in the early feedback group compared with the delayed feedback group. The hospital mortality rates for CHF were not significantly different. Public release of hospital-specific quality indicators did not significantly improve composite process-of-care indicators for AMI

  8. Expression of lymphocyte coding genes in peripheral blood and lymphocyte infiltration in cardiac tissues influenced by cyclosporin A in heterotopic heart transplantation model in rats.

    Science.gov (United States)

    Xu, Xiu-fang; Xin, Yi; Zhang, Ying; Huang, Yi-min; Li, Wen-bin; Li, Na; Lin, Zheng; Zhou, Yu-jie; Zhang, Zhao-guang

    2013-12-01

    To systematically compare the expression of coding genes with pathological changes of transplanted cardiac tissue and peripheral blood lymphocytes in an allo-heterotopic rat cardiac transplant model. Using SD rats as donors and Wistar rats as recipients, animals were divided into two groups, control and cyclosporine A intervention plus heart transplant groups. After transplant at 1, 3, 7, 10 and 12d, we assessed the ability of lymphocytes to infiltrate into cardiac tissues and levels of leukocyte coding genes in peripheral blood. Histopathological changes were monitored in cardiac tissue to determine the level of transplant rejection. (1) 24h after transplant peripheral blood lymphocytes' transcription and expression were temporarily reduced. (2) CD4(+) and CD8(+) lymphocytes infiltrate into cardiac tissue and Grade 1R pathological changes were observed 3d-7d after heart transplant. (3)Cyclosporine A was not able to completely block heart transplant rejection.(4) Although cyclosporine A was not able to effectively suppress CD4(+) T cell gene expression, it did suppress CD8(+) T cell gene transcription. (5) Cyclosporine A did not effectively reduce the rapid infiltration of CD4(+) or CD8(+) infiltration in 3d, but significantly reduced the degree of CD4(+) T cell infiltration in cardiac tissues between 3 and 7d. (6) Differential display (DD-PCR): Graft control group: there were differences in 2,3-bisphosphoglycerate, ribosomal protein S25, 12S ribosomal, gig18, MHC-III and ATPase H(+), which occurred 24h before CD4/CD8 surface protein expression. Cyclosporine A group: there were differences in thrombospondin-1, TCR, 2,3-bisphosphoglycerate, sodium channel beta-1, gig18 and TCR. In the cyclosporine A group 2,3-bisphosphoglycerate positive expression was observed 24h after the control group, which indicates that cyclosporine A slowed down the 2,3-bisphosphoglycerate transcription rate in peripheral lymphocytes and delayed its expression time. Cyclosporine A also

  9. Anesthetic drug midazolam inhibits cardiac human ether-à-go-go-related gene channels: mode of action.

    Science.gov (United States)

    Vonderlin, Nadine; Fischer, Fathima; Zitron, Edgar; Seyler, Claudia; Scherer, Daniel; Thomas, Dierk; Katus, Hugo A; Scholz, Eberhard P

    2015-01-01

    Midazolam is a short-acting benzodiazepine that is in wide clinical use as an anxiolytic, sedative, hypnotic, and anticonvulsant. Midazolam has been shown to inhibit ion channels, including calcium and potassium channels. So far, the effects of midazolam on cardiac human ether-à-go-go-related gene (hERG) channels have not been analyzed. The inhibitory effects of midazolam on heterologously expressed hERG channels were analyzed in Xenopus oocytes using the double-electrode voltage clamp technique. We found that midazolam inhibits hERG channels in a concentration-dependent manner, yielding an IC50 of 170 μM in Xenopus oocytes. When analyzed in a HEK 293 cell line using the patch-clamp technique, the IC50 was 13.6 μM. Midazolam resulted in a small negative shift of the activation curve of hERG channels. However, steady-state inactivation was not significantly affected. We further show that inhibition is state-dependent, occurring within the open and inactivated but not in the closed state. There was no frequency dependence of block. Using the hERG pore mutants F656A and Y652A we provide evidence that midazolam uses a classical binding site within the channel pore. Analyzing the subacute effects of midazolam on hERG channel trafficking, we further found that midazolam does not affect channel surface expression. Taken together, we show that the anesthetic midazolam is a low-affinity inhibitor of cardiac hERG channels without additional effects on channel surface expression. These data add to the current understanding of the pharmacological profile of the anesthetic midazolam.

  10. Unstable Angina in the Era of Cardiac Troponin Assays with Improved Sensitivity-A Clinical Dilemma.

    Science.gov (United States)

    Eggers, K M; Jernberg, T; Lindahl, B

    2017-06-21

    There is an expectation that with the adoption of more sensitive cardiac troponin (cTn) assays, unstable angina would become a rarity. However, recent data from the SWEDEHEART registry demonstrated that 15% of patients admitted with non-ST-elevation acute coronary syndrome still were regarded as having unstable angina. We aimed to further investigate the clinical characteristics and outcome of these patients. This was a retrospective, registry-based analysis (SWEDEHEART) including 3204 unstable patients, 18,194 non-ST-elevation myocardial infarction (NSTEMI) patients, and 977 controls without acute cardiovascular disease. All patients had available data on peak cTnT levels (more sensitive assay) and 1-year outcome. The annual proportions of patients with unstable angina (2009-2013) among those with non-ST-elevation acute coronary syndrome ranged from 9.4% to 15.3%. Only 1239 unstable angina patients (39.7%) had a peak cTnT level ≤14 ng/L. Patients with unstable angina tended to be younger than those with NSTEMI but had higher prevalence of most cardiovascular risk factors and more advanced coronary artery disease. Compared with controls, the adjusted hazard ratios (95% confidence interval) regarding major cardiovascular events were 2.97 (1.30-6.78) and 5.44 (2.54-11.65) in unstable angina patients with peak cTnT ≤14 ng/L and >14 ng/L, respectively. The diagnosis of unstable angina is still commonly used, even in the era of more sensitive cTn assays. Minor cTnT elevation is common, which makes unstable angina difficult to distinguish from NSTEMI. Patients with unstable angina have a nonneglectable cardiovascular risk. We suggest that the clinical management of patients presenting with unstable symptoms should depend on their estimated cardiovascular risk rather than on strictly applied diagnostic criteria. Copyright © 2017 Elsevier Inc. All rights reserved.

  11. Electronic medical record-based performance improvement project to document and reduce excessive cardiac troponin testing.

    Science.gov (United States)

    Love, Sara A; McKinney, Zeke J; Sandoval, Yader; Smith, Stephen W; Kohler, Rebecca; Murakami, MaryAnn M; Apple, Fred S

    2015-03-01

    We assessed the utilization rationale behind provider ordering of cardiac troponin I (cTnI) testing for the diagnosis of myocardial infarction after implementation of a hospital-wide serial order protocol. During 2 months in 2013, any request for additional cTnI testing within 30 days of the initial serial cTnI order prompted an electronic health record best practice alert (BPA), which included clinical decision support that could be bypassed by giving a clinical indication. cTnI orders were not limited (timing, number), and upon BPA, trigger data was collected for clinical indications and actions, patient stay (duration, location), International Classification of Diseases, Revision 9 diagnosis, cTnI orders, and timing of cTnI measurements. The BPA was triggered 1477 times by 423 providers who cared for 702 patients. There were a mean of 3.6 cTnI results per patient, 2.1 BPAs per patient, and 1.2 visits per patient. Providers (42% of whom were residents) acknowledged and overrode the BPA 97% of the time. In response to the BPA, 65% of providers selected a prepared rationale: 64% acute coronary syndrome/ST-elevation myocardial infarction/non-ST-elevation myocardial infarction; 30% demand ischemia; and 6% non-ACS myocardial necrosis. Of the remaining 35% of providers, 71% listed no rationale for their additional cTnI orders. Of patients with a BPA, 93% had non-ACS-related primary International Classification of Diseases, Revision 9 diagnosis, and 58% of the time, patients' cTnI results never increased during their stay. In 53% of cases, BPAs were generated by a request for an additional cTnI series when <2 results were available. Providers largely ignored the BPA that warned of potential overutilization of cTnI testing independent of diagnosis, including ACS. © 2014 American Association for Clinical Chemistry.

  12. Coronary grafts flow and cardiac pacing modalities: how to improve perioperative myocardial perfusion.

    LENUS (Irish Health Repository)

    D'Ancona, Giuseppe

    2012-02-03

    OBJECTIVE: Aim of this study was to investigate modifications of coronary grafts flow during different pacing modalities after CABG. MATERIALS AND METHODS: Two separate prospective studies were conducted in patients undergoing CABG and requiring intraoperative epicardial pacing. In a first study (22 patients) coronary grafts flows were measured during dual chamber pacing (DDD) and during ventricular pacing (VVI). In a second study (10 patients) flows were measured during DDD pacing at different atrio-ventricular (A-V) delay periods. A-V delay was adjusted in 25 ms increments from 25 to 250 ms and flow measurements were performed for each A-V delay increment. A transit time flowmeter was used for the measurements. RESULTS: An average of 3.4 grafts\\/patient were performed. In the first study, average coronary graft flow was 47.4+\\/-20.8 ml\\/min during DDD pacing and 41.8+\\/-18.2 ml\\/min during VVI pacing (P = 0.0004). Furthermore average systolic pressure was 94.3+\\/-10.1 mmHg during DDD pacing and 89.6+\\/-12.2 mmHg during VVV pacing (P = 0.0007). No significant differences in diastolic pressure were recorded during the two different pacing modalities. In the second study, maximal flows were achieved during DDD pacing with an A-V delay of 175 ms (54+\\/-9.6 ml\\/min) and minimal flows were detected at 25 ms A-V delay (38.1+\\/-4.7 ml\\/min) (P=ns). No significant differences in systolic or diastolic blood pressure were noticed during the different A-V delays. CONCLUSION: Grafts flowmetry provides an extra tool to direct supportive measures such as cardiac pacing after CABG. DDD mode with A-V delay around 175 ms. should be preferred to allow for maximal myocardial perfusion via the grafts.

  13. Higher Cortisol Predicts Less Improvement in Verbal Memory Performance after Cardiac Rehabilitation in Patients with Coronary Artery Disease

    Directory of Open Access Journals (Sweden)

    Mahwesh Saleem

    2013-01-01

    Full Text Available Objective. While physical activity can improve verbal memory performance in subjects with coronary artery disease (CAD, there is large variability in response. Elevated cortisol production has been suggested to negatively affect verbal memory performance, yet cortisol concentrations have not been assessed as a predictor of response to exercise intervention in those with CAD. Methods. CAD patients participating in a one-year cardiac rehabilitation program were recruited. Memory was assessed with the California Verbal Learning Test second edition at baseline and one year. Cortisol was measured from a 20 mg, 3.0 cm hair sample collected at baseline. Results. In patients with CAD (n=56, mean ± SD age = 66±11, 86% male, higher cortisol (hair cortisol concentrations ≥ 153.2 ng/g significantly predicted less memory improvement (F1,50=5.50, P=0.02 when controlling for age (F1,50=0.17, P=0.68, gender (F1,50=2.51, P=0.12, maximal oxygen uptake (F1,50=1.88, P=0.18, and body mass index (F1,50=3.25, P=0.08. Conclusion. Prolonged hypothalamic pituitary adrenal axis activation may interfere with exercise-related improvements in memory in CAD.

  14. 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.

  15. Vitreoscilla hemoglobin gene ( vgb) improves lutein production in Chlorella vulgaris

    Science.gov (United States)

    Ma, Ruijuan; Lin, Xiangzhi

    2014-03-01

    Vitreoscilla hemoglobin is an oxygen-binding protein that promotes oxygen delivery and reduces oxygen consumption under low oxygen conditions to increase the efficiency of cell respiration and metabolism. In this study, we introduced a Vitreoscilla hemoglobin gene ( vgb) into Chlorella vulgaris by Agrobacterium tumefaciens -mediated transformation (ATMT). PCR analysis confirmed that the vgb gene was successfully integrated into the Chlorella vulgaris genome. Analysis of biomass obtained in shake flasks revealed transformant biomass concentrations as high as 3.28 g/L, which was 38.81% higher than that of the wild-type strain. Lutein content of transformants also increased slightly. Further experiments recovered a maximum lutein yield of 2.91 mg/L from the transformants, which was 36.77% higher than that of the wild-type strain. The above results suggest that integrated expression of the vgb gene may improve cell growth and lutein yield in Chlorella vulgaris, with applications to lutein production from Chlorella during fermentation.

  16. TILLING in forage grasses for gene discovery and breeding improvement.

    Science.gov (United States)

    Manzanares, Chloe; Yates, Steven; Ruckle, Michael; Nay, Michelle; Studer, Bruno

    2016-09-25

    Mutation breeding has a long-standing history and in some major crop species, many of the most important cultivars have their origin in germplasm generated by mutation induction. For almost two decades, methods for TILLING (Targeting Induced Local Lesions IN Genomes) have been established in model plant species such as Arabidopsis (Arabidopsis thaliana L.), enabling the functional analysis of genes. Recent advances in mutation detection by second generation sequencing technology have brought its utility to major crop species. However, it has remained difficult to apply similar approaches in forage and turf grasses, mainly due to their outbreeding nature maintained by an efficient self-incompatibility system. Starting with a description of the extent to which traditional mutagenesis methods have contributed to crop yield increase in the past, this review focuses on technological approaches to implement TILLING-based strategies for the improvement of forage grass breeding through forward and reverse genetics. We present first results from TILLING in allogamous forage grasses for traits such as stress tolerance and evaluate prospects for rapid implementation of beneficial alleles to forage grass breeding. In conclusion, large-scale induced mutation resources, used for forward genetic screens, constitute a valuable tool to increase the genetic diversity for breeding and can be generated with relatively small investments in forage grasses. Furthermore, large libraries of sequenced mutations can be readily established, providing enhanced opportunities to discover mutations in genes controlling traits of agricultural importance and to study gene functions by reverse genetics.

  17. Toll-Like Receptor 4 Inhibition Improves Oxidative Stress and Mitochondrial Health in Isoproterenol-Induced Cardiac Hypertrophy in Rats

    Directory of Open Access Journals (Sweden)

    Parmeshwar B. Katare

    2017-06-01

    Full Text Available BackgroundInflammation remains a crucial factor for progression of cardiac diseases and cardiac hypertrophy remains an important cause of cardiac failure over all age groups. As a key regulator of inflammation, toll-like receptor 4 (TLR4 plays an important role in pathogenesis of cardiac diseases. Being an important regulator of innate immunity, the precise pathway of TLR4-mediated cardiac complications is yet to be established. Therefore, the primary objective of the present study was to find the role of TLR4 in cardiac hypertrophy and the molecular mechanism thereof.MethodsCardiac hypertrophy was induced with administration of isoproterenol (5 mg/kg/day, sc. TLR4 receptor inhibitor RS-LPS (lipopolysaccharide from the photosynthetic bacterium Rhodobacter sphaeroides; 5 μg/day and agonist lipopolysaccharide (LPS (from Escherichia coli; 3.12 μg/day were administered through osmotic pump along with isoproterenol. Cardiac hypertrophy as well as oxidative stress and mitochondrial parameters were evaluated.ResultsCardiac hypertrophy was confirmed with increased heart weight/body weight ratio as well as assessment of hypertrophic markers in heart. There was a marked increase in the TLR4 expression and oxidative stress along with mitochondrial dysfunction in ISO group. TLR4 inhibition significantly decreased heart weight/body weight ratio and ANP, collagen, and β-MHC expression and restored the disturbed cellular antioxidant flux. The mitochondrial perturbations that were observed in hypertrophy heart was normalized after administration of TLR4 inhibitor but not with the agonist. TLR4 agonism further exaggerated the oxidative stress in heart and hence accelerated the disease development and progression.ConclusionOur data show that increased TLR4 ligand pool in cardiac hypertrophy may exaggerate the disease progression. However, inhibition of TLR4 attenuated cardiac hypertrophy through reduced cardiac redox imbalance and mitochondrial

  18. Improved applications of the tetracycline-regulated gene depletion system.

    Science.gov (United States)

    Nishijima, Hitoshi; Yasunari, Takami; Nakayama, Tatsuo; Adachi, Noritaka; Shibahara, Kei-ichi

    2009-10-01

    Tightly controlled expression of transgenes in mammalian cells is an important tool for biological research, drug discovery, and future genetic therapies. The tetracycline-regulated gene depletion (Tet-Off) system has been widely used to control gene activities in mammalian cells, because it allows strict regulation of transgenes but no pleiotropic effects of prokaryotic regulatory proteins. However, the Tet-Off system is not compatible with every cell type and this is the main remaining obstacle left for this system. Recently, we overcame this problem by inserting an internal ribosome entry site (IRES) to drive a selectable marker from the same tetracycline-responsive promoter for the transgene. We also employed a CMV immediate early enhancer/beta-actin (CAG) promoter to express a Tet-controlled transactivator. Indeed, the Tet-Off system with these technical modifications was applied successfully to the human pre-B Nalm-6 cell line in which conventional Tet-Off systems had not worked efficiently. These methodological improvements should be applicable for many other mammalian proliferating cells. In this review we give an overview and introduce a new method for the improved application of the Tet-Off system.

  19. 基因表达谱监测心脏移植排斥反应%Gene expression profile to monitor cardiac allograft rejection

    Institute of Scientific and Technical Information of China (English)

    陈浩; 于伟勇; 程韵枫

    2011-01-01

    @@ Introduction Despite improved immunosuppression, rejection still accounts for significant morbidity and mortality after heart transplantation[1].Any method that improves early detection and hence treatment of rejection is likely to lead to improved long-term survival.Serial surveillance endomyocardial biopsies (EMB) following cardiac transplantation have become an integral component of post-transplant management.However, EMB is invasive, expensive, variable[2] and causes low but definitemorbidity[3].

  20. Cardiac sodium channelopathies.

    Science.gov (United States)

    Amin, Ahmad S; Asghari-Roodsari, Alaleh; Tan, Hanno L

    2010-07-01

    Cardiac sodium channel are protein complexes that are expressed in the sarcolemma of cardiomyocytes to carry a large inward depolarizing current (INa) during phase 0 of the cardiac action potential. The importance of INa for normal cardiac electrical activity is reflected by the high incidence of arrhythmias in cardiac sodium channelopathies, i.e., arrhythmogenic diseases in patients with mutations in SCN5A, the gene responsible for the pore-forming ion-conducting alpha-subunit, or in genes that encode the ancillary beta-subunits or regulatory proteins of the cardiac sodium channel. While clinical and genetic studies have laid the foundation for our understanding of cardiac sodium channelopathies by establishing links between arrhythmogenic diseases and mutations in genes that encode various subunits of the cardiac sodium channel, biophysical studies (particularly in heterologous expression systems and transgenic mouse models) have provided insights into the mechanisms by which INa dysfunction causes disease in such channelopathies. It is now recognized that mutations that increase INa delay cardiac repolarization, prolong action potential duration, and cause long QT syndrome, while mutations that reduce INa decrease cardiac excitability, reduce electrical conduction velocity, and induce Brugada syndrome, progressive cardiac conduction disease, sick sinus syndrome, or combinations thereof. Recently, mutation-induced INa dysfunction was also linked to dilated cardiomyopathy, atrial fibrillation, and sudden infant death syndrome. This review describes the structure and function of the cardiac sodium channel and its various subunits, summarizes major cardiac sodium channelopathies and the current knowledge concerning their genetic background and underlying molecular mechanisms, and discusses recent advances in the discovery of mutation-specific therapies in the management of these channelopathies.

  1. Advanced airway management does not improve outcome of out-of-hospital cardiac arrest.

    Science.gov (United States)

    Hanif, M Arslan; Kaji, Amy H; Niemann, James T

    2010-09-01

    The goal of out-of-hospital endotracheal intubation (ETI) is to reduce mortality and morbidity for patients with airway and ventilatory compromise. Yet several studies, mostly involving trauma patients, have demonstrated similar or worse neurologic outcomes and survival-to-hospital discharge rates after out-of-hospital ETI. To date, there is no study comparing out-of-hospital ETI to bag-valve-mask (BVM) ventilation for the outcome of survival to hospital discharge among nontraumatic adult out-of-hospital cardiac arrest (OOHCA) patients. The objective was to compare survival to hospital discharge among adult OOHCA patients receiving ETI to those managed with BVM. In this retrospective cohort study, the records of all OOHCA patients presenting to a municipal teaching hospital from November 1, 1994, through June 30, 2008, were reviewed. The type of field airway provided, age, sex, race, rhythm on paramedic arrival, presence of bystander cardiopulmonary resuscitation (CPR), whether the arrest was witnessed, site of arrest, return of spontaneous circulation (ROSC), survival to hospital admission, comorbid illnesses, and survival to hospital discharge were noted. A univariate odds ratio (OR) was first computed to describe the association between the type of airway and survival to hospital discharge. A multivariable logistic regression analysis was performed, adjusting for rhythm, bystander CPR, and whether the arrest was witnessed. A cohort of 1,294 arrests was evaluated. A total of 1,027 (79.4%) received ETI, while 131 (10.1%) had BVM, 131 (10.1%) had either a Combitube or an esophageal obturator airway, and five (0.4%) had incomplete prehospital records. Fifty-five of 1,294 (4.3%) survived to hospital discharge; there were no survivors in the Combitube/esophageal obturator airway cohort. Even after multivariable adjustment for age, sex, site of arrest, bystander CPR, witnessed arrest, and rhythm on paramedic arrival, the OR for survival to hospital discharge for BVM

  2. Resveratrol activates endogenous cardiac stem cells and improves myocardial regeneration following acute myocardial infarction.

    Science.gov (United States)

    Ling, Lin; Gu, Shaohua; Cheng, Yan

    2017-03-01

    Stem cell antigen-1-positive (Sca-1+) cardiac stem cells (CSCs) therapy for myocardial regeneration following acute myocardial infarction (AMI) is limited by insufficient cell viability and a high rate of apoptosis, due to the poor regional microenvironment. Resveratrol, which is a compound extracted from red wine, has been reported to protect myocardial tissue post‑AMI by increasing the expression of angiogenic and chemotactic factors. The present study aimed to investigate the effects of resveratrol on Sca‑1+ CSCs, and to optimize Sca‑1+ CSCs therapy for myocardial regeneration post‑AMI. C57/BL6 mice (age, 6 weeks) were divided into two groups, which received intragastric administration of PBS or 2.5 mg/kg.d resveratrol. The endogenous expression of Sca‑1+ CSCs in the heart was assessed on day 7. Furthermore, C57/BL6 mice underwent left anterior descending coronary artery ligation for the construction of an AMI model, and received an injection of 1x106 CSCs into the peri‑ischemic area (n=8/group). Mice received intragastric administration of PBS or resveratrol (2.5 mg/kg.d) for 4 weeks after cell transplantation. Echocardiography was used to evaluate cardiac function 4 weeks after cell transplantation. Capillary density and cardiomyocyte apoptosis in the peri‑ischemic myocardium were assessed by cluster of differentiation 31 immunofluorescent staining and terminal deoxynucleotidyl transferase‑mediated dUTP nick end labeling assay, respectively. Western blot analysis was conducted to detect the protein expression levels of vascular endothelial growth factor (VEGF) and stromal cell‑derived factor (SDF)‑1α in the myocardium. Treatment with resveratrol increased the number of endogenous Sca‑1+ CSCs in heart tissue after 7 days (PBS vs. Res, 1.85±0.41/field vs. 3.14±0.26/field, P<0.05). Furthermore, intragastric administration of resveratrol significantly increased left ventricle (LV) function 4 weeks after AMI, as determined by an

  3. 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 ...

  4. Comparative study of cellular kinetics of reporter probe [{sup 131}I]FIAU in neonatal cardiac myocytes after transfer of HSV1-tk reporter gene with two vectors

    Energy Technology Data Exchange (ETDEWEB)

    Lan Xiaoli [Department of Nuclear Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022 (China); Hubei Province Key Laboratory of Molecular Imaging, Wuhan 430022 (China)], E-mail: lxl730724@hotmail.com; Yin Xiaohua; Wang Ruihua; Liu Ying [Department of Nuclear Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022 (China); Hubei Province Key Laboratory of Molecular Imaging, Wuhan 430022 (China); Zhang Yongxue [Department of Nuclear Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022 (China) and Hubei Province Key Laboratory of Molecular Imaging, Wuhan 430022 (China)], E-mail: zhyx1229@163.com

    2009-02-15

    Aim: Reporter gene imaging is a promising approach for noninvasive monitoring of cardiac gene therapy. In this study, HSV1-tk (herpes simplex virus type 1 thymidine kinase) and FIAU (2'-fluoro-2'-deoxy-1-{beta}-D-arabinofuranosyl-5-iodouracil) were used as the reporter gene and probe, respectively. Cellular uptakes of radiolabeled FIAU of neonatal rat cardiac myocytes transferred with HSV1-tk were compared between two vectors, adenovirus and liposome. The aims of this study were to choose the better vector and to provide a theoretical basis for good nuclide images. Methods: Neonatal cardiac myocytes were obtained from rat heart by single collagenase digestion. HSV1-tk inserted into adenovirus vector (recombinant adenovirus type 5, Ad5-tk) and plasmid (pDC316-tk) coated with Lipofectamine 2000 (pDC316-tk/lipoplex) were developed; thus, HSV1-tk could be transferred into neonatal cardiac myocytes. FAU (2'-fluoro-2'-deoxy-1-{beta}-D-arabinofuranosyluracil) was labeled with {sup 131}I, and the product was assessed after purification with reversed-phase Sep-Pak C-18 column. The uptake rates of [{sup 131}I]FIAU in the transferred cardiac myocytes at different times (0.5, 1, 2, 3, 4 and 5 h) were detected. Furthermore, mRNA expression and protein expression of HSV1-tk were detected by semiquantitative reverse-transcriptase polymerase chain reaction and immunocytochemistry. Results: FAU could be labeled with {sup 131}I, and the labeling efficiency and radiochemical purity rates were 53.82{+-}2.05% and 94.85{+-}1.76%, respectively. Time-dependent increase of the accumulation of [{sup 131}I]FIAU was observed in both the Ad5-tk group and the pDC316/lipoplex group, and the highest uptake rate occurred at 5 h, with peak values of 12.55{+-}0.37% and 2.09{+-}0.34%, respectively. Greater uptakes of [{sup 131}I]FIAU in Ad5-tk-infected cells compared with pDC316/lipoplex-transfected ones occurred at all the time points (t=12.978-38.253, P<.01). The exogenous gene

  5. Nanosecond pulsed platelet-rich plasma (nsPRP) improves mechanical and electrical cardiac function following myocardial reperfusion injury.

    Science.gov (United States)

    Hargrave, Barbara; Varghese, Frency; Barabutis, Nektarios; Catravas, John; Zemlin, Christian

    2016-02-01

    Ischemia and reperfusion (I/R) of the heart is associated with biochemical and ionic changes that result in cardiac contractile and electrical dysfunction. In rabbits, platelet-rich plasma activated using nanosecond pulsed electric fields (nsPRP) has been shown to improve left ventricular pumping. Here, we demonstrate that nsPRP causes a similar improvement in mouse left ventricular function. We also show that nsPRP injection recovers electrical activity even before reperfusion begins. To uncover the mechanism of nsPRP action, we studied whether the enhanced left ventricular function in nsPRP rabbit and mouse hearts was associated with increased expression of heat-shock proteins and altered mitochondrial function under conditions of oxidative stress. Mouse hearts underwent 30 min of global ischemia and 1 h of reperfusion in situ. Rabbit hearts underwent 30 min of ischemia in vivo and were reperfused for 14 days. Hearts treated with nsPRP expressed significantly higher levels of Hsp27 and Hsp70 compared to hearts treated with vehicle. Also, pretreatment of cultured H9c2 cells with nsPRP significantly enhanced the "spare respiratory capacity (SRC)" also referred to as "respiratory reserve capacity" and ATP production in response to the uncoupler FCCP. These results suggest a cardioprotective effect of nsPRP on the ischemic heart during reperfusion.

  6. Load-distributing band improves ventilation and hemodynamics during resuscitation in a porcine model of prolonged cardiac arrest

    Directory of Open Access Journals (Sweden)

    Wang Shuo

    2012-09-01

    Full Text Available Abstract Background The use of mechanical cardiopulmonary resuscitation (CPR has great potential for the clinical setting. The purpose of present study is to compare the hemodynamics and ventilation during and after the load-distributing band CPR, versus the manual CPR in a porcine model of prolonged cardiac arrest, and to investigate the influence of rescue breathing in different CPR protocols. Methods Sixty-four male pigs (n = 16/group, weighing 30 ± 2 kg, were induced ventricular fibrillation and randomized into four resuscitation groups: continuous load-distributing band CPR without rescue ventilation (C-CPR, load-distributing band 30:2 CPR (A-CPR, load-distributing band CPR with continuous rescue breathing (10/min (V-CPR or manual 30:2 CPR (M-CPR. Respiratory variables and hemodynamics were recorded continuously; blood gas was analyzed. Results Tidal volume produced by compressions in the A-, C- and V-CPR groups were significantly higher compared with the M-CPR group (all p 2 of the A-, C- and V-CPR groups were significantly higher and PaCO2 were significantly lower compared with the M-CPR (both p  Conclusions The load-distributing band CPR significantly improved respiratory parameters during resuscitation by augmenting passive ventilation, and significantly improved coronary perfusion pressure. The volume of ventilation produced by the load-distributing band CPR was adequate to maintain sufficient gas exchange independent of rescue breathing.

  7. Physiologically tolerable insulin reduces myocardial injury and improves cardiac functional recovery in myocardial ischemic/reperfused dogs.

    Science.gov (United States)

    Zhang, Hang-Xiang; Zang, Yi-Min; Huo, Jian-Hua; Liang, Shao-Jun; Zhang, Hai-Feng; Wang, Yue-Min; Fan, Qian; Guo, Wen-Yi; Wang, Hai-Chang; Gao, Feng

    2006-12-01

    This study was designed to examine whether physiologically tolerable insulin, which maintains lower blood glucose, can protect the myocardium against ischemia/reperfusion (I/R) injury in a preclinical large animal model. Adult dogs were subjected to 50 minutes of myocardial ischemia (80% reduction in coronary blood flow) followed by 4 hours of reperfusion and treated with vehicle, glucose-insulin-potassium (GIK; glucose, 250 g/L; insulin, 60 U/L; potassium, 80 mmol/L), GK, or low-dose insulin (30 U/L) 10 minutes before reperfusion. Treatment with GIK exerted significant cardioprotective effects as evidenced by improved cardiac function, improved coronary blood flow, reduced infarct size, and myocardial apoptosis. In contrast, treatment with GK increased blood glucose level and aggravated myocardial I/R injury. It is interesting that treatment with insulin alone at the dose that reduced blood glucose to a clinically tolerable level exerted significant cardioprotective effects that were comparable to that seen in the GIK-treated group. This low-dose insulin had no effect on coronary blood flow after reperfusion but markedly reduced coronary reactive hyperemia and switched myocardial substrate uptake from fat to carbohydrate. Our results suggest that lower glucose supply to the ischemic myocardium at early reperfusion may create a "metabolic postconditioning" and thus reduce myocardial ischemia/reperfusion injury after prolonged reperfusion.

  8. Multimedia Exercise Training Program Improves Distance Walked, Heart Rate Recovery, and Self-efficacy in Cardiac Surgery Patients.

    Science.gov (United States)

    Wang, Li-Wei; Ou, Shu-Hua; Tsai, Chien-Sung; Chang, Yue-Cune; Kao, Chi-Wen

    2016-01-01

    Patient education has been shown to be more effective when delivered using multimedia than written materials. However, the effects of using multimedia to assist patients in cardiac rehabilitation have not been investigated. The purpose of this study is to examine the effect of an inpatient multimedia exercise training program on distance walked in the 6-minute walking test (6MWT), heart rate recovery, and walking self-efficacy of patients who had undergone heart surgery. For this longitudinal quasi-experimental study, 60 consecutive patients were assigned to an experimental (n = 20; inpatient multimedia exercise training program) or control (n = 40; routine care) group. Data were collected at 3 times (before surgery, 1 to 2 days before hospital discharge, and 1 month after hospital discharge) and analyzed with the generalized estimating equation approach. Most subjects were men (66.7%), had a mean age of 61.32 ± 13.4 years and left ventricular ejection fraction of 56.96% ± 13.28%, and underwent coronary artery bypass graft surgery (n = 34, 56.7%). Subjects receiving the exercise training program showed significantly greater improvement than those in the control group in the 6MWT walking distance (P surgery and maintained their improvement in 6MWT and self-efficacy 1 month later.

  9. Building an infrastructure to improve cardiac rehabilitation: from guidelines to audit and feedback

    NARCIS (Netherlands)

    Verheul, M.M.

    2016-01-01

    The overall aim of this thesis is to use the principles of the Learning Health System (LHS) to realise an infrastructure to connect physicians, other health professionals, managers, professional associations, electronic patient record (EPR) developers, patients and researchers to continuously improv

  10. Inpatient and outpatient cardiac rehabilitation programmes improve cardiometabolic risk in revascularized coronary patients with type 2 diabetes

    OpenAIRE

    Claudiu Avram; Adina Avram; L.aura Crăciun; Stela Iurciuc; Lucian Hoble; Alexandra Rusu; Bogdan Almăjan-Guţă; Silvia Mancaş

    2010-01-01

    The purpose of this paper is to evaluate cardiometabolic risk reduction of diabetic patients following coronary revascularizationprocedures after participation in outpatients or inpatients cardiac rehabilitation programmes. Materials and methods: weperformed a retrospective analytical study which included a group of 103 revascularized coronary patients with diabetesmellitus. Depending on participation in a cardiac rehabilitation program we have defined the following subgroups of patients:Grou...

  11. Non-invasively measured cardiac magnetic field maps improve the estimation of the current distribution

    OpenAIRE

    Kosch, Olaf; Steinhoff, Uwe; Trahms, Lutz; Trontelj, Zvonko; Jazbinšek, Vojko

    2015-01-01

    Comprehensive body surface potential mapping (BSPM) and magnetic field mapping (MFM) measurements have been carried out in order to improve the estimation of the current distribution generated by the human heart. Electric and magnetic fields and also the planar gradient of the magnetic field during the QRS complex were imaged as a time series of field maps. A model of the current distribution should explain the features of both BSPM and MFM. Simulated maps generated by a single dipole or a st...

  12. Evidence for a non-canonical role of HDAC5 in regulation of the cardiac Ncx1 and Bnp genes

    Science.gov (United States)

    Harris, Lillianne G.; Wang, Sabina H.; Mani, Santhosh K.; Kasiganesan, Harinath; Chou, C. James; Menick, Donald R.

    2016-01-01

    Class IIa histone deacetylases (HDACs) are very important for tissue specific gene regulation in development and pathology. Because class IIa HDAC catalytic activity is low, their exact molecular roles have not been fully elucidated. Studies have suggested that class IIa HDACs may serve as a scaffold to recruit the catalytically active class I HDAC complexes to their substrate. Here we directly address whether the class IIa HDAC, HDAC5 may function as a scaffold to recruit co-repressor complexes to promoters. We examined two well-characterized cardiac promoters, the sodium calcium exchanger (Ncx1) and the brain natriuretic peptide (Bnp) whose hypertrophic upregulation is mediated by both class I and IIa HDACs. Selective inhibition of class IIa HDACs did not prevent adrenergic stimulated Ncx1 upregulation, however HDAC5 knockout prevented pressure overload induced Ncx1 upregulation. Using the HDAC5(-/-) mouse we show that HDAC5 is required for the interaction of the HDAC1/2/Sin3a co-repressor complexes with the Nkx2.5 and YY1 transcription factors and critical for recruitment of the HDAC1/Sin3a co-repressor complex to either the Ncx1 or Bnp promoter. Our novel findings support a non-canonical role of class IIa HDACs in the scaffolding of transcriptional regulatory complexes, which may be relevant for therapeutic intervention for pathologies. PMID:26704971

  13. Cardiac MRI assessed left ventricular hypertrophy in differentiating hypertensive heart disease from hypertrophic cardiomyopathy attributable to a sarcomeric gene mutation

    Energy Technology Data Exchange (ETDEWEB)

    Sipola, Petri [Kuopio University Hospital, Department of Clinical Radiology, Kuopio (Finland); University of Eastern Finland, Institute of Clinical Medicine, Faculty of Health Sciences, Kuopio (Finland); Magga, Jarkko; Peuhkurinen, Keijo [Kuopio University Hospital, Department of Medicine, Kuopio (Finland); Husso, Minna [Kuopio University Hospital, Department of Clinical Radiology, Kuopio (Finland); Jaeaeskelaeinen, Pertti; Kuusisto, Johanna [Kuopio University Hospital, Department of Medicine, Kuopio (Finland); Kuopio University Hospital, Heart Center, P.O. Box 1777, Kuopio (Finland)

    2011-07-15

    To evaluate the value of cardiac magnetic resonance imaging (CMRI)-assessed left ventricular hypertrophy (LVH) in differentiating between hypertensive heart disease and hypertrophic cardiomyopathy (HCM). 95 unselected subjects with mild-to-moderate hypertension, 24 patients with HCM attributable to the D175N mutation of the {alpha}-tropomyosin gene and 17 control subjects were studied by cine CMRI. Left ventricular (LV) quantitative and qualitative characteristics were evaluated. LV maximal end-diastolic wall thickness, wall thickness-to-LV volume ratio, end-diastolic septum thickness and septum-to-lateral wall thickness ratio were useful measures for differentiating between LVH due to hypertension and HCM. The most accurate measure for identifying patients with HCM was the LV maximal wall thickness {>=}17 mm, with a sensitivity, specificity, negative predictive value, positive predictive value, and accuracy of 90%, 93%, 86%, 95% and 91%, respectively. LV maximal wall thickness in the anterior wall, or regional bulging in left ventricular wall was found only in patients with HCM. LV mass index was not discriminant between patients with HCM and those with LVH due to hypertension. LV maximal thickness measured by CMRI is the best anatomical parameter in differentiating between LVH due to mild-to-moderate hypertension and HCM attributable to a sarcomeric mutation. CMRI assessment of location and quality of LVH is also of value in differential diagnosis. (orig.)

  14. Clinical and functional characterization of a novel mutation in lamin a/c gene in a multigenerational family with arrhythmogenic cardiac laminopathy.

    Science.gov (United States)

    Forleo, Cinzia; Carmosino, Monica; Resta, Nicoletta; Rampazzo, Alessandra; Valecce, Rosanna; Sorrentino, Sandro; Iacoviello, Massimo; Pisani, Francesco; Procino, Giuseppe; Gerbino, Andrea; Scardapane, Arnaldo; Simone, Cristiano; Calore, Martina; Torretta, Silvia; Svelto, Maria; Favale, Stefano

    2015-01-01

    Mutations in the lamin A/C gene (LMNA) were associated with dilated cardiomyopathy (DCM) and, recently, were related to severe forms of arrhythmogenic right ventricular cardiomyopathy (ARVC). Both genetic and phenotypic overlap between DCM and ARVC was observed; molecular pathomechanisms leading to the cardiac phenotypes caused by LMNA mutations are not yet fully elucidated. This study involved a large Italian family, spanning 4 generations, with arrhythmogenic cardiomyopathy of different phenotypes, including ARVC, DCM, system conduction defects, ventricular arrhythmias, and sudden cardiac death. Mutation screening of LMNA and ARVC-related genes PKP2, DSP, DSG2, DSC2, JUP, and CTNNA3 was performed. We identified a novel heterozygous mutation (c.418_438dup) in LMNA gene exon 2, occurring in a highly conserved protein domain across several species. This newly identified variant was not found in 250 ethnically-matched control subjects. Genotype-phenotype correlation studies suggested a co-segregation of the LMNA mutation with the disease phenotype and an incomplete and age-related penetrance. Based on clinical, pedigree, and molecular genetic data, this mutation was considered likely disease-causing. To clarify its potential pathophysiologic impact, functional characterization of this LMNA mutant was performed in cultured cardiomyocytes expressing EGFP-tagged wild-type and mutated LMNA constructs, and indicated an increased nuclear envelope fragility, leading to stress-induced apoptosis as the main pathogenetic mechanism. This study further expands the role of the LMNA gene in the pathogenesis of cardiac laminopathies, suggesting that LMNA should be included in mutation screening of patients with suspected arrhythmogenic cardiomyopathy, particularly when they have ECG evidence for conduction defects. The combination of clinical, genetic, and functional data contribute insights into the pathogenesis of this form of life-threatening arrhythmogenic cardiac laminopathy.

  15. Clinical and functional characterization of a novel mutation in lamin a/c gene in a multigenerational family with arrhythmogenic cardiac laminopathy.

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    Cinzia Forleo

    Full Text Available Mutations in the lamin A/C gene (LMNA were associated with dilated cardiomyopathy (DCM and, recently, were related to severe forms of arrhythmogenic right ventricular cardiomyopathy (ARVC. Both genetic and phenotypic overlap between DCM and ARVC was observed; molecular pathomechanisms leading to the cardiac phenotypes caused by LMNA mutations are not yet fully elucidated. This study involved a large Italian family, spanning 4 generations, with arrhythmogenic cardiomyopathy of different phenotypes, including ARVC, DCM, system conduction defects, ventricular arrhythmias, and sudden cardiac death. Mutation screening of LMNA and ARVC-related genes PKP2, DSP, DSG2, DSC2, JUP, and CTNNA3 was performed. We identified a novel heterozygous mutation (c.418_438dup in LMNA gene exon 2, occurring in a highly conserved protein domain across several species. This newly identified variant was not found in 250 ethnically-matched control subjects. Genotype-phenotype correlation studies suggested a co-segregation of the LMNA mutation with the disease phenotype and an incomplete and age-related penetrance. Based on clinical, pedigree, and molecular genetic data, this mutation was considered likely disease-causing. To clarify its potential pathophysiologic impact, functional characterization of this LMNA mutant was performed in cultured cardiomyocytes expressing EGFP-tagged wild-type and mutated LMNA constructs, and indicated an increased nuclear envelope fragility, leading to stress-induced apoptosis as the main pathogenetic mechanism. This study further expands the role of the LMNA gene in the pathogenesis of cardiac laminopathies, suggesting that LMNA should be included in mutation screening of patients with suspected arrhythmogenic cardiomyopathy, particularly when they have ECG evidence for conduction defects. The combination of clinical, genetic, and functional data contribute insights into the pathogenesis of this form of life-threatening arrhythmogenic

  16. A vigilant, hypoxia-regulated heme oxygenase-1 gene vector in the heart limits cardiac injury after ischemia-reperfusion in vivo.

    Science.gov (United States)

    Tang, Yao Liang; Qian, Keping; Zhang, Y Clare; Shen, Leping; Phillips, M Ian

    2005-12-01

    The effect of a cardiac specific, hypoxia-regulated, human heme oxygenase-1 (hHO-1) vector to provide cardioprotection from ischemia-reperfusion injury was assessed. When myocardial ischemia and reperfusion is asymptomatic, the damaging effects are cumulative and patients miss timely treatment. A gene therapy approach that expresses therapeutic genes only when ischemia is experienced is a desirable strategy. We have developed a cardiac-specific, hypoxia-regulated gene therapy "vigilant vector'' system that amplifies cardioprotective gene expression. Vigilant hHO-1 plasmids, LacZ plasmids, or saline (n = 40 per group) were injected into mouse heart 2 days in advance of ischemia-reperfusion injury. Animals were exposed to 60 minutes of ischemia followed by 24 hours of reperfusion. For that term (24 hours) effects, the protein levels of HO-1, inflammatory responses, apoptosis, and infarct size were determined. For long-term (3 week) effects, the left ventricular remodeling and recovery of cardiac function were assessed. Ischemia-reperfusion resulted in a timely overexpression of HO-1 protein. Infarct size at 24 hours after ischemia-reperfusion was significantly reduced in the HO-1-treated animals compared with the LacZ-treated group or saline-treated group (P < .001). The reduction of infarct size was accompanied by a decrease in lipid peroxidant activity, inflammatory cell infiltration, and proapoptotic protein level in ischemia-reperfusion-injured myocardium. The long-term study demonstrated that timely, hypoxia-induced HO-1 overexpression is beneficial in conserving cardiac function and attenuating left ventricle remodelling. The vigilant HO-1 vector provides a protective therapy in the heart for reducing cellular damage during ischemia-reperfusion injury and preserving heart function.

  17. Ferritin as a reporter gene for in vivo tracking of stem cells by 1.5-T cardiac MRI in a rat model of myocardial infarction.

    Science.gov (United States)

    Campan, Manuela; Lionetti, Vincenzo; Aquaro, Giovanni D; Forini, Francesca; Matteucci, Marco; Vannucci, Laura; Chiuppesi, Flavia; Di Cristofano, Claudio; Faggioni, Michela; Maioli, Margherita; Barile, Lucio; Messina, Elisa; Lombardi, Massimo; Pucci, Angela; Pistello, Mauro; Recchia, Fabio A

    2011-06-01

    The methods currently utilized to track stem cells by cardiac MRI are affected by important limitations, and new solutions are needed. We tested human ferritin heavy chain (hFTH) as a reporter gene for in vivo tracking of stem cells by cardiac MRI. Swine cardiac stem/progenitor cells were transduced with a lentiviral vector to overexpress hFTH and cultured to obtain cardiospheres (Cs). Myocardial infarction was induced in rats, and, after 45 min, the animals were subjected to intramyocardial injection of ∼200 hFTH-Cs or nontransduced Cs or saline solution in the border zone. By employing clinical standard 1.5-Tesla MRI scanner and a multiecho T2* gradient echo sequence, we localized iron-accumulating tissue only in hearts treated with hFTH-Cs. This signal was detectable at 1 wk after infarction, and its size did not change significantly after 4 wk (6.33 ± 3.05 vs. 4.41 ± 4.38 mm(2)). Cs transduction did not affect their cardioreparative potential, as indicated by the significantly better preserved left ventricular global and regional function and the 36% reduction in infarct size in both groups that received Cs compared with control infarcts. Prussian blue staining confirmed the presence of differentiated, iron-accumulating cells containing mitochondria of porcine origin. Cs-derived cells displayed CD31, α-smooth muscle, and α-sarcomeric actin antigens, indicating that the differentiation into endothelial, smooth muscle and cardiac muscle lineage was not affected by ferritin overexpression. In conclusion, hFTH can be used as a MRI reporter gene to track dividing/differentiating stem cells in the beating heart, while simultaneously monitoring cardiac morpho-functional changes.

  18. Improving Surveillance and Prevention of Surgical Site Infection in Pediatric Cardiac Surgery.

    Science.gov (United States)

    Cannon, Melissa; Hersey, Diane; Harrison, Sheilah; Joy, Brian; Naguib, Aymen; Galantowicz, Mark; Simsic, Janet

    2016-03-01

    Postoperative cardiovascular surgical site infections are preventable events that may lead to increased morbidity, mortality, and health care costs. To improve surgical wound surveillance and reduce the incidence of surgical site infections. An institutional review of surgical site infections led to implementation of 8 surveillance and process measures: appropriate preparation the night before surgery and the day of surgery, use of appropriate preparation solution in the operating room, appropriate timing of preoperative antibiotic administration, placement of a photograph of the surgical site in the patient's chart at discharge, sending a photograph of the surgical site to the patient's primary care physician, 30-day follow-up of the surgical site by an advanced nurse practitioner, and placing a photograph of the surgical site obtained on postoperative day 30 in the patient's chart. Mean overall compliance with the 8 measures from March 2013 through February 2014 was 88%. Infections occurred in 10 of 417 total operative cases (2%) in 2012, in 8 of 437 total operative cases (2%) in 2013, and in 7 of 452 total operative cases (1.5%) in 2014. Institution of the surveillance process has resulted in improved identification of suspected surgical site infections via direct rather than indirect measures, accurate identification of all surgical site infections based on definitions of the National Healthcare Safety Network, collaboration with all persons involved, and enhanced communication with patients' family members and referring physicians. ©2016 American Association of Critical-Care Nurses.

  19. Advising a cardiac disease gene positive yet phenotype negative or borderline abnormal athlete: is sporting disqualification really necessary?

    Science.gov (United States)

    Richard, Pascale; Denjoy, Isabelle; Fressart, Véronique; Wilson, Mathew G; Carré, François; Charron, Philippe

    2012-11-01

    The sudden cardiac death (SCD) of an athlete is a rare and tragic event, often caused by a number of inherited heart muscle disorders, namely the cardiomyopathies and primary arrhythmia syndromes (also known as cardiac ion channelopathies). Recent advances in the understanding of the molecular genetics of these heritable cardiovascular diseases present new challenges for clinicians who manage athletes with these types of heart muscle conditions. Unfortunately, the clinical heterogeneity of many of these SCD diseases are also matched by the genotypic heterogeneity associated with the pathogenesis of the disease. A particularly challenging situation arises when the sports physician and attending cardiologist are presented with an athlete who demonstrates a familial context of inherited cardiac disease or presents mild cardiac abnormalities suggestive of inherited cardiac disease. Alongside the complete cardiac evaluation, genetic testing may be proposed as an additional diagnostic tool in this clinical conundrum. However, debate still remains on how extensive the screening should be, in particular the use and interpretation of genetic testing in that setting. The aim of this review is to examine the role of genetic testing within the diagnostic algorithm of preparticipation screening of athletes. This will be achieved by providing the sports medicine physician with simple current cardiac genetic knowledge for the main inherited cardiac conditions known to cause SCD. Furthermore, it will examine current knowledge for the role of genetic testing upon the prediction of SCD, concluding with its impact on the sport eligibility and disqualification conundrum using case examples from our genetic testing laboratory.

  20. A VEGF delivery system targeting MI improves angiogenesis and cardiac function based on the tropism of MSCs and layer-by-layer self-assembly.

    Science.gov (United States)

    Liu, Ge; Li, Li; Huo, Da; Li, Yanzhao; Wu, Yangxiao; Zeng, Lingqing; Cheng, Panke; Xing, Malcolm; Zeng, Wen; Zhu, Chuhong

    2017-05-01

    Myocardial infarction (MI) is a serious ischemic condition affecting many individuals around the world. Vascular endothelial growth factor (VEGF) is considered a promising factor for enhancing cardiac function by promoting angiogenesis. However, the lack of a suitable method of VEGF delivery to the MI area is a serious challenge. In this study, we screened a suitable delivery carrier with favorable biocompatibility that targeted the MI area using the strategy of an inherent structure derived from the body and that was based on characteristics of the MI. Mesenchymal stem cells (MSCs) are important infiltrating cells that are derived from blood and have an inherent tropism for the MI zone. We hypothesized that VEGF-encapsulated MSCs targeting MI tissue could improve cardiac function by angiogenesis based on the tropism of the MSCs to the MI area. We first developed VEGF-encapsulated MSCs using self-assembled gelatin and alginate polyelectrolytes to improve angiogenesis and cardiac function. In vitro, the results showed that VEGF-encapsulated MSCs had a sustained release of VEGF and tropism to SDF-1. In vivo, VEGF-encapsulated MSCs migrated to the MI area, enhanced cardiac function, perfused the infarcted area and promoted angiogenesis. These preclinical findings suggest that VEGF-loaded layer-by-layer self-assembled encapsulated MSCs may be a promising and minimally invasive therapy for treating MI. Furthermore, other drugs loaded to layer-by-layer self-assembled encapsulated MSCs may be promising therapies for treating other diseases.

  1. Improvement of cognitive test performance in patients undergoing primary CABG and other CPB-assisted cardiac procedures.

    Science.gov (United States)

    van den Goor, Jm; Saxby, Bk; Tijssen, Jg; Wesnes, Ka; de Mol, Ba; Nieuwland, R

    2008-09-01

    Cardiac surgical procedures assisted by cardiopulmonary bypass (CPB) impair cognitive functions. Several studies, however, showed that cognitive functions were unaffected in patients undergoing either primary coronary artery bypass grafting (CABG) or more complex surgery assisted by CPB. Therefore, we conducted a straightforward study to compare patient groups who differed significantly in terms of risk factors such as prolonged CPB times. Consecutive patients (n = 54) were included, undergoing either non-primary CABG, e.g. valve and/or CABG, (n = 30) or primary CABG (n = 24), assisted by CPB. Cognitive function was determined pre-operatively on the day of hospital admission, and post-operatively after one and six months using the Cognitive Drug Research computerized assessment battery. Data from the fourteen individual task variables were summarized in four composite scores: Power of Attention (PoA), Continuity of Attention (CoA), Quality of Episodic Memory (QoEM), and Speed of Memory (SoM). In the non-primary CABG patients, both CoA and QoEM improved after 1 month (p = 0.001 and p = 0.016, respectively), whereas, after 6 months, CoA (p = 0.002), QoEM (p = 0.002) and SoM (p CPB in both non-primary CABG and in primary CABG patients.

  2. [The expression of the sperm-specific lactate dehydrogenase gene Ldh-c in plateau pika (Ochotona curzoniae) cardiac muscle and its effect on the anaerobic glycolysis].

    Science.gov (United States)

    Li, Xiao; Wei, Lian; Wang, Yang; Xu, Li-Na; Wei, Lin-Na; Wei, Deng-Bang

    2015-06-25

    The plateau pika (Ochotona curzoniae) has a strong adaptability to hypoxic plateau environment. We found that the sperm-specific lactate dehydrogenase (LDH-C4) gene Ldh-c expressed in plateau pika cardiac muscle. In order to shed light on the effect of LDH-C4 on the anaerobic glycolysis in plateau pika cardiac muscle, 20 pikas were randomly divided into the inhibitor group and the control group, and the sample size of each group was 10. The pikas of inhibitor group were injected with 1 mL 1 mol/L N-isopropyl oxamate, a specific LDH-C4 inhibitor, in biceps femoris muscle of hind legs, each leg with 500 μL. The pikas of control group were injected with the same volume of normal saline (0.9% NaCl). The mRNA and protein expression levels of Ldh-c gene in plateau pika cardiac muscle were determined by real-time PCR and Western blot. The activities of LDH, and the contents of lactate (LD) and ATP in cardiac muscle were compared between the inhibitor group and the control group. The results showed that 1) the expression levels of Ldh-c mRNA and protein were 0.47 ± 0.06 and 0.68 ± 0.08, respectively; 2) 30 min after injection of 1 mL 1 mol/L N-isopropyl oxamate in biceps femoris muscle, the concentration of N-isopropyl oxamate in blood was 0.08 mmol/L; 3) in cardiac muscle of the inhibitor group and the control group, the LDH activities were (6.18 ± 0.48) U/mg and (9.08 ± 0.58) U/mg, the contents of LD were (0.21 ± 0.03) mmol/g and (0.26 ± 0.04) mmol/g, and the contents of ATP were (4.40 ± 0.69) nmol/mg and (6.18 ± 0.73) nmol/mg (P < 0.01); 5) the inhibition rates of N-isopropyl oxamate to LDH, LD and ATP were 31.98%, 20.90% and 28.70%, respectively. The results suggest that Ldh-c expresses in cardiac muscle of plateau pika, and the pika cardiac muscle may get at least 28% ATP for its activities by LDH-C4 catalyzed anaerobic glycolysis, which reduces the dependence on oxygen and enhances the adaptation to the hypoxic environments.

  3. Common genetic variation near the phospholamban gene is associated with cardiac repolarisation: meta-analysis of three genome-wide association studies.

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    Ilja M Nolte

    Full Text Available To identify loci affecting the electrocardiographic QT interval, a measure of cardiac repolarisation associated with risk of ventricular arrhythmias and sudden cardiac death, we conducted a meta-analysis of three genome-wide association studies (GWAS including 3,558 subjects from the TwinsUK and BRIGHT cohorts in the UK and the DCCT/EDIC cohort from North America. Five loci were significantly associated with QT interval at P<1x10(-6. To validate these findings we performed an in silico comparison with data from two QT consortia: QTSCD (n = 15,842 and QTGEN (n = 13,685. Analysis confirmed the association between common variants near NOS1AP (P = 1.4x10(-83 and the phospholamban (PLN gene (P = 1.9x10(-29. The most associated SNP near NOS1AP (rs12143842 explains 0.82% variance; the SNP near PLN (rs11153730 explains 0.74% variance of QT interval duration. We found no evidence for interaction between these two SNPs (P = 0.99. PLN is a key regulator of cardiac diastolic function and is involved in regulating intracellular calcium cycling, it has only recently been identified as a susceptibility locus for QT interval. These data offer further mechanistic insights into genetic influence on the QT interval which may predispose to life threatening arrhythmias and sudden cardiac death.

  4. Complexity quantification of cardiac variability time series using improved sample entropy (I-SampEn).

    Science.gov (United States)

    Marwaha, Puneeta; Sunkaria, Ramesh Kumar

    2016-09-01

    The sample entropy (SampEn) has been widely used to quantify the complexity of RR-interval time series. It is a fact that higher complexity, and hence, entropy is associated with the RR-interval time series of healthy subjects. But, SampEn suffers from the disadvantage that it assigns higher entropy to the randomized surrogate time series as well as to certain pathological time series, which is a misleading observation. This wrong estimation of the complexity of a time series may be due to the fact that the existing SampEn technique updates the threshold value as a function of long-term standard deviation (SD) of a time series. However, time series of certain pathologies exhibits substantial variability in beat-to-beat fluctuations. So the SD of the first order difference (short term SD) of the time series should be considered while updating threshold value, to account for period-to-period variations inherited in a time series. In the present work, improved sample entropy (I-SampEn), a new methodology has been proposed in which threshold value is updated by considering the period-to-period variations of a time series. The I-SampEn technique results in assigning higher entropy value to age-matched healthy subjects than patients suffering atrial fibrillation (AF) and diabetes mellitus (DM). Our results are in agreement with the theory of reduction in complexity of RR-interval time series in patients suffering from chronic cardiovascular and non-cardiovascular diseases.

  5. Physical therapy for airway clearance improves cardiac autonomic modulation in children with acute bronchiolitis

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    Cynthia P. Jacinto

    2013-12-01

    Full Text Available BACKGROUND: The effects of physical therapy on heart rate variability (HRV, especially in children, are still inconclusive. OBJECTIVE: We investigated the effects of conventional physical therapy (CPT for airway clearance and nasotracheal suction on the HRV of pediatric patients with acute bronchiolitis. METHOD: 24 children were divided into two groups: control group (CG, n=12 without respiratory diseases and acute bronchiolitis group (BG, n=12. The heart rate was recorded in the BG at four different moments: basal recording (30 minutes, 5 minutes after the CPT (10 minutes, 5 minutes after nasotracheal suction (10 minutes, and 40 minutes after nasotracheal suction (30 minutes. The CG was subjected to the same protocol, except for nasotracheal suction. To assess the HRV, we used spectrum analysis, which decomposes the heart rate oscillations into frequency bands: low frequency (LF=0.04-0.15Hz, which corresponds mainly to sympathetic modulation; and high frequency (HF=0.15-1.2Hz, corresponding to vagal modulation. RESULTS: Under baseline conditions, the BG showed higher values in LF oscillations, lower values in HF oscillations, and increased LF/HF ratio when compared to the CG. After CPT, the values for HRV in the BG were similar to those observed in the CG during basal recording. Five minutes after nasotracheal suction, the BG showed a decrease in LF and HF oscillations; however, after 40 minutes, the values were similar to those observed after application of CPT. CONCLUSIONS: The CPT and nasotracheal suction, both used for airway clearance, promote improvement in autonomic modulation of HRV in children with acute bronchiolitis.

  6. Pulmonary Perfusion and Ventilation During Cardiopulmonary Bypass Are Not Associated with Improved Postoperative Outcomes After Cardiac Surgery

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    Yiliam F Rodriguez-Blanco

    2016-11-01

    Full Text Available ObjectivesClinical trials of either pulmonary perfusion or ventilation during cardiopulmonary bypass are equivocal. We hypothesized that to achieve significant improvement in outcomes both interventions had to be concurrent.DesignRetrospective case-control studySettingsMajor academic tertiary referral medical centerParticipants274 consecutive patients who underwent open heart surgery with cardiopulmonary bypass 2009 - 2013.InterventionsThe outcomes of 86 patients who received pulmonary perfusion and ventilation during cardiopulmonary bypass were retrospectively compared to the control group of 188 patients.Measurements and Main ResultsRespiratory complications rates were similar in both groups (33.7% vs. 33.5%, as were the rates of postoperative pneumonia (4.7% vs. 4.3%, pleural effusions (13.9% vs. 12.2% and re-intubations (9.3% vs. 9.1%. Rates of adverse postoperative cardiac events including ventricular tachycardia (9.3% vs. 8.5% and atrial fibrillation (33.7% vs. 28.2% were equivalent in both groups. Incidence of sepsis (8.1% vs. 5.3%, postoperative stroke (2.3% vs. 2.1%, acute kidney injury (2.3% vs. 3.7% and renal failure (5.8% vs. 3.7% were likewise comparable. Despite similar transfusion requirements, coagulopathy (12.8% vs. 5.3%, p=0.031 and the need for mediastinal re-exploration (17.4% vs. 9.6%, p=0.0633 were observed more frequently in the pulmonary perfusion and ventilation group, but the difference did not reach the statistical significance. ICU and hospital stays, and the ICU readmission rates (7.0% vs. 8.0% were similar in both groups.ConclusionsSimultaneous pulmonary perfusion and ventilation during cardiopulmonary bypass were not associated with improved clinical outcomes.

  7. Cell salvage of cardiotomy suction blood improves the balance between pro- and anti-inflammatory cytokines after cardiac surgery.

    Science.gov (United States)

    Gäbel, Jakob; Westerberg, Martin; Bengtsson, Anders; Jeppsson, Anders

    2013-09-01

    The inflammatory response after cardiac surgery is characterized by a profound release of pro- and anti-inflammatory cytokines. Recent data suggest that the balance between pro- and anti-inflammatory cytokines is of greater importance than the absolute levels. Retransfusion of unwashed cardiotomy suction blood contributes to the inflammatory response, but the balance between pro- and anti-inflammatory cytokines in cardiotomy suction blood and whether cell salvage before retransfusion influences the systemic balance have not been investigated previously. Twenty-five coronary artery bypass grafting patients were randomized to either cell salvage of cardiotomy suction blood or no cell salvage before retransfusion. Plasma levels of three anti-inflammatory cytokines [interleukin (IL)-1 receptor antagonist, IL-4 and IL-10] and two proinflammatory cytokines (tumour necrosis factor-alpha and IL-6), and the IL-6-to-IL-10 ratio was measured in cardiotomy suction blood before and after cell salvage, and in the systemic circulation before, during and after surgery. Plasma levels of all cytokines except IL-4 and IL-10 were significantly higher in cardiotomy suction blood than in the systemic circulation. The IL-6-to-IL-10 ratio was 6-fold higher in cardiotomy suction blood than in the systemic circulation [median 10.2 (range 1.1-75) vs 1.7 (0.2-24), P suction blood and improved the systemic IL-6-to-IL-10 ratio 24 h after surgery [median 5.2 (3.6-17) vs 12.4 (4.9-31)] compared with no cell salvage (P = 0.032). The balance of pro- and anti-inflammatory cytokines in cardiotomy suction blood is unfavourable. Cell salvage reduces the absolute levels of both pro- and anti-inflammatory cytokines in cardiotomy suction blood and improves the balance in the systemic circulation after surgery.

  8. Improved quality of life after treatment of prolonged asystole during breath holding spells with a cardiac pacemaker

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    Bruno Kolterer

    2015-01-01

    Conclusion: Cardiac pacing using appropriate pacemaker settings seems effective in the prevention of LOC and reduction of the frequency of BHS. Our results imply a reduction of subjective stress levels of patients and parents as well as an increased quality of everyday life. After all, randomized controlled trials of the influence of cardiac pacemaker implantation on subjective stress levels in patients with BHS are needed.

  9. The surgical prebrief as part of a five-point comprehensive approach to improving pediatric cardiac surgical team communication.

    Science.gov (United States)

    Hoganson, David M; Boston, Umar S; Manning, Peter B; Eghtesady, Pirooz

    2014-10-01

    Communication is essential to the safe conduct of any critical task including cardiac surgery. After inspiration by airline crew resource management training, a communication system for the care plans of pediatric cardiac patients was developed and refined over time that encompasses the entire heart center team. Five distinct communication points are used to ensure preoperative, intraoperative, and postoperative care, which is transitioned efficiently and maintained at the highest level.

  10. Serial measurement of neuron specific enolase improves prognostication in cardiac arrest patients treated with hypothermia: A prospective study

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    Storm Christian

    2012-01-01

    Full Text Available Abstract Background Neuron specific enolase (NSE has repeatedly been evaluated for neurological prognostication in patients after cardiac arrest. However, it is unclear whether current guidelines for NSE cutoff levels also apply to cardiac arrest patients treated with hypothermia. Thus, we investigated the prognostic significance of absolute NSE levels and NSE kinetics in cardiac arrest patients treated with hypothermia. Methods In a prospective study of 35 patients resuscitated from cardiac arrest, NSE was measured daily for four days following admission. Outcome was assessed at ICU discharge using the CPC score. All patients received hypothermia treatment for 24 hours at 33°C with a surface cooling device according to current guidelines. Results The cutoff for absolute NSE levels in patients with unfavourable outcome (CPC 3-5 72 hours after cardiac arrest was 57 μg/l with an area under the curve (AUC of 0.82 (sensitivity 47%, specificity 100%. The cutoff level for NSE kinetics in patients with unfavourable outcome (CPC 3-5 was an absolute increase of 7.9 μg/l (AUC 0.78, sensitivity 63%, specificity 100% and a relative increase of 33.1% (AUC 0.803, sensitivity 67%, specificity 100% at 48 hours compared to admission. Conclusion In cardiac arrest patients treated with hypothermia, prognostication of unfavourable outcome by NSE kinetics between admission and 48 hours after resuscitation may be superior to prognostication by absolute NSE levels.

  11. Targeted delivery of human VEGF gene via complexes of magnetic nanoparticle-adenoviral vectors enhanced cardiac regeneration.

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    Yue Zhang

    Full Text Available This study assessed the concept of whether delivery of magnetic nanobeads (MNBs/adenoviral vectors (Ad-encoded hVEGF gene (Ad(hVEGF could regenerate ischaemically damaged hearts in a rat acute myocardial infarction model under the control of an external magnetic field. Adenoviral vectors were conjugated to MNBs with the Sulfo-NHS-LC-Biotin linker. In vitro transduction efficacy of MNBs/Ad-encoded luciferase gene (Ad(luc was compared with Ad(luc alone in human umbilical vein endothelial cells (HUVECs under magnetic field stimulation. In vivo, in a rat acute myocardial infarction (AMI model, MNBs/Ad(hVEGF complexes were injected intravenously and an epicardial magnet was employed to attract the circulating MNBs/Ad(hVEGF complexes. In vitro, compared with Ad(luc alone, MNBs/Ad(luc complexes had a 50-fold higher transduction efficiency under the magnetic field. In vivo, epicardial magnet effectively attracted MNBs/Ad(hVEGF complexes and resulted in strong therapeutic gene expression in the ischemic zone of the infarcted heart. When compared to other MI-treated groups, the MI-M(+/Ad(hVEGF group significantly improved left ventricular function (p<0.05 assessed by pressure-volume loops after 4 weeks. Also the MI-M(+/Ad(hVEGF group exhibited higher capillary and arteriole density and lower collagen deposition than other MI-treated groups (p<0.05. Magnetic targeting enhances transduction efficiency and improves heart function. This novel method to improve gene therapy outcomes in AMI treatment offers the potential into clinical applications.

  12. Pharmacological Interventions for Improving Adenovirus Usage in Gene Therapy

    NARCIS (Netherlands)

    Haisma, Hidde J.; Bellu, Anna Rita

    2011-01-01

    Gene therapy may be an innovative and promising new treatment strategy for cancer but is limited due to a low efficiency and specificity of gene delivery to the target cells. Adenovirus is the preferred gene therapy vector for systemic delivery because of its unparalleled in vivo transduction effici

  13. Pharmacological Interventions for Improving Adenovirus Usage in Gene Therapy

    NARCIS (Netherlands)

    Haisma, Hidde J.; Bellu, Anna Rita

    2011-01-01

    Gene therapy may be an innovative and promising new treatment strategy for cancer but is limited due to a low efficiency and specificity of gene delivery to the target cells. Adenovirus is the preferred gene therapy vector for systemic delivery because of its unparalleled in vivo transduction

  14. Cardiac abnormalities in diabetic patients with mutation in the mitochondrial tRNA {sup Leu(UUR)}Gene

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    Ueno, Hiroshi [Hyogo Medical Center for Adults, Akashi (Japan); Shiotani, Hideyuki

    1999-11-01

    An A-to-G transition at position 3243 of the mitochondrial DNA is known to be a pathogenic factor for mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes (MELAS), diabetes and cardiomyopathy. This mutation causes dysfunction of the central nervous system in MELAS. Because the heart, as well as the brain and nervous system, is highly dependent on the energy produced by mitochondrial oxidation, these tissues are more vulnerable to mitochondrial defects. Cardiac abnormalities were assessed in 10 diabetic patients associated with this mutation using echocardiography and {sup 123}I-metaiodobenzylguanidine (MIBG) scintigraphy, and compared with 19 diabetic patients without the mutation. Duration of diabetes, therapy, control of blood glucose and diabetic complications, such as diabetic retinopathy and nephropathy, were not different between the 2 groups. Diabetic patients with the mutation had a significantly thicker interventricular septum (16.8{+-}3.7 vs 11.0{+-}1.6 mm, p<0.001) than those without the mutation. Fractional shortening was lower in diabetic patients with the mutation than those without it (30.7{+-}7.0 vs 42.5{+-}6.6, p<0.001). MIBG uptake on the delayed MIBG image was significantly lower in diabetic patients with the mutation than in those without the mutation (mean value of the heart to mediastinum ratio: 1.6{+-}0.2 vs 2.0{+-}0.4, p>0.05). In conclusion, left ventricular hypertrophy with or without abnormal wall motion and severely reduced MIBG uptake may be characteristic in diabetic patients with a mutation in the mitochondrial tRNA {sup Leu(UUR)} gene. (author)

  15. Improving metabolic flux predictions using absolute gene expression data

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    Lee Dave

    2012-06-01

    Full Text Available Abstract Background Constraint-based analysis of genome-scale metabolic models typically relies upon maximisation of a cellular objective function such as the rate or efficiency of biomass production. Whilst this assumption may be valid in the case of microorganisms growing under certain conditions, it is likely invalid in general, and especially for multicellular organisms, where cellular objectives differ greatly both between and within cell types. Moreover, for the purposes of biotechnological applications, it is normally the flux to a specific metabolite or product that is of interest rather than the rate of production of biomass per se. Results An alternative objective function is presented, that is based upon maximising the correlation between experimentally measured absolute gene expression data and predicted internal reaction fluxes. Using quantitative transcriptomics data acquired from Saccharomyces cerevisiae cultures under two growth conditions, the method outperforms traditional approaches for predicting experimentally measured exometabolic flux that are reliant upon maximisation of the rate of biomass production. Conclusion Due to its improved prediction of experimentally measured metabolic fluxes, and of its lack of a requirement for knowledge of the biomass composition of the organism under the conditions of interest, the approach is likely to be of rather general utility. The method has been shown to predict fluxes reliably in single cellular systems. Subsequent work will investigate the method’s ability to generate condition- and tissue-specific flux predictions in multicellular organisms.

  16. Improved sensitivity of PCR for Chlamydophila using pmp genes.

    Science.gov (United States)

    Laroucau, K; Souriau, A; Rodolakis, A

    2001-09-20

    Primers targeting the conserved pmp gene family of Chlamydophila abortus were evaluated for their ability to improve the polymerase chain reaction (PCR) sensitivity. In purified DNA, specific pmp primers (named CpsiA and CpsiB) allowed at least a 10-fold increase of the PCR sensitivity compared to the specific ompA primers for C. abortus, but also for C. psittaci and C. caviae strains. No amplification was observed on C. felis, C. pecorum, C. pneumoniae and Chlamydia trachomatis strains. Tested on contaminated specimens such as genital swabs, the PCR sensitivity observed with CpsiA/CpsiB was also better than with the ompA primers. This study demonstrated that these specific pmp primers could serve as valuable, sensitive and common tools for a specific Chlamydophila diagnosis in ruminant, avian and human diseases. Digestion by AluI of the CpsiA/CpsiB fragments allowed a specific discrimination of the strains in function of their hosts and/or their serotypes.

  17. Cardiac natriuretic peptide gene expression and plasma concentrations during the first 72 hours of life in piglets

    DEFF Research Database (Denmark)

    Smith, Julie; Christoffersen, Christina; Nørgaard, Linn Maiken

    2013-01-01

    Plasma measurement of cardiac natriuretic peptides constitutes promising markers of congenital heart disease. However, concentrations change rapidly and dramatically during the first days after delivery even in healthy neonates, which complicates clinical interpretation. It is unknown whether...

  18. Selective homocysteine lowering gene transfer improves infarct healing, attenuates remodelling, and enhances diastolic function after myocardial infarction in mice.

    Directory of Open Access Journals (Sweden)

    Ilayaraja Muthuramu

    Full Text Available BACKGROUND AND AIMS: Homocysteine levels predict heart failure incidence in prospective epidemiological studies and correlate with severity of heart failure in cross-sectional surveys. The objective of this study was to evaluate whether a selective homocysteine lowering intervention beneficially affects cardiac remodelling and cardiac function after myocardial infarction (MI in a murine model of combined hypercholesterolemia and hyperhomocysteinemia. METHODOLOGY AND PRINCIPAL FINDINGS: A selective homocysteine lowering gene transfer strategy was evaluated in female C57BL/6 low density lipoprotein receptor (Ldlr⁻/⁻ cystathionine-ß-synthase (Cbs⁺/⁻ deficient mice fed a hyperhomocysteinemic and high saturated fat/high cholesterol diet using an E1E3E4-deleted hepatocyte-specific adenoviral vector expressing Cbs (AdCBS. MI was induced by permanent ligation of the left anterior descending coronary artery 14 days after saline injection or gene transfer. AdCBS gene transfer resulted in a persistent more than 5-fold (p<0.01 decrease of plasma homocysteine levels and significantly improved endothelial progenitor cell function. Selective homocysteine lowering enhanced infarct healing as indicated by a 21% (p<0.01 reduction of infarct length at day 28 after MI and by an increased number of capillaries and increased collagen content in the infarct zone. Adverse remodelling was attenuated in AdCBS MI mice as evidenced by a 29% (p<0.05 reduction of left ventricular cavity area at day 28, by an increased capillary density in the remote myocardium, and by reduced interstitial collagen. The peak rate of isovolumetric relaxation was increased by 19% (p<0.05 and the time constant of left ventricular relaxation was reduced by 21% (p<0.05 in AdCBS MI mice compared to control MI mice, indicating improved diastolic function. CONCLUSION/SIGNIFICANCE: Selective homocysteine lowering gene transfer improves infarct healing, attenuates remodelling, and

  19. The Improvement of Torsion Assessed by Cardiovascular Magnetic Resonance Feature Tracking after Coronary Artery Bypass Grafting: A Sensitive Index of Cardiac Function.

    Science.gov (United States)

    Cheng, Nan; Cheng, Liuquan; Wang, Rong; Zhang, Lin; Gao, Changqing

    2017-02-28

    The aim of this study was to quantify left ventricular torsion by newly applied cardiovascular magnetic resonance feature tracking (CMR-FT), and to evaluate the clinical value of the ventricular torsion as a sensitive indicator of cardiac function by comparison of preoperative and postoperative torsion. A total of 54 volunteers and 36 patients with previous myocardial infarction (MI) and LV ejection fraction (EF) between 30%-50% were screened preoperatively or postoperatively by MRI. The patients' short axis views of the whole heart were acquired, and all patients had a scar area >75% in at least one of the anterior or inferior segments. Their apical and basal rotation values were analyzed by feature tracking, and the correlation analysis was performed for the improvement of LV torsion and ejection fraction after CABG. The intra- and inter-observer reliabilities of torsion measured by CMR-FT were assessed. In normal hearts, the apex rotated counterclockwise in the systolic period with the peak rotation as 10.2 ± 4.8°, and the base rotated clockwise as the peak value was 7.0 ± 3.3°. There was a timing hiatus between the apex and base untwisting, during which period the heart recoils and its suction sets the stage for the following rapid filling period. The postoperative torsion and rotation significantly improved compared with preoperative ones. However, the traditional indicator of cardiac function, ejection fraction, didn't show significant improvement. Left ventricular torsion derived from CMR-FT, which does not require specialized CMR sequences, was sensitive to patients with low ejection fraction whose cardiac function significantly improved after CABG. The rapid acquisition of this measurement has potential for the assessment of cardiac function in clinical practice.

  20. Hippo pathway effector Yap promotes cardiac regeneration.

    Science.gov (United States)

    Xin, Mei; Kim, Yuri; Sutherland, Lillian B; Murakami, Masao; Qi, Xiaoxia; McAnally, John; Porrello, Enzo R; Mahmoud, Ahmed I; Tan, Wei; Shelton, John M; Richardson, James A; Sadek, Hesham A; Bassel-Duby, Rhonda; Olson, Eric N

    2013-08-20

    The adult mammalian heart has limited potential for regeneration. Thus, after injury, cardiomyocytes are permanently lost, and contractility is diminished. In contrast, the neonatal heart can regenerate owing to sustained cardiomyocyte proliferation. Identification of critical regulators of cardiomyocyte proliferation and quiescence represents an important step toward potential regenerative therapies. Yes-associated protein (Yap), a transcriptional cofactor in the Hippo signaling pathway, promotes proliferation of embryonic cardiomyocytes by activating the insulin-like growth factor and Wnt signaling pathways. Here we report that mice bearing mutant alleles of Yap and its paralog WW domain containing transcription regulator 1 (Taz) exhibit gene dosage-dependent cardiac phenotypes, suggesting redundant roles of these Hippo pathway effectors in establishing proper myocyte number and maintaining cardiac function. Cardiac-specific deletion of Yap impedes neonatal heart regeneration, resulting in a default fibrotic response. Conversely, forced expression of a constitutively active form of Yap in the adult heart stimulates cardiac regeneration and improves contractility after myocardial infarction. The regenerative activity of Yap is correlated with its activation of embryonic and proliferative gene programs in cardiomyocytes. These findings identify Yap as an important regulator of cardiac regeneration and provide an experimental entry point to enhance this process.

  1. Influence of torpor on cardiac expression of genes involved in the circadian clock and protein turnover in the Siberian hamster (Phodopus sungorus).

    Science.gov (United States)

    Crawford, Fiona I J; Hodgkinson, Cassandra L; Ivanova, Elena; Logunova, Larisa B; Evans, Gary J; Steinlechner, Stephan; Loudon, Andrew S I

    2007-11-14

    The Siberian hamster exhibits the key winter adaptive strategy of daily torpor, during which metabolism and heart rate are slowed for a few hours and body temperature declines by up to 20 degrees C, allowing substantial energetic savings. Previous studies of hibernators in which temperature drops by >30 degrees C for many days to weeks have revealed decreased transcription and translation during hypometabolism and identified several key physiological pathways involved. Here we used a cDNA microarray to define cardiac transcript changes over the course of a daily torpor bout and return to normothermia, and we show that, in common with hibernators, a relatively small proportion of the transcriptome (<5%) exhibited altered expression over a torpor bout. Pathways exhibiting significantly altered gene expression included transcriptional regulation, RNA stability and translational control, globin regulation, and cardiomyocyte function. Remarkably, gene representatives of the entire ubiquitylation pathway were significantly altered over the torpor bout, implying a key role for cardiac protein turnover and translation during a low-temperature torpor bout. The circadian clock maintained rhythmic transcription during torpor. Quantitative PCR profiling of heart, liver, and lung and in situ hybridization studies of clock genes in the hypothalamic circadian clock in the suprachiasmatic nucleus revealed that many circadian regulated transcripts exhibited synchronous alteration in expression during arousal. Our data highlight the potential importance of genes involved in protein turnover as part of the adaptive strategy of low-temperature torpor in a seasonal mammal.

  2. Inpatient and outpatient cardiac rehabilitation programmes improve cardiometabolic risk in revascularized coronary patients with type 2 diabetes

    Directory of Open Access Journals (Sweden)

    Claudiu Avram

    2010-12-01

    Full Text Available The purpose of this paper is to evaluate cardiometabolic risk reduction of diabetic patients following coronary revascularizationprocedures after participation in outpatients or inpatients cardiac rehabilitation programmes. Materials and methods: weperformed a retrospective analytical study which included a group of 103 revascularized coronary patients with diabetesmellitus. Depending on participation in a cardiac rehabilitation program we have defined the following subgroups of patients:Group O (N=37 - attended the outpatient cardiac rehabilitation program; Group H (N=37 - attended the inpatient cardiacrehabilitation program; Group C (N=34 - did not participate in any cardiac rehabilitation program. Between those two momentsof assessment: T0 - revascularization / early post-revascularization and T1 - time of the interview (16±2.3 months afterrevascularization, patients in groups A and S participated in outpatient cardiac rehabilitation program (12 weeks, 3sessions/week of exercise training, with clinical and paraclinical evaluation scheduled at 1, 6, 12 months afterrevascularization, or inpatient cardiac rehabilitation program (3 weeks, intensive sessions, scheduled at 1, 3, 6 and 12months after revascularization. Results: at the end of the study, we found significant differences among the three groups forthe following parameters: body mass index (p=0.01, systolic blood pressure (p=0.002, total cholesterol (p<0.001, LDLcholesterol(p<0.001 and non-HDL cholesterol (p=0.004 in favor of groups A and S, that have participated in comprehensivecardiac rehabilitation programs. Conclusions: comprehensive cardiac rehabilitation programmes, performed outpatient orinpatient, are effective methods of reducing the high cardiometabolic risk, specific in revascularized coronary patients withdiabetes.

  3. CGP 41251, a new potential anticancer drug, improves contractility of rat isolated cardiac muscle subjected to hypoxia.

    Science.gov (United States)

    Kocic, I; Dworakowska, D; Dworakowski, R; Petrusewicz, J

    2001-06-01

    The aim of the present work was to examine the effects of 4'-N-benzoyl staurosporine (CGP 41251), a protein kinase C inhibitor with broad antiproliferative activity in many cell lines, on the rat isolated heart contractility under normoxic and hypoxic conditions. Additionally, we examined the effects of CGP 41251, WB-4101 (alpha1a -adrenoceptor antagonist), chloroethylclonidine (CEC) (alpha1b-adrenoceptor antagonist) and selective damage of endocardial endothelium by Triton X-100 on the protection against hypoxia induced by preconditioning of rat heart tissue. Experiments were performed on rat isolated left ventricular papillary muscle. The following parameters were measured: force of contraction (Fc), velocity of contraction (+dF/dt) and velocity of relaxation (-dF/dt). The temperature of the bath solution was 37 degrees C +/- 0.5 degrees C, and rate of electrical stimulation was 0.5 Hz. At concentrations less than 1 microM CGP 41251 did not cause any changes in contractility of rat heart. At 1 and 3 microM, significant positive inotropic action was observed. Treatment of rat papillary muscle by CGP 41251 at 3 microM reduced decreasing of contractility by simulated hypoxia and reperfusion. Moreover, protective effects of preconditioning was not affected by addition of CGP 41251 neither at 1 nor at 3 microM. Pretreatment with CEC at 3 microM, and selective damage of endocardial endothelium induced by fast (1-s) immersion of papillary muscle in 0.5% Triton X-100, but not pretreatment with WB-4101, abolished the protective effects of preconditioning. The results imply that CGP 41251 improves contractility of heart muscle under normoxic and hypoxic conditions, and does not alter hypoxic preconditioning in rat isolated cardiac tissue. Moreover, it was shown that alpha1b-adrenoceptors and endocardial endothelium are involved in triggering of preconditioning in rat isolated heart muscle.

  4. The patient education - Learning and Coping Strategies - improves adherence in cardiac rehabilitation (LC-REHAB): A randomised controlled trial.

    Science.gov (United States)

    Lynggaard, Vibeke; Nielsen, Claus Vinther; Zwisler, Ann-Dorthe; Taylor, Rod S; May, Ole

    2017-06-01

    Despite proven benefits of cardiac rehabilitation (CR), adherence to CR remains suboptimal. This trial aimed to assess the impact of the patient education 'Learning and Coping Strategies' (LC) on patient adherence to an eight-week CR program. 825 patients with ischaemic heart disease or heart failure were open label randomised to either the LC arm (LC plus CR) or the control arm (CR alone) across three hospital units in Denmark. Both arms received same amount of training and education hours. LC consisted of individual clarifying interviews, participation of experienced patients as co-educators, situational, reflective and inductive teaching. The control arm received structured deductive teaching. The primary outcomes were patient adherence to at least 75% of the exercise training or education sessions. We tested for subgroup effects on the primary outcomes using interaction terms. The primary outcomes were compared across arms using logistic regression. More patients in the LC arm adhered to at least 75% of the exercise training sessions than control (80% versus 73%, adjusted odds ratio (OR):1.48; 95% CI:1.07 to 2.05, P=0.018) and 75% of education sessions (79% versus 70%, adjusted OR:1.61, 1.17 to 2.22, P=0.003). Some evidence of larger effects of LC on adherence was seen for patients with heart failure, low education and household income. Addition of LC strategies improved adherence in rehabilitation both in terms of exercise training and education. Patients with heart failure, low levels of education and household income appear to benefit most from this adherence promoting intervention. www.clinicaltrials.gov identifier NCT01668394. Copyright © 2017 Elsevier B.V. All rights reserved.

  5. A Novel α-Calcitonin Gene-Related Peptide Analogue Protects Against End-Organ Damage in Experimental Hypertension, Cardiac Hypertrophy, and Heart Failure.

    Science.gov (United States)

    Aubdool, Aisah A; Thakore, Pratish; Argunhan, Fulye; Smillie, Sarah-Jane; Schnelle, Moritz; Srivastava, Salil; Alawi, Khadija M; Wilde, Elena; Mitchell, Jennifer; Farrell-Dillon, Keith; Richards, Daniel A; Maltese, Giuseppe; Siow, Richard C; Nandi, Manasi; Clark, James E; Shah, Ajay M; Sams, Anette; Brain, Susan D

    2017-07-25

    Research into the therapeutic potential of α-calcitonin gene-related peptide (α-CGRP) has been limited because of its peptide nature and short half-life. Here, we evaluate whether a novel potent and long-lasting (t½ ≥7 hours) acylated α-CGRP analogue (αAnalogue) could alleviate and reverse cardiovascular disease in 2 distinct murine models of hypertension and heart failure in vivo. The ability of the αAnalogue to act selectively via the CGRP pathway was shown in skin by using a CGRP receptor antagonist. The effect of the αAnalogue on angiotensin II-induced hypertension was investigated over 14 days. Blood pressure was measured by radiotelemetry. The ability of the αAnalogue to modulate heart failure was studied in an abdominal aortic constriction model of murine cardiac hypertrophy and heart failure over 5 weeks. Extensive ex vivo analysis was performed via RNA analysis, Western blot, and histology. The angiotensin II-induced hypertension was attenuated by cotreatment with the αAnalogue (50 nmol·kg(-1)·d(-1), SC, at a dose selected for lack of long-term hypotensive effects at baseline). The αAnalogue protected against vascular, renal, and cardiac dysfunction, characterized by reduced hypertrophy and biomarkers of fibrosis, remodeling, inflammation, and oxidative stress. In a separate study, the αAnalogue reversed angiotensin II-induced hypertension and associated vascular and cardiac damage. The αAnalogue was effective over 5 weeks in a murine model of cardiac hypertrophy and heart failure. It preserved heart function, assessed by echocardiography, while protecting against adverse cardiac remodeling and apoptosis. Moreover, treatment with the αAnalogue was well tolerated with neither signs of desensitization nor behavioral changes. These findings, in 2 distinct models, provide the first evidence for the therapeutic potential of a stabilized αAnalogue, by mediating (1) antihypertensive effects, (2) attenuating cardiac remodeling, and (3) increasing

  6. Molecular and Functional Effects of a Splice Site Mutation in the MYL2 Gene Associated with Cardioskeletal Myopathy and Early Cardiac Death in Infants.

    Science.gov (United States)

    Zhou, Zhiqun; Huang, Wenrui; Liang, Jingsheng; Szczesna-Cordary, Danuta

    2016-01-01

    The homozygous appearance of the intronic mutation (IVS6-1) in the MYL2 gene encoding for myosin ventricular/slow-twitch skeletal regulatory light chain (RLC) was recently linked to the development of slow skeletal muscle fiber type I hypotrophy and early cardiac death. The IVS6-1 (c403-1G>C) mutation resulted from a cryptic splice site in MYL2 causing a frameshift and replacement of the last 32 codons by 19 different amino acids in the RLC mutant protein. Infants who were IVS6-1(+∕+)-positive died between 4 and 6 months of age due to cardiomyopathy and heart failure. In this report we have investigated the molecular mechanism and functional consequences associated with the IVS6-1 mutation using recombinant human cardiac IVS6-1 and wild-type (WT) RLC proteins. Recombinant proteins were reconstituted into RLC-depleted porcine cardiac muscle preparations and subjected to enzymatic and functional assays. IVS6-1-RLC showed decreased binding to the myosin heavy chain (MHC) compared with WT, and IVS6-1-reconstituted myosin displayed reduced binding to actin in rigor. The IVS6-1 myosin demonstrated a significantly lower Vmax of the actin-activated myosin ATPase activity compared with WT. In stopped-flow experiments, IVS6-1 myosin showed slower kinetics of the ATP induced dissociation of the acto-myosin complex and a significantly reduced slope of the kobs-[MgATP] relationship compared to WT. In skinned porcine cardiac muscles, RLC-depleted and IVS6-1 reconstituted muscle strips displayed a significant decrease in maximal contractile force and a significantly increased Ca(2+) sensitivity, both hallmarks of hypertrophic cardiomyopathy-associated mutations in MYL2. Our results showed that the amino-acid changes in IVS6-1 were sufficient to impose significant conformational alterations in the RLC protein and trigger a series of abnormal protein-protein interactions in the cardiac muscle sarcomere. Notably, the mutation disrupted the RLC-MHC interaction and the steady

  7. Novel redox nanomedicine improves gene expression of polyion complex vector

    Science.gov (United States)

    Toh, Kazuko; Yoshitomi, Toru; Ikeda, Yutaka; Nagasaki, Yukio

    2011-12-01

    Gene therapy has generated worldwide attention as a new medical technology. While non-viral gene vectors are promising candidates as gene carriers, they have several issues such as toxicity and low transfection efficiency. We have hypothesized that the generation of reactive oxygen species (ROS) affects gene expression in polyplex supported gene delivery systems. The effect of ROS on the gene expression of polyplex was evaluated using a nitroxide radical-containing nanoparticle (RNP) as an ROS scavenger. When polyethyleneimine (PEI)/pGL3 or PEI alone was added to the HeLa cells, ROS levels increased significantly. In contrast, when (PEI)/pGL3 or PEI was added with RNP, the ROS levels were suppressed. The luciferase expression was increased by the treatment with RNP in a dose-dependent manner and the cellular uptake of pDNA was also increased. Inflammatory cytokines play an important role in ROS generation in vivo. In particular, tumor necrosis factor (TNF)-α caused intracellular ROS generation in HeLa cells and decreased gene expression. RNP treatment suppressed ROS production even in the presence of TNF-α and increased gene expression. This anti-inflammatory property of RNP suggests that it may be used as an effective adjuvant for non-viral gene delivery systems.

  8. Novel redox nanomedicine improves gene expression of polyion complex vector

    Directory of Open Access Journals (Sweden)

    Kazuko Toh, Toru Yoshitomi, Yutaka Ikeda and Yukio Nagasaki

    2011-01-01

    Full Text Available Gene therapy has generated worldwide attention as a new medical technology. While non-viral gene vectors are promising candidates as gene carriers, they have several issues such as toxicity and low transfection efficiency. We have hypothesized that the generation of reactive oxygen species (ROS affects gene expression in polyplex supported gene delivery systems. The effect of ROS on the gene expression of polyplex was evaluated using a nitroxide radical-containing nanoparticle (RNP as an ROS scavenger. When polyethyleneimine (PEI/pGL3 or PEI alone was added to the HeLa cells, ROS levels increased significantly. In contrast, when (PEI/pGL3 or PEI was added with RNP, the ROS levels were suppressed. The luciferase expression was increased by the treatment with RNP in a dose-dependent manner and the cellular uptake of pDNA was also increased. Inflammatory cytokines play an important role in ROS generation in vivo. In particular, tumor necrosis factor (TNF-α caused intracellular ROS generation in HeLa cells and decreased gene expression. RNP treatment suppressed ROS production even in the presence of TNF-α and increased gene expression. This anti-inflammatory property of RNP suggests that it may be used as an effective adjuvant for non-viral gene delivery systems.

  9. Combined insulin treatment and intense exercise training improved basal cardiac function and Ca(2+)-cycling proteins expression in type 1 diabetic rats.

    Science.gov (United States)

    Le Douairon Lahaye, Solène; Gratas-Delamarche, Arlette; Malardé, Ludivine; Zguira, Sami; Vincent, Sophie; Lemoine Morel, Sophie; Carré, François; Rannou Bekono, Françoise

    2012-02-01

    This study investigated the effects of 8 weeks of intense exercise training combined with insulin treatment on the Ca(2+)-cycling protein complex expression and their functional consequences on cardiac function in type 1 diabetic rat hearts. Diabetic Wistar rats were randomly assigned into the following groups: received no treatment, insulin-treated diabetic, trained diabetic, and trained insulin-treated diabetic. A control group was also included. Insulin treatment and (or) treadmill intense exercise training were conducted over 8 weeks. Basal cardiac function was evaluated by Langendorff technique. Cardiac expression of the main Ca(2+)-cycling proteins (RyR2, FKBP 12.6, SERCA2, PLB, NCX1) was assessed by Western blot. Diabetes altered basal cardiac function (±dP/dt) and decrease the expression of the main Ca(2+)-cycling proteins expression: RyR2, SERCA2, and NCX1 (p < 0.05). Whereas combined treatment was not able to normalize -dP/dt, it succeeded to normalize +dP/dt of diabetic rats (p < 0.05). Moreover, both insulin and intense exercise training, applied solely, increased the expression of the Ca(2+)-cycling proteins: RyR2, SERCA2, PLB. and NCX1 (p < 0.05). But this effect was higher when the 2 treatments were combined. These data are the first to show that combined insulin treatment and intense exercise training during diabetes synergistically act on the expression of the main Ca(2+)-cycling proteins, providing insights into mechanisms by which the dual treatment during diabetes improves cardiac function.

  10. Taurine exerts hypoglycemic effect in alloxan-induced diabetic rats, improves insulin-mediated glucose transport signaling pathway in heart and ameliorates cardiac oxidative stress and apoptosis

    Energy Technology Data Exchange (ETDEWEB)

    Das, Joydeep; Vasan, Vandana; Sil, Parames C., E-mail: parames@bosemain.boseinst.ac.in

    2012-01-15

    Hyperlipidemia, inflammation and altered antioxidant profiles are the usual complications in diabetes mellitus. In the present study, we investigated the therapeutic potential of taurine in diabetes associated cardiac complications using a rat model. Rats were made diabetic by alloxan (ALX) (single i.p. dose of 120 mg/kg body weight) and left untreated or treated with taurine (1% w/v, orally, in water) for three weeks either from the day of ALX exposure or after the onset of diabetes. Animals were euthanized after three weeks. ALX-induced diabetes decreased body weight, increased glucose level, decreased insulin content, enhanced the levels of cardiac damage markers and altered lipid profile in the plasma. Moreover, it increased oxidative stress (decreased antioxidant enzyme activities and GSH/GSSG ratio, increased xanthine oxidase enzyme activity, lipid peroxidation, protein carbonylation and ROS generation) and enhanced the proinflammatory cytokines levels, activity of myeloperoxidase and nuclear translocation of NFκB in the cardiac tissue of the experimental animals. Taurine treatment could, however, result to a decrease in the elevated blood glucose and proinflammatory cytokine levels, diabetes-evoked oxidative stress, lipid profiles and NFκB translocation. In addition, taurine increased GLUT 4 translocation to the cardiac membrane by enhanced phosphorylation of IR and IRS1 at tyrosine and Akt at serine residue in the heart. Results also suggest that taurine could protect cardiac tissue from ALX induced apoptosis via the regulation of Bcl2 family and caspase 9/3 proteins. Taken together, taurine supplementation in regular diet could play a beneficial role in regulating diabetes and its associated complications in the heart. Highlights: ► Taurine controls blood glucose via protection of pancreatic β cells in diabetic rat. ► Taurine controls blood glucose via increasing the insulin level in diabetic rat. ► Taurine improves cardiac AKT/GLUT4 signaling

  11. Improved animal models for testing gene therapy for atherosclerosis.

    Science.gov (United States)

    Du, Liang; Zhang, Jingwan; De Meyer, Guido R Y; Flynn, Rowan; Dichek, David A

    2014-04-01

    Gene therapy delivered to the blood vessel wall could augment current therapies for atherosclerosis, including systemic drug therapy and stenting. However, identification of clinically useful vectors and effective therapeutic transgenes remains at the preclinical stage. Identification of effective vectors and transgenes would be accelerated by availability of animal models that allow practical and expeditious testing of vessel-wall-directed gene therapy. Such models would include humanlike lesions that develop rapidly in vessels that are amenable to efficient gene delivery. Moreover, because human atherosclerosis develops in normal vessels, gene therapy that prevents atherosclerosis is most logically tested in relatively normal arteries. Similarly, gene therapy that causes atherosclerosis regression requires gene delivery to an existing lesion. Here we report development of three new rabbit models for testing vessel-wall-directed gene therapy that either prevents or reverses atherosclerosis. Carotid artery intimal lesions in these new models develop within 2-7 months after initiation of a high-fat diet and are 20-80 times larger than lesions in a model we described previously. Individual models allow generation of lesions that are relatively rich in either macrophages or smooth muscle cells, permitting testing of gene therapy strategies targeted at either cell type. Two of the models include gene delivery to essentially normal arteries and will be useful for identifying strategies that prevent lesion development. The third model generates lesions rapidly in vector-naïve animals and can be used for testing gene therapy that promotes lesion regression. These models are optimized for testing helper-dependent adenovirus (HDAd)-mediated gene therapy; however, they could be easily adapted for testing of other vectors or of different types of molecular therapies, delivered directly to the blood vessel wall. Our data also supports the promise of HDAd to deliver long

  12. Lipid lowering and HDL raising gene transfer increase endothelial progenitor cells, enhance myocardial vascularity, and improve diastolic function.

    Directory of Open Access Journals (Sweden)

    Stephanie C Gordts

    Full Text Available BACKGROUND: Hypercholesterolemia and low high density lipoprotein (HDL cholesterol contribute to coronary heart disease but little is known about their direct effects on myocardial function. Low HDL and raised non-HDL cholesterol levels carried increased risk for heart failure development in the Framingham study, independent of any association with myocardial infarction. The objective of this study was to test the hypothesis that increased endothelial progenitor cell (EPC number and function after lipid lowering or HDL raising gene transfer in C57BL/6 low density lipoprotein receptor deficient (LDLr(-/- mice may be associated with an enhanced relative vascularity in the myocardium and an improved cardiac function. METHODOLOGY/PRINCIPAL FINDINGS: Lipid lowering and HDL raising gene transfer were performed using the E1E3E4-deleted LDLr expressing adenoviral vector AdLDLr and the human apolipoprotein A-I expressing vector AdA-I, respectively. AdLDLr transfer in C57BL/6 LDLr(-/- mice resulted in a 2.0-fold (p<0.05 increase of the circulating number of EPCs and in an improvement of EPC function as assessed by ex vivo EPC migration and EPC adhesion. Capillary density and relative vascularity in the myocardium were 28% (p<0.01 and 22% (p<0.05 higher, respectively, in AdLDLr mice compared to control mice. The peak rate of isovolumetric relaxation was increased by 12% (p<0.05 and the time constant of isovolumetric relaxation was decreased by 14% (p<0.05 after AdLDLr transfer. Similarly, HDL raising gene transfer increased EPC number and function and raised both capillary density and relative vascularity in the myocardium by 24% (p<0.05. The peak rate of isovolumetric relaxation was increased by 16% (p<0.05 in AdA-I mice compared to control mice. CONCLUSIONS/SIGNIFICANCE: Both lipid lowering and HDL raising gene transfer have beneficial effects on EPC biology, relative myocardial vascularity, and diastolic function. These findings raise concerns over the

  13. Short-term supervised inpatient physiotherapy exercise protocol improves cardiac autonomic function after coronary artery bypass graft surgery--a randomised controlled trial.

    Science.gov (United States)

    Mendes, Renata Gonçalves; Simões, Rodrigo Polaquini; De Souza Melo Costa, Fernando; Pantoni, Camila Bianca Falasco; Di Thommazo, Luciana; Luzzi, Sérgio; Catai, Aparecida Maria; Arena, Ross; Borghi-Silva, Audrey

    2010-01-01

    Coronary artery bypass grafting (CABG) is accompanied by severe impairment of cardiac autonomous regulation (CAR). This study aimed to determine whether a short-term physiotherapy exercise protocol post-CABG, during inpatient cardiac rehabilitation (CR), might improve CAR. Seventy-four patients eligible for CABG were recruited and randomised into physiotherapy exercise group (EG) or physiotherapy usual care group (UCG). EG patients underwent a short-term supervised inpatient physiotherapy exercise protocol consisting of an early mobilisation with progressive exercises plus usual care (respiratory exercises). UCG only received respiratory exercises. Forty-seven patients (24 EG and 23 UGC) completed the study. Outcome measures of CAR included linear and non-linear measures of heart rate variability (HRV) assessed before discharge. By hospital discharge, EG presented significantly higher parasympathetic HRV values [rMSSD, high frequency (HF), SD1)], global power (STD RR, SD2), non-linear HRV indexes [detrended fluctuation analysis (DFA)alpha1, DFAalpha2, approximate entropy (ApEn)] and mean RR compared to UCG (pCAR at the time of discharge. Thus, exercise-based inpatient CR might be an effective non-pharmacological tool to improve autonomic cardiac tone in patient's post-CABG.

  14. Circadian regulation of myocardial sarcomeric Titin-cap (Tcap, telethonin: identification of cardiac clock-controlled genes using open access bioinformatics data.

    Directory of Open Access Journals (Sweden)

    Peter S Podobed

    Full Text Available Circadian rhythms are important for healthy cardiovascular physiology and are regulated at the molecular level by a circadian clock mechanism. We and others previously demonstrated that 9-13% of the cardiac transcriptome is rhythmic over 24 h daily cycles; the heart is genetically a different organ day versus night. However, which rhythmic mRNAs are regulated by the circadian mechanism is not known. Here, we used open access bioinformatics databases to identify 94 transcripts with expression profiles characteristic of CLOCK and BMAL1 targeted genes, using the CircaDB website and JTK_Cycle. Moreover, 22 were highly expressed in the heart as determined by the BioGPS website. Furthermore, 5 heart-enriched genes had human/mouse conserved CLOCK:BMAL1 promoter binding sites (E-boxes, as determined by UCSC table browser, circadian mammalian promoter/enhancer database PEDB, and the European Bioinformatics Institute alignment tool (EMBOSS. Lastly, we validated findings by demonstrating that Titin cap (Tcap, telethonin was targeted by transcriptional activators CLOCK and BMAL1 by showing 1 Tcap mRNA and TCAP protein had a diurnal rhythm in murine heart; 2 cardiac Tcap mRNA was rhythmic in animals kept in constant darkness; 3 Tcap and control Per2 mRNA expression and cyclic amplitude were blunted in Clock(Δ19/Δ19 hearts; 4 BMAL1 bound to the Tcap promoter by ChIP assay; 5 BMAL1 bound to Tcap promoter E-boxes by biotinylated oligonucleotide assay; and 6 CLOCK and BMAL1 induced tcap expression by luciferase reporter assay. Thus this study identifies circadian regulated genes in silico, with validation of Tcap, a critical regulator of cardiac Z-disc sarcomeric structure and function.

  15. The effect of RBC transfusions on cytokine gene expression after cardiac surgery in patients developing post-operative multiple organ failure.

    Science.gov (United States)

    Sitniakowsky, L S; Later, A F L; van de Watering, L M G; Bogaerts, M; Brand, A; Klautz, R J M; Smit, N P M; van Hilten, J A

    2011-08-01

    To determine the effect of red blood cell (RBC) transfusions during cardiac surgery on cytokine gene expression (GE) in relation to multiple organ failure (MOF) development after systemic inflammatory response syndrome (SIRS). RBC transfusion in cardiac surgery patients is dose-dependently associated with post-operative MOF, possibly acting as a second hit after cardiopulmonary bypass. For this observational study, 29 patients divided into four groups of cardiac surgery patients were selected from a randomised controlled trial (RCT). Group 1: no-RBC, no-MOF (N = 8); group 2: MOF, no-RBC (N = 7); group 3: RBC, no-MOF (N = 6); group 4: RBC and MOF (N = 8). Selection was based on age, gender, number of (leukocyte-depleted) RBC transfusions, type and duration of surgery. A 114 cytokine GE array was applied to blood samples withdrawn before and 24 h after surgery. Expression of selected genes was confirmed with reverse transcriptase real time-polymerase chain reaction (RT-PCR). Nineteen of the 39 detectable genes showed a significant change in GE after surgery. Confirmed by RT-PCR, transfused MOF patients exhibit significantly less downregulation of CD40 ligand than control patients. Patients who would develop MOF show significantly larger increases in GE of transforming growth factor-α (TGF-α), tumour necrosis factor (TNF)-superfamily members 10 and 13B (TNFsf10/13B). When tested at 24 h after surgery, cytokine GE in peripheral blood leucocytes showed no significant differences between those transfused and those not transfused. Some alterations were seen in those developing MOF compared to those who did not, but the findings offer no role of leukocyte depleted (LD) RBC transfusion in the development of MOF. © 2011 The Authors. Transfusion Medicine © 2011 British Blood Transfusion Society.

  16. Hypothyroidism and its rapid correction alter cardiac remodeling.

    Directory of Open Access Journals (Sweden)

    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.

  17. A knowledge translation collaborative to improve the use of therapeutic hypothermia in post-cardiac arrest patients: protocol for a stepped wedge randomized trial

    Directory of Open Access Journals (Sweden)

    Wax Randy

    2011-01-01

    Full Text Available Abstract Background Advances in resuscitation science have dramatically improved survival rates following cardiac arrest. However, about 60% of adults that regain spontaneous circulation die before leaving the hospital. Recently it has been shown that inducing hypothermia in cardiac arrest survivors immediately following their arrival in hospital can dramatically improve both overall survival and neurological outcomes. Despite the strong evidence for its efficacy and the apparent simplicity of this intervention, recent surveys show that therapeutic hypothermia is delivered inconsistently, incompletely, and often with delay. Methods and design This study will evaluate a multi-faceted knowledge translation strategy designed to increase the utilization rate of induced hypothermia in survivors of cardiac arrest across a network of 37 hospitals in Southwestern Ontario, Canada. The study is designed as a stepped wedge randomized trial lasting two years. Individual hospitals will be randomly assigned to four different wedges that will receive the active knowledge translation strategy according to a sequential rollout over a number of time periods. By the end of the study, all hospitals will have received the intervention. The primary aim is to measure the effectiveness of a multifaceted knowledge translation plan involving education, reminders, and audit-feedback for improving the use of induced hypothermia in survivors of cardiac arrest presenting to the emergency department. The primary outcome is the proportion of eligible OHCA patients that are cooled to a body temperature of 32 to 34°C within six hours of arrival in the hospital. Secondary outcomes will include process of care measures and clinical outcomes. Discussion Inducing hypothermia in cardiac arrest survivors immediately following their arrival to hospital has been shown to dramatically improve both overall survival and neurological outcomes. However, this lifesaving treatment is

  18. Next-generation sequencing of 34 genes in sudden unexplained death victims in forensics and in patients with channelopathic cardiac diseases

    DEFF Research Database (Denmark)

    Hertz, Christin Løth; Christiansen, Sofie Lindgren; Ferrero-Miliani, Laura

    2015-01-01

    to that in patients with inherited cardiac channelopathies. Fifteen forensic SUD cases and 29 patients with channelopathies were investigated. DNA from 34 of the genes most frequently associated with SCD were captured using NimbleGen SeqCap EZ library build and were sequenced with next-generation sequencing (NGS......) on an Illumina MiSeq. Likely pathogenic variants were identified in three out of 15 (20 %) forensic SUD cases compared to 12 out of 29 (41 %) patients with channelopathies. The difference was not statistically significant (p = 0.1). Additionally, two larger deletions of entire exons were identified in two...

  19. Necessity of angiotensin-converting enzyme-related gene for cardiac functions and longevity of Drosophila melanogaster assessed by optical coherence tomography

    Science.gov (United States)

    Liao, Fang-Tsu; Chang, Cheng-Yi; Su, Ming-Tsan; Kuo, Wen-Chuan

    2014-01-01

    Prior studies have established the necessity of an angiotensin-converting enzyme-related (ACER) gene for heart morphogenesis of Drosophila. Nevertheless, the physiology of ACER has yet to be comprehensively understood. Herein, we employed RNA interference to down-regulate the expression of ACER in Drosophila's heart and swept source optical coherence tomography to assess whether ACER is required for cardiac functions in living adult flies. Several contractile parameters of Drosophila heart, including the heart rate (HR), end-diastolic diameter (EDD), end-systolic diameter (ESD), percent fractional shortening (%FS), and stress-induced cardiac performance, are shown, which are age dependent. These age-dependent cardiac functions declined significantly when ACER was down-regulated. Moreover, the lifespans of ACER knock-down flies were significantly shorter than those of wild-type control flies. Thus, we posit that ACER, the Drosophila ortholog of mammalian angiotensin-converting enzyme 2 (ACE2), is essential for both heart physiology and longevity of animals. Since mammalian ACE2 controls many cardiovascular physiological features and is implicated in cardiomyopathies, our findings that ACER plays conserved roles in genetically tractable animals will pave the way for uncovering the genetic pathway that controls the renin-angiotensin system.

  20. Improved metabolism and redox state with a novel preservation solution: Implications for donor lungs after cardiac death (DCD)

    NARCIS (Netherlands)

    D.A. Schipper (David A.); Louis, A.V. (Anthony V.); Dicken, D.S. (Destiny S.); Johnson, K. (Kitsie); R.T. Smolenski (Ryszard); Black, S.M. (Stephen M.); Runyan, R. (Ray); Konhilas, J. (John); Garcia, J.G.N. (Joe G. N.); Z. Khalpey (Zain)

    2017-01-01

    textabstractLungs donated after cardiac death (DCD) are an underutilized resource for a dwindling donor lung transplant pool. Our study investigates the potential of a novel preservation solution, Somah, to better preserve statically stored DCD lungs, for an extended time period, when compared to

  1. Improve Survival Prediction Using Principal Components of Gene Expression Data

    Institute of Scientific and Technical Information of China (English)

    Yi-Jing Shen; Shu-Guang Huang

    2006-01-01

    The purpose of many microarray studies is to find the association between gene expression and sample characteristics such as treatment type or sample phenotype.There has been a surge of efforts developing different methods for delineating the association. Aside from the high dimensionality of microarray data, one well recognized challenge is the fact that genes could be complicatedly inter-related, thus making many statistical methods inappropriate to use directly on the expression data. Multivariate methods such as principal component analysis (PCA) and clustering are often used as a part of the effort to capture the gene correlation, and the derived components or clusters are used to describe the association between gene expression and sample phenotype. We propose a method for patient population dichotomization using maximally selected test statistics in combination with the PCA method, which shows favorable results. The proposed method is compared with a currently well-recognized method.

  2. Alignment of inducible vascular progenitor cells on a micro-bundle scaffold improves cardiac repair following myocardial infarction.

    Science.gov (United States)

    Jamaiyar, Anurag; Wan, Weiguo; Ohanyan, Vahagn; Enrick, Molly; Janota, Danielle; Cumpston, Devan; Song, Hokyung; Stevanov, Kelly; Kolz, Christopher L; Hakobyan, Tatev; Dong, Feng; Newby, Bi-Min Zhang; Chilian, William M; Yin, Liya

    2017-07-01

    Ischemic heart disease is still the leading cause of death even with the advancement of pharmaceutical therapies and surgical procedures. Early vascularization in the ischemic heart is critical for a better outcome. Although stem cell therapy has great potential for cardiovascular regeneration, the ideal cell type and delivery method of cells have not been resolved. We tested a new approach of stem cell therapy by delivery of induced vascular progenitor cells (iVPCs) grown on polymer micro-bundle scaffolds in a rat model of myocardial infarction. iVPCs partially reprogrammed from vascular endothelial cells (ECs) had potent angiogenic potential and were able to simultaneously differentiate into vascular smooth muscle cells (SMCs) and ECs in 2D culture. Under hypoxic conditions, iVPCs also secreted angiogenic cytokines such as vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) as measured by enzyme-linked immunosorbent assay (ELISA). A longitudinal micro-scaffold made from poly(lactic-co-glycolic acid) was sufficient for the growth and delivery of iVPCs. Co-cultured ECs and SMCs aligned well on the micro-bundle scaffold similarly as in the vessels. 3D cell/polymer micro-bundles formed by iVPCs and micro-scaffolds were transplanted into the ischemic myocardium in a rat model of myocardial infarction (MI) with ligation of the left anterior descending artery. Our in vivo data showed that iVPCs on the micro-bundle scaffold had higher survival, and better retention and engraftment in the myocardium than free iVPCs. iVPCs on the micro-bundles promoted better cardiomyocyte survival than free iVPCs. Moreover, iVPCs and iVPC/polymer micro-bundles treatment improved cardiac function (ejection fraction and fractional shortening, endocardial systolic volume) measured by echocardiography, increased vessel density, and decreased infarction size [endocardial and epicardial infarct (scar) length] better than untreated controls at 8 weeks after MI

  3. Sudden cardiac death

    Directory of Open Access Journals (Sweden)

    Neeraj Parakh

    2015-01-01

    Full Text Available Sudden cardiac death is one of the most common cause of mortality worldwide. Despite significant advances in the medical science, there is little improvement in the sudden cardiac death related mortality. Coronary artery disease is the most common etiology behind sudden cardiac death, in the above 40 years population. Even in the apparently healthy population, there is a small percentage of patients dying from sudden cardiac death. Given the large denominator, this small percentage contributes to the largest burden of sudden cardiac death. Identification of this at risk group among the apparently healthy individual is a great challenge for the medical fraternity. This article looks into the causes and methods of preventing SCD and at some of the Indian data. Details of Brugada syndrome, Long QT syndrome, Genetics of SCD are discussed. Recent guidelines on many of these causes are summarised.

  4. 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: ...

  5. Improved Sleep in Military Personnel is Associated with Changes in the Expression of Inflammatory Genes and Improvement in Depression Symptoms

    Directory of Open Access Journals (Sweden)

    Whitney S. Livingston

    2015-04-01

    Full Text Available Study Objectives: Sleep disturbances are common in military personnel and are associated with increased risk for psychiatric morbidity, including posttraumatic stress disorder and depression, as well as inflammation. Improved sleep quality is linked to reductions in inflammatory bio-markers; however, the underlying mechanisms remain elusive. Methods: In this study we examine whole genome expression changes related to improved sleep in 68 military personnel diagnosed with insomnia. Subjects were classified into the following groups and then compared: improved sleep (n=46, or non-improved sleep (n=22 following three months of standard of care treatment for insomnia. Within subject differential expression was determined from microarray data using the Partek Genomics Suite analysis program and the interactive pathway analysis was used to determine key regulators of observed expression changes. Changes in symptoms of depression and posttraumatic stress disorder were also compared. Results: At baseline both groups were similar in demographics, clinical characteristics, and gene-expression profiles. The microarray data revealed that 217 coding genes were differentially expressed at the follow-up-period compared to baseline in the participants with improved sleep. Expression of inflammatory cytokines were reduced including IL-1β, IL-6, IL-8 and IL-13, with fold changes ranging from -3.19 to -2.1, and there were increases in the expression of inflammatory regulatory genes including toll-like receptors 1, 4, 7, and 8 in the improved sleep group. Interactive pathway analysis revealed 6 gene networks, including ubiquitin which was a major regulator in these gene-expression changes. The improved sleep group also had a significant reduction in the severity of depressive symptoms.Conclusions: Interventions that restore sleep likely reduce the expression of inflammatory genes, which relate to ubiquitin genes and relate to reductions in depressive symptoms.

  6. High intensity interval training (HIIT) improves resting blood pressure, metabolic (MET) capacity and heart rate reserve without compromising cardiac function in sedentary aging men.

    Science.gov (United States)

    Grace, Fergal; Herbert, Peter; Elliott, Adrian D; Richards, Jo; Beaumont, Alexander; Sculthorpe, Nicholas F

    2017-05-13

    This study examined a programme of pre-conditioning exercise with subsequent high intensity interval training (HIIT) on blood pressure, echocardiography, cardiac strain mechanics and maximal metabolic (MET) capacity in sedentary (SED) aging men compared with age matched masters athletes (LEX). Using a STROBE compliant observational design, 39 aging male participants (SED; n=22, aged 62.7±5.2yrs) (LEX; n=17, aged=61.1±5.4yrs) were recruited to a study that necessitated three distinct assessment phases; enrolment (Phase A), following pre-conditioning exercise in SED (Phase B), then following 6weeks of HIIT performed once every five days by both groups before reassessment (Phase C). Hemodynamic, echocardiographic and cardiac strain mechanics were obtained at rest and maximal cardiorespiratory and chronotropic responses were obtained at each measurement phase. The training intervention improved systolic, mean arterial blood pressure, rate pressure product and heart rate reserve (each P<0.05) in SED and increased MET capacity in both SED and LEX (P<0.01) which was amplified by HIIT. Echocardiography and cardiac strain measures were unremarkable apart from trivial increase to intra-ventricular septum diastole (IVSd) (P<0.05) and decrease to left ventricular internal dimension diastole (LVId) (P<0.05) in LEX following HIIT. A programme of preconditioning exercise with HIIT induces clinically relevant improvements in blood pressure, rate pressure product and encourages recovery of heart rate reserve in SED, while improving maximal MET capacity in both SED and LEX without inducing any pathological cardiovascular remodeling. These data add to the emerging repute of HIIT as a safe and promising exercise prescription to improve cardiovascular function and metabolic capacity in sedentary aging. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

  7. Human SCN5A gene mutations alter cardiac sodium channel kinetics and are associated with the Brugada syndrome

    NARCIS (Netherlands)

    Rook, Martin B.; Alshinawi, CB; Groenewegen, WA; van Gelder, IC; van Ginneken, ACG; Jongsma, Habo J.; Mannens, MMAM; Wilde, AAM

    1999-01-01

    Background: Primary dysrhythmias other than those associated with the long QT syndrome, are increasingly recognized. One of these are represented by patients with a history of resuscitation from cardiac arrest but without any structural heart disease. These patients exhibit a distinct electrocardiog

  8. Cardiac rehabilitation in the Navy.

    Science.gov (United States)

    Bruzek-Kohler, C M; Love, V; Hendrickson, R; Branford, M; Gates, A; Telvick, C

    1994-10-01

    Cardiac rehabilitation has been effective in the management and recovery of the post-myocardial infarction population for almost 40 years. During that time, the fundamental components of rehabilitation have changed to reflect a growing complexity and number of cardiac patients. Great Lakes Naval Hospital has instituted a structured outpatient cardiac rehabilitation program. It is based on the needs of a large cardiac population with modifiable risk factors identified through quality improvement studies. Future implications and research in the area of cardiac rehabilitation include measurements of self-efficacy, long-term risk factor modification, cost effectiveness, gender-related differences, or morbidity and mortality.

  9. Improved cardiac motion detection from ultrasound images using TDIOF: a combined B-mode/ tissue Doppler approach

    Science.gov (United States)

    Tavakoli, Vahid; Stoddard, Marcus F.; Amini, Amir A.

    2013-03-01

    Quantitative motion analysis of echocardiographic images helps clinicians with the diagnosis and therapy of patients suffering from cardiac disease. Quantitative analysis is usually based on TDI (Tissue Doppler Imaging) or speckle tracking. These methods are based on two independent techniques - the Doppler Effect and image registration, respectively. In order to increase the accuracy of the speckle tracking technique and cope with the angle dependency of TDI, herein, a combined approach dubbed TDIOF (Tissue Doppler Imaging Optical Flow) is proposed. TDIOF is formulated based on the combination of B-mode and Doppler energy terms in an optical flow framework and minimized using algebraic equations. In this paper, we report on validations with simulated, physical cardiac phantom, and in-vivo patient data. It is shown that the additional Doppler term is able to increase the accuracy of speckle tracking, the basis for several commercially available echocardiography analysis techniques.

  10. An improved method for functional similarity analysis of genes based on Gene Ontology.

    Science.gov (United States)

    Tian, Zhen; Wang, Chunyu; Guo, Maozu; Liu, Xiaoyan; Teng, Zhixia

    2016-12-23

    Measures of gene functional similarity are essential tools for gene clustering, gene function prediction, evaluation of protein-protein interaction, disease gene prioritization and other applications. In recent years, many gene functional similarity methods have been proposed based on the semantic similarity of GO terms. However, these leading approaches may make errorprone judgments especially when they measure the specificity of GO terms as well as the IC of a term set. Therefore, how to estimate the gene functional similarity reliably is still a challenging problem. We propose WIS, an effective method to measure the gene functional similarity. First of all, WIS computes the IC of a term by employing its depth, the number of its ancestors as well as the topology of its descendants in the GO graph. Secondly, WIS calculates the IC of a term set by means of considering the weighted inherited semantics of terms. Finally, WIS estimates the gene functional similarity based on the IC overlap ratio of term sets. WIS is superior to some other representative measures on the experiments of functional classification of genes in a biological pathway, collaborative evaluation of GO-based semantic similarity measures, protein-protein interaction prediction and correlation with gene expression. Further analysis suggests that WIS takes fully into account the specificity of terms and the weighted inherited semantics of terms between GO terms. The proposed WIS method is an effective and reliable way to compare gene function. The web service of WIS is freely available at http://nclab.hit.edu.cn/WIS/ .

  11. Ancestral gene synteny reconstruction improves extant species scaffolding.

    Science.gov (United States)

    Anselmetti, Yoann; Berry, Vincent; Chauve, Cedric; Chateau, Annie; Tannier, Eric; Bérard, Sèverine

    2015-01-01

    We exploit the methodological similarity between ancestral genome reconstruction and extant genome scaffolding. We present a method, called ARt-DeCo that constructs neighborhood relationships between genes or contigs, in both ancestral and extant genomes, in a phylogenetic context. It is able to handle dozens of complete genomes, including genes with complex histories, by using gene phylogenies reconciled with a species tree, that is, annotated with speciation, duplication and loss events. Reconstructed ancestral or extant synteny comes with a support computed from an exhaustive exploration of the solution space. We compare our method with a previously published one that follows the same goal on a small number of genomes with universal unicopy genes. Then we test it on the whole Ensembl database, by proposing partial ancestral genome structures, as well as a more complete scaffolding for many partially assembled genomes on 69 eukaryote species. We carefully analyze a couple of extant adjacencies proposed by our method, and show that they are indeed real links in the extant genomes, that were missing in the current assembly. On a reduced data set of 39 eutherian mammals, we estimate the precision and sensitivity of ARt-DeCo by simulating a fragmentation in some well assembled genomes, and measure how many adjacencies are recovered. We find a very high precision, while the sensitivity depends on the quality of the data and on the proximity of closely related genomes.

  12. microRNA-340-5p Functions Downstream of Cardiotrophin-1 to Regulate Cardiac Eccentric Hypertrophy and Heart Failure via Target Gene Dystrophin.

    Science.gov (United States)

    Zhou, Jian; Gao, Jie; Zhang, Xiaoya; Liu, Yan; Gu, Song; Zhang, Xitao; An, Xiangguang; Yan, Jun; Xin, Yue; Su, Pixiong

    2015-01-01

    Pathological cardiac hypertrophy inevitably leads to the unfavorable outcomes of heart failure (HF) or even sudden death. microRNAs are key regulation factors participating in many pathophysiological processes. Recently, we observed upregulation of microRNA-340-5p (miR-340) in failing human hearts because of dilated cardiomyopathy, but the functional consequence of miR-340 remains to be clarified.We transfected neonatal cardiomyocytes with miR-340 and found fetal gene expression including Nppa, Nppb and Myh7. We also observed eccentric hypertrophy development upon treatment which was analogous to the phenotype after cardiotrophin-1 (CT-1) stimulation. As a potent inducer of cardiac eccentric hypertrophy, treatment by IL-6 family members CT-1 and leukemia inhibitory factor (LIF) led to the elevation of miR-340. Knockdown of miR-340 using antagomir attenuated fetal gene expression and hypertrophy formation, which means miR-340 could convey the hypertrophic signal of CT-1. To demonstrate the initial factor of miR-340 activation, we constructed a volume overloaded abdominal aorta-inferior vena cava fistula rat HF model. miR-340 and CT-1 were found to be up-regulated in the left ventricle. Dystrophin (DMD), a putative target gene of miR-340 which is eccentric hypertrophy-susceptible, was decreased in this HF model upon Western blotting and immunohistochemistry tests. Luciferase assay constructed in two seed sequence of DMD gene 3'UTR showed decreased luciferase activities, and miR-340 transfected cells resulted in the degradation of DMD.miR-340 is a pro-eccentric hypertrophy miRNA, and its expression is dependent on volume overload and cytokine CT-1 activation. Cardiomyocyte structure protein DMD is a target of miR-340.

  13. Improving Adenovirus Based Gene Transfer: Strategies to Accomplish Immune Evasion

    Directory of Open Access Journals (Sweden)

    Andrea Amalfitano

    2010-09-01

    Full Text Available Adenovirus (Ad based gene transfer vectors continue to be the platform of choice for an increasing number of clinical trials worldwide. In fact, within the last five years, the number of clinical trials that utilize Ad based vectors has doubled, indicating growing enthusiasm for the numerous positive characteristics of this gene transfer platform. For example, Ad vectors can be easily and relatively inexpensively produced to high titers in a cGMP compliant manner, can be stably stored and transported, and have a broad applicability for a wide range of clinical conditions, including both gene therapy and vaccine applications. Ad vector based gene transfer will become more useful as strategies to counteract innate and/or pre-existing adaptive immune responses to Ads are developed and confirmed to be efficacious. The approaches attempting to overcome these limitations can be divided into two broad categories: pre-emptive immune modulation of the host, and selective modification of the Ad vector itself. The first category of methods includes the use of immunosuppressive drugs or specific compounds to block important immune pathways, which are known to be induced by Ads. The second category comprises several innovative strategies inclusive of: (1 Ad-capsid-display of specific inhibitors or ligands; (2 covalent modifications of the entire Ad vector capsid moiety; (3 the use of tissue specific promoters and local administration routes; (4 the use of genome modified Ads; and (5 the development of chimeric or alternative serotype Ads. This review article will focus on both the promise and the limitations of each of these immune evasion strategies, and in the process delineate future directions in developing safer and more efficacious Ad-based gene transfer strategies.

  14. Haemodynamics and oxygenation improvement induced by high frequency percussive ventilation in a patient with hypoxia following cardiac surgery: a case report

    Directory of Open Access Journals (Sweden)

    Persi Bruno

    2010-10-01

    Full Text Available Abstract Introduction High frequency percussive ventilation is a ventilatory technique that delivers small bursts of high flow respiratory gas into the lungs at high rates. It is classified as a pneumatically powered, pressure-regulated, time-cycled, high-frequency flow interrupter modality of ventilation. High frequency percussive ventilation improves the arterial partial pressure of oxygen with the same positive end expiratory pressure and fractional inspiratory oxygen level as conventional ventilation using a minor mean airway pressure in an open circuit. It reduces the barotraumatic events in a hypoxic patient who has low lung-compliance. To the best of our knowledge, there have been no papers published about this ventilation modality in patients with severe hypoxaemia after cardiac surgery. Case presentation A 75-year-old Caucasian man with an ejection fraction of 27 percent, developed a lung infection with severe hypoxaemia [partial pressure of oxygen/fractional inspiratory oxygen of 90] ten days after cardiac surgery. Conventional ventilation did not improve the gas exchange. He was treated with high frequency percussive ventilation for 12 hours with a low conventional respiratory rate (five per minute. His cardiac output and systemic and pulmonary pressures were monitored. Compared to conventional ventilation, high frequency percussive ventilation gives an improvement of the partial pressure of oxygen from 90 to 190 mmHg with the same fractional inspiratory oxygen and positive end expiratory pressure level. His right ventricular stroke work index was lowered from 19 to seven g-m/m2/beat; his pulmonary vascular resistance index from 267 to 190 dynes•seconds/cm5/m2; left ventricular stroke work index from 28 to 16 gm-m/m2/beat; and his pulmonary arterial wedge pressure was lowered from 32 to 24 mmHg with a lower mean airway pressure compared to conventional ventilation. His cardiac index (2.7 L/min/m2 and ejection fraction (27 percent

  15. Expression of the Cardiac Maintenance and Survival Factor FGF-16 Gene Is Regulated by Csx/Nkx2.5 and Is an Early Target of Doxorubicin Cardiotoxicity.

    Science.gov (United States)

    Wang, Jie; Jin, Yan; Cattini, Peter A

    2017-02-01

    The fibroblast growth factor (FGF) 16 gene (Fgf-16) is preferentially expressed by neonatal cardiomyocytes after birth, with levels increasing into adulthood. Null mice and isolated heart studies suggest a role for FGF-16 in cardiac maintenance and survival, including increased resistance to doxorubicin (DOX)-induced injury. However, the effect of DOX on endogenous FGF-16 synthesis and specifically regulation of cardiac Fgf-16 expression has not been reported. Here we assess the effect of DOX on FGF-16 RNA levels and stability as well as promoter activity and use sequence analysis, knockdown, and overexpression to investigate the role of cardiac transcription factor(s) implicated in the response. Endogenous FGF-16 RNA levels were reduced >70% in 8-week-old rats treated with 15 mg DOX/kg for 6 h. This was modeled in neonatal rat cardiomyocyte cultures, where an equivalent decrease was also seen within 6 h of 1 μM DOX treatment. Six kilobases of mouse Fgf-16 upstream flanking and promoter DNA was also assessed for DOX responsiveness in transfected cardiomyocytes. A decrease in FGF-16 promoter activity was seen with only 747 base pairs containing the Fgf-16 TATA box that includes a putative and highly conserved binding site for the cardiac transcription factor Csx/Nkx2.5. There was also no effect of DOX on FGF-16 RNA stability, consistent with transcriptional control. Levels and binding of Csx/Nkx2.5 to the FGF-16 promoter were reduced with DOX treatment. Knockdown of Csx/Nkx2.5 specifically decreased endogenous FGF-16 RNA and protein levels, whereas Csx/Nkx2.5 overexpression stimulated levels, and increased resistance to the rapid DOX-induced depletion of FGF-16. These observations indicate that Fgf-16 expression is directly regulated by Csx/Nkx2.5 in neonatal cardiomyocytes, and a negative effect of DOX on Csx/Nkx2.5 and, thus, endogenous FGF-16 synthesis may contribute indirectly to its cardiotoxic effects. Targeting FGF-16 levels could, however, offer

  16. Effects of transplanted myoblasts transfected with human growth hormone gene on improvement of ventricular function of rats

    Institute of Scientific and Technical Information of China (English)

    2008-01-01

    Background Cell transplantation for myocardial repair is limited by early cell death.Gene therapy with human growth hormone(hGH)has been shown to promote angiogensis and attenuate apoptosis in the experimental animal.This study was conducted to explore the effects of myoblast-based hGH gene therapy on heart function restoration and angiogenesis after myocardial infarction,and to compare the differences between myoblast-based hGH gene therapy and myoblast therapy.Methods Myoblasts were isolated from several SD rats,cultured,purified,and transfected with plasmid pLghGHSN and pLgGFPSN.Radioimmunoassay(RIA)was used to detect the expression of hGH in these myoblasts.SD rats underwent the ligation of the left anterior descending coronary artery so as to establish a heart ischemia model.Thirty surviving rats that underwent ligation were randomly divided into 3 equal groups 2 weeks after left coronary artery occlusion:pLghGHSN group received myoblast infected with hGH gene transplantation;pLgGFPSN group received myoblast infected with GFP gene transplantation;control group:received cultured medium only.Four weeks after the injection the surviving rat underwent evaluation of cardiac function by echocardiography.The rats were killed and ventricular samples were undergone immunohistochemistry with hematoxylin-eosin and factorⅧ.Cryosection was analyzed by fluorescence microscopy to examine the expression of green fluorescent protein.Reverse transcriptase-polymerase chain reaction(RT-PCR)was used to examine the mRNA expression of vascular endothelial growth factor(VEGF),bax and Bcl-2.hGH expression in myocardium was examined by Western blot.Results Myoblast can be successfully isolated,cultured and transfected.The expression of hGH in transfected myoblast was demonstrated with RIA.Four weeks after therapy,the cardiac function was improved significantly in pLghGHSN group and pLgGFPSN group.Fractional shortening(FS)and ejection fraction(EF)in pLghGHSN group were elevated

  17. Isolation of Related Genes of Cardiac Hypertrophy in Pressure overloaded Rat Models with Subtractive Hybridization%压力负荷型心肌肥厚大鼠心肌组织相关基因的分离

    Institute of Scientific and Technical Information of China (English)

    田靫; 潘德思; 陈兰英

    2000-01-01

    Cardiac hypertrophy is intensively related with the morbidity of heart failure,atherosclerosis and stroke. The rat models of left ventricular hypertrophy caused by abdominal aorta constriction and the method of subtractive hybridization to isolate genes expressing differently were used during cardiac hypertrophy. 24 cDNA segments were isolated and identified by colony and dot hybridization. Sequence homogenous comparison showed that some of them were very similar to known genes or segments, others were limitedly homogenous and the rest were not found to be significantly homogenous.

  18. Intravenous glial growth factor 2 (GGF2 isoform of neuregulin-1β improves left ventricular function, gene and protein expression in rats after myocardial infarction.

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    Michael F Hill

    Full Text Available AIMS: Recombinant Neuregulin (NRG-1β has multiple beneficial effects on cardiac myocytes in culture, and has potential as a clinical therapy for heart failure (HF. A number of factors may influence the effect of NRG-1β on cardiac function via ErbB receptor coupling and expression. We examined the effect of the NRG-1β isoform, glial growth factor 2 (GGF2, in rats with myocardial infarction (MI and determined the impact of high-fat diet as well as chronicity of disease on GGF2 induced improvement in left ventricular systolic function. Potential mechanisms for GGF2 effects on the remote myocardium were explored using microarray and proteomic analysis. METHODS AND RESULTS: Rats with MI were randomized to receive vehicle, 0.625 mg/kg, or 3.25 mg/kg GGF2 in the presence and absence of high-fat feeding beginning at day 7 post-MI and continuing for 4 weeks. Residual left ventricular (LV function was improved in both of the GGF2 treatment groups compared with the vehicle treated MI group at 4 weeks of treatment as assessed by echocardiography. High-fat diet did not prevent the effects of high dose GGF2. In experiments where treatment was delayed until 8 weeks after MI, high but not low dose GGF2 treatment was associated with improved systolic function. mRNA and protein expression analysis of remote left ventricular tissue revealed a number of changes in myocardial gene and protein expression altered by MI that were normalized by GGF2 treatment, many of which are involved in energy production. CONCLUSIONS: This study demonstrates that in rats with MI induced systolic dysfunction, GGF2 treatment improves cardiac function. There are differences in sensitivity of the myocardium to GGF2 effects when administered early vs. late post-MI that may be important to consider in the development of GGF2 in humans.

  19. Intravenous Glial Growth Factor 2 (GGF2) Isoform of Neuregulin-1β Improves Left Ventricular Function, Gene and Protein Expression in Rats after Myocardial Infarction

    Science.gov (United States)

    Murphy, Abigail; Smith, Holly M.; Galindo, Cristi L.; Pentassuglia, Laura; Peng, Xuyang; Lenneman, Carrie G.; Odiete, Oghenerukevwe; Friedman, David B.; Kronenberg, Marvin W.; Zheng, Siyuen; Zhao, Zhongming; Song, Yanna; Harrell, Frank E.; Srinivas, Maya; Ganguly, Anindita; Iaci, Jennifer; Parry, Tom J.; Caggiano, Anthony O.; Sawyer, Douglas B.

    2013-01-01

    Aims Recombinant Neuregulin (NRG)-1β has multiple beneficial effects on cardiac myocytes in culture, and has potential as a clinical therapy for heart failure (HF). A number of factors may influence the effect of NRG-1β on cardiac function via ErbB receptor coupling and expression. We examined the effect of the NRG-1β isoform, glial growth factor 2 (GGF2), in rats with myocardial infarction (MI) and determined the impact of high-fat diet as well as chronicity of disease on GGF2 induced improvement in left ventricular systolic function. Potential mechanisms for GGF2 effects on the remote myocardium were explored using microarray and proteomic analysis. Methods and Results Rats with MI were randomized to receive vehicle, 0.625 mg/kg, or 3.25 mg/kg GGF2 in the presence and absence of high-fat feeding beginning at day 7 post-MI and continuing for 4 weeks. Residual left ventricular (LV) function was improved in both of the GGF2 treatment groups compared with the vehicle treated MI group at 4 weeks of treatment as assessed by echocardiography. High-fat diet did not prevent the effects of high dose GGF2. In experiments where treatment was delayed until 8 weeks after MI, high but not low dose GGF2 treatment was associated with improved systolic function. mRNA and protein expression analysis of remote left ventricular tissue revealed a number of changes in myocardial gene and protein expression altered by MI that were normalized by GGF2 treatment, many of which are involved in energy production. Conclusions This study demonstrates that in rats with MI induced systolic dysfunction, GGF2 treatment improves cardiac function. There are differences in sensitivity of the myocardium to GGF2 effects when administered early vs. late post-MI that may be important to consider in the development of GGF2 in humans. PMID:23437060

  20. How to evaluate and improve the quality and credibility of an outcomes database: validation and feedback study on the UK Cardiac Surgery Experience.

    Science.gov (United States)

    Fine, Leon G; Keogh, Bruce E; Cretin, Shan; Orlando, Maria; Gould, Mairi M

    2003-01-04

    To assess the quality and completeness of a database of clinical outcomes after cardiac surgery and to determine whether a process of validation, monitoring, and feedback could improve the quality of the database. Stratified sampling of retrospective data followed by prospective re-sampling of database after intervention of monitoring, validation, and feedback. Ten tertiary care cardiac surgery centres in the United Kingdom. Validation of data derived from a stratified sample of case notes (recording of deaths cross checked with mortuary records), monitoring of completeness and accuracy of data entry, feedback to local data managers and lead surgeons. Average percentage missing data, average kappa coefficient, and reliability score by centre for 17 variables required for assignment of risk scores. Actual minus risk adjusted mortality in each centre. The database was incomplete, with a mean (SE) of 24.96% (0.09%) of essential data elements missing, whereas only 1.18% (0.06%) were missing in the patient records (P<0.0001). Intervention was associated with (a) significantly less missing data (9.33% (0.08%) P<0.0001); (b) marginal improvement in reliability of data and mean (SE) overall centre reliability score (0.53 (0.15) v 0.44 (0.17)); and (c) improved accuracy of assigned Parsonnet risk scores (kappa 0.84 v 0.70). Mortality scores (actual minus risk adjusted mortality) for all participating centres fell within two standard deviations of the mean score. A short period of independent validation, monitoring, and feedback improved the quality of an outcomes database and improved the process of risk adjustment, but with substantial room for further improvement. Wider application of this approach should increase the credibility of similar databases before their public release.

  1. A dual role for integrin-linked kinase and β1-integrin in modulating cardiac aging.

    Science.gov (United States)

    Nishimura, Mayuko; Kumsta, Caroline; Kaushik, Gaurav; Diop, Soda B; Ding, Yun; Bisharat-Kernizan, Jumana; Catan, Hannah; Cammarato, Anthony; Ross, Robert S; Engler, Adam J; Bodmer, Rolf; Hansen, Malene; Ocorr, Karen

    2014-06-01

    Cardiac performance decreases with age, which is a major risk factor for cardiovascular disease and mortality in the aging human population, but the molecular mechanisms underlying cardiac aging are still poorly understood. Investigating the role of integrin-linked kinase (ilk) and β1-integrin (myospheroid, mys) in Drosophila, which colocalize near cardiomyocyte contacts and Z-bands, we find that reduced ilk or mys function prevents the typical changes of cardiac aging seen in wildtype, such as arrhythmias. In particular, the characteristic increase in cardiac arrhythmias with age is prevented in ilk and mys heterozygous flies with nearly identical genetic background, and they live longer, in line with previous findings in Caenorhabditis elegans for ilk and in Drosophila for mys. Consistent with these findings, we observed elevated β1-integrin protein levels in old compared with young wild-type flies, and cardiac-specific overexpression of mys in young flies causes aging-like heart dysfunction. Moreover, moderate cardiac-specific knockdown of integrin-linked kinase (ILK)/integrin pathway-associated genes also prevented the decline in cardiac performance with age. In contrast, strong cardiac knockdown of ilk or ILK-associated genes can severely compromise cardiac integrity, including cardiomyocyte adhesion and overall heart function. These data suggest that ilk/mys function is necessary for establishing and maintaining normal heart structure and function, and appropriate fine-tuning of this pathway can retard the age-dependent decline in cardiac performance and extend lifespan. Thus, ILK/integrin-associated signaling emerges as an important and conserved genetic mechanism in longevity, and as a new means to improve age-dependent cardiac performance, in addition to its vital role in maintaining cardiac integrity.

  2. Central exogenous nitric oxide decreases cardiac sympathetic drive and improves baroreflex control of heart rate in ovine heart failure.

    Science.gov (United States)

    Ramchandra, Rohit; Hood, Sally G; May, Clive N

    2014-08-01

    Heart failure (HF) is associated with increased cardiac and renal sympathetic drive, which are both independent predictors of poor prognosis. A candidate mechanism for the centrally mediated sympathoexcitation in HF is reduced synthesis of the inhibitory neuromodulator nitric oxide (NO), resulting from downregulation of neuronal NO synthase (nNOS). Therefore, we investigated the effects of increasing the levels of NO in the brain, or selectively in the paraventricular nucleus of the hypothalamus (PVN), on cardiac sympathetic nerve activity (CSNA) and baroreflex control of CSNA and heart rate in ovine pacing-induced HF. The resting level of CSNA was significantly higher in the HF than in the normal group, but the resting level of RSNA was unchanged. Intracerebroventricular infusion of the NO donor sodium nitroprusside (SNP; 500 μg · ml(-1)· h(-1)) in conscious normal sheep and sheep in HF inhibited CSNA and restored baroreflex control of heart rate, but there was no change in RSNA. Microinjection of SNP into the PVN did not cause a similar cardiac sympathoinhibition in either group, although the number of nNOS-positive cells was decreased in the PVN of sheep in HF. Reduction of endogenous NO with intracerebroventricular infusion of N(ω)-nitro-l-arginine methyl ester decreased CSNA in normal but not in HF sheep and caused no change in RSNA in either group. These findings indicate that endogenous NO in the brain provides tonic excitatory drive to increase resting CSNA in the normal state, but not in HF. In contrast, exogenously administered NO inhibited CSNA in both the normal and HF groups via an action on sites other than the PVN. Copyright © 2014 the American Physiological Society.

  3. Why did high-dose rosuvastatin not improve cardiac remodeling in chronic heart failure? Mechanistic insights from the UNIVERSE study.

    Science.gov (United States)

    Ashton, Emma; Windebank, Emma; Skiba, Marina; Reid, Christopher; Schneider, Hans; Rosenfeldt, Franklin; Tonkin, Andrew; Krum, Henry

    2011-02-03

    Statins are often prescribed for prevention of atherosclerotic outcomes in patients who have chronic heart failure (CHF), if this has an ischaemic etiology. These agents may also possess additional properties, independent of effects on blood lipid levels, which may have an effect on cardiac remodeling. However, beneficial effects were not observed in the recent UNIVERSE trial. We prospectively planned a sub-study of UNIVERSE to explore relevant mechanistic effects of rosuvastatin, including effects on collagen turnover and plasma coenzyme Q10 (CoQ) levels. Additionally, CoQ levels in CHF patients receiving chronic statin therapy were measured. CoQ levels were significantly reduced after 26 weeks of rosuvastatin statin therapy (n = 32), compared to placebo (n = 37) in CHF patients in UNIVERSE trial. Patients with CHF (n = 56) matched for age, gender and severity of disease who had been taking statins for 12 months or longer had CoQ levels of 847 ± 344 nmol/L, significantly lower than 1065.4 ± 394 nmol/L in UNIVERSE patients at baseline (p = 0.0001). Serum types I and III N-terminal procollagen peptide (PINP and PIIINP), measures of collagen turnover which can contribute to cardiac fibrosis were significantly increased in the rosuvastatin group compared to baseline in UNIVERSE patients (PINP: p = 0.03, PIIINP: p = 0.001). In conclusion putative beneficial effects of statin therapy on cardiac remodeling in UNIVERSE may have been negated by increases in collagen turnover markers as well as a reduction in plasma CoQ levels in these patients with CHF. Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.

  4. Targeted disruption of the mouse Csrp2 gene encoding the cysteine- and glycine-rich LIM domain protein CRP2 result in subtle alteration of cardiac ultrastructure

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    Stoll Doris

    2008-08-01

    Full Text Available Abstract Background The cysteine and glycine rich protein 2 (CRP2 encoded by the Csrp2 gene is a LIM domain protein expressed in the vascular system, particularly in smooth muscle cells. It exhibits a bimodal subcellular distribution, accumulating at actin-based filaments in the cytosol and in the nucleus. In order to analyze the function of CRP2 in vivo, we disrupted the Csrp2 gene in mice and analysed the resulting phenotype. Results A ~17.3 kbp fragment of the murine Csrp2 gene containing exon 3 through 6 was isolated. Using this construct we confirmed the recently determined chromosomal localization (Chromosome 10, best fit location between markers D10Mit203 proximal and D10Mit150 central. A gene disruption cassette was cloned into exon 4 and a mouse strain lacking functional Csrp2 was generated. Mice lacking CRP2 are viable and fertile and have no obvious deficits in reproduction and survival. However, detailed histological and electron microscopic studies reveal that CRP2-deficient mice have subtle alterations in their cardiac ultrastructure. In these mice, the cardiomyocytes display a slight increase in their thickness, indicating moderate hypertrophy at the cellular level. Although the expression of several intercalated disc-associated proteins such as β-catenin, N-RAP and connexin-43 were not affected in these mice, the distribution of respective proteins was changed within heart tissue. Conclusion We conclude that the lack of CRP2 is associated with alterations in cardiomyocyte thickness and hypertrophy.

  5. An improved algorithm for clustering gene expression data.

    Science.gov (United States)

    Bandyopadhyay, Sanghamitra; Mukhopadhyay, Anirban; Maulik, Ujjwal

    2007-11-01

    Recent advancements in microarray technology allows simultaneous monitoring of the expression levels of a large number of genes over different time points. Clustering is an important tool for analyzing such microarray data, typical properties of which are its inherent uncertainty, noise and imprecision. In this article, a two-stage clustering algorithm, which employs a recently proposed variable string length genetic scheme and a multiobjective genetic clustering algorithm, is proposed. It is based on the novel concept of points having significant membership to multiple classes. An iterated version of the well-known Fuzzy C-Means is also utilized for clustering. The significant superiority of the proposed two-stage clustering algorithm as compared to the average linkage method, Self Organizing Map (SOM) and a recently developed weighted Chinese restaurant-based clustering method (CRC), widely used methods for clustering gene expression data, is established on a variety of artificial and publicly available real life data sets. The biological relevance of the clustering solutions are also analyzed.

  6. Improving gene regulatory network inference using network topology information.

    Science.gov (United States)

    Nair, Ajay; Chetty, Madhu; Wangikar, Pramod P

    2015-09-01

    Inferring the gene regulatory network (GRN) structure from data is an important problem in computational biology. However, it is a computationally complex problem and approximate methods such as heuristic search techniques, restriction of the maximum-number-of-parents (maxP) for a gene, or an optimal search under special conditions are required. The limitations of a heuristic search are well known but literature on the detailed analysis of the widely used maxP technique is lacking. The optimal search methods require large computational time. We report the theoretical analysis and experimental results of the strengths and limitations of the maxP technique. Further, using an optimal search method, we combine the strengths of the maxP technique and the known GRN topology to propose two novel algorithms. These algorithms are implemented in a Bayesian network framework and tested on biological, realistic, and in silico networks of different sizes and topologies. They overcome the limitations of the maxP technique and show superior computational speed when compared to the current optimal search algorithms.

  7. Molecular nuclear cardiac imaging

    Energy Technology Data Exchange (ETDEWEB)

    Lee, Dong Soo; Paeng, Jin Chul [College of Medicine, Seoul National Univ., Seoul (Korea, Republic of)

    2004-04-01

    Molecular nuclear cardiac imaging has included Tc-99m Annexin imaging to visualize myocardial apoptosis, but is now usually associated with gene therapy and cell-based therapy. Cardiac gene therapy was not successful so far but cardiac reporter gene imaging was made possible using HSV-TK (herpes simplex virus thymidine kinase) and F-18 FHBG (fluoro-hydroxymethylbutyl guanine) or I-124 FIAU (fluoro-deoxyiodo-arabino-furanosyluracil). Gene delivery was performed by needle injection with or without catheter guidance. TK expression did not last longer than 2 weeks in myocardium. Cell-based therapy of ischemic heart or failing heart looks promising, but biodistribution and differentiation of transplanted cells are not known. Reporter genes can be transfected to the stem/progenitor cells and cells containing these genes can be transplanted to the recipients using catheter-based purging or injection. Repeated imaging should be available and if promoter are varied to let express reporter transgenes, cellular (trans)differentiation can be studied. NIS (sodium iodide symporter) or D2R receptor genes are promising in this aspect.

  8. Partial deletion of eNOS gene causes hyperinsulinemic state, unbalance of cardiac insulin signaling pathways and coronary dysfunction independently of high fat diet.

    Directory of Open Access Journals (Sweden)

    Cecilia Vecoli

    Full Text Available Abnormalities in eNOS gene, possibly interacting with high fat diet (HFD, affect peripheral vascular function and glucose metabolism. The relative role of eNOS gene, HFD and metabolic derangement on coronary function has not been fully elucidated. We test whether eNOS gene deficiency per se or in association with HFD modulates coronary function through mechanisms involving molecular pathways related to insulin signaling. Wild type (WT, eNOS-/- and eNOS+/- mice were studied. WT and eNOS+/- mice were fed with either standard or HF diet for 16 weeks and compared with standard diet fed eNOS-/-. Glucose and insulin tolerance tests were performed during the last week of diet. Coronary resistance (CR was measured at baseline and during infusions of acetylcholine (Ach or sodium-nitroprusside (SNP to evaluate endothelium-dependent or independent vasodilation, in the Langendorff isolated hearts. Cardiac expression of Akt and ERK genes as evaluation of two major insulin-regulated signaling pathways involved in the control of vascular tone were assessed by western blot. HFD-fed mice developed an overt diabetic state. Conversely, chow-fed genetically modified mice (in particular eNOS-/- showed a metabolic pattern characterized by normoglycemia and hyperinsulinemia with a limited degree of insulin resistance. CR was significantly higher in animals with eNOS gene deletions than in WT, independently of diet. Percent decrease in CR, during Ach infusion, was significantly lower in both eNOS-/- and eNOS+/- mice than in WT, independently of diet. SNP reduced CR in all groups except eNOS-/-. The cardiac ERK1-2/Akt ratio, increased in animals with eNOS gene deletions compared with WT, independently of diet. These results suggest that the eNOS genetic deficiency, associated or not with HFD, has a relevant effect on coronary vascular function, possibly mediated by increase in blood insulin levels and unbalance in insulin-dependent signaling in coronary vessels

  9. Impedance Threshold Device Combined With High-Quality Cardiopulmonary Resuscitation Improves Survival With Favorable Neurological Function After Witnessed Out-of-Hospital Cardiac Arrest.

    Science.gov (United States)

    Sugiyama, Atsushi; Duval, Sue; Nakamura, Yuji; Yoshihara, Katsunori; Yannopoulos, Demetris

    2016-09-23

    The quality of cardiopulmonary resuscitation (CPR) has been recently shown to affect clinical outcome. The Resuscitation Outcomes Consortium (ROC) Prehospital Resuscitation Impedance Valve and Early Versus Delayed Analysis (PRIMED) trial showed no differences in outcomes with an active vs. sham impedance threshold device (ITD), a CPR adjunct that enhances circulation. It was hypothesized the active ITD would improve survival with favorable neurological outcomes in witnessed out-of-hospital cardiac arrest patients when used with high-quality CPR. Using the publicly accessible ROC PRIMED database, a post-hoc analysis was performed on all witnessed subjects with both compression rate and depth data (n=1,808) who received CPR within the study protocol definition of adequate CPR quality (compression rate 80-120/min and depth 4-6 cm; n=929). Demographics were similar between sham and active ITD groups. In witnessed subjects who received quality CPR, survival with favorable neurological function was 11.9% for the active ITD subjects (56/470) vs. 7.4% for the sham (34/459) (odds ratio 1.69 [95% confidence interval 1.08, 2.64]). There were no statistically significant differences for this primary outcome when CPR was performed outside the boundaries of the definition of adequate CPR quality. Multivariable models did not change these associations. An active ITD combined with adequate-quality conventional CPR has the potential to significantly improve survival after witnessed cardiac arrest. (Circ J 2016; 80: 2124-2132).

  10. Catheter-based Intramyocardial Injection of FGF1 or NRG1-loaded MPs Improves Cardiac Function in a Preclinical Model of Ischemia-Reperfusion

    Science.gov (United States)

    Garbayo, Elisa; Gavira, Juan José; de Yebenes, Manuel Garcia; Pelacho, Beatriz; Abizanda, Gloria; Lana, Hugo; Blanco-Prieto, María José; Prosper, Felipe

    2016-05-01

    Cardiovascular protein therapeutics such as neuregulin (NRG1) and acidic-fibroblast growth factor (FGF1) requires new formulation strategies that allow for sustained bioavailability of the drug in the infarcted myocardium. However, there is no FDA-approved injectable protein delivery platform due to translational concerns about biomaterial administration through cardiac catheters. We therefore sought to evaluate the efficacy of percutaneous intramyocardial injection of poly(lactic-co-glycolic acid) microparticles (MPs) loaded with NRG1 and FGF1 using the NOGA MYOSTAR injection catheter in a porcine model of ischemia-reperfusion. NRG1- and FGF1-loaded MPs were prepared using a multiple emulsion solvent-evaporation technique. Infarcted pigs were treated one week after ischemia-reperfusion with MPs containing NRG1, FGF1 or non-loaded MPs delivered via clinically-translatable percutaneous transendocardial-injection. Three months post-treatment, echocardiography indicated a significant improvement in systolic and diastolic cardiac function. Moreover, improvement in bipolar voltage and decrease in transmural infarct progression was demonstrated by electromechanical NOGA-mapping. Functional benefit was associated with an increase in myocardial vascularization and remodeling. These findings in a large animal model of ischemia-reperfusion demonstrate the feasibility and efficacy of using MPs as a delivery system for growth factors and provide strong evidence to move forward with clinical studies using therapeutic proteins combined with catheter-compatible biomaterials.

  11. The use of gene interaction networks to improve the identification of cancer driver genes

    Directory of Open Access Journals (Sweden)

    Emilie Ramsahai

    2017-01-01

    Full Text Available Bioinformaticians have implemented different strategies to distinguish cancer driver genes from passenger genes. One of the more recent advances uses a pathway-oriented approach. Methods that employ this strategy are highly dependent on the quality and size of the pathway interaction network employed, and require a powerful statistical environment for analyses. A number of genomic libraries are available in R. DriverNet and DawnRank employ pathway-based methods that use gene interaction graphs in matrix form. We investigated the benefit of combining data from 3 different sources on the prediction outcome of cancer driver genes by DriverNet and DawnRank. An enriched dataset was derived comprising 13,862 genes with 372,250 interactions, which increased its accuracy by 17% and 28%, respectively, compared to their original networks. The study identified 33 new candidate driver genes. Our study highlights the potential of combining networks and weighting edges to provide greater accuracy in the identification of cancer driver genes.

  12. Novel all-extremity high-intensity interval training improves aerobic fitness, cardiac function and insulin resistance in healthy older adults.

    Science.gov (United States)

    Hwang, Chueh-Lung; Yoo, Jeung-Ki; Kim, Han-Kyul; Hwang, Moon-Hyon; Handberg, Eileen M; Petersen, John W; Christou, Demetra D

    2016-09-01

    Aging is associated with decreased aerobic fitness and cardiac remodeling leading to increased risk for cardiovascular disease. High-intensity interval training (HIIT) on the treadmill has been reported to be more effective in ameliorating these risk factors compared with moderate-intensity continuous training (MICT) in patients with cardiometabolic disease. In older adults, however, weight-bearing activities are frequently limited due to musculoskeletal and balance problems. The purpose of this study was to examine the feasibility and safety of non-weight-bearing all-extremity HIIT in older adults. In addition, we tested the hypothesis that all-extremity HIIT will be more effective in improving aerobic fitness, cardiac function, and metabolic risk factors compared with all-extremity MICT. Fifty-one healthy sedentary older adults (age: 65±1years) were randomized to HIIT (n=17), MICT (n=18) or non-exercise control (CONT; n=16). HIIT (4×4min 90% of peak heart rate; HRpeak) and isocaloric MICT (70% of HRpeak) were performed on a non-weight-bearing all-extremity ergometer, 4×/week for 8weeks under supervision. All-extremity HIIT was feasible in older adults and resulted in no adverse events. Aerobic fitness (peak oxygen consumption; VO2peak) and ejection fraction (echocardiography) improved by 11% (PHIIT, while no changes were observed in MICT and CONT (P≥0.1). Greater improvements in ejection fraction were associated with greater improvements in VO2peak (r=0.57; PHIIT by 26% (P=0.016). Diastolic function, body composition, glucose and lipids were unaffected (P≥0.1). In conclusion, all-extremity HIIT is feasible and safe in older adults. HIIT, but not MICT, improved aerobic fitness, ejection fraction, and insulin resistance.

  13. 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.

  14. Novel enabling technologies of gene isolation and plant transformation for improved crop protection

    Energy Technology Data Exchange (ETDEWEB)

    Torok, Tamas

    2013-02-04

    Meeting the needs of agricultural producers requires the continued development of improved transgenic crop protection products. The completed project focused on developing novel enabling technologies of gene discovery and plant transformation to facilitate the generation of such products.

  15. Use of cardiac biomarkers in neonatology.

    Science.gov (United States)

    Vijlbrief, Daniel C; Benders, Manon J N L; Kemperman, Hans; van Bel, Frank; de Vries, Willem B

    2012-10-01

    Cardiac biomarkers are used to identify cardiac disease in term and preterm infants. This review discusses the roles of natriuretic peptides and cardiac troponins. Natriuretic peptide levels are elevated during atrial strain (atrial natriuretic peptide (ANP)) or ventricular strain (B-type natriuretic peptide (BNP)). These markers correspond well with cardiac function and can be used to identify cardiac disease. Cardiac troponins are used to assess cardiomyocyte compromise. Affected cardiomyocytes release troponin into the bloodstream, resulting in elevated levels of cardiac troponin. Cardiac biomarkers are being increasingly incorporated into clinical trials as indicators of myocardial strain. Furthermore, cardiac biomarkers can possibly be used to guide therapy and improve outcome. Natriuretic peptides and cardiac troponins are potential tools in the diagnosis and treatment of neonatal disease that is complicated by circulatory compromise. However, clear reference ranges need to be set and validation needs to be carried out in a population of interest.

  16. 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.

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

    Science.gov (United States)

    Bao, Dan; Lu, Dan; Liu, Ning; Dong, Wei; Lu, Ying-Dong; Qin, Chuan; Zhang, Lian-Feng

    2015-08-01

    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: cTnT(R92Q) 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. © 2015. Published by The Company of Biologists Ltd.

  18. Combining gene mutation with gene expression data improves outcome prediction in myelodysplastic syndromes

    Science.gov (United States)

    Gerstung, Moritz; Pellagatti, Andrea; Malcovati, Luca; Giagounidis, Aristoteles; Porta, Matteo G Della; Jädersten, Martin; Dolatshad, Hamid; Verma, Amit; Cross, Nicholas C. P.; Vyas, Paresh; Killick, Sally; Hellström-Lindberg, Eva; Cazzola, Mario; Papaemmanuil, Elli; Campbell, Peter J.; Boultwood, Jacqueline

    2015-01-01

    Cancer is a genetic disease, but two patients rarely have identical genotypes. Similarly, patients differ in their clinicopathological parameters, but how genotypic and phenotypic heterogeneity are interconnected is not well understood. Here we build statistical models to disentangle the effect of 12 recurrently mutated genes and 4 cytogenetic alterations on gene expression, diagnostic clinical variables and outcome in 124 patients with myelodysplastic syndromes. Overall, one or more genetic lesions correlate with expression levels of ~20% of all genes, explaining 20–65% of observed expression variability. Differential expression patterns vary between mutations and reflect the underlying biology, such as aberrant polycomb repression for ASXL1 and EZH2 mutations or perturbed gene dosage for copy-number changes. In predicting survival, genomic, transcriptomic and diagnostic clinical variables all have utility, with the largest contribution from the transcriptome. Similar observations are made on the TCGA acute myeloid leukaemia cohort, confirming the general trends reported here. PMID:25574665

  19. Gene Product Expression of Cyclin D2 and p16 During the Transition from Cardiac Myocyte Hyperplasia to Hypertrophy

    Institute of Scientific and Technical Information of China (English)

    2002-01-01

    The current study was to investigate mRNA expression of cyclin D2 and p16 during the transition from cardiac myocyte hyperplasia to hypertrophy. Cultured cardiac myocytes (CM) and fibroblasts (FC) obtained from 1-day-old Sparague-Dawley rats were used in this study. We have determined (1) hyperplasia by cell growth curve and fluorescence activated cell sorting (FACS); and (2) ultrastructure by electron microscope observation; and (3) expressions of cyclin D2 mRNA and p16 mRNA by using in situ hybridization and image analysis. The results were shown (1) Results of cell growth curve and FACS analysis showed CM could proliferate in the first 3 cultured days (4 days in postnatal development). But the ability decreased quickly, concomitant with the differentiation. (2) The ultrastructure of CM showed the large amount of myofilaments and mitochondrion and FC showed moderate amount of rough endoplasmic reticulum. (3) The expression of cyclin D2 mRNA in 3-, 4-, 5-day CM group was 0.89 times(p<0.05), 0.80 times (p<0.05)and 0.56 times (p<0.01)of that in 1-day group respectively. P16 mRNA in 2-, 3-, 4-, 5-day CM group were 1.63 times(p<0.01),1.72 times(p<0.01),1.99 times (p<0.01)and 2.84 times (p<0.01) of that in 1-day group respectively. It can be concluded that cultured neonatal rat cardiac myocytes could proliferate during the first 3 cultured days, but the ability of proliferation decreased, from the fourth day, concomitant with differentiation. Cyclin D2 and p16 have the key roles during the transition from myocyte hyperplasia to hypertrophy.

  20. Cardiac applications of optogenetics.

    Science.gov (United States)

    Ambrosi, Christina M; Klimas, Aleksandra; Yu, Jinzhu; Entcheva, Emilia

    2014-08-01

    In complex multicellular systems, such as the brain or the heart, the ability to selectively perturb and observe the response of individual components at the cellular level and with millisecond resolution in time, is essential for mechanistic understanding of function. Optogenetics uses genetic encoding of light sensitivity (by the expression of microbial opsins) to provide such capabilities for manipulation, recording, and control by light with cell specificity and high spatiotemporal resolution. As an optical approach, it is inherently scalable for remote and parallel interrogation of biological function at the tissue level; with implantable miniaturized devices, the technique is uniquely suitable for in vivo tracking of function, as illustrated by numerous applications in the brain. Its expansion into the cardiac area has been slow. Here, using examples from published research and original data, we focus on optogenetics applications to cardiac electrophysiology, specifically dealing with the ability to manipulate membrane voltage by light with implications for cardiac pacing, cardioversion, cell communication, and arrhythmia research, in general. We discuss gene and cell delivery methods of inscribing light sensitivity in cardiac tissue, functionality of the light-sensitive ion channels within different types of cardiac cells, utility in probing electrical coupling between different cell types, approaches and design solutions to all-optical electrophysiology by the combination of optogenetic sensors and actuators, and specific challenges in moving towards in vivo cardiac optogenetics.