Abstract 2883: Retroinfusion-facilitated Inotropic AAV9-S100A1 Gene Therapy Restores Global Cardiac Function In A Clinically Relevant Pig Heart Failure Model
Sven T. PlegerChangguang ShanJan KziencekOliver MuellerRaffi BekeredjianAndrew RemppisWalter J. KochHugo A. KatusPatrick Most
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Background: Cardiac expression of the Ca-dependent inotropic protein S100A1 is decreased in human end-stage heart failure (HF) and cardiomyocyte-targeted viral-based S100A1 gene transfer rescued failing myocardium in small animal models in vivo and in vitro via improved systolic and diastolic sarcoplasmic reticulum Ca-handling. We therefore hypothesized that cardioselective AAV9-S100A1 gene therapy will improve cardiac performance in a large animal experimental HF model under clinical conditions. Methods and Results: Left ventricular (LV) posterolateral myocardial infarction (MI) was induced in pigs by occlusion of the left coronary circumflex artery and resulted in LV failure (HF) 2 weeks post-MI reflected by a 40% and 27% reduction in LV +dp/dt max. and EF, respectively, as assessed by LV catheterization and echocardiography. Post-MI HF pigs were then randomized for retroinfusion of AAV9-luciferase (luc; n=6, 1.5×10 13 total viral particles, tvp) and AAV9-S100A1 (S100A1; n=6, 1.5×10 13 tvp) driven by a cardioselective promoter via the anterior cardiac vein while the left anterior descending artery was temporarily occluded. 14 weeks after cardiac gene transfer, the S100A1-treated HF group showed significantly enhanced S100A1 protein expression (+46.7±17.9%, P<0.05 vs. control groups) in targeted remote LV myocardium and improved indices of cardiac function and remodeling (luc vs. S100A1: +dp/dtmax: 983±81 vs. 1526±83 mmHg/s, EF: 39±2.1 vs. 61±3.7 %, P<0.05 S100A1 vs. luc, LV endsystolic diameter: luc 4.45±0.1 vs. S100A1 3.43 ±0.1 cm, P<0.05 S100A1 vs. luc, HR: 72±4 vs. 69±2, beats/min, P=n.s. S100A1 vs. luc). Importantly, analyses of renal, hepatic and hematopoetic function showed no alteration as assessed by unchanged transaminases, retention values and white blood cell counts compared to sham pigs. Conclusions: Our translational study provides proof of concept that AAV9-S100A1 based HF gene therapy is feasible and restores cardiac function in a large animal HF model under clinical conditions. Next, certified toxicological analysis and different AAV9-S100A1 dosage protocols will be assessed to eventually advance to first phase I/II clinical studies determining therapeutic efficiency of cardiac S100A1 gene therapy in HF patients.Keywords:
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Epidemiological investigations have revealed that sulfur dioxide (SO(2) ) exposure is linked to cardiovascular diseases. The present study was designed to investigate the negative inotropic effects of gaseous SO(2) and its derivatives in the isolated perfused rat heart and the possible mechanisms involved in their effects. The results showed that both SO(2) and SO(2) derivatives elicited a negative inotropic effect in a dose-dependent manner, and SO(2) produced a higher negative effect than SO(2) derivatives. The mechanism of SO(2) -induced negative inotropic effects at low concentrations was different from that at high concentrations. At low concentrations, the mechanism of SO(2) -induced negative inotropic effects might occur through promoting the activities of protein kinase C (PKC), cycloxygenase, and cGMP, while the mechanism of SO(2) derivatives-induced effects might be related to the opening of ATP-sensitive K(+) (K(ATP) ) channel and the inhibition of Ca(2+) influx via L-type calcium-channel. At high concentrations, the mechanisms of SO(2) and SO(2) derivatives-induced negative inotropic effects were similar, which might be related to the K(ATP) channel and L-type calcium-channel as well as the possible alterations in PKC, cycloxygenase, and cGMP. Further work is needed to determine the relative contribution of each pathway in SO(2) -mediated inotropic effect.
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Objective:To explore the function of NOS2 in the development of cardiac dysfunction after myocardial infarction.Method:Rats with myocardial infarction induced by left coronary ligation received S-methylisothiourea(SMT)or saline for 4 weeks. The hemodynamic studies were performed. Infarct size, heart weight, plasma NO, heart NOS2 were quantified.Result:Long term administration of SMT could decrease plasma NO level[( 26.6± 2.2)vs ( 46.6± 4.2)μmol/L,P 0.05], heart weight, infarct size, and ameliorate cardiac dysfunction[LVEDP ( 6.1± 0.7) vs ( 11.0± 1.2) mmHg,P 0.05; CVP ( 0.8± 0.1) vs ( 1.6± 0.2) mmHg,P 0.05]. Four weeks after myocardial infarction, NOS2 level in noninfarct myocardium was much higher than controls[( 0.261± 0.025) vs ( 0.092± 0.011 )A·μm -2,P 0.05)].Conclusion:These findings demonstrate that induction of NOS2 after myocardial infarction exerts negative effects on cardiac function and structure. Long term administration of a selective NOS2 inhibitor SMT may prove to be beneficial in the treatment of cardiac dysfunction after myocardial infarction.
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Although positive inotropic agents exert favorable hemodynamic effects, long-term therapy with these drugs has not produced clinical benefits and has increased the mortality of patients with chronic congestive heart failure (CHF). This experience has led many physicians to suggest that positive inotropic therapy be abandoned as a therapeutic approach for this condition. However, positive inotropic drugs can produce clinical benefits in many patients but, ironically, this improvement may be principally seen at doses that produce negligible effects on cardiac contractility. This apparent discrepancy may be explained by the fact that many positive inotropic agents exert actions on the circulation in addition to stimulating the heart, and these ancillary properties may be particularly important with the use of low doses of these drugs. If the noninotropic actions of low doses are responsible for the therapeutic benefits of these drugs, the positive inotropic effects seen at high doses may be primarily responsible for their adverse (rather than their favorable) effects. Therefore, hemodynamic activity should not be viewed as a prerequisite for the selection of the dose of a drug for CHF. The ideal dose of a positive inotropic agent may be one that exerts no positive inotropic effect at all.
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In acute heart failure the myocardial function is acutely reduced and the oxygenation of the tissues becomes inadequate. Traditional inotropic drugs improve the haemodynamics and give symptomatic relief, but the evidence of injurious effects on morbidity and mortality restricts their use. The need for new inotropic drugs which can also reduce morbidity and mortality is for that reason obvious. Levosimendan is such a new drug in a new class (Ca2+ sensitizers) of positive inotropic drugs with favourable effects compared to existing treatment possibilities.
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Objective To explore the relationship between changes of heart function and angiogenesis after myocardial infarction,and provide morphological reference for clinical treatment of myocardial infarction. Methods Acute myocardiac infarction( AMI) model was established with Sprague-Dawley rats by ligation of the left anterior descending coronary artery. Cardiac function at different weeks after AMI was evaluated by echocardiography. The change of Ⅷ factor and vascular endothelial growth factor( VEGF) expression at the infarction edge in rats hearts at each week after AMI was detected by immunohistochemistry and Western blotting. Results The cardiac function of 1W after myocardial infarction was worst,cardiac function was improved during 2 weeks and 3weeks,but reduced at the 4th week; Ⅷ factor and VEGF in post-myocardial infarction 1 week,2 weeks were highly expressed. Expression of both factors began to decrease at the 3rd week. At the 4th week,expression levels were close to normal. Conclusion The change of cardiac function after myocardial infarction is inconsistent with that of angiogenesis,early increased vascular density can not obviously improve cardiac function.
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Abstract Inotropes are often used to offer haemodynamic support to patients with decompensated heart failure and cardiogenic shock. Although several drugs with inotropic activity are available, it has become increasingly evident that these drugs are associated with important negative effects. The positive inotropic actions of many of these agents are based on increased intracellular calcium concentrations, which may enhance myocardial energy consumption and arrhythmias. This chapter describes the pharmacology and evidence base for the use of inotropes in patients with heart failure.
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