Cellular determinants of action potential prolongation in heart failure

超过400万美国人患有心力衰竭，每年有超过40万人死亡。随着美国人口老龄化，其发病率和流行率将继续增加。尽管药物治疗有了显著的改善，但心力衰竭患者的预后仍然很差，六年死亡率超过80%。在心力衰竭患者的死亡中，50%是突然和意想不到的。导致动作电位延长的电重构是心力衰竭的一个反复出现的特征。动作电位延长虽然最初是自适应的，但最终会导致恶性室性心律失常和细胞内钙负荷增加。衰竭心脏中的两个重要变化可能影响动作电位时程，从而影响复极：复极K电流减少，细胞内钙离子清除减慢。在正常心脏中，跨壁动作电位时程和波形、钾电流表达和钙瞬变的差异已被证实。关于心力衰竭时跨室壁钾电流和钙离子处理的改变，以及跨室壁改变如何影响复极的整体异质性的信息很少。这项建议的目标有三个：1.细胞电生理异常的特征。这会改变衰竭心脏的复极。2.描述在衰竭的心脏中改变复极的细胞电生理异常。2.研究心衰时钾电流跨壁分布及钙离子转运变化的分子基础。3.描述心力衰竭患者动作电位时程变异性(APDV)增加的生物物理学基础，并确定心力衰竭患者QT间期变异性的已知增加是否有夸大APDV的基础。最终，我们试图确定细胞电生理特性中的哪些变化最重要地影响衰竭心脏的心律失常倾向。了解心力衰竭时细胞电生理的变化将提高我们预防猝死的能力，猝死是心力衰竭最灾难性的并发症。

Over 4 million Americans suffer from heart failure and more than 400,000 die annually. The incidence and prevalence will continue to increase with the aging of the U.S. population. Despite remarkable improvements in medical therapy, the prognosis of patients with myocardial failure remains poor with greater than 80% six-year mortality. Of the deaths in patients with heart failure, 50% are sudden and unexpected. Electrical remodeling resulting in action potential prolongation is a recurring feature of heart failure. Action potential prolongation, while initially adaptive is ultimately detrimental predisposing to malignant ventricular arrhythmias and increased intracellular Ca2+ load. Two important changes in the failing heart could influence action potential duration and therefore repolarization: a reduction in repolarizing K currents, and slowed removal of intracellular Ca2+. Transmural differences in action potential duration and profile, K current expression and Ca2+ transients have been demonstrated in normal hearts. There is little information regarding the transmural changes in K currents and Ca2+ handling in heart failure, nor how the transmural alterations impact on overall heterogeneity of repolarization. The goals of this proposal are three-fold: 1. Characterize the cellular electrophysiological abnormalities. that alter repolarization in the failing heart. 2. Characterize the cellular electrophysiological abnormalities that alter repolarization in the failing heart. 2. Characterize the molecular basis of the alterations in the transmural distribution of K currents and Ca2+ handling in the failing heart. 3. Characterize the biophysical basis of increased action potential duration variability (APDV) in the failing heart and determine if the known increase in the variability of the QT interval in the failing heart has its basis in exaggerated APDV. Ultimately we seek to determine which of the changes in the cellular electrophysiological properties most importantly influence the arrythmic pre-disposition of the failing heart. Understanding the cellular electrophysiological changes in heart failure will improve our ability to prevent sudden death, the most catastrophic complication of heart failure.