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。随着美国人口的老龄化，其发病率和患病率将继续增加。尽管药物治疗有了显著的改善，但心肌衰竭患者的预后仍然很差，6年死亡率超过80%。在心力衰竭患者的死亡中，50%是突然和意外的。导致动作电位延长的电重构是心力衰竭的反复出现的特征。动作电位延长，而最初的适应性是最终有害的诱发恶性室性心律失常和细胞内Ca2+负荷增加。衰竭心脏中的两个重要变化可能影响动作电位持续时间，从而影响复极：复极K电流减少，细胞内Ca 2+清除减慢。在正常心脏中，动作电位时程和曲线、K电流表达和Ca 2+瞬变的差异已被证实。 关于心力衰竭中K电流和Ca2+处理的跨壁变化以及跨壁变化如何影响复极的总体异质性的信息很少。该提案的目标有三个方面：1。表征细胞电生理异常。改变衰竭心脏的复极2.描述衰竭心脏中改变复极的细胞电生理异常。2.表征衰竭心脏中K电流和Ca2+处理的跨壁分布改变的分子基础。3.表征衰竭心脏中动作电位时程变异性（APDV）增加的生物物理学基础，并确定衰竭心脏中QT间期变异性的已知增加是否以夸大的APDV为基础。最终，我们试图确定细胞电生理特性的变化最重要的影响心律失常的倾向衰竭的心脏。了解心力衰竭的细胞电生理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.