Arrhythmogenic Remodeling of Repolarization in Human Heart Failure

描述（由申请人提供）：心力衰竭（HF）在美国每年夺去约250，000人的生命，其中近一半的死亡是突然的，可能是由于室性快速性心律失常。然而，在人类HF中电重构导致血栓形成的机制仍然不完全清楚。动作电位（AP）延长是衰竭心肌的标志性电生理变化，复极钾电流是AP持续时间的关键决定因素。然而，在衰竭心肌的复极变化没有明确的体内心律失常的风险，在人类HF电重构的早期步骤是未知的，有许多矛盾的结果归因于不同的HF模型。我们在圣路易斯华盛顿大学的独特研究项目使我们能够研究活体供体和衰竭的人类心脏，并获得与我们检查的每一颗心脏相关的详细临床信息。因此，我们将应用功能性电生理学和分子研究，以特定的临床表型分组的心脏，以追求以下特定的目标：1）调查复极化电流异常在人类HF和2）对比复极重构之间的非衰竭，前衰竭，终末期衰竭的心脏和HF患者之间有和没有心律失常的历史。我们预测，与非衰竭心脏相比，衰竭前心脏的钾通道基因和蛋白表达将减少，并且在有临床心律失常病史的HF患者中，功能性细胞表面复极化电流的表达将减少最多。因此，我们希望表明，早期HF重塑涉及基因和蛋白质表达的变化，以及后来的功能性离子通道紊乱促进HF患者的血管生成。因为我们的目标是研究早期HF重塑，并将我们的发现与体内心律失常风险联系起来，我们可能能够确定可逆的变化和人类HF治疗干预的潜在靶点。

DESCRIPTION (provided by applicant): Heart failure (HF) claims ~250,000 lives per year in the US, and nearly half of these deaths are sudden and presumably due to ventricular tachyarrhythmias. However, the mechanisms by which electrical remodeling leads to arrhythmogenesis in human HF remain incompletely understood. Action potential (AP) prolongation is a hallmark electrophysiologic change of the failing myocardium, and repolarizing potassium currents are critical determinants of AP duration. However, repolarization changes in the failing myocardium have not been clearly associated with in vivo arrhythmia risk, the early steps in human HF electrical remodeling are unknown, and there are many contradictory findings attributable to different HF models. Our unique research program at Washington University in St. Louis enables us to study living donor and failing human hearts and to obtain detailed clinical information associated with every heart we examine. Thus, we will apply functional electrophysiology and molecular studies to hearts grouped by specific clinical phenotypes in order to pursue the following specific aims: 1) to investigate repolarizing current abnormalities in human HF and 2) to contrast repolarization remodeling among nonfailing, prefailing, and end-stage failing hearts and between HF patients with and without arrhythmia history. We predict that prefailing hearts will have decreased potassium channel gene and protein expression compared with nonfailing hearts and that functional, cell-surface expression of repolarizing currents will be most decreased in HF patients with clinical arrhythmia history. Thus, we hope to show that early HF remodeling involves gene and protein expression changes and that later functional ion channel derangements promote arrhythmogenesis in HF patients. Because we aim to study early HF remodeling and relate our findings to in vivo arrhythmia risk, we may be able to identify reversible changes and potential targets for therapeutic intervention in human HF.