Arrhythmogenic Remodeling of Repolarization in Human Heart Failure

描述(申请人提供)：心力衰竭(HF)在美国每年夺走约25万人的生命，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，电重构导致人心衰心律失常的机制仍不完全清楚。动作电位(AP)延长是衰竭心肌的一种标志性电生理改变，复极化钾电流是AP持续时间的关键决定因素。然而，衰竭心肌的复极改变与体内心律失常的风险尚未明确相关，人类心力衰竭电重构的早期步骤尚不清楚，而且有许多相互矛盾的发现归因于不同的心力衰竭模型。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的捐赠者和衰竭的人类心脏，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，我们将把功能电生理学和分子研究应用于按特定临床表型分组的心脏，以追求以下特定目的：1)研究人心衰时的复极电流异常；2)比较心衰不衰、心衰前期和终末期心衰患者之间以及有和没有心律失常病史的心衰患者之间的复极重构。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，有临床心律失常病史的心衰患者细胞表面功能复极电流的表达将最低。因此，我们希望表明早期的心衰重构涉及基因和蛋白表达的改变，而后期的功能性离子通道紊乱促进了心衰患者的心律失常的发生。由于我们的目标是研究早期心力衰竭的重构，并将我们的发现与体内心律失常的风险联系起来，因此我们可能能够确定人类心力衰竭的可逆性变化和潜在的治疗干预靶点。

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.