Molecular Basis and Treatment of Cardiac Arrhythmias

项目概要/摘要 心力衰竭（HF）患者猝死的主要原因是室性心律失常。令人困惑的是， 最近的大型临床试验表明，大多数抗疟疾药物很少或没有 生存福利。令人惊讶的是，曾经被认为是危险和禁忌的药物， 与HF，一直被证明可以降低猝死的风险。然而，分子 阻断剂的生存益处的潜在机制尚不清楚。本建议的总体目标是 了解β-受体阻滞剂的有益作用，并开发新型抗肿瘤药物。公 已知自发性Ca2+释放，也称为钙库超载诱导Ca2+释放（SOICR），可 导致延迟后除极（DAD），这反过来又会引发心律失常。重要的是，增强 SOICR活性和DAD相关的室性心律失常在HF和心脏ryanodine中很常见 RyR2受体相关的室性心律失常。假设：阻断剂的有益效果是， 部分，归因于SOICR抑制，并且SOICR抑制剂有效抑制心脏 心律不齐提出了三个具体目标。1.评估不同受体阻滞剂对 自发性Ca2+释放或SOICR和RyR2相关心律失常。一系列的影响- 将测定SOICR、RyR2活性和应激诱导的室性心律失常的阻滞剂 使用各种方法。2.卡维地洛类似物的设计、合成和表征 抑制心律失常。我们的初步数据表明，卡维地洛是唯一有效的， 抑制SOICR的阻断剂。为了提高其功效并产生一类新型的抗肿瘤药物， 为了降低或减弱其阻断作用，将合成许多卡维地洛衍生物 活性，同时保持或增加其SOICR抑制。3.了解SOICR的分子基础。 定点诱变结合单通道分析将用于检验我们的假设， SOICR由位于RyR2通道孔内的管腔Ca2+传感器控制。意义：这些 拟议的研究不仅将揭示心脏病的分子基础的新机制， 心律失常，而且还导致一类新的和有前途的抗心律失常剂的发展， 对心律失常的预防和治疗有直接影响。

PROJECT SUMMARY / ABSTRACT A major cause of sudden death in patients with heart failure (HF) is ventricular arrhythmia. Disappointingly, large clinical trials have recently demonstrated that most of the anti-arrhythmic drugs have little or no survival benefits. Surprisingly, ¿-blockers, once thought to be dangerous and contraindicated for patients with HF, have consistently been shown to reduce the risk of sudden death. However, the molecular mechanisms underlying ¿-blockers' survival benefits are unknown. The overall objective of this proposal is to understand the beneficial effects of ¿-blockers and to develop novel anti-arrhythmic agents. It is well known that spontaneous Ca2+ release, also known as store-overload-induced-Ca2+-release (SOICR), can cause delayed afterdepolarizations (DADs), which in turn can trigger arrhythmias. Importantly, enhanced SOICR activity and DAD-associated ventricular arrhythmias are common in HF and in cardiac ryanodine receptor (RyR2)-associated ventricular arrhythmias. Hypotheses: the beneficial effects of ¿-blockers are, in part, attributable to SOICR inhibition, and that SOICR inhibitors are effective in suppressing cardiac arrhythmias. Three specific aims are proposed. 1. To Assess the Impact of Different ¿-blockers on Spontaneous Ca2+ Release or SOICR and RyR2-Associated Arrhythmias. The impact of a number of ¿- blockers on SOICR, the activity of RyR2, and stress-induced ventricular arrhythmias will be determined using various approaches. 2. To Design, Synthesize, and Characterize Novel Carvedilol Analogues for Suppressing Arrhythmias. Our preliminary data demonstrate that carvedilol is uniquely effective among ¿- blockers in suppressing SOICR. To improve its efficacy and to produce a novel class of anti-arrhythmic agents, a number of carvedilol derivatives will be synthesized in order to reduce or diminish its ¿-blocking activity, while retaining or increasing its SOICR inhibition. 3. To Understand the Molecular Basis of SOICR. Site-directed mutagenesis in conjunction with single channel analysis will be used to test our hypothesis that SOICR is governed by a luminal Ca2+ sensor located within the RyR2 channel pore. Significance: These proposed studies will not only shed novel mechanistic insight into the molecular basis of cardiac arrhythmias, but also lead to the development of a new and promising class of anti-arrhythmic agents, and have direct implications for the prevention and treatment of cardiac arrhythmias.