Molecular Basis and Treatment of Cardiac Arrhythmias

项目摘要/摘要 心力衰竭患者猝死的一个主要原因是室性心律失常。令人失望的是， 最近的大型临床试验表明，大多数抗心律失常药物几乎没有或几乎没有。 生存福利。令人惊讶的是，曾经被认为是危险和禁忌的阻滞剂 对于HF，一直被证明可以降低猝死的风险。然而，分子 阻滞剂生存益处的潜在机制尚不清楚。这项提议的总体目标是 了解阻滞剂的有益作用，开发新型抗心律失常药物。这很好 已知自发钙释放，也称为储存-过载诱导-钙释放(SOICR)，可以 导致延迟后除极(DAD)，进而引发心律失常。重要的是，增强了 SOICR活动和DAD相关的室性心律失常在心力衰竭和心脏兰尼定中常见 RyR2受体相关的室性心律失常。假设：受体阻滞剂的有益效果如下 部分归因于SOICR抑制，以及SOICR抑制剂在抑制心脏疾病方面有效 心律不齐。提出了三个具体目标。1.评估不同受体阻滞剂对心脏功能的影响 自发性钙释放或SOICR和RyR2相关的心律失常。一些因素的影响-- 将确定SOICR的阻滞剂、RyR2的活性以及应激性室性心律失常 使用不同的方法。2.设计、合成和表征新型卡维地洛类似物 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的阻滞剂。提高疗效，生产新型抗心律失常药物 为了减少或减少卡维地洛的封闭性，将合成一些卡维地洛的衍生物 活性，同时保持或增加其对SOICR的抑制。3.了解SOICR的分子基础。 定点突变结合单通道分析将被用来检验我们的假设 SOICR由位于RyR2通道孔内的管腔钙传感器控制。意义：这些 拟议的研究不仅将为心脏疾病的分子基础提供新的机制洞察力 心律失常，但也导致了一类新的和有前途的抗心律失常药物的开发，以及 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.