Molecular Basis and Treatment of Cardiac Arrhythmias

描述（由申请人提供）：心力衰竭（HF）患者猝死的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很少或根本没有生存效益。令人惊讶的是，曾经被认为对心衰患者是危险和禁忌的-受体阻滞剂一直被证明可以降低猝死的风险。然而，受体阻滞剂的生存益处背后的分子机制尚不清楚。本提案的总体目标是了解-受体阻滞剂的有益作用，并开发新的抗心律失常药物。众所周知，自发Ca2+释放，也称为储存超载诱导的Ca2+释放（SOICR），可导致延迟后去极化（DADs），进而引发心律失常。重要的是，SOICR活性增强和dad相关的室性心律失常在HF和ryyanodine受体（RyR2）相关的室性心律失常中很常见。假设：阻滞剂的有益作用部分归因于SOICR抑制，SOICR抑制剂对抑制心律失常有效。提出了三个具体目标。1. 评估不同受体阻滞剂对自发Ca2+释放或SOICR和ryr2相关心律失常的影响。许多阻滞剂对SOICR、RyR2活性和应激性室性心律失常的影响将通过各种方法确定。2. 设计、合成和表征新型卡维地洛抑制心律失常类似物。我们的初步数据表明卡维地洛在抑制SOICR方面是唯一有效的受体阻滞剂。为了提高其疗效和生产一类新型抗心律失常药物，将合成许多卡维地洛衍生物，以减少或减少其阻滞活性，同时保留或增加其SOICR抑制作用。3. 了解SOICR的分子基础。位点定向突变结合单通道分析将用于验证我们的假设，即SOICR是由位于RyR2通道孔内的腔内Ca2+传感器控制的。意义：这些研究不仅将为心律失常的分子基础提供新的机制见解，而且还将导致一类新的和有前途的抗心律失常药物的开发，并对心律失常的预防和治疗具有直接意义。公共卫生相关性：心力衰竭患者猝死的主要原因是室性心律失常。因此，在过去的3-4年里，各种各样的抗心律失常疗法已经被开发出来。然而，最近的大型临床试验表明，这些药物中的大多数只有很少或没有生存益处。-受体阻滞剂一直被证明可以降低猝死的风险。然而，受体阻滞剂的生存益处的分子机制尚不清楚。本提案旨在确定β受体阻滞剂有益作用的机制，并开发针对这些机制的新型抗心律失常疗法。这些建议的研究不仅将为心律失常的分子基础提供新的机制见解，而且还将导致一类新的和有前途的抗心律失常药物的开发，并对心律失常的预防和治疗具有直接意义。

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: A major cause of sudden death in patients with heart failure is ventricular arrhythmia. Consequently, a variety of anti-arrhythmic therapies have been developed over the past 3-4 decades. However, recent large clinical trials have demonstrated that the majority of these drugs have little or no survival benefits. Beta-blockers have consistently been shown to reduce the risk of sudden death. However, the molecular mechanisms underlying beta-blockers' survival benefits are unknown. This proposal seeks to identify the mechanisms responsible for beta-blockers' beneficial effects, and to develop novel anti-arrhythmic therapies that target these mechanisms. 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.