Molecular Basis and Treatment of Cardiac Arrhythmias

描述(申请人提供)：心力衰竭(HF)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对生存的益处很小，甚至没有。令人惊讶的是，曾经被认为是危险的、对心力衰竭患者是禁忌的阻滞剂，一直被证明可以降低猝死的风险。然而，阻滞剂生存益处背后的分子机制尚不清楚。这项建议的总体目标是了解阻滞剂的有益效果，并开发新的抗心律失常药物。众所周知，自发性钙离子释放，也称为储存过载诱导钙释放(SOICR)，可导致延迟后除极(DAD)，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心力衰竭和心脏兰尼定受体(RyR2)相关的室性心律失常中常见。假设：阻滞剂的有益作用部分归因于SOICR抑制，SOICR抑制剂在抑制心律失常方面有效。提出了三个具体目标。1.评价不同受体阻滞剂对自发性钙离子释放或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来确定。2.设计、合成和表征新型抗心律失常的卡维地洛类似物。我们的初步数据表明，卡维地洛是阻滞剂中唯一有效的抑制SOICR的药物。为了提高卡维地洛的抗心律失常效果，合成一类新型的抗心律失常药物，将合成一些卡维地洛的衍生物，以降低或减弱其阻断活性，同时保持或增强其对SOICR的抑制作用。3.了解SOICR的分子基础。定点突变结合单通道分析将用于验证我们的假设，即SOICR由位于RyR2通道孔内的管腔钙传感器控制。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，还将导致一类新的、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一个主要原因是室性心律失常。因此，在过去的3-40年里，各种抗心律失常的治疗方法被开发出来。然而，最近的大型临床试验表明，这些药物中的大多数几乎没有或几乎没有生存益处。β-受体阻滞剂一直被证明可以降低猝死的风险。然而，β-受体阻滞剂生存益处背后的分子机制尚不清楚。这项建议旨在确定β-受体阻滞剂有益效果的机制，并开发针对这些机制的新型抗心律失常疗法。这些研究不仅将对心律失常的分子基础有新的机制认识，而且将导致开发一类新的、有前途的抗心律失常药物，并对心律失常的预防和治疗具有直接的意义。

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.