Molecular Basis and Treatment of Cardiac Arrhythmias

心律失常的分子基础和治疗

• 批准号: 7918945
• 负责人: SUI RONG WAYNE CHEN
• 金额: $ 35.21万
• 依托单位: RUSH UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-21 至 2014-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7918945
• 关键词: Adrenergic beta-Antagonists; Adverse effects; Animals; Anti-Arrhythmia Agents; Arrhythmia; Cardiac; Cells; Clinical Trials; Data; Defect; Development; Electrocardiogram; Exhibits; Heart failure; Image; Incidence; Lead; Link; Molecular; Mutant Strains Mice; Mutation; Pathogenesis; Patients; Pharmaceutical Preparations; Prevention; Process; Risk; RyR2; Ryanodine Receptor Calcium Release Channel; Ryanodine Receptors; Site-Directed Mutagenesis; Stress; Sudden Death; Testing; Therapeutic; Ventricular Arrhythmia; Work; analog; base; carvedilol; design; improved; inhibitor/antagonist; insight; mortality; novel; prevent; prototype; public health relevance; sensor; sudden cardiac death

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.

描述（由适用提供）：心力衰竭患者（HF）猝死的主要原因是心室心律不齐。令人失望的是，大型临床试验最近表明，大多数抗心律失常药物几乎没有生存益处。令人惊讶的是，曾经被认为是HF患者的危险且禁忌的障碍，始终被证明会降低猝死的风险。然而，未知的分子机制却尚不清楚。该提案的总体目的是了解 - 块造成的益处，并开发新型的抗心律失常剂。众所周知，赞助的Ca2+释放（也称为商店超负荷诱导的Ca2+ -Release（SOICR））可能会导致去极化后延迟（DADS），这又会触发心律不齐。重要的是，增强的SOICR活性和与DAD相关的心室心律不齐在HF和心脏ryanodine受体（RYR2）相关的心室心律不齐。假设：块的有益作用部分是归因于SOICR抑制剂可有效抑制心律不齐的。提出了三个具体目标。 1。评估不同»块对自发CA2+释放或SOICR和RYR2相关心律不齐的影响。许多oo -Blockers对SOICR的影响，RYR2的活性以及应力诱导的心律不齐的影响将使用各种方法确定。 2。设计，合成和表征新型的卡维迪尔类似物，以抑制心律不齐。我们的初步数据表明，在抑制SOICR的阻滞剂中，Carvedilol具有独特的有效性。为了提高其效率并产生新型的抗心律失常剂，将合成许多卡韦迪尔衍生物，以减少或减少其损坏活性，同时保留或增加其SOICR抑制作用。 3。了解SOICR的分子基础。位置定向的诱变与单个通道分析一起测试我们的假设，即SOICR由位于RYR2通道孔中的腔Ca2+传感器控制。意义：这些提出的研究不仅将对心律不齐的分子基础进行新的机械洞察力，而且还会导致发展新的和有望的抗心律失常剂类别，并直接对心律失常的预防和治疗产生直接影响。公共卫生相关性：心力衰竭患者猝死的主要原因是心室心律不齐。因此，在过去的3 - 4年中已经开发了多种抗心律失常疗法。但是，最近的大型临床试验表明，这些药物中的大多数几乎没有生存益处。 β受体阻滞剂始终被证明可降低猝死的风险。但是，尚不清楚β受体阻滞剂的生存益处的分子机制。该提案旨在确定负责β受体阻滞剂的有益作用的机制，并开发针对这些机制的新型抗心律失常疗法。这些提出的研究不仅会使心律不齐的分子基础的新机械洞察力洞悉，而且还会导致发展新的和有望的抗心律失常剂类别，并直接影响心律失常的预防和治疗。