Flecainide for Catecholaminergic Polymorphic Ventricular Tachycardia

描述(由申请人提供)：我们对各种遗传性心律失常综合征潜在的分子机制的理解的进步带来了许多新的和更好的治疗方法的希望。尽管有这样的希望，目前的治疗是基于经验性观察、回顾数据和小病例系列。我们提出的研究通过将细胞和动物模型中的发现转化为遗传性心律失常综合征的前瞻性试验来解决这一差异。儿茶酚胺能多形性室性心动过速(CPVT)是一种以频发室性心动过速和猝死风险为特征的遗传综合征。虽然这种疾病的遗传和分子基础现在已经被了解，但自30年前首次描述这种综合征以来，目前的药物治疗策略基本上没有变化。我们最近发现，抗心律失常药物氟卡胺直接靶向CPVT的分子缺陷。我们在我们的CPVT小鼠模型中测试了氟卡胺，发现它完全消除了VT。然后，我们在CPVT患者中进行了氟卡胺的国际多中心试验，尽管标准治疗耐受性最高，但仍有持续性运动性室性心动过速。氟卡胺显著减少或消除了大多数患者的室性心动过速。因此，氟卡胺是一个很有希望的候选药物，可以将基本发现转化为对遗传性心律失常综合征的更好治疗。到目前为止，氟卡胺在改善CPVT患者临床结局方面的有效性尚未得到测试。这是一个关键问题，因为氟卡胺增加了心肌梗死后患者的死亡率，尽管强烈抑制了心室异位。在这项提案中，我们将检验氟卡胺将减少CPVT患者心脏事件的假设。我们还将寻求通过对参与试验的受试者进行下一代候选基因测序来确定CPVT的新遗传原因和遗传修饰因素。实现这些特定目标将导致遗传性心律失常综合征研究的根本性转变，包括基于机制的个性化治疗和具有硬终点的前瞻性试验。 与公共健康相关：这项拟议的研究将研究一种有前景的致命心律疾病的新疗法，同时研究一个人的基因如何影响这种疾病。这项研究有可能为这种疾病找到新的救命药物，帮助科学家更多地了解这种疾病，并为许多其他疾病提供了一种新的模式，从而显著影响公众健康。

DESCRIPTION (provided by applicant): Advances in our understanding of the molecular mechanisms underlying various genetic arrhythmia syndromes bring the promise of many new and better treatments. Despite this promise, current treatment is based on empiric observations, retrospective data, and small case series. The research we propose addresses this disparity by translating discovery in cellular and animal models to prospective trials in genetic arrhythmia syndromes. Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a genetic syndrome characterized by frequent ventricular tachycardia and risk for sudden death. Although the genetic and molecular basis of the disease is now understood, current drug treatment strategies remain essentially unchanged since the initial description of the syndrome >30 years ago. We recently discovered that the antiarrhythmic drug flecainide directly targets the molecular defect in CPVT. We tested flecainide in our mouse model of CPVT and found that it completely eliminated VT. We then performed an international multicenter trial of flecainide in CPVT patients with persistent exercise-induced VT despite maximally-tolerated standard therapy. Flecainide significantly reduced or eliminated VT in the majority of these patients. Thus, flecainide is a promising candidate to translate basic discovery into better treatments for genetic arrhythmia syndromes. To date, the effectiveness of flecainide in improving the clinical outcome of CPVT patients has not been tested. This is a critical issue, as flecainide increases mortality in patients after myocardial infarction despite a strong suppression of ventricular ectopy. In this proposal, we will test the hypothesis that flecainide will reduce cardiac events in patients with CPVT. We will also seek to identify novel genetic causes and genetic modifiers of CPVT with next-generation sequencing of candidate genes in subjects enrolled in the trial. Accomplishing these specific aims will result in a radical shift in genetic arrhythmia syndrome research including mechanism- based and personalized treatments and prospective trials with hard endpoints. PUBLIC HEALTH RELEVANCE: The proposed research will study a promising new treatment for a deadly heart rhythm disease, while studying how a person's genes affect that disease. This research has potential to identify new life-saving treatments for this disease, help scientists learn more about the disease, and provides a new model to do this in many other diseases, thereby significantly impacting public health.