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的分子机制的理解取得了进展，带来了许多新的更好的治疗方法。尽管前景光明，但目前的治疗是基于经验观察、回顾性数据和小病例系列。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。儿茶酚胺能多态性室性心动过速（CPVT）是一种以频繁室性心动过速和猝死风险为特征的遗传综合征。虽然现在已经了解了该病的遗传和分子基础，但自30年前首次描述该综合征以来，目前的药物治疗策略基本上没有改变。我们最近发现抗心律失常药物flecainide直接靶向CPVT的分子缺陷。我们在CPVT的小鼠模型中测试了flecainide，发现它完全消除了VT。随后，我们在CPVT患者中进行了一项flecainide的国际多中心试验，这些患者患有持续的运动诱导的VT，尽管有最大耐受的标准治疗。在大多数患者中，氟氯胺显著降低或消除室速。因此，flecainide是一个很有希望的候选者，将基础发现转化为更好的遗传性心律失常综合征的治疗方法。到目前为止，氟氯胺在改善CPVT患者临床预后方面的有效性尚未得到检验。这是一个关键的问题，因为氟氯胺会增加心肌梗死后患者的死亡率，尽管对心室异位有很强的抑制作用。在本提案中，我们将检验氟氯胺会减少CPVT患者心脏事件的假设。我们还将通过对参加试验的受试者的候选基因进行下一代测序，寻求确定CPVT的新遗传原因和遗传修饰因子。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转变，包括基于机制和个性化的治疗以及具有硬终点的前瞻性试验。

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.