Flecainide for Catecholaminergic Polymorphic Ventricular Tachycardia

氟卡尼治疗儿茶酚胺能多形性室性心动过速

• 批准号: 8286897
• 负责人: PRINCE Joseph KANNANKERIL
• 金额: $ 55.85万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-06-20 至 2016-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8286897
• 关键词: Address; Adrenergic Agents; Adult; Affect; Animal Model; Anti-Arrhythmia Agents; Arrhythmia; Basic Science; Calcium; Calsequestrin; Candidate Disease Gene; Cardiac; Cardiac Death; Case Series; Cell model; Child; Clinical; Clinical Trials; Code; Collaborations; Congenital Heart Defects; Controlled Clinical Trials; DNA; Data; Defect; Disease; Effectiveness; Emotional Stress; Enrollment; Event; Exercise; Exhibits; Flecainide; Gene Mutation; Genes; Genetic; Implantable Defibrillators; Inherited; International; Ion Channel; Knockout Mice; Learning; Life; Modeling; Molecular; Molecular Genetics; Molecular Target; Multicenter Trials; Mutation; Myocardial Infarction; Oral; Outcome; Patients; Penetrance; Persons; Pharmaceutical Preparations; Phenotype; Placebo Control; Placebos; Public Health; Randomized; Research; Risk; Role; RyR2; Ryanodine Receptor Calcium Release Channel; Sampling; Scientist; Site; Sudden Death; Syndrome; Testing; Therapeutic; Therapy Clinical Trials; Time; Translating; Treadmill Tests; Variant; Ventricular; Ventricular Fibrillation; Ventricular Tachycardia; Work; adrenergic; base; clinical care; clinical phenotype; drug candidate; exome; heart rhythm; improved; mortality; mouse model; next generation; novel; open label; premature; prospective; randomized placebo controlled trial; response; treatment strategy

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.

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的进展带来了许多新的和更好的治疗方法的希望。尽管如此，目前的治疗是基于经验性观察，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种差异。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。尽管现在已经了解了该疾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保持不变。我们最近发现，抗心律失常药物氟卡尼直接靶向CPVT的分子缺陷。我们在CPVT小鼠模型中测试了氟卡尼，发现它完全消除了VT。然后，我们进行了一项国际多中心试验，氟卡尼在CPVT患者持续运动诱导的室性心动过速，尽管最大耐受标准治疗。在大多数患者中，氟卡尼显著减少或消除了VT。因此，氟卡尼是一个很有前途的候选人转化为更好的治疗遗传性心律失常综合征的基本发现。到目前为止，氟卡尼在改善CPVT患者临床结局方面的有效性尚未得到验证。这是一个关键问题，因为氟卡尼增加了心肌梗死后患者的死亡率，尽管它对心室异位有很强的抑制作用。在本提案中，我们将检验氟卡尼将减少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剂。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，包括基于机制的和个性化的治疗以及具有硬终点的前瞻性试验。