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

基本信息

批准号：
8444288
负责人：
PRINCE Joseph KANNANKERIL
金额：
$ 52.99万
依托单位：
VANDERBILT UNIVERSITY
依托单位国家：
美国
项目类别：
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/8444288
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 sequencing novel open label premature prospective randomized placebo controlled trial response treatment strategy

项目摘要

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背后的分子机制的理解的进展带来了许多新的和更好的治疗的希望。尽管有这样的希望，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。儿茶酚胺能多形性室性心动过速 (CPVT) 是一种遗传综合征，其特征是频繁发生室性心动过速和猝死风险。尽管该疾病的遗传和分子基础现已被了解，但自 30 多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针对 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，我们对尽管接受了最大耐受标准治疗但仍有持续性运动诱发 VT 的 CPVT 患者进行了氟卡尼国际多中心试验。氟卡尼显着减少或消除了大多数患者的VT。因此，氟卡尼是将基本发现转化为更好的遗传性心律失常综合征治疗方法的有前途的候选者。迄今为止，氟卡尼改善 CPVT 患者临床结果的有效性尚未得到测试。这是一个关键问题，因为尽管氟卡尼能强烈抑制心室异位，但它仍会增加心肌梗塞后患者的死亡率。在本提案中，我们将检验氟卡尼会减少 CPVT 患者心脏事件的假设。我们还将寻求通过对参加试验的受试者的候选基因进行新一代测序来确定 CPVT 的新遗传原因和遗传修饰因素。实现这些具体目标将导致遗传性心律失常综合征研究发生根本性转变，包括基于机制的个性化治疗以及具有硬终点的前瞻性试验。