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：
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
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/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

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）：我们对各种遗传心律不齐综合征的分子机制的理解的进步带来了许多新和更好治疗的希望。尽管有这样的承诺，目前的治疗仍基于经验观察，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心律不齐综合征的前瞻性试验来解决这一差异。儿茶酚胺能多态性心室心动过速（CPVT）是一种遗传综合征，其特征是频繁心室心动过速和猝死风险。尽管现在已经了解了该疾病的遗传和分子基础，但自30年前对综合征的最初描述以来，当前的药物治疗策略基本上保持不变。我们最近发现，抗心律失常的药物氟卡因直接靶向CPVT中的分子缺损。我们在CPVT的小鼠模型中测试了氟卡因，发现它完全消除了VT。然后，我们在具有最大耐受性的标准疗法的CPVT患者中对CPVT患者进行了一项国际多中心试验。这些患者中的大多数大多数氟卡因可显着降低或消除VT。因此，氟卡因是将基本发现转化为遗传心律不齐综合征更好的治疗方法的有前途的候选人。迄今为止，尚未测试氟甲酰胺在改善CPVT患者的临床结果方面的有效性。这是一个关键问题，因为尽管心脏梗塞强烈抑制了心肌梗塞后，氟卡尼仍会增加患者的死亡率。在此提案中，我们将检验以下假设：氟卡尼将减少CPVT患者的心脏事件。我们还将寻求确定CPVT的新型遗传原因和遗传修饰符，并在参加试验的受试者中对候选基因进行下一代测序。实现这些特定目标将导致遗传心律不齐综合征研究的根本转变，包括基于机制的和个性化的治疗方法以及具有硬终点的前瞻性试验。