Toward a Mechanism-Based Approach to Treating Cardiac Arrhythmia

寻找基于机制的心律失常治疗方法

• 批准号: 10375446
• 负责人: Bjorn C Knollmann
• 金额: $ 102万
• 依托单位: VANDERBILT UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-03-06 至 2026-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10375446
• 关键词: Academia; Accounting; Adult; Animal Model; Anti-Arrhythmia Agents; Area; Arrhythmia; Catecholaminergic Polymorphic Ventricular Tachycardia; Cessation of life; Clinical; Development; Disease; Drug Industry; Functional disorder; Goals; Heart; Heart Diseases; Human; Implantable Defibrillators; Inherited; Ion Channel; Knowledge; Membrane; Molecular; Patient Care; Patients; Pharmacotherapy; Public Health; Research; Sudden Death; Syndrome; Therapeutic; Ventricular Arrhythmia; Vision; Work; base; cost; drug development; heart cell; high risk; improved; induced pluripotent stem cell; mortality; novel strategies; novel therapeutics; patient subsets; personalized care; premature; programs; sudden cardiac death; targeted treatment; tool

Sudden cardiac death due to ventricular arrhythmias is a major public health problem, accounting for 10-20% of all deaths in adults in the US. Current predictors can identify patient subsets at high risk, but unfortunately sudden death is the first manifestation of heart disease in up to half the victims. Costly implantable defibrillators in high-risk patients are the only real therapeutic option at present. Conventional anti-arrhythmic drug therapy targeting membrane ion channels has either no survival benefit or even increases mortality. Thus, a key challenge in the arrhythmia field is to understand fundamental mechanisms in order to find better ways to predict and treat ventricular arrhythmias. Since the pharmaceutical industry has all but abandoned drug development for cardiac arrhythmia, in 2018 there are fewer antiarrhythmic agents available for clinical use than 20 years ago. Hence, another key challenge for academia is to improve the efficacy of existing antiarrhythmic drugs and find new compounds that could be developed therapeutically. The overall vision of my R35 research program is to better understand molecular and cellular mechanisms responsible for arrhythmia and to use this knowledge to improve the care of patients with arrhythmia disorders. To accomplish this vision, the proposed research program will build on our prior accomplishments (e.g, finding new treatments for catecholaminergic polymorphic ventricular tachycardia or developing human induced pluripotent stem cells as better tools for arrhythmia research) to pioneer discovery in three areas: (1) Discovery of new arrhythmia mechanisms; (2) Discovery of new antiarrhythmic treatments; and (3) Development of new approaches to individualize care of patients with arrhythmia disorders. Accomplishing these goals will provide major conceptual advances for our understanding of the pathophysiology and treatment of acquired and inherited arrhythmia syndromes.

由于心室心律不齐而导致的心脏猝死是一个主要的公共卫生问题，占10-20％ 在美国成年人的所有死亡中。当前的预测因素可以识别出高风险的患者子集，但不幸的是 突然死亡是多达一半受害者心脏病的第一种体现。昂贵的植入式除颤器 目前，高危患者是唯一真正的治疗选择。常规抗心律失常药物治疗 靶向膜离子通道没有生存益处，甚至没有增加死亡率。因此，一个钥匙 心律失常领域的挑战是了解基本机制，以找到更好的方法 预测和治疗心室心律不齐。由于制药行业几乎都放弃了药物 心律不齐的发展，2018年可用于临床使用的抗心律失常剂较少 比20年前。因此，学术界的另一个主要挑战是提高现有的功效 抗心律失常药物并找到可以通过治疗性开发的新化合物。 我的R35研究计划的总体视野是更好地了解分子和细胞机制 负责心律不齐，并利用这些知识来改善心律不齐患者的护理。 为了实现这一愿景，拟议的研究计划将基于我们先前的成就（例如，查找 儿茶酚胺能多态性心室心动过速或发展人类诱导的新疗法 多能干细胞是心律不齐研究的更好工具）在三个领域开创了发现：（1） 发现新的心律失常机制； （2）发现新的抗心律失常治疗； （3） 开发新方法来个性化心律不齐患者的护理。 实现这些目标将为我们理解 获得和遗传性心律不齐综合征的病理生理学和治疗。