Toward a Mechanism-Based Approach to Treating Cardiac Arrhythmia

室性心律失常引起的心源性猝死是一个主要的公共卫生问题，占10-20% 占美国成年人死亡总数的三分之一。目前的预测因子可以识别出高风险的患者亚群，但不幸的是， 猝死是多达一半的受害者心脏病的第一个表现。昂贵的植入式呼吸机 是目前唯一真实的治疗选择。常规抗肿瘤药物治疗 靶向膜离子通道没有存活益处或甚至增加死亡率。因此，一把钥匙 心律失常领域的挑战是了解基本机制，以便找到更好的方法， 预测和治疗室性心律失常。由于制药业几乎放弃了药物 由于心律失常的发展，2018年可用于临床的抗心律失常药物较少 比20年前多了。因此，学术界面临的另一个关键挑战是提高现有 并发现新的化合物，可以开发治疗。 我的R35研究计划的总体愿景是更好地了解分子和细胞机制 负责心律失常，并利用这些知识，以改善与心律失常疾病患者的护理。 为了实现这一愿景，拟议的研究计划将建立在我们先前的成就（例如，发现 治疗儿茶酚胺能多形性室性心动过速的新方法 多能干细胞作为心律失常研究的更好工具）在三个领域开拓性发现：（1） 发现新的心律失常机制;（2）发现新的抗心律失常治疗方法;（3） 心律失常患者个体化护理新方法的开发。 实现这些目标将为我们理解 获得性和遗传性心律失常综合征的病理生理学和治疗。

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.