Emotional Stress as a Risk Factor for Arrhythmia: Ischemic and Genetic Mechanisms

 描述(由申请人提供)：这是埃默里大学流行病学和医学助理教授、亚特兰大退伍军人医学中心预防心脏病专家阿米特·沙阿博士的K23职业发展奖的修订申请。在以病人为中心的临床研究中，沙阿博士正在确立自己年轻研究员的地位。这款K23将为Shah博士提供实现下列目标所需的支持：(1)成为心电图数据信号处理方面的专家，包括使用定制和商业软件得出心率变异性(HRV)、T波交替(TWA)和空间QRS-T角(SA)；(2)通过正式的教学和实践经验，学习评估急性情绪应激引起的心律失常风险的遗传和缺血决定因素的必要技能；以及(3)学习核心临床研究技能，以计划和实施以患者为导向的研究，包括在临床研究实验室对患者进行实践培训。沙阿博士组建了一个指导团队，成员包括一名主要导师、流行病学主席、心脏病心理风险因素方面的知名专家维奥拉·瓦卡里诺博士，以及两名与瓦卡里诺博士长期合作的共同导师，其中包括耶鲁大学电生理学家、心律失常情绪决定因素专家雷切尔·兰伯特博士，以及埃默里精神病学家和放射科医生J·道格拉斯·布雷姆纳博士(共同导师)，后者在核成像和创伤应激方面拥有专业知识。情绪性心律失常的流行病学、机制和治疗方法很难研究，因为许多室性心律失常是致命的。作为这一难题的解决方案，沙阿博士提议在他的导师瓦卡里诺博士(R01 HL109413)和顾问奎尤米博士(P01 HL101398)的带领下，对近1000名CHD患者进行实验室诱导的急性精神应激期间心律失常的代用心电标记物研究。在这个具有良好特征、基因分型和表型的队列中，他将在目标1中研究应激和精神应激缺血期间自主神经调节与应激期间心律失常风险(T波交替和空间QRS-T角)的关系。具体地说，他将评估由于副交感神经撤退(心率变异性降低)和交感神经激活(去甲肾上腺素和血管收缩增加)可能导致的电不稳定程度。为了评估潜在的分子靶点和更好地对高危受试者进行风险分层，他将研究可能影响精神应激期间电不稳定的选定肾上腺素能/胆碱能遗传受体多态(目标2)。最后，在目标3中，他将根据正在研究的自主神经和电生理指标评估应激反应对主要不良心脏事件和死亡的预测价值。总体而言，这项研究将为系统评估冠心病患者的风险预测策略和可能的治疗方法(如认知疗法和生物反馈)的更大规模的研究奠定基础。

 DESCRIPTION (provided by applicant): This is a revised application for a K23 Career Development award for Dr. Amit Shah, Assistant Professor of Epidemiology and Medicine at Emory University, and preventive cardiologist at the Atlanta VA Medical Center. Dr. Shah is establishing himself as a young investigator in patient-oriented clinical research. This K23 will provide Dr. Shah with support necessary to accomplish the following goals: (1) to become an expert in signal processing of electrocardiogram (ECG) data, including the use of custom and commercial software to derive heart rate variability (HRV), T-wave alternans (TWA), and spatial QRS-T angle (SA); (2) learn, through formal didactics and hands on experience, the necessary skills to evaluate genetic and ischemic determinants of arrhythmia risk due to acute emotional stress; and (3) learn core clinical research skills to plan and execute patient-oriented studies, including hands-on training with patients in the clinical research lab. Dr. Shah has assembled a mentoring team comprised of a primary mentor, Dr. Viola Vaccarino, Chair of Epidemiology, and renown expert on psychological risk factors of heart disease, and 2 co-mentors who are long-standing collaborators with Dr. Vaccarino, including Dr. Rachel Lampert, a Yale electrophysiologist who is an expert in emotional determinants of arrhythmia, and Dr. J Douglas Bremner (co-mentor), an Emory psychiatrist and radiologist with expertise in nuclear imaging and traumatic stress. The epidemiology, mechanisms, and therapies for emotionally-triggered arrhythmia are difficult to study because many ventricular arrhythmias are fatal. As a solution to this conundrum, Dr. Shah proposes to study surrogate ECG markers of arrhythmia during laboratory-induced acute mental stress in a large study of nearly 1,000 CHD patients led by his mentor, Dr. Vaccarino (R01 HL109413), and advisor, Dr. Quyyumi (P01 HL101398). In this well-characterized, genotyped and phenotyped cohort, he will study the relationships of autonomic modulation during stress and mental stress ischemia with arrhythmia risk during stress (T-wave alternans and spatial QRS-T angle) in Aim 1. Specifically, he will evaluate to what extent electrical instability may develop due to parasympathetic withdrawal (reduced HRV), and sympathetic activation (increased norepinephrine and vasoconstriction). To assess potential molecular targets and better risk stratify high-risk subjects, he will study select adrenergic/cholinergic genetic receptor polymorphisms that may influence electrical instability during mental stress (Aim 2). Finally, in aim 3, he will evaluate the prognostic value of stress reactivity based on autonomic and electrophysiologic measures under study towards major adverse cardiac events and death. Overall, this research will form the basis for larger studies that systematically evaluate risk prediction strategies and possible treatments such as cognitive therapy and biofeedback in CHD patients.