T Wave Alternans and Repolarization Abnormalities

描述（由申请人提供）： 心室复极异常是导致严重心律失常的重要原因。本研究旨在提高我们对左室功能障碍患者复极异常的预后意义和自主神经机制的理解。T波电交替（TWA）是一种与室性心律失常发生有关的T波振幅或形状的2：1波动。我们以前已经证明，TWA与接受EP研究的患者的自发性脑血管事件有关。本基金提出了两项大型前瞻性流行病学研究，旨在明确检验TWA与LV功能障碍患者（1）尚未发生心脏事件和（2）出现晕厥的患者发生心脏事件的风险增加相关的假设。这些流行病学研究将与旨在表征LV功能障碍患者复极自主调节的机制研究相结合。我们先前在健康受试者中证实，与阿托品相比，异丙肾上腺素与给定心率下较长的QT间期和较大的U波振幅相关。一系列的研究提出，探讨交感神经-副交感神经的相互作用如何调节复极，并区分两个方面的影响13-阻滞剂对复极：直接影响和长期影响自主平衡。总之，这些研究将建立一套新的方法，用于评估不同疾病状态和药物反应的自主神经复极调节。来自K24的支持将使申请人能够投入大量的精力来开发这项研究，作为指导临床研究者的综合计划的一部分。 该计划将包括密集的临床研究经验，教学课程，数据演示和赠款写作培训。一个由专家组成的严格审查委员会将为该计划的研究人员提供建议和监督他们的进展。哥伦比亚大学及其附属医疗中心是心力衰竭和心律失常患者最大的转诊中心之一，并在流行病学和生物统计学方面有积极的培训计划，这对申请人实现本提案的目的和培训以患者为导向的研究中的初级研究者非常宝贵。

DESCRIPTION (provided by the applicant): Abnormalities in ventricular repolarization contribute importantly to the pathogenesis of life-threatening arrhythmias. This research program seeks to improve our understanding of the prognostic significance of and the autonomic mechanisms underlying repolarization abnormalities in patients with LV dysfunction.T wave alternans (TWA) is a 2:1 fluctuation in the amplitude or shape of T wave that has been linked to the genesis of ventricular arrhythmias. We have previously demonstrated that TWA is associated with spontaneous arrhythmic events in patients undergoing an EP study. Two large prospective epidemiologic studies are proposed in this grant designed and powered to definitively test the hypotheses that TWA is associated with an increased risk of having an arrhythmic event in patients with LV dysfunction (1) who have not yet had an arrhythmic event, and (2) who present with syncope. These epidemiologic studies will be combined with mechanistic studies designed to characterize autonomic modulation of repolarization in patients with LV dysfunction. We previously demonstrated in healthy subjects that isoproterenol was associated with longer QT intervals and greater U wave amplitude at a given heart rate compared to atropine. A series of studies are proposed to explore how sympathetic-parasympathetic interactions modulate repolarization, and to distinguish two aspects of the effects of 13-blockers on repolarization: direct effects and long-term effects on autonomic balance. Taken together, these studies will establish a new set of methods for evaluating the autonomic modulation of repolarization in different disease states and in response to drugs. The support from this K24 will enable the applicant to devote a substantial amount of effort towards developing this research as part of a comprehensive program to mentor clinical investigators. This program will include an intensive clinical research experience, didactic courses, training in data presentation and grant writing. A Critical Review Committee of experts will advise and monitor the progress of the research fellows in the program. Columbia University and its affiliated medical center represent one of the largest referral centers anywhere for patients with both heart failure and arrhythmias, and have active training programs in Epidemiology and Biostatistics which will be invaluable to the applicant in accomplishing the Aims of this proposal and in training junior investigators in patient-oriented research.