Calcineurin-Dependent Electrical Remodeling in Cardiac Hypertrophy and Failure

描述(申请人提供)：心脏肥厚与不良心血管事件有关，包括心律失常和猝死的风险增加。钙调神经磷酸酶是一种细胞质蛋白磷酸酶，已被证明是肥厚性心脏病发病机制的主要因素。关于钙调神经磷酸酶在疾病相关的心脏电重构中的作用，人们知之甚少。这项建议的长期目标是阐明与心肌肥厚相关的心律失常的机制以及钙调神经磷酸酶在其中的作用。假说是钙调神经磷酸酶的激活独立地触发了成人心脏的电重构，并与压力超负荷肥厚有关。目的：检测钙调神经磷酸酶激活对发育完全的成人心脏电生理特性的影响。将研究表达受调控的、心脏特异的、具有结构性活性的钙调神经磷酸酶转基因小鼠。将进行活体电生理学(EP)研究，以测量每只小鼠心脏的电特性。将测试对诱导性室性心律失常的敏感性。目的：探讨钙调神经磷酸酶依赖的电重构与心肌肥厚和衰竭发展的关系。钙调神经磷酸酶激活的事件的时间进程将决定电重构是否独立于肥厚性生长而发展。数据将使用体内EP研究、超声心动图、组织成像和分子分析来收集。目的：探讨钙调神经磷酸酶激活在压力超负荷性肥厚相关的电重构中的作用。将使用压力超负荷的小鼠心肌肥大的外科模型。过表达钙调神经磷酸酶相互作用蛋白1(MCIP1)的转基因小鼠将被研究，MCIP1是钙调神经磷酸酶的内源性抑制物。这些实验的结果将为了解与心肌肥厚相关的节律紊乱的机制提供亟需的见解。这样的研究对于开发新的心律失常治疗方法和预防心脏性猝死至关重要。相关性：每年有超过30万美国人经历猝死，即心脏停止跳动，几乎没有任何警告迹象。这里提出的研究将调查肥厚性心脏病患者如何发生猝死。这项工作的结果可能会导致制定更有效的战略来预防这些灾难性事件。

DESCRIPTION (provided by applicant): Cardiac hypertrophy is associated with adverse cardiovascular events, including an increased risk of arrhythmias and sudden death. Calcineurin, a cytoplasmic protein phosphatase, has been shown to be a major contributor to the pathogenesis of hypertrophic heart disease. Very little is known regarding the role of calcineurin in disease-related electrical remodeling of the heart. The long-term objective of this proposal is to elucidate mechanisms of arrhythmias associated with cardiac hypertrophy and the role of calcineurin therein. The hypothesis is that calcineurin activation triggers electrical remodeling of the adult heart independently and in association with pressure-overload hypertrophy. The specific aims are Aiml: To test the effect of calcineurin activation on the electrophysiological properties of the fully developed adult heart. Transgenic mice that express a regulated, cardiac-specific, constitutively active calcineurin transgene will be studied. In vivo electrophysiology (EP) studies will be performed to measure the electrical characteristics of each murine heart. Susceptibility to inducible ventricular arrhythmias will be tested. Aim2: To define the development of calcineurin-dependent electrical remodeling in relation to the development of cardiac hypertrophy and failure. A time course of the events occurring with calcineurin activation will determine whether electrical remodeling develops independently of hypertrophic growth. Data will be collected using in vivo EP studies, echocardiograms, histological imaging, and molecular analyses. Aim3: To test the role of calcineurin activation in the electrical remodeling that occurs in asssociation with pressure overload hypertrophy. A surgical model of pressure-overload cardiac hypertrophy in mice will be used. Transgenic mice that overexpress modulatory calcineurin-interacting protein 1 (MCIP1), an endogenous inhibitor of calcineurin, will be studied. The results of these experiments will provide much needed insight into the mechanisms of rhythm disturbances associated with cardiac hypertrophy. Investigations such as these are critical to the development of new treatments for arrhythmias and the prevention of sudden cardiac death. Relevance: Over 300,000 Americans per year experience sudden death, in which the heart stops beating with few if any warning signs. Research proposed here will investigate how sudden death occurs in patients with hypertrophic heart disease. The results of this work may lead to more effective strategies for preventing these catastrophic events.