Myocyte Repolarization and Cardiac Dysfunction with Age

7.项目总结/摘要 衰老是慢性心力衰竭的主要独立危险因素，也是老年人死亡的主要原因， 这构成了预计在未来几十年将增加的美国人口的重要部分。因此，在本发明中， 识别参与衰老性肌病的起源和发展的因素， 预防和治疗策略的老年患者是必要的，以抵消预计的增长 心血管疾病的发病率。这一建议的中心假设是，增加晚期Na+ 电流（INaL）随年龄的变化是电生理和功能缺陷的主要决定因素， 衰老的肌细胞和心室。细胞内Na+的增加继发于细胞内Na+浓度的增加。 老年心肌细胞的迟发Na+电流可能影响Ca ~（2+）循环，为老年心肌细胞提供正性肌力支持 心肌然而，过程的不平衡可能导致恶性的正反馈循环 包括Ca 2 +/钙调蛋白依赖性蛋白激酶II（CaMKII）和磷酸化以及 钠离子通道和兰尼碱受体。因此，异常的Na+和Ca 2+稳态被认为是主要的 在衰老的心脏中，延迟的机电耦合和舒张功能障碍的组成部分。到 测试这些可能性，首先我们将确定INaL是否在老年人心脏的肌细胞中增强， 使用被拒绝的捐赠器官进行移植。随后，我们将使用工程遗传增益-和 功能丧失小鼠系调节心肌细胞中的INaL。INaL增加或未能 增强INaL对体内Ca 2+循环、机电耦合和舒张功能的影响， 不同年龄的小鼠，以解剖增强的晚Na+电流对表现的贡献， 衰老性肌病此外，调节CaMKII活性、细胞内Na+负荷和兰尼碱受体， 功能将通过实验诱导，以获得关于连接INaL的事件级联的机制信息， 心律失常和舒张功能障碍的发生率。恶性反馈循环的组成部分是否 随着年龄的增长也会发生严重的变化。总的来说，我们的工作将确定 心室肌细胞的电生理重构对老年心肌功能缺陷的影响。 此外，拟议的研究有可能确定药物干预的治疗靶点， 预防或延迟老化心脏的进行性功能退化。

7. Project Summary/Abstract Aging is the major independent risk factor of chronic heart failure and the leading cause of death in the elderly, which constitutes a significant segment of the US population predicted to increase in the next decades. Thus, identification of factors involved in the origin and progression of aging myopathy together with the development of preventive and therapeutic strategies for elderly patients are necessary to counteract the projected growing incidence of cardiovascular diseases. The central hypothesis of this proposal is that increased late Na+ current (INaL) with age is a major determinant of the electrophysiological and functional defects of senescent myocytes and ventricles. The increase in intracellular Na+ secondary to the enhancement of the late Na+ current in aged cardiomyocytes may influence Ca2+ cycling and provide inotropic support to the aged myocardium. However, imbalance of the process may result into a vicious positive feedback loop comprising the Ca2+/calmodulin-dependent protein kinase II (CaMKII) and phosphorylation and operation of Na+ channels and ryanodine receptors. Thus, aberrant Na+ and Ca2+ homeostasis are viewed as major components of the delayed electromechanical coupling and diastolic dysfunction in the senescent heart. To test these possibilities, initially we will establish whether INaL is enhanced in myocytes of aged human heart, employing donor organ declined for transplantation. Subsequently, we will use engineered genetic gain- and loss-of-function mouse lines to modulate INaL in cardiomyocytes. The effects of INaL increase or failure to enhance INaL on Ca2+ cycling, electromechanical coupling, and diastolic function in vivo will be established in mice at different age, to dissect the contribution of enhanced late Na+ currents on the manifestation of the aging myopathy. Moreover, modulation of CaMKII activity, intracellular Na+ load, and ryanodine receptor function will be induced experimentally to gain mechanistic information on the cascade of events linking INaL, incidence of arrhythmias, and diastolic dysfunction. Whether components of the vicious feedback loop are critically altered with aging will also be established. Collectively, our work will define the contributions of electrophysiological remodeling of ventricular myocytes on the defective performance of the aged myocardium. Also proposed studies have the potential to identify therapeutic targets of pharmacological intervention to prevent or delay the progressive functional deterioration of the aging heart.