Myocyte Repolarization and Cardiac Dysfunction with Age

7.项目摘要/摘要 老龄化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， 这在美国人口中占了很大一部分，预计未来几十年还会增加。因此， 老年性肌病发生发展的相关因素鉴定及进展 为老年患者制定预防和治疗策略是必要的，以抵消预计的增长 心血管疾病的发病率。这一提议的中心假设是晚期Na+增加 电流随年龄增长是电生理和功能缺陷的主要决定因素 衰老的心肌细胞和脑室。细胞内Na+的增加继发于细胞内钙离子浓度的增加 老年心肌细胞晚钠电流可能影响钙循环并为老年人提供变力支持 心肌。然而，过程的不平衡可能会导致一个恶性的正反馈循环 包括钙/钙调素依赖的蛋白激酶II(CaMKII)和磷酸化及其操作 Na+通道和兰尼定受体。因此，异常的Na+和Ca2+稳态被认为是主要的 衰老心脏延迟机电耦合和舒张期功能障碍的成分。至 测试这些可能性，最初我们将确定INT在老年人心脏的心肌细胞中是否增强， 拒绝使用供体器官进行移植。随后，我们将使用基因工程获得--以及 功能丧失的小鼠系对心肌细胞的调节作用。原始值的增加或失败的影响 增强体内钙循环、机电耦合和舒缩功能的研究将在 不同月龄小鼠，解剖晚期Na+电流增强对其表现的贡献 老年性肌病。此外，CaMKII活性、细胞内Na+负荷和兰尼定受体的调节 函数将在实验中被诱导以获得关于链接初始的事件级联的机制信息， 心律失常和舒张期功能障碍的发生率。无论恶性反馈循环的组件是否 随着年龄的增长而发生严重变化的情况也将得到确立。总体而言，我们的工作将定义 心室肌细胞电生理重构对老年心肌功能缺陷的影响。 此外，拟议的研究也有可能确定药物干预的治疗靶点 预防或延缓老化心脏功能的进行性恶化。

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.