Myocyte Repolarization and Cardiac Dysfunction with Age

随年龄增长的心肌细胞复极化和心脏功能障碍

• 批准号: 9920638
• 负责人: Marcello Rota
• 金额: $ 40.41万
• 依托单位: NEW YORK MEDICAL COLLEGE
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-01 至 2023-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9920638
• 关键词: Ablation; Action Potentials; Address; Adoption; Adrenergic Agents; Adrenergic beta-Agonists; Age; Aging; Animals; Arrhythmia; Cardiac; Cardiac Myocytes; Cardiac development; Cardiovascular Diseases; Cause of Death; Cells; Complex; Congestive Heart Failure; Coupled; Coupling; Data; Defect; Deterioration; Development; Drug Targeting; Elderly; Electrophysiology (science); Event; Failure; Feedback; Frequencies; Functional disorder; Genetic; Genetic Engineering; Genetically Engineered Mouse; Heart; Homeostasis; Human; Impairment; Incidence; Intervention; Kinetics; Left; Life; Link; Macromolecular Complexes; Mechanics; Mediating; Modification; Mus; Muscle; Muscle Cells; Mutation; Myocardial; Myocardial dysfunction; Myocardium; Myopathy; Organ Donor; Performance; Pharmacology; Phenotype; Phosphorylation; Phosphorylation Site; Population; Preventive; Process; Property; Recovery; Relaxation; Risk Factors; Rodent; Role; Ryanodine Receptor Calcium Release Channel; Ryanodine Receptors; Sarcoplasmic Reticulum; Secondary to; Stress; Structure; Testing; Therapeutic; Tissues; Transplantation; Ventricular; Ventricular Remodeling; Work; Workload; age related; aged; attenuation; calmodulin-dependent protein kinase II; defined contribution; direct application; exercise intolerance; heart function; hemodynamics; in vivo; indexing; loss of function; novel strategies; novel therapeutics; older patient; operation; prevent; receptor function; response; senescence; therapeutic target; voltage

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.

7。项目摘要/摘要 衰老是慢性心力衰竭的主要独立危险因素，是老年人的主要死亡原因， 这构成了美国人口中预计将在未来几十年增加的大部分地区。因此， 识别衰老肌病起源和进展的因素以及发育 为了抵消预计增长的预防和治疗策略是必要的 心血管疾病的发生率。该提议的中心假设是NA+晚期增加 与年龄的电流（inal）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。继发于增强的细胞内Na+的增加 老年心肌细胞中的Na+电流晚期可能会影响Ca2+循环，并为老年人提供肌力支撑 心肌。但是，该过程的不平衡可能导致恶性积极反馈循环 包括Ca2+/钙调蛋白依赖性蛋白激酶II（CAMKII）以及磷酸化和操作 Na+通道和ryanodine受体。因此，异常Na+和Ca2+稳态被视为主要 衰老心脏中延迟的机电耦合和舒张功能障碍的成分。到 测试这些可能性，最初我们将确定在人心脏的肌细胞中是否会增强inal， 雇用供体器官的移植下降。随后，我们将使用工程的遗传增益和 功能丧失的小鼠线可调节心肌细胞中的无性。造成增加或未能的影响 在体内将建立在Ca2+循环，机电耦合和舒张功能上的不合时宜的增强 不同年龄的小鼠，剖析增强的晚期Na+电流对表现的贡献 衰老的肌病。此外，CAMKII活性，细胞内Na+载荷和Ryanodine受体的调节 将通过实验诱导功能，以获取有关链接Inal的事件级联的机械信息， 心律不齐和舒张功能障碍的发生率。恶性反馈循环的组成部分是 随着衰老的重大改变。总的来说，我们的工作将定义 对年龄心肌的有缺陷性能的心室心肌的电生理重塑。 拟议的研究也有可能确定药理学干预的治疗靶标 预防或延迟衰老心脏的进行性功能恶化。