Electrophysiological effects of Metabolic Stress and Calcium Handling by CRT

CRT 代谢应激和钙处理的电生理效应

基本信息

批准号：
8011126
负责人：
Gordon Frank Tomaselli
金额：
$ 40.26万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-07-01 至 2015-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8011126
关键词：
Action Potentials Acute Adrenergic Agents Affect American Anterior Arrhythmia Calcium Calcium/calmodulin-dependent protein kinase Canis familiaris Cardiac Cell membrane Cells Chronic Clinical Trials Coupling Cross-Linking Reagents Cyclic AMP-Dependent Protein Kinases Data Defect Development Electrophysiology (science)Equilibrium Exhibits Exposure to Felis catus Functional disorder Funding Generations Glutathione Goals Heart Heart failure Homeostasis Hospitalization Ions Ischemia Lateral Lead Left Link Measurement Measures Mechanics Mediating Membrane Potentials Messenger RNA Metabolic Metabolic stress Metabolism Methods Mitochondria Molecular Morbidity - disease rate Myocardial NADH Oxidation-Reduction Patients Performance Phosphotransferases Post-Translational Protein Processing Predisposition Production Proteins Regulation Reperfusion Therapy Role Sarcoplasmic Reticulum Signal Transduction Structure Structure of thyroid parafollicular cell Sulfhydryl Compounds Symptoms System Tissues Treatment Efficacy Variant Ventricular Ventricular Arrhythmia Work adrenergic antioxidant therapy follow-up improved mitochondrial membrane mortality programs response uptake

项目摘要

Over 5 million Americans suffer from heart failure (HF) and more than 250,000 die annually. Cardiac resynchronization therapy (CRT) produces unprecedented improvement in the efficiency of myocardial energy utilization and a number of clinical trials demonstrate the efficacy of this therapy in improving symptoms, reducing HF hospitalizations and overall mortality. The mechanisms by which CRT improves cardiac function are only beginning to be unraveled. The failing heart exhibits remodeling of structure, metabolism, electrophysiology and ion homeostasis with maladaptive consequences. However, the causes of acute mechanical decompensation and lethal ventricular arrhythmias in the failing heart are often obscure. The failing heart exhibits altered energy utilization and redox balance that affects ionic curtents, ion homeostasis, and Ca2+ handling, each of which in turn will modulate the action potential (AP) and arrhythmia susceptibility. CRT resynchronizes mechanical contraction and alters ventricular activation. Work from our previous period of funding demonstrates that remodeling of electrophysiology and Ca 2+ handling is regionally heterogeneous and distinct in failing hearts with (DHF) and without dyssynchronous contraction. The improvement in LV performance with CRT is linked to remarkable cellular and molecular regional restitution of cardiac electrophysiology and Ca 2+ handling, even in the context of ongoing HF. This project will examine the mechanisms by which CRT improves global and regional maladaptive changes in metabolism, and Ca 2+ handling in DHF and the consequences for the electrophysiology of the heart. Examination of different variants of HF and resynchronization will permit determine the contributions of synchronization of contraction and biventricular pacing to the beneficial effects of CRT. The hypotheses underlying this project are that 1. CRT is an antioxidant therapy that antagonizes maladaptive ion homeostatic remodeling and exaggerated responses to acute metabolic stress by improving mitochondrial function, energy regulation and redox balance in DHF. 2. CRT reverses the functional defects that contribute to defective Ca2+ handling by improving Na"" homeostasis and reversal of maladaptive adrenergic, CaMK and ROS signaling.

超过500万美国人患有心力衰竭（HF），每年有超过250,000人死亡。心脏重新同步疗法（CRT）在心肌利用效率方面具有前所未有的提高，许多临床试验证明了这种疗法在改善症状，降低HF住院和整体死亡率方面的功效。 CRT改善心脏功能的机制才开始爆发。失败的心脏表现出对结构，代谢，电生理学和离子稳态的重塑，并具有适应不良的后果。然而，急性机械代偿作用和致命性心律失常的原因通常是晦涩的。失败的心脏表现出改变的能量利用率和氧化还原平衡，影响离子柜，离子稳态和CA2+处理，每种操作都将调节动作电位（AP）和心律不齐的敏感性。 CRT重新同步机械收缩并改变心室激活。我们上一期资金的工作表明，对电生理学和Ca 2+处理的重塑是区域异质性的，并且在患有（DHF）的失败心脏中，并且没有异步收缩。 CRT使用CRT的LV性能的改善与心脏电生理学和Ca 2+处理的显着细胞和分子区域恢复有关，即使在持续的HF背景下也是如此。该项目将研究CRT改善代谢的全球和区域适应不良变化的机制，以及DHF中的Ca 2+处理以及对心脏电生理学的后果。检查HF的不同变体和重新同步的样子将允许确定收缩和双心脏起搏同步对CRT的有益作用的贡献。该项目的基础假设是1。CRT是一种抗氧化剂疗法，可拮通过改善DHF中的线粒体功能，能量调节和氧化还原平衡，适应不良的离子稳态重塑和对急性代谢应激的反应。 2。CRT逆转了通过改善NA“”“”稳态和适应不良肾上腺素能，CAMK和ROS信号传导的稳态和逆转而导致有缺陷Ca2+处理的功能缺陷。