Identification of Novel Cellular/Molecular Mechanisms and Arrhythmia Targets in Heart Failure

心力衰竭的新型细胞/分子机制和心律失常目标的鉴定

• 批准号: 10618857
• 负责人: C. William Balke
• 金额: --
• 依托单位: ST. LOUIS VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10618857
• 关键词: Action Potentials; Affect; Animal Experimentation; Animal Model; Animals; Arrhythmia; Attenuated; Automobile Driving; Biochemical; Biophysics; Cardiac; Cardiac Electrophysiologic Techniques; Cardiac Myocytes; Cardiovascular Diseases; Cell surface; Critical Pathways; Diagnosis; Disease; EFRAC; Electrophysiology (science); Experimental Animal Model; Experimental Designs; Family; Foundations; Functional disorder; Goals; Health Care Costs; Heart; Heart Diseases; Heart failure; Hospitalization; Human; In Vitro; Individual; Infrastructure; Knowledge; Left; Left ventricular structure; Life; Maintenance; Membrane; Metabolic Diseases; Methods; Modeling; Molecular; Molecular Genetics; Morbidity - disease rate; Muscle Cells; Myocardial; Myocardium; Pathway interactions; Patients; Phase; Physiological; Physiology; Play; Population; Post-Translational Protein Processing; Procedures; Property; Public Health; Quality of life; RNA; Regulation; Research; Resources; Risk; Risk Reduction; Role; Shapes; Sudden Death; System; Testing; Tissues; Translating; Ventricular; Ventricular Arrhythmia; adenoviral mediated; cell type; clinically relevant; differential expression; experimental study; extracellular; heart rhythm; hospital readmission; indium arsenide; induced pluripotent stem cell; insight; mortality; new therapeutic target; novel; patient stratification; pharmacologic; preservation; prevent; programs; risk stratification; sudden cardiac death; targeted treatment; transcriptomic profiling; voltage

ABSTRACT Arrhythmogenic cardiovascular disease, which disproportionately affects individuals in the VA population with acquired cardiac and metabolic diseases, particularly heart failure, is associated with increased morbidity and mortality. The mechanisms contributing to increased risk of sudden cardiac death in individuals suffering arrhythmogenic cardiovascular disease, however, remain very poorly understood, hampering our ability to risk stratify patients and to develop novel, targeted therapeutic strategies. Although numerous experimental (animal/cellular) heart failure models have been developed and extensively studied, only limited insights into human arrhythmia mechanisms have been provided. Motivated to bridge this knowledge gap and advance the field, we have initiated a comprehensive research effort aimed at defining the mechanisms involved in the physiological regulation of membrane excitability in the human heart and the pathophysiological electrical remodeling associated with human heart failure. To enable direct molecular/biochemical and functional studies on human ventricular myocardium/myocytes, we developed the infrastructure to acquire non-failing and failing human hearts and we established robust, reliable methods for the isolation, in vitro maintenance, adenovirus- mediated transduction, and electrophysiological characterization of human ventricular myocytes. Here, we utilize these unique resources in experiments designed to define the molecular and cellular mechanisms controlling the expression, the properties and the remodeling of critical ionic currents that impact action potential repolarization, the late component of the voltage-gated Na+ (Nav) current, INa,L, and the novel non-inactivating K+ (Kv) current, IK,L, that we have recently identified in non-failing human left ventricles. We will define the roles of channel accessory subunits and post-translational modifications in controlling the cell surface expression and the biophysical and pharmacological properties of native human ventricular INa,L (aim #1) and IK,L (aim #2). In aim #2, we shall also explore the hypothesis that there are actually two, functionally and molecularly distinct components of human ventricular IK,L. Additional experiments (aim #3) will elucidate the molecular mechanisms underlying in INa,L and IK,L remodeling in failing human ventricles. These studies will provide new, clinically relevant insights into the cellular/molecular mechanisms contributing to the physiological regulation and pathophysiological remodeling of native human ventricular Ito,f, Iss and INa channels. These insights will transform the refinement of human cardiac myocyte and whole heart models and translate to novel, mechanism-based strategies to target specific cell types to reduce the risk of life-threatening ventricular arrhythmias in VA patients suffering heart failure.

抽象的 致心律失常性心血管疾病，对 VA 人群中的个体造成不成比例的影响 获得性心脏和代谢疾病，特别是心力衰竭，与发病率增加和 死亡。导致个体心源性猝死风险增加的机制 然而，我们对致心律失常性心血管疾病仍然知之甚少，这阻碍了我们冒风险的能力 对患者进行分层并制定新颖的、有针对性的治疗策略。尽管进行了大量的实验 （动物/细胞）心力衰竭模型已被开发并进行了广泛研究，但对这些模型的了解有限 已经提供了人类心律失常的机制。致力于弥合这一知识差距并推进 领域，我们发起了一项全面的研究工作，旨在确定涉及的机制 人心脏膜兴奋性的生理调节和病理生理电 与人类心力衰竭相关的重塑。实现直接的分子/生化和功能研究 在人类心室心肌/肌细胞上，我们开发了基础设施来获得非衰竭和衰竭 我们建立了强大、可靠的方法来分离、体外维持、腺病毒- 人心室肌细胞介导的转导和电生理学特征。在这里，我们利用 这些独特的实验资源旨在定义控制的分子和细胞机制 影响动作电位的临界离子电流的表达、性质和重塑 再极化、电压门控 Na+ (Nav) 电流的后期分量 INa,L 和新型非失活 K+ (Kv) 电流，IK,L，我们最近在非衰竭人类左心室中发现。我们将定义角色 通道辅助亚基和翻译后修饰控制细胞表面表达和 天然人心室 INa,L（目标 #1）和 IK,L（目标 #2）的生物物理和药理学特性。在 目标＃2，我们还将探索这样一个假设：实际上有两种在功能和分子上不同的 人心室 IK,L 的组成部分。额外的实验（目标#3）将阐明分子机制 人类心室衰竭中 INa,L 和 IK,L 重塑的基础。 这些研究将为细胞/分子机制提供新的、临床相关的见解，从而有助于 天然人心室 Ito,f, Iss 和 INa 的生理调节和病理生理重塑 渠道。这些见解将改变人类心肌细胞和整个心脏模型的完善， 转化为新颖的、基于机制的策略，针对特定细胞类型，以降低危及生命的风险 患有心力衰竭的 VA 患者的室性心律失常。