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: 10454757
• 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 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10454757
• 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; Family; Foundations; Functional disorder; Goals; Health Care Costs; Heart; Heart Diseases; Heart failure; Hospitalization; Human; In Vitro; Individual; Infrastructure; Knowledge; Left; Left Ventricular Remodeling; Left ventricular structure; Life; Maintenance; Membrane; Metabolic Diseases; Methods; Modeling; Molecular; Molecular Genetics; Morbidity - disease rate; Muscle Cells; Myocardial; Myocardium; Pathway interactions; Patients; Pharmacology; Phase; Physiological; Physiology; Play; Population; Post-Translational Protein Processing; Procedures; Property; Public Health; Quality of life; RNA; Regulation; Research; Resources; Risk; Role; Shapes; Sudden Death; System; Testing; Tissues; Translating; Ventricular; Ventricular Arrhythmia; adenoviral-mediated; base; cell type; clinically relevant; density; design; differential expression; experimental study; extracellular; heart rhythm; indium arsenide; induced pluripotent stem cell; insight; mortality; new therapeutic target; novel; patient stratification; preservation; prevent; programs; risk stratification; sudden cardiac death; targeted treatment; transcriptome; 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.

摘要 致心律失常性心血管疾病，不成比例地影响VA人群中的个体， 获得性心脏和代谢疾病，特别是心力衰竭，与发病率增加有关， mortality.导致心脏性猝死风险增加的机制 然而，对致瘤性心血管疾病的了解仍然非常少，阻碍了我们冒险的能力。 对患者进行分层并开发新的、有针对性的治疗策略。虽然许多实验 （动物/细胞）心力衰竭模型已经被开发和广泛研究，仅有限地了解到 已经提供了人类心律失常机制。有动力弥合这一知识差距， 在这一领域，我们已经开始了一项全面的研究工作，旨在确定参与的机制， 人心脏膜兴奋性的生理调节和病理生理电生理 与人类心力衰竭有关的重塑。能够进行直接的分子/生物化学和功能研究 在人类心室肌/肌细胞上，我们开发了获得非衰竭和衰竭的基础设施， 我们建立了强大的，可靠的方法，用于分离，体外维持，腺病毒- 介导的转导和人心室肌细胞的电生理学表征。在这里，我们利用 这些独特的资源在实验设计，以确定分子和细胞机制控制 影响动作电位的临界离子电流的表达、性质和重构 复极化，电压门控Na+（Nav）电流的晚期成分，INa，L和新的非失活K+ (Kv)电流，IK，L，我们最近在非衰竭的人类左心室中发现的。我们将定义 通道辅助亚基和翻译后修饰控制细胞表面表达， 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性质。在 目标#2，我们也将探讨假设，实际上有两个，功能和分子上不同的 人心室肌IK、L.其他实验（目标3）将阐明分子机制 在衰竭的人心室中的INa，L和IK，L重塑中起基础作用。 这些研究将提供新的，临床相关的见解细胞/分子机制有助于 人心室肌Ito、f、Iss和INa生理调节和病理生理重构 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， 转化为新的，基于机制的策略，以靶向特定的细胞类型，以减少危及生命的风险， 患有心力衰竭的VA患者的室性心律失常。