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 心律失常的心血管疾病，对VA人群中的个体不成比例 获得的心脏和代谢性疾病，尤其是心力衰竭，与发病率的增加有关 死亡。遭受痛苦的个体猝死风险增加的机制 然而，心律失常的心血管疾病仍然非常了解，阻碍了我们的风险能力 对患者进行分层并制定针对性的新型治疗策略。虽然很多实验 （动物/细胞）心力衰竭模型已经开发和广泛研究，只有有限的见解 已经提供了人体心律失常机制。动机弥合这一知识差距并提高 领域，我们发起了一项全面的研究工作，旨在定义涉及的机制 人心脏和病理生理电气中膜兴奋性的生理调节 重塑与人体心力衰竭相关。启用直接分子/生化和功能研究 关于人心室心肌/心肌细胞，我们开发了获得非损坏和失败的基础设施 人类的心和我们建立了可靠，可靠的方法来隔离，体外维持，腺病毒 - 介导的转导和人心室肌细胞的电生理表征。在这里，我们利用 这些独特的资源在旨在定义控制分子和细胞机制的实验中 影响动作电位的临界离子电流的表达，性质和重塑 复极化，电压门控的Na+（NAV）电流的晚期分量，INA，L和新型非活活的K+ （KV）Current，IK，L，我们最近在非击败人类左心室中识别出来。我们将定义角色 通道附件亚基和翻译后修改，以控制细胞表面表达和 本地人心室INA，L（AIM＃1）和IK，L（AIM＃2）的生物物理和药理特性。在 AIM＃2，我们还将探讨以下假设：实际上有两个，功能和分子不同 人室IK的成分，l。其他实验（AIM＃3）将阐明分子机制 在INA，L和IK的基础上，在人体心室失败的情况下进行了重塑。 这些研究将为有助于的细胞/分子机制提供新的，临床上相关的见解 人类室心ITO，F，ISS和INA的生理调节和病理生理重塑 频道。这些见解将改变人类心肌细胞和整个心脏模型的改进， 转化为针对特定细胞类型的新型基于机制的策略，以降低威胁生命的风险 VA患者心力衰竭的心室心律不齐。