Repetitive Stretch-Induced Myocardial Stiffening in Chronic Coronary Artery Disease

慢性冠状动脉疾病中反复牵拉引起的心肌硬化

• 批准号: 10588929
• 负责人: Brian Raymond Weil
• 金额: --
• 依托单位: VA WESTERN NEW YORK HEALTHCARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-01 至 2027-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10588929
• 关键词: Address; Adhesives; Aging; Angiography; Angioplasty; Area; Autopsy; Biochemical; Biological; Blood capillaries; Cardiac; Cardiovascular Diseases; Cardiovascular system; Cause of Death; Cessation of life; Chronic; Classification; Clinical; Collagen; Congestive Heart Failure; Coronary; Coronary Arteriosclerosis; Coronary Vessels; Data; Deposition; Development; Disease; Dyspnea; EFRAC; Evidence based treatment; Exertion; Exhibits; Exposure to; Extracellular Matrix; Family suidae; Feedback; Fibrillar Collagen; Fibroblasts; Fibrosis; Frequencies; Functional disorder; Glycoproteins; Glycosaminoglycans; Goals; Healthcare Systems; Heart Diseases; Heart failure; Heterogeneity; Hospitalization; Hypertension; Implant; Investigation; Ischemia; Left; Left Ventricular Mass; Left ventricular structure; Link; Mechanics; Medicine; Modeling; Monitor; Morbidity - disease rate; Myocardial; Myocardial tissue; Myocardium; Obesity; Outcome; Patients; Phenotype; Phenylephrine; Population; Prevalence; Process; Prognosis; Property; Quality of life; Research; Risk; Risk Factors; Role; Stenosis; Stretching; Symptoms; Telemetry; Testing; Vascularization; Ventricular; Veterans; clinically relevant; cohort; comorbidity; coronary fibrosis; disability; effective therapy; experience; experimental study; hemodynamics; improved; interstitial; military veteran; mortality; multidisciplinary; new therapeutic target; novel; novel therapeutic intervention; porcine model; preservation; pressure; prevent; therapy design; treatment strategy

Abstract Heart failure with preserved ejection fraction (HFpEF) has emerged as the most common form of heart failure among Veterans, yet there is currently a paucity of treatment strategies that have been proven to improve prognosis. A primary reason for the lack of effective therapies for this increasingly prevalent condition is the limited understanding of mechanisms underlying myocardial stiffening, a key pathophysiologic component of HFpEF that is directly linked to exertional dyspnea, the cardinal presenting symptom of the disorder. The overarching goal of this proposal is to address this problem by elucidating the role of repetitive stretch-induced remodeling of the cardiac extracellular matrix (ECM) as a mechanistic link between chronic coronary artery disease (CAD) and HFpEF, two conditions that are extremely common in the Veteran population. Based on our preliminary data from multiple clinically-relevant swine models of heart disease, we hypothesize that myocardial stiffening develops in the setting of chronic CAD as a result of repetitive stretch-induced fibrosis caused by intermittent elevations in left ventricular (LV) preload. If so, this may explain why such a large proportion of the HFpEF population exhibits angiographically-significant epicardial CAD (~60-70% in multiple cohorts) and might have important clinical implications related to the use of coronary revascularization in these patients, since the reversibility of repetitive stretch-induced myocardial fibrosis is unclear. To test this hypothesis, we will utilize a porcine model of chronic epicardial CAD to better understand how exposure to episodic preload elevation influences remodeling of ischemic and non-ischemic regions of the left ventricle in this setting. In Aim 1, implantable telemetry will be used for continuous hemodynamic monitoring to quantify the frequency of preload elevation in swine with either multi-vessel (MV-CAD) or single-vessel CAD (SV-CAD) and determine whether repetitive preload elevation is required for the development of interstitial fibrosis in remote, non-ischemic myocardium. In Aim 2, percutaneous angioplasty will be performed in swine with MV-CAD and swine with SV-CAD to determine if repetitive stretch-induced stiffening associated with MV- CAD dictates whether LV fibrosis is reversed by revascularization. Post-mortem analysis of isolated cardiac fibroblasts and decellularized cardiac ECM from these models will be completed in Aim 3 to assess the mechanistic role of ECM-dependent fibroblast activation in repetitive stretch-induced LV stiffening and determine whether increased ECM stiffness per se causes protracted fibroblast activation that promotes persistent fibrosis through a self-sustaining positive feedback loop. These aims will be addressed by a multi-disciplinary investigative team using an integrative research approach that combines serial investigation of regional and global myocardial mechanics with ex vivo mechanical and biological analysis of myocardial tissue strips, isolated cardiac fibroblasts, and decellularized cardiac ECM. Collectively, these experiments in translationally-relevant swine models of heart disease are expected to establish repetitive stretch-induced ECM remodeling as a mechanistic link between CAD and HFpEF and facilitate the development of novel therapeutic strategies to reduce the unacceptably high morbidity and mortality of Veterans with these increasingly prevalent conditions.

抽象的 保留的射血分数（HFPEF）的心力衰竭已成为心力衰竭的最常见形式 在退伍军人中，目前有缺乏治疗策略已被证明可以改善 预后。缺乏有效疗法的这种越来越普遍状况的主要原因是 对心肌僵硬基础机制的了解有限，这是关键的病理生理组成部分 HFPEF与劳累呼吸困难直接相关，这是疾病的基本症状。这 该提案的总体目标是通过阐明重复伸展引起的作用来解决此问题 心脏外基质（ECM）的重塑作为慢性冠状动脉之间的机械联系 疾病（CAD）和HFPEF，在退伍军人人口中极为常见的两个疾病。基于我们 来自多个临床上与心脏病的猪模型的初步数据，我们假设 重复伸展引起 由左心室（LV）预紧力的间歇性升高引起的纤维化。如果是这样，这可以解释为什么这样 大部分HFPEF人群表现出血管造影显着的心外膜CAD（约60-70％ 多个队列），可能具有与冠状动脉血运重建有关的重要临床意义 在这些患者中，由于重复拉伸诱导的心肌纤维化的可逆性尚不清楚。 为了检验这一假设，我们将利用慢性心外膜CAD的猪模型更好地了解 暴露于情节预紧的高程会影响左侧缺血和非缺血区域的重塑 在这种情况下的心室。在AIM 1中，可植入遥测将用于连续血流动力学监测到 用多卷赛（MV-CAD）或单卷赛CAD量化猪中预紧升高的频率 （SV-CAD）并确定是否需要重复的预紧抬高才能开发间隙 遥远的非缺血性心肌中的纤维化。在AIM 2中，将在猪中进行经皮血管成形术 使用MV-CAD和SVINE带有SV-CAD，以确定重复的拉伸诱导的僵硬是否与MV-相关 CAD决定了LV纤维化是否因血运重建而逆转。孤立心脏的验尸分析 这些模型的成纤维细胞和脱细胞性心脏ECM将在AIM 3中完成，以评估机械 ECM依赖性成纤维细胞激活在重复拉伸诱导的LV僵硬中的作用，并确定是否是否 ECM刚度的增加本身会导致长期的成纤维细胞激活，从而通过A促进持续的纤维化 自我维持的积极反馈循环。 这些目标将由综合研究通过多学科的调查团队来解决 结合了区域和全球心肌力学的系列研究与离体机械的方法 以及心肌组织条，孤立心脏成纤维细胞和脱细胞心脏ECM的生物学分析。 总的来说，这些与翻译相关的心脏病模型中的实验预计将是 建立重复的拉伸诱导的ECM重塑作为CAD和HFPEF之间的机械联系 促进新的治疗策略的发展，以降低不可接受的高发病率和死亡率 越来越普遍的条件的退伍军人。