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.

摘要 射血分数保留性心力衰竭（HFpEF）已成为最常见的心力衰竭形式 在退伍军人中，目前缺乏已被证明可以改善的治疗策略。 预后对于这种日益普遍的疾病缺乏有效疗法的主要原因是， 对心肌硬化的机制了解有限，心肌硬化是心肌硬化的一个关键病理生理组成部分， HFpEF与劳力性呼吸困难直接相关，这是该疾病的主要表现症状。的 该提案的首要目标是通过阐明重复牵张诱导的 心肌细胞外基质（ECM）重塑作为慢性冠状动脉病变 疾病（CAD）和HFpEF，这两种疾病在退伍军人群体中非常常见。基于我们 从多个临床相关的猪心脏病模型的初步数据，我们假设， 在慢性CAD的情况下，由于反复牵张诱导的 由左心室（LV）前负荷间歇性升高引起的纤维化。如果是这样的话，这可能解释了为什么 大部分HFpEF人群表现出血管造影显著的心外膜CAD（约60-70%， 多个队列），并可能具有与冠状动脉血运重建术相关的重要临床意义 在这些患者中，由于反复牵张诱导的心肌纤维化的可逆性尚不清楚。 为了验证这一假设，我们将利用慢性心外膜CAD的猪模型，以更好地了解如何 暴露于间歇性前负荷升高影响左侧缺血和非缺血区域的重塑 在这种情况下，在目标1中，植入式遥测将用于连续血流动力学监测， 量化多血管（MV-CAD）或单血管CAD猪的前负荷升高频率 （SV-CAD），并确定是否需要重复的前负荷升高来发展间质性 远端非缺血心肌纤维化。在目标2中，将在猪中进行经皮血管成形术 与MV-CAD和SV-CAD猪，以确定是否与MV-CAD相关的重复拉伸诱导的僵硬。 CAD决定了左心室纤维化是否可以通过血运重建逆转。离体心脏的尸检分析 将在目标3中完成来自这些模型的成纤维细胞和脱细胞心脏ECM， ECM依赖性成纤维细胞活化在反复牵张诱导的LV硬化中的作用，并确定 ECM硬度的增加本身会导致成纤维细胞活化延长，从而促进持续性纤维化， 自我维持的正反馈回路 这些目标将由一个多学科调查小组采用综合研究方法加以解决。 将局部和整体心肌力学的系列研究与离体力学结合起来的方法 以及心肌组织条、分离的心脏成纤维细胞和脱细胞心脏ECM的生物学分析。 总的来说，这些在预防性相关的猪心脏病模型中的实验预计将 建立重复牵张诱导的ECM重塑作为CAD和HFpEF之间的机制联系， 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 退伍军人与这些日益普遍的条件。