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 射血分数保留的心力衰竭（HFpEF）已成为最常见的心力衰竭形式 在退伍军人中，但目前缺乏已被证明可以改善病情的治疗策略 预后。这种日益流行的疾病缺乏有效疗法的主要原因是 对心肌僵硬的机制了解有限，心肌僵硬是心肌梗塞的关键病理生理学组成部分 HFpEF 与劳力性呼吸困难直接相关，劳力性呼吸困难是该疾病的主要症状。这 该提案的总体目标是通过阐明重复拉伸诱导的作用来解决这个问题 心脏细胞外基质（ECM）的重塑作为慢性冠状动脉之间的机械联系 疾病 (CAD) 和 HFpEF，这两种疾病在退伍军人群体中极为常见。基于我们的 根据来自多种临床相关猪心脏病模型的初步数据，我们假设 慢性 CAD 患者由于反复牵拉引起心肌僵硬 左心室（LV）前负荷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 很大一部分 HFpEF 人群表现出血管造影显着的心外膜 CAD（约 60-70% 多个队列），并且可能具有与冠状动脉血运重建相关的重要临床意义 在这些患者中，由于重复拉伸引起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 的猪模型来更好地了解如何 暴露于间歇性前负荷升高会影响左侧缺血和非缺血区域的重塑 心室在这种情况下。在目标 1 中，植入式遥测技术将用于连续血流动力学监测，以 使用多血管 (MV-CAD) 或单血管 CAD 量化猪预载升高的频率 (SV-CAD) 并确定间隙的形成是否需要重复预载抬高 远端非缺血心肌纤维化。在目标 2 中，将在猪身上进行经皮血管成形术 使用 MV-CAD 和猪使用 SV-CAD 来确定重复拉伸引起的僵硬是否与 MV- CAD 决定了左室纤维化是否可以通过血运重建来逆转。离体心脏的尸检分析 来自这些模型的成纤维细胞和脱细胞心脏 ECM 将在目标 3 中完成，以评估其机制 ECM 依赖性成纤维细胞激活在重复牵拉引起的 LV 僵硬中的作用，并确定是否 ECM 硬度增加本身会导致成纤维细胞活化延长，从而通过 自我维持的正反馈循环。 这些目标将由多学科调查小组利用综合研究来实现 将区域和整体心肌力学的系列研究与离体力学相结合的方法 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，这些在与转化相关的心脏病猪模型中进行的实验预计将 建立重复拉伸诱导的 ECM 重塑作为 CAD 和 HFpEF 之间的机械联系 促进新治疗策略的开发，以降低令人难以接受的高发病率和死亡率 患有这些日益普遍的病症的退伍军人。