Exercise Intolerance in Non Obstructive Hypertrophic Cardiomyopathy

非梗阻性肥厚型心肌病的运动不耐受

• 批准号: 10367724
• 负责人: THEODORE P ABRAHAM
• 金额: $ 80.75万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-05-01 至 2026-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10367724
• 关键词: Address; Affect; Ammonia; Apoptotic; Attenuated; Belief; Benign; Cardiac; Cicatrix; Clinical; Clinical Trials; Coronary; Data; Disease; EFRAC; Exercise; Exercise Physiology; Exercise Tolerance; Experimental Models; Frequencies; Genetic; Goals; Heart; Heart Diseases; Heart failure; Home; Hypertrophic Cardiomyopathy; Hypertrophy; Imaging Techniques; Imaging technology; Individual; Intervention; Intervention Trial; Ischemia; Knowledge; Lead; Left; Left Ventricular Outflow Obstruction; Magnetic Resonance; Measurement; Measures; Mechanics; Mediating; Medical; Modernization; Monitor; Multi-Institutional Clinical Trial; Muscle Cells; Myocardial; Myocardial perfusion; Myopathy; Obstruction; Operative Surgical Procedures; Outcome; Oxygen Consumption; Patients; Perfusion; Pharmaceutical Preparations; Physical activity; Positron-Emission Tomography; Process; Productivity; Publishing; Quality of life; Randomized; Randomized Controlled Trials; Recovery; Rest; Risk; Role; Signal Transduction; Stress; Stroke Volume; Structure; Supervision; Symptoms; Testing; Thinking; Time; Training Activity; United States; VO2max; Vasodilation; Ventricular; Ventricular Arrhythmia; Work; base; cohort; common symptom; coronary perfusion; disability; disabling symptom; effective therapy; exercise capacity; exercise intensity; exercise intervention; exercise intolerance; exercise training; heart imaging; heart rhythm; high risk; improved; innovation; standard care; trend

Project Summary Hypertrophic Cardiomyopathy (HCM) is the most common genetic heart disease with a projected burden of ~2 million genetically at risk in the United States. Approximately ⅓ of HCM patients have no left ventricular outflow obstruction and we have challenged the conventional thinking that HCM symptoms and complications are primarily driven by left ventricular outflow tract obstruction. We have shown that non-obstructive HCM is associated with high rates of ventricular arrhythmias, abnormal myocardial mechanics, poor exercise tolerance and adverse clinical outcomes, higher frequency of microvascular ischemia (by positron emission tomography; PET) and large scar burden (by cardiac magnetic resonance; CMR). How changes in myocardial mechanics and perfusion mediate exercise capacity in HCM remains poorly understood. Exercise training improves exercise capacity in HCM but the mechanism(s) for improved exercise capacity are unclear. The overall objective of this proposal is to determine the role of myopathy and microvascular ischemia in contributing to exercise tolerance in non-obstructive HCM. Our central hypothesis is that both these mechanisms are important determinants of exercise capacity in non-obstructive HCM. The rationale for our proposal is that if exercise favorably modifies myocardial perfusion and function it may provide the basis for considering structured exercise as a therapy for non-obstructive HCM patients, who as we demonstrated have high risk for an adverse clinical course and no effective therapy at this time. We will test our hypothesis with the following aims: Aim 1: To determine the role of myocardial function in exercise limitation in non-obstructive HCM. We will use echo-based myocardial strain to determine regional and global myocardial function at rest and peak stress (peak exercise). We will examine the relationship between regional/global strain and exercise capacity, specifically the relative importance of rest and peak exercise strain on exercise capacity. Aim 2: To evaluate the relationship between myocardial perfusion and exercise capacity in non-obstructive HCM. Using Ammonia-13 (13N) PET scanning we will characterize myocardial perfusion and flow reserve on a segmental basis. Aim 3: To understand the effects of moderate intensity exercise training (MIET) on myocardial function and perfusion - the EXerCise traIning To rEcovery in HCM (EXCITE-HCM) trial. Patients will be randomized 1:1 to 24 weeks of MIET versus no exercise with measurement of VO2max at baseline and end-study. The overall goal of this proposal is to build on convincing observational data and harness sophisticated and well- validated modern imaging techniques to better understand the factors underlying exercise intolerance in non- obstructive HCM. Concurrently we will evaluate if MIET-induced improvements in exercise tolerance are mediated through favorable effects on these key pathophysiologic processes. The results of this trial will inform whether MIET is a viable intervention in non-obstructive HCM and the potential mechanisms by which exercise may mediate its beneficial effects.

项目概要 肥厚性心肌病 (HCM) 是最常见的遗传性心脏病，预计负担约为 2 在美国，大约 1/3 的 HCM 患者没有左心室流出道。 我们挑战了传统观念，即 HCM 症状和并发症是 主要由左心室流出道梗阻驱动。我们已经证明非梗阻性 HCM 是由左心室流出道梗阻引起的。 与室性心律失常发生率高、心肌力学异常、运动耐量差有关 和不良的临床结果，微血管缺血的频率更高（通过正电子发射断层扫描； PET）和大疤痕负担（通过心脏磁共振；CMR）心肌力学如何变化。 运动训练对 HCM 中运动能力的影响仍知之甚少。 HCM 的运动能力，但提高运动能力的机制尚不清楚。 该提案的总体目标是确定肌病和微血管缺血在 我们的中心假设是，这两者都有助于非阻塞性 HCM 的运动耐量。 机制是非阻塞性 HCM 运动能力的重要决定因素。 建议是，如果运动有利于改变心肌灌注和功能，那么它可以为 考虑将结构化运动作为非阻塞性 HCM 患者的一种治疗方法，正如我们已经证明的那样 不良临床过程的风险很高，目前没有有效的治疗方法，我们将用以下方法检验我们的假设。 目标如下： 目标 1：确定心肌功能在非阻塞性运动限制中的作用 HCM。我们将使用基于回声的心肌应变来确定静息时的局部和整体心肌功能。 我们将研究区域/整体压力与运动之间的关系。 能力，特别是休息和峰值运动压力对运动能力的相对重要性。 评估非梗阻性 HCM 中心肌灌注与运动能力之间的关系。 Ammonia-13 (13N) PET 扫描我们将在节段上表征心肌灌注和血流储备 目标 3：了解中等强度运动训练 (MIET) 对心肌功能的影响。 和灌注 - HCM 恢复运动训练 (EXCITE-HCM) 试验对患者进行随机分组。 MIET 与不运动的比例为 1:1 至 24 周，并在基线和研究结束时测量 VO2max。 该提案的总体目标是建立在令人信服的观测数据的基础上，并利用复杂和良好的 经过验证的现代成像技术可以更好地了解非运动不耐症的潜在因素 同时，我们将评估 MIET 是否能改善运动耐量。 通过对这些关键病理生理过程的有利影响来介导，该试验的结果将提供信息。 MIET 是否是非梗阻性 HCM 的可行干预措施以及锻炼的潜在机制 可能会介导其有益作用。