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.

项目摘要 肥厚型心肌病（HCM）是最常见的遗传性心脏病，预计负担约为2 在美国，有100万人面临基因风险。约有假肥厚型心肌病患者无左室流出道 我们已经挑战了传统的思维，即HCM症状和并发症是 主要由左心室流出道阻塞引起。我们已经证明，非梗阻性HCM是 与室性心律失常、心肌力学异常、运动耐量差的发生率高相关 和不良的临床结果，更高频率的微血管缺血（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）。心肌力学的变化 HCM中灌注介导的运动能力仍然知之甚少。运动训练提高 HCM的运动能力，但改善运动能力的机制尚不清楚。 本提案的总体目标是确定肌病和微血管缺血在 有助于非梗阻性HCM的运动耐量。我们的核心假设是， 机制是非梗阻性HCM患者运动能力的重要决定因素。我们的理由是， 建议是，如果运动能够有利地改变心肌灌注和功能， 考虑将结构化运动作为非梗阻性HCM患者的治疗方法，正如我们所证明的， 不良临床过程的高风险且此时没有有效治疗。我们将测试我们的假设， 目的1：探讨心肌功能在非梗阻性心肌梗死患者运动受限中的作用。 HCM。我们将使用基于回波的心肌应变来确定静息时的局部和整体心肌功能 峰值运动（Peak Exercise）我们将研究区域/全球紧张和运动之间的关系 能力，特别是休息和峰值运动应变对运动能力的相对重要性。目标2： 评价非梗阻性肥厚型心肌病心肌灌注与运动能力的关系。使用 氨-13（13 N）PET扫描，我们将在节段性心肌灌注和血流储备上表征心肌灌注和血流储备。 基础目的3：了解中等强度运动训练（MIET）对心肌功能的影响 和灌注--EXCITE-HCM试验。患者将被随机分配 1：1至24周的MIET与无运动，基线和研究结束时测量VO 2 max。的 该提案的总体目标是建立在令人信服的观测数据基础上，利用复杂而良好的 有效的现代成像技术，以更好地了解运动不耐受的因素， 梗阻性肥厚型心肌病同时，我们将评估MIET诱导的运动耐量改善是否 通过对这些关键的病理生理过程的有利影响来介导。这次试验的结果将告诉 MIET是否是一种可行的干预非梗阻性HCM和潜在的机制， 可以调节其有益效果。