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: 10616613
• 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/10616613
• 关键词: Address; Affect; Ammonia; Apoptotic; Attenuated; Belief; Benign; Blood Vessels; 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; 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; Symptoms; Testing; Thinking; Time; United States; VO2max; Vasodilation; Ventricular; Ventricular Arrhythmia; Work; cohort; common symptom; coping; coronary perfusion; disability; disabling symptom; effective therapy; efficacy evaluation; 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 肥厚性心肌病（HCM）是最常见的遗传性心脏病，预计燃烧〜2 美国一般面临风险的百万。大约HCM患者没有左心室出口 阻碍，我们挑战了HCM符号和并发症的传统思维 首先是由左心室出口式异议驱动的。我们已经证明非刺激性HCM是 与高心律失常，异常心肌力学和运动耐受性差有关 和不良临床结果，微血管缺血的频率较高（通过正电子发射断层扫描； PET）和大疤痕Burnen（通过心脏磁共振； CMR）。心肌力学的变化如何 HCM中的灌注媒体运动能力仍然知之甚少。锻炼训练有所改善 HCM中的运动能力，但提高运动能力的机制尚不清楚。 该提案的总体目的是确定肌病和微血管缺血在 有助于非刺激性HCM的运动耐受性。我们的中心假设是这两个 机制是非目标HCM中运动能力的重要决定者。我们的理由 建议是，如果运动有利地修饰心肌灌注和功能，则可以为 将结构化运动视为对非目标HCM患者的一种疗法，正如我们所证明的那样 不良临床病程的高风险，目前没有有效的治疗。我们将用 以下目的：目标1：确定心肌功能在非障碍物中的运动限制中的作用 HCM。我们将使用基于回声的心肌菌株来确定静止的区域和全局心肌功能 和峰值压力（峰值运动）。我们将研究区域/全球压力与运动之间的关系 能力，特别是休息和运动峰值对运动能力的相对重要性。目标2：到 评估心肌灌注与非刺激性HCM中的运动能力之间的关系。使用 氨-13（13N）PET扫描我们将在节段上表征心肌灌注和流动储备 基础。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 - 在HCM（Excite -HCM）试验中恢复的运动训练。患者将被随机 1：1至24周的MIET与无运动，并在基线和末端研究时测量Vo2max。这 该提案的总体目标是建立令人信服的观察数据和治疗精致且良好的问题 经过验证的现代成像技术，以更好地了解非运动中的运动因素 阻塞性HCM。同时，我们将评估MIT引起的运动公差的改善 通过对这些关键病理生理过程的有利影响介导的。该试验的结果将告知 MIT是否是对非刺激性HCM的可行干预措施以及锻炼的潜在机制 可以调解其有益效果。