Exercise Intolerance in Non Obstructive Hypertrophic Cardiomyopathy

项目摘要 肥厚型心肌病(HCM)是最常见的遗传性心脏病，预计负荷为2 在美国，有100万人面临遗传风险。肥厚性心肌病患者中约有⅓无左室流出道 梗阻和我们挑战了传统的想法，即HCM症状和并发症是 主要由左室流出道梗阻引起。我们已经证明，非梗阻性HCM是 室性心律失常发生率高、心肌力学异常、运动耐量差 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； 和较大的疤痕负担(通过心脏磁共振；CMR)。心肌力学的变化 在肥厚型心肌病中，血流灌注调节运动能力仍然知之甚少。运动训练有所改善 HCM的运动能力，但提高运动能力的机制(S)尚不清楚。 这项建议的总体目标是确定肌病和微血管缺血在 有助于非梗阻性肥厚性心肌病的运动耐量。我们的中心假设是，这两个 机制是非梗阻性肥厚性心肌病运动能力的重要决定因素。我们的理由是 建议是，如果锻炼有利于改善心肌血流灌注和功能，它可能为 考虑将结构化运动作为治疗非梗阻性肥厚性心肌梗死患者的一种方法，正如我们所展示的那样 出现不良临床病程的风险很高，目前还没有有效的治疗方法。我们将使用以下工具来验证我们的假设 目标1：确定心肌功能在非梗阻性运动受限中的作用 胡志明市。我们将使用基于回声的心肌应变来确定静息状态下的局部和整体心肌功能 和峰值应激(峰值运动)。我们将研究地区性/全球性紧张与运动之间的关系 运动能力，特别是休息和高峰运动压力对运动能力的相对重要性。目标2：实现 评价非梗阻性心肌梗死患者心肌灌注与运动能力的关系。vbl.使用 氨-13(13N)正电子发射计算机断层扫描，我们将在节段性 基础。目的3：了解中等强度运动训练对心肌功能的影响 和灌流-运动训练以恢复HCM(Excite-HCM)试验。患者将被随机分配 1：1-24周的MIET与不运动的对比，测量基线和研究结束时的最大摄氧量(VO2max)。这个 这项建议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，以更好地了解非运动耐量障碍的潜在因素 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产生有利的影响。这项试验的结果将会告知 MIET是否是非梗阻性肥厚性心肌病的可行干预措施以及运动的潜在机制 可能会调节其有益的效果。

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.