R01HL157238

Exercise Intolerance in Non-Obstructive Hypertrophic Cardiomyopathy - Project Summary

Hypertrophic Cardiomyopathy (HCM) is the most common genetic heart disease, with a projected burden of approximately 2 million genetically at risk individuals in the United States. A significant proportion of HCM patients do not have left ventricular outflow obstruction, challenging the conventional thinking that HCM symptoms and complications are primarily driven by this obstruction. Our research has shown that non-obstructive HCM is associated with high rates of ventricular arrhythmias, abnormal myocardial mechanics, poor exercise tolerance, and adverse clinical outcomes. We have also observed a higher frequency of microvascular ischemia (by positron emission tomography; PET) and a large scar burden (by cardiac magnetic resonance; CMR) in non-obstructive HCM patients. However, the mechanisms by which changes in myocardial mechanics and perfusion mediate exercise capacity in HCM remain poorly understood.

Exercise training has been shown to improve exercise capacity in HCM, but the specific mechanism(s) for this improvement 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 of 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 currently have a high risk for an adverse clinical course and no effective therapy.

To test our hypothesis, we have outlined 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 assess 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 focusing on 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 or no exercise, with measurement of VO2max at baseline and end-study.

The overall goal of this proposal is to build upon convincing observational data and utilize 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 shed light on the potential mechanisms by which exercise may mediate its beneficial effects.

San Francisco Regents Of The University Of California

TO FOSTER HEART AND VASCULAR RESEARCH IN THE BASIC, TRANSLATIONAL, CLINICAL AND POPULATION SCIENCES, AND TO FOSTER TRAINING TO BUILD TALENTED YOUNG INVESTIGATORS IN THESE AREAS, FUNDED THROUGH COMPETITIVE RESEARCH TRAINING GRANTS. SMALL BUSINESS INNOVATION RESEARCH (SBIR) PROGRAM: TO STIMULATE TECHNOLOGICAL INNOVATION, USE SMALL BUSINESS TO MEET FEDERAL RESEARCH AND DEVELOPMENT NEEDS, FOSTER AND ENCOURAGE PARTICIPATION IN INNOVATION AND ENTREPRENEURSHIP BY SOCIALLY AND ECONOMICALLY DISADVANTAGED PERSONS, AND INCREASE PRIVATE-SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT FUNDING. SMALL BUSINESS TECHNOLOGY TRANSFER (STTR) PROGRAM: TO STIMULATE TECHNOLOGICAL INNOVATION, FOSTER TECHNOLOGY TRANSFER THROUGH COOPERATIVE R&D BETWEEN SMALL BUSINESSES AND RESEARCH INSTITUTIONS, AND INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL R&D.

93.837 - Cardiovascular Diseases Research

National Heart Lung and Blood Institute (NHLBI) [HHS - NIH]

San Francisco, California 941432204 United States

Single Zip Code

Research Project Grant (Parent R01 Clinical Trial Required) (PA-20-183)

Amendment Since initial award the total obligations have increased 298% from $807,497 to $3,213,836.