Exercise Intolerance in Non Obstructive Hypertrophic Cardiomyopathy

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.

Grant Number: 5R01HL157238-04
NIH Institute/Center: NIH
Principal Investigator: THEODORE ABRAHAM