Unraveling The Mechanism of Heart Failure in Hypertrophic Cardiomyopathy with Exercise CMR - Project Summary Hypertrophic cardiomyopathy (HCM) is the most common genetic heart disease, with heart failure (HF) being the most common adverse complication and cause of death. HCM comprises two distinct phenotypes: with and without left ventricular outflow tract (LVOT) obstruction. There are established pharmacotherapy and surgical options for treating obstructive HCM patients. Mavacamten (i.e., mava ), a cardiac myosin inhibitor (CMI), is the first pharmaceutical to gain FDA approval to treat obstructive HCM. Despite enthusiasm for CMI, critical knowledge gaps exist, including long-term efficacy, safety, and cost. Furthermore, it is unknown how potential improvements in cardiac remodeling between mava compare to the “gold standard” invasive therapy of surgical myectomy. There is also a growing interest in expanding indications for CMI to modify the natural history of the disease. Therefore, there is an unmet need for improved phenotyping of HCM beyond classical LVOT obstruction to characterize the key pathophysiologic mechanisms of HF symptoms and their response to CMI. Cardiac magnetic resonance imaging (CMR) has become a modality well-suited to characterize the HCM phenotype. Imaging of fibrosis and scar using T1, extracellular volume, and late gadolinium enhancement imaging has prognostic value in HCM. In addition to evaluating LV function and volumes, CMR can uniquely provide information on the right ventricle and left atrium, both of which are highly involved in the pathophysiology of HCM. Quantitative myocardial perfusion is emerging as an objective approach to assess myocardial blood flow for quantifying microvascular dysfunction. Cardiac diffusion tensor imaging enables the evaluation of myofiber architecture, a histologically abnormal tissue property in HCM. Cardiac spectroscopy provides a window into the cardiac energetics of the heart, a hallmark of HCM pathophysiology. More importantly, our recent technical advances allow accurate and reproducible quantification of the cardiac functional reserve with physiological exercise (Ex-CMR). Ex-CMR enables quantification of cardiac function and structural changes in response to exercise, highly relevant parameters associated with HF symptoms. In HCM patients with persistent symptoms despite gradient relief with mava and in symptomatic non-obstructive HCM patients, we hypothesize that abnormal pathophysiology in cardiac energy deficiency along with decreased myocardial blood flow from small vessels leads to oxygen supply-demand mismatch and ultimately promotes impaired diastolic relaxation, with the inability to appropriately augment stroke volume with exercise. Therefore, we aim to improve our understanding of HF in HCM through novel Ex-CMR image phenotyping. Our findings will improve HCM patient management by targeting disease-specific abnormalities in a more personalized approach using novel CMI pharmacotherapies or established surgical treatments.
