Precision phenotyping of hypertrophic cardiomyopathy for risk stratification and targeted therapeutics.

Hypertrophic cardiomyopathy (HCM), a common genetic disease, is an important cause of sudden death, heart failure and stroke in the young. Among carriers of HCM-causing gene mutations, only some develop advanced disease and symptoms in their lifetime, which can be hard to predict. Emerging disease-modifying therapies like gene editing therapies and small molecule modulators can potentially arrest disease progression or even cure HCM. However, knowing who to target, when to intervene, and how best to measure therapeutic efficacy remains challenging. Cardiac magnetic resonance (CMR) can detect a range of early HCM phenotypes, which may help identify who will progress. During this fellowship, I will a) establish the biological basis of one of the earliest CMR measures of disease activity (blunted stress oxygenation) in HCM, b) examine its utility as a dynamic readout for use in clinical trials, c) evaluate its role along with other CMR measures in predicting disease progression and exercise capacity, and d) identify alternative imaging-based disease-specific measures (such as computed tomography) that can be used to predict disease progression. This research is expected to significantly impact how we stage disease in HCM and undertake clinical trials, paving the way for precision diagnostics and therapeutics.