Proteomics profiling in hypertrophic cardiomyopathy and cardiac event prediction

PROJECT SUMMARY Hypertrophic cardiomyopathy (HCM) is the most common genetic cardiac disease and causes major adverse cardiovascular events (MACE) – e.g., arrhythmias, heart failure, and sudden cardiac death. Invasive interventions to prevent MACE are available but can cause complications. Current risk stratification strategy has limited power to predict which patient would develop MACE and benefit most from preventive interventions. Furthermore, little is known about the signaling pathways through which gene mutations mediate HCM pathogenesis and MACE. These major knowledge gaps have hindered efforts to prevent MACE in HCM. The Harvard-Columbia Multi-center Hypertrophic Cardiomyopathy (HCM2) Biorepository is an ongoing 3-center cohort study that enrolled 560 patients with HCM during 2014-2020. In this large multi-center HCM biorepository, investigators have collected high-quality biospecimens – e.g., plasma, left ventricular myocardium. Follow-up data include biannual interviews, medical record reviews, and in-person exam every year, with >85% follow-up to date (median follow-up, 3.1 years). The present R01 project will extend this large well-characterized HCM biorepository by proteomically profiling both plasma and myocardium samples, and by examining their relations to both HCM disease status and MACE. In Aim 1, we will examine the association of signaling pathway dysregulation in the myocardium with HCM disease status using molecular biology approach (e.g., RT-PCR of mRNA, ELISA) and proteomics profiling. In Aim 2, we will determine the association of signaling pathway dysregulation with MACE using proteomics profiling, and specify signaling pathways that predict incident MACE. Finally, using a systems biology approach, Aim 3 will define HCM subtypes by integrating proteomic, genetic, and clinical data, and determine their associations with MACE. Our prior study and preliminary work lend compelling support to our hypotheses. The present R01 project will provide a unique opportunity to reveal the molecular mechanisms of HCM pathogenesis and progression to MACE through examining signaling pathways using proteomics profiling in both plasma and myocardium. Furthermore, the proposed study will also invent a novel risk stratification system in HCM, which will allow us to precisely identify high-risk HCM subpopulations that would benefit from preventive interventions. The project will provide a strong evidence base for developing targeted pharmacotherapies to prevent HCM pathogenesis and MACE through the modulation of specific signaling pathways. The investigators have integrated and complementary expertise in all relevant fields. The study matches well with the NHLBI strategic plan for HCM research.