Transcriptomics, pathobiology, and cardiac event in hypertrophic cardiomyopathy

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 result in 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 pathobiology 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 prospective cohort that enrolled 615 patients with HCM during 2014-2022. In this large multi-center HCM biorepository, investigators have collected high-quality biospecimens – i.e., 615 plasma and 120 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 transcriptomically profiling both myocardium and plasma samples in parallel, 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 qRT-PCR, single-transcript RNA-FISH, and RNA-Seq. In Aim 2, we will specify signaling pathways and plasma circulating microRNAs that predict new-onset MACE using transcriptomic profiling. Finally, using an unsupervised clustering-based approach, Aim 3 will define HCM subtypes by integrating genetic, transcriptomic, proteomic, and clinical data, and determine their associations with MACE. Our prior studies 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 pathobiology and progression to MACE through examining signaling pathways by applying transcriptomic profiling to paired myocardium and plasma. Moreover, the proposed study will also derive a novel risk stratification system in HCM, which will allow us to precisely identify high-risk HCM subtypes 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 complementary and integrated expertise in all relevant fields. The study matches well with the NHLBI strategic plan for HCM research.