R01HL157216

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) such as arrhythmias, heart failure, and sudden cardiac death. While invasive interventions are available to prevent MACE, they can also lead to complications. The current risk stratification strategy has limited power in predicting which patients would develop MACE and benefit the most from preventive interventions. Additionally, little is known about the signaling pathways through which gene mutations mediate HCM pathogenesis and MACE. These 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 from 2014 to 2020. In this large multi-center HCM Biorepository, investigators have collected high-quality biospecimens, including plasma and left ventricular myocardium. Follow-up data includes biannual interviews, medical record reviews, and annual in-person exams, with over 85% follow-up to date (median follow-up, 3.1 years).

The present R01 project aims to extend this large, well-characterized HCM Biorepository by proteomically profiling both plasma and myocardium samples and examining their relations to both HCM disease status and MACE. In Aim 1, the project will examine the association of signaling pathway dysregulation in the myocardium with HCM disease status using molecular biology approaches such as RT-PCR of mRNA and ELISA, as well as proteomics profiling. In Aim 2, the project will determine the association of signaling pathway dysregulation with MACE using proteomics profiling and specify signaling pathways that predict incident MACE. Finally, in Aim 3, a systems biology approach will be used to define HCM subtypes by integrating proteomic, genetic, and clinical data and determine their associations with MACE.

The prior study and preliminary work provide compelling support for the hypotheses of this project. The present R01 project will provide a unique opportunity to reveal the molecular mechanisms of HCM pathogenesis and progression to MACE by 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, allowing for the precise identification of 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, and the study aligns well with the NHLBI Strategic Plan for HCM research.

The Trustees Of Columbia University In The City Of New York

TO FOSTER HEART AND VASCULAR RESEARCH IN THE BASIC, TRANSLATIONAL, CLINICAL AND POPULATION SCIENCES, AND TO FOSTER TRAINING TO BUILD TALENTED YOUNG INVESTIGATORS IN THESE AREAS, FUNDED THROUGH COMPETITIVE RESEARCH TRAINING GRANTS. SMALL BUSINESS INNOVATION RESEARCH (SBIR) PROGRAM: TO STIMULATE TECHNOLOGICAL INNOVATION, USE SMALL BUSINESS TO MEET FEDERAL RESEARCH AND DEVELOPMENT NEEDS, FOSTER AND ENCOURAGE PARTICIPATION IN INNOVATION AND ENTREPRENEURSHIP BY SOCIALLY AND ECONOMICALLY DISADVANTAGED PERSONS, AND INCREASE PRIVATE-SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT FUNDING. SMALL BUSINESS TECHNOLOGY TRANSFER (STTR) PROGRAM: TO STIMULATE TECHNOLOGICAL INNOVATION, FOSTER TECHNOLOGY TRANSFER THROUGH COOPERATIVE R&D BETWEEN SMALL BUSINESSES AND RESEARCH INSTITUTIONS, AND INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL R&D.

93.837 - Cardiovascular Diseases Research

National Heart Lung and Blood Institute (NHLBI) [HHS - NIH]

New York, New York 100323725 United States

Single Zip Code

NIH Research Project Grant (Parent R01 Clinical Trial Not Allowed) (PA-20-185)

Amendment Since initial award the total obligations have increased 379% from $729,819 to $3,497,937.