R01HL157247

Clonal Hematopoiesis of Indeterminate Potential and Risk of Autopsy-Defined Sudden Cardiac Death - Project Summary/Abstract

Clonal Hematopoiesis of Indeterminate Potential (CHIP) is the expansion of leukocytes derived from a clone with pre-leukemic potential that does not fulfill diagnostic criteria for a hematologic malignancy. Recent large-scale studies have demonstrated an association between mutations in CHIP genes, mostly in TET2, DNMT3A, ASXL1, and a 30-40% increased risk of non-cancer mortality, a 2-fold increased risk of ischemic stroke and coronary artery disease (CAD), and a cumulative increase in cardiovascular (CV) death in the general population.

Mechanistic models propose a phenotypic switch in immune cells, chiefly macrophages, with CHIP mutations leading to increased vascular inflammation and accelerated CAD. Despite these data suggesting that CHIP is significantly associated with increased CV events and overall mortality, it is unknown whether CHIP is associated with sudden cardiac death (SCD), the most feared manifestation of CVD.

Our NHLBI-funded ongoing post SCD study, which has autopsied 97% of >1000 consecutive SCDs since 2011, is the first and only prospective unselected adult SCD cohort to use autopsy to refine the SCD phenotype to true cardiac and arrhythmic causes. We recently reported that nearly half of conventionally-defined presumed SCDs were in fact non-cardiac. Importantly, the large-scale exome sequencing studies that initially defined the carrier rates and risk of a cardiovascular event relied on presumed causes of death and often assessed for the presence of CHIP years prior to death.

Our central hypothesis is that CHIP-mutant resident macrophages increase the risk of fatal arrhythmias across all underlying substrates of SCD found in post SCD (CAD, hypertrophy, CM) by increasing interstitial myocardial fibrosis and decreasing electrical coupling. We will test this hypothesis by: (1) determining the population carrier rate of CHIP at the time of SCD and its associated independent risk, (2) establishing that CHIP increases the infiltration of macrophages and interstitial fibrosis within the cardiac interstitium, including the conduction system, and (3) defining the transcriptional mechanism by which CHIP macrophages increase vulnerable myocardial substrate for SCD.

We anticipate that this innovative approach will yield the following outcomes: (1) inform potential clinical use of CHIP for SCD risk stratification, (2) establish the role of macrophages on myocardium and conduction system beyond the vascular compartment and its correlation with fibrotic arrhythmic substrate common to all sub-phenotypes of SCD, and the modulating effect of CHIP on this process, and (3) determine the RNA profiles of CHIP-mutant resident macrophages vs. wildtype macrophages to reveal insights into CHIP-specific effects on the cellular milieu of hearts vulnerable to SCD to thus potentially identify new biologic targets for diagnosis and/or therapeutics.

Thus, the proposed research will fundamentally advance our knowledge of how CHIP increases CV mortality, specifically SCD, and potentially identify a new risk factor for SCD.

San Francisco Regents Of The University Of California

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]

California United States

State-Wide

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

Amendment Since initial award the total obligations have increased 299% from $801,056 to $3,193,873.