Journal
JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY
Volume 78, Issue 1, Pages 42-52Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/j.jacc.2021.04.085
Keywords
heart failure; risk factor; clonal hematopoiesis of indeterminate potential
Categories
Funding
- National Heart, Lung, and Blood Institute (NHLBI)
- NHLBI TOPMed: Trans-Omics for Precision Medicine (TOPMed) Whole Genome Sequencing Project: Cardiovascular Health Study [phs001368, HHSN268201600033I, 3U54HG003273-12S2, HHSN268201500015C]
- TOPMed Informatics Research Center [3R01HL-117626-02S1, HHSN268201800002I]
- TOPMed Data Coordinating Center [3R01HL-120393-02S1, HHSN268201800001I]
- NHLBI, National Institutes of Health, Department of Health and Human Services [HHSN268201700001I, HHSN268201700002I, HHSN268201700003I, HHSN268201700004I, HHSN268201700005I]
- National Institutes of Health [5RC2HL102419]
- CHS (Cardiovascular Health Study) [HHSN268201200036C, HHSN268200800007C, HHSN268201800001C, N01HC55222, N01HC85079, N01HC85080, N01HC85081, N01HC85082, N01HC85083, N01HC85086, 75N92021D00006]
- NHLBI [U01HL080295, U01HL130114, R01HL135008, R01HL143224, R01HL150342, R01HL14818, K24HL152008, T32HL094301-07, R01HL142711, R01HL148050, R01HL148565]
- National Institute of Neurological Disorders and Stroke
- National Institute on Aging [R01AG023629]
- Jackson State University [HHSN268201800013I]
- Tougaloo College [HHSN268201800014I]
- Mississippi State Department of Health [HHSN268201800015I]
- University of Mississippi Medical Center from the NHLBI [HHSN268201800010I, HHSN268201800011I, HHSN268201800012I]
- National Institute on Minority Health and Health Disparities
- NHLBI, National Institutes of Health, U.S. Department of Health and Human Services [HHSN268201600018C, HHSN268201600001C, HHSN268201600002C, HHSN268201600003C, HHSN268201600004C]
- National Institutes of Health's NHLBI [1F30HL149180-01]
- National Institutes of Health's Medical Scientist Training Program at the Yale School of Medicine.
- Novartis
- Philips Ultrasound through Brigham and Women's Hospital
- Celgene
- Deerfield
- Fondation Leducq [TNE-18CVD04]
- Amgen
- Apple
- Boston Scientific
- [R01HL141824]
- [T32 HL129982]
- [KL2TR00249]
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The study found that CHIP is associated with incident heart failure, with ASXL1, TET2, and JAK2 sequence variations increasing the risk of heart failure, while DNMT3A sequence variations were not associated. Large CHIP may increase the risk of heart failure.
BACKGROUND Age-related clonal hematopoiesis of indeterminate potential (CHIP), defined as clonally expanded leukemogenic sequence variations (particularly in DNMT3A, TET2, ASXL1, and JAK2) in asymptomatic individuals, is associated with cardiovascular events, including recurrent heart failure (HF). OBJECTIVES This study sought to evaluate whether CHIP is associated with incident HF. METHODS CHIP status was obtained from whole exome or genome sequencing of blood DNA in participants without prevalent HF or hematological malignancy from 5 cohorts. Cox proportional hazards models were performed within each cohort, adjusting for demographic and clinical risk factors, followed by fixed-effect meta-analyses. Large CHIP clones (defined as variant allele frequency >10%), HF with or without baseline coronary heart disease, and left ventricular ejection fraction were evaluated in secondary analyses. RESULTS Of 56,597 individuals (59% women, mean age 58 years at baseline), 3,406 (6%) had CHIP, and 4,694 developed HF (8.3%) over up to 20 years of follow-up. CHIP was prospectively associated with a 25% increased risk of HF in meta-analysis (hazard ratio: 1.25; 95% confidence interval: 1.13-1.38) with consistent associations across cohorts. ASXL1, TET2, and JAK2 sequence variations were each associated with an increased risk of HF, whereas DNMT3A sequence variations were not associated with HF. Secondary analyses suggested large CHIP was associated with a greater risk of HF (hazard ratio: 1.29; 95% confidence interval: 1.15-1.44), and the associations for CHIP on HF with and without prior coronary heart disease were homogenous. ASXL1 sequence variations were associated with reduced left ventricular ejection fraction. CONCLUSIONS CHIP, particularly sequence variations in ASXL1, TET2, and JAK2, represents a new risk factor for HF. (J Am Coll Cardiol 2021;78:42-52) (c) 2021 by the American College of Cardiology Foundation. RESULTS Of 56,597 individuals (59% women, mean age 58 years at baseline), 3,406 (6%) had CHIP, and 4,694 developed HF (8.3%) over up to 20 years of follow-up. CHIP was prospectively associated with a 25% increased risk of HF in meta-analysis (hazard ratio: 1.25; 95% confidence interval: 1.13-1.38) with consistent associations across cohorts. ASXL1, TET2, and JAK2 sequence variations were each associated with an increased risk of HF, whereas DNMT3A sequence variations were not associated with HF. Secondary analyses suggested large CHIP was associated with a greater risk of HF (hazard ratio: 1.29; 95% confidence interval: 1.15-1.44), and the associations for CHIP on HF with and without prior coronary heart disease were homogenous. ASXL1 sequence variations were associated with reduced left ventricular ejection fraction.
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