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- Title
Clonal Hematopoiesis and Incident Heart Failure With Preserved Ejection Fraction.
- Authors
Schuermans, Art; Honigberg, Michael C.; Raffield, Laura M.; Yu, Bing; Roberts, Mary B.; Kooperberg, Charles; Desai, Pinkal; Carson, April P.; Shah, Amil M.; Ballantyne, Christie M.; Bick, Alexander G.; Natarajan, Pradeep; Manson, JoAnn E.; Whitsel, Eric A.; Eaton, Charles B.; Reiner, Alexander P.
- Abstract
Key Points: Question: Are clonal hematopoiesis of indeterminate potential (CHIP) or certain CHIP driver genes associated with a specific heart failure (HF) subtype? Findings: In this cohort study of 2 racially diverse cohorts collectively including 8090 participants, TET2 CHIP was independently associated with a 2.4-fold higher risk of incident HF with preserved ejection fraction. By contrast, there were no significant associations of CHIP with incident HF with reduced ejection fraction. Meaning: These results suggest that TET2 CHIP is a risk factor associated with incident HF with preserved ejection fraction. This cohort study evaluates the potential associations of clonal hematopoiesis of indeterminate potential (CHIP) and key gene-specific CHIP subtypes with incident heart failure with preserved and reduced ejection fraction. Importance: Clonal hematopoiesis of indeterminate potential (CHIP), the age-related clonal expansion of hematopoietic stem cells with leukemogenic acquired genetic variants, is associated with incident heart failure (HF). Objective: To evaluate the associations of CHIP and key gene-specific CHIP subtypes with incident HF with preserved ejection fraction (HFpEF) and reduced ejection fraction (HFrEF). Design, Setting, and Participants: This population-based cohort study included participants from 2 racially diverse prospective cohort studies with uniform HF subtype adjudication: the Jackson Heart Study (JHS) and Women's Health Initiative (WHI). JHS participants were enrolled during 2000 to 2004 and followed up through 2016. WHI participants were enrolled during 1993 to 1998 and followed up through 2022. Participants who underwent whole-genome sequencing, lacked prevalent HF at baseline, and were followed up for HF adjudication were included. Follow-up occurred over a median (IQR) of 12.0 (11.0-12.0) years in the JHS and 15.3 (9.0-22.0) years in the WHI. Statistical analysis was performed from June to December 2023. Exposures: Any CHIP and the most common gene-specific CHIP subtypes (DNMT3A and TET2 CHIP). Main Outcomes and Measures: First incident hospitalized HF events were adjudicated from hospital records and classified as HFpEF (left ventricular ejection fraction ≥50%) or HFrEF (ejection fraction <50%). Results: A total of 8090 participants were included; 2927 from the JHS (median [IQR] age, 56 [46-65] years; 1846 [63.1%] female; 2927 [100.0%] Black or African American) and 5163 from the WHI (median [IQR] age, 67 [62-72] years; 5163 [100.0%] female; 29 [0.6%] American Indian or Alaska Native, 37 [0.7%] Asian or Pacific Islander, 1383 [26.8%] Black or African American, 293 [5.7%] Hispanic or Latinx, 3407 [66.0%] non-Hispanic White, and 14 [0.3%] with other race and ethnicity). The multivariable-adjusted hazard ratio (HR) for composite CHIP and HFpEF was 1.28 (95% CI, 0.93-1.76; P =.13), and for CHIP and HFrEF it was 0.79 (95% CI, 0.49-1.25; P =.31). TET2 CHIP was associated with HFpEF in both cohorts (meta-analyzed HR, 2.35 [95% CI, 1.34 to 4.11]; P =.003) independent of cardiovascular risk factors and coronary artery disease. Analyses stratified by C-reactive protein (CRP) in the WHI found an increased risk of incident HFpEF in individuals with CHIP and CRP greater than or equal to 2 mg/L (HR, 1.94 [95% CI, 1.20-3.15]; P =.007), but not in those with CHIP and CRP less than 2 mg/L or those with CRP greater than or equal to 2 mg/L without CHIP, when compared with participants without CHIP and CRP less than 2 mg/L. Conclusions and Relevance: In this cohort study, TET2 CHIP was an independent risk factor associated with incident HFpEF. This finding may have implications for the prevention and management of HFpEF, including development of targeted therapies.
- Subjects
HEART failure treatment; HEART failure risk factors; CARDIOVASCULAR diseases risk factors; VENTRICULAR ejection fraction; CONFIDENCE intervals; MULTIPLE regression analysis; CARDIOVASCULAR diseases; RISK assessment; GENOME-wide association studies; PEARSON correlation (Statistics); CHI-squared test; KAPLAN-Meier estimator; STATISTICAL hypothesis testing; HEMATOPOIESIS; DATA analysis software; HEMATOPOIETIC stem cells; HEART failure; LONGITUDINAL method; SECONDARY analysis; PROPORTIONAL hazards models
- Publication
JAMA Network Open, 2024, Vol 7, Issue 1, pe2353244
- ISSN
2574-3805
- Publication type
Article
- DOI
10.1001/jamanetworkopen.2023.53244