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. 2024 Jan 2;7(1):e2353244.
doi: 10.1001/jamanetworkopen.2023.53244.

Clonal Hematopoiesis and Incident Heart Failure With Preserved Ejection Fraction

Art Schuermans  1   2   3 , Michael C Honigberg  1   2   4 , Laura M Raffield  5 , Bing Yu  6 , Mary B Roberts  7 , Charles Kooperberg  8 , Pinkal Desai  9 , April P Carson  10 , Amil M Shah  11 , Christie M Ballantyne  12 , Alexander G Bick  13 , Pradeep Natarajan  1   2   4 , JoAnn E Manson  14   15 , Eric A Whitsel  16 , Charles B Eaton  17   18   19 , Alexander P Reiner  8
Affiliations

Clonal Hematopoiesis and Incident Heart Failure With Preserved Ejection Fraction

Art Schuermans et al. JAMA Netw Open. .

Abstract

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.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Honigberg reported grants from Genentech during the conduct of the study; and reported advisory board service for Miga Health, personal fees from CRISPR Therapeutics, and personal fees from Comanche Biopharma outside the submitted work. Dr Raffield reported personal fees from the Trans-Omics in Precision Medicine (TOPMed) Administrative Coordinating Center (through Westat) during the conduct of the study. Dr Desai reported research funding from Janssen Research and consultant fees from Rigel Pharmaceuticals, Servier, and BMS outside the submitted work. Dr Carson reported grants from Amgen outside the submitted work. Dr Shah reported research support from Novartis through Brigham and Women’s Hospital, personal fees from Philips Ultrasound (advisory board), and personal fees from Janssen (advisory board) outside the submitted work. Dr Bick reported personal fees from TenSixteen Bio outside the submitted work. Dr Natarajan reported grants from Allelica, Amgen, Apple, Boston Scientific, Genentech/Roche, and Novartis, personal fees from Allelica, Apple, AstraZeneca, Blackstone Life Sciences, Creative Education Concepts, CRISPR Therapeutics, Eli Lilly & Co, Foresite Labs, Genentech / Roche, GV, HeartFlow, Magnet Biomedicine, Merck, and Novartis; reported serving on the science advisory board for Esperion Therapeutics, Preciseli, and TenSixteen Bio; received equity from MyOme, Preciseli, and TenSixteen Bio; and spousal employment from Vertex Pharmaceuticals outside the submitted work. Dr Manson reported grants from the National Institutes of Health (NIH) during the conduct of the study; grants from Mars Edge outside the submitted work. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. Cumulative Incidence of Heart Failure (HF) and HF Subtypes by Clonal Hematopoiesis of Indeterminate Potential (CHIP) Carrier Status in the Jackson Heart Study (JHS)
Cumulative incidence curves for any HF, HF with preserved ejection fraction (HFpEF), and HF with reduced ejection fraction (HFrEF) were constructed using the Kaplan-Meier method and compared using the (unadjusted) log-rank test. Any HF was defined as a composite outcome including HFpEF, HFrEF, and HF with unknown ejection fraction. Follow-up occurred over a median (IQR) of 12.0 (11.0-12.0) years.
Figure 2.
Figure 2.. Cumulative Incidence of Heart Failure (HF) and HF Subtypes by Clonal Hematopoiesis of Indeterminate Potential (CHIP) Carrier Status in the Women’s Health Initiative (WHI)
Cumulative incidence curves for any HF, HF with preserved ejection fraction (HFpEF), and HF with reduced ejection fraction (HFrEF) were constructed using the Kaplan-Meier method and compared using the (unadjusted) log-rank test. Any HF was defined as a composite outcome including HFpEF, HFrEF, and HF with unknown ejection fraction. Follow-up was truncated at 22 years due to deviations from proportional hazards and occurred over a median (IQR) of 15.3 (9.0-22.0) years.
Figure 3.
Figure 3.. Cumulative Incidence of Heart Failure (HF) and HF Subtypes by Clonal Hematopoiesis of Indeterminate Potential (CHIP) Carrier Status and C-Reactive Protein (CRP) Levels in the Women’s Health Initiative (WHI)
Cumulative incidence curves for any HF, HF with preserved ejection fraction (HFpEF), and HF with reduced ejection fraction (HFrEF) were constructed using the Kaplan-Meier method and compared using the log-rank test. Any HF was defined as a composite outcome including HFpEF, HFrEF, and HF with unknown ejection fraction. A total of 3643 WHI participants had available CRP measurements. Follow-up was truncated at 22 years due to deviations from proportional hazards and occurred over a median (IQR) of 15.3 (9.0-22.0) years.
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