Gene-Specific CHIP Subtype Significantly Associated with HFpEF Risk

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Across two large, diverse cohorts, TET2 CHIP was associated with a more than 2-fold higher risk of incident HF with preserved ejection fraction.

A new analysis identified clonal hematopoiesis of indeterminate potential (CHIP) as a risk factor associated with specific incident heart failure (HF) subtypes across two large and racially diverse prospective cohorts.1

The population-based study, involving approximately 8000 patients from both cohorts, revealed the gene-specific TET2 CHIP subtype was a risk factor associated with incident HF with preserved ejection fraction (HFpEF), independent of traditional cardiovascular risk factors.

“Overall, our findings suggest that previously described associations between CHIP and incident HF may be driven primarily by HFpEF and indicate important differences among common CHIP subtypes,” wrote the investigative team, led by Michael C. Honigberg, MD, Cardiovascular Research Center and Center for Genomic Medicine, Massachusetts General Hospital.

Recent evidence has independently linked CHIP, the age-related clonal expansion of hematopoietic stem cells with leukemogenic acquired genetic variants, with the risk of incident HF.2 In particular, experimental models have suggested a role for TET2 CHIP in developing cardiac dysfunction due to inflammatory dysregulation and fibrotic remodeling.

Honigberg and colleagues suggested evaluating the differential role of CHIP variants in HFpEF versus HF with reduced ejection fraction (HFrEF) could provide new knowledge on the aging-related disease mechanisms and inform prevention and treatment strategies.1 The team evaluated the association of CHIP and gene-specific CHIP subtypes with HFpEF and HFrEF using participants from the Jackson Heart Study (JHS) and Women’s Health Initiative (WHI).

The JHS prospective cohort consisted of 5306 self-identified Black adults who enrolled in the study from 2000 to 2004, with follow-up occurring through 2016. The prospective WHI study consisted of 161,808 postmenopausal women enrolled from 1993 to 1998 and followed up until 2022. Among each cohort, those who underwent whole-genome sequencing, lacked prevalent HF at baseline, and were followed up for HF adjudication were included for analysis.

Noting prior findings have suggested heterogeneity between gene-specific CHIP subtypes, investigators evaluated common gene-specific CHIP subtypes (DNMT3A and TET2) as the co-primary study exposures. Co-primary study outcomes included the first incident hospitalized HF events, adjudicated from hospital records, and defined as HFpEF (left ventricular ejection fraction [LVEF] ≥50%) or HFrEF (LVEF <50%).

Overall, 8090 participants, including 2927 from the JHS (median age, 56 years) and 5163 from the WHI (median age, 67 years), were included in the study. Of the cohort, a total of 512 participants had CHIP (JHS: 112 of 2927 [3.8%]; WHI: 400 of 5163 [7.7%]). Upon analysis, investigators found the cumulative incidence of any HF and HFpEF, but not HFrEF, was higher among CHIP careers than non-carriers in both study cohorts.

Multivariable-adjusted analyses revealed a lack of statistically significant associations of any CHIP with HFpEF (hazard ratio [HR], 1.28 [95% CI, 0.93 - 1.76]; P = .13) or HFrEF (HR, 0.79 [95% CI, 0.49 - 1.25]; P = .31). However, further analysis showed TET2 CHIP was significantly associated with HFpEF across both cohorts (meta-analyzed HR, 2.35 [95% CI, 1.34 to 4.11]; P = .003). These results remained consistent in sensitivity analyses incorporating diabetes and coronary artery disease as time-varying covariates.

Honigberg and colleagues also found analyses stratified by C-reactive protein in the WHI showed an increased risk of incident HFpEF in individuals with CHIP and CRP ≥2 mg/L (HR, 1.94 [95% CI, 1.20 - 3.15]; P = .007). They indicated these data further implicate the role of inflammation in the association of CHIP with cardiac dysfunction beyond CAD.

“Future studies should test whether CHIP, especially TET2 CHIP, represents a potential target for modulation toward HFpEF prevention and treatment, potentially through inhibition of inflammatory pathways,” investigators wrote.


  1. Schuermans A, Honigberg MC, Raffield LM, et al. Clonal Hematopoiesis and Incident Heart Failure With Preserved Ejection Fraction. JAMA Netw Open. 2024;7(1):e2353244. doi:10.1001/jamanetworkopen.2023.53244
  2. Yu B, Roberts MB, Raffield LM, et al; National Heart, Lung, and Blood Institute TOPMed Consortium. Supplemental association of clonal hematopoiesis with incident heart failure. J Am Coll Cardiol. 2021;78(1):42-52. doi:10.1016/j.jacc.2021.04.085P