TET2 CHIP an Independent Risk Factor for HFpEF, Study Says

TET2 clonal hematopoiesis of indeterminate potential (CHIP)—one of the 2 most common gene-specific CHIP subtypes—was found to be an independent risk factor associated with incident heart failure with preserved ejection fraction (HFpEF), according to new study results published in JAMA Network Open.

CHIP is a clonal expansion of hematopoietic stem cells with preleukemic acquired genetic variants, primarily affecting individuals aged 70 years and older. Commonly associated with variants in genes like DNMT3A and TET2, CHIP is linked to an elevated risk of hematologic malignancies and cardiovascular diseases like atherosclerotic cardiovascular disease. Recent studies have suggested CHIP, particularly TET2 CHIP, as an independent risk factor for incident HF, suggesting its involvement in cardiac dysfunction through inflammatory dysregulation and fibrotic remodeling. Further, observational studies have found associations of CHIP with HF to be independent of coronary artery disease (CAD), hinting at a broader role for CHIP in HF pathophysiology.

Heart graphic | Image credit: iaremenko – stock.adobe.com

To assess the links between CHIP and specific gene-related CHIP subtypes with the development of incident HFpEF and HF with reduced ejection fraction (HFrEF), researchers utilized data from 2 racially diverse prospective cohort studies: the Jackson Heart Study (JHS) and the Women’s Health Initiative (WHI). Participants in both studies underwent whole-genome sequencing, did not have prevalent HF at baseline, and were followed up for HF adjudication. The median (IQR) follow-up duration was 12 (11.0-12.0) years in JHS and 15.3 (9.0-22.0) years in WHI.

In total, 8090 participants were included, with 2927 from the JHS and 5163 from the WHI. It’s important to note some of the differences in each patient cohort, including an 11-year difference in median age, the WHI only including women, and the JHS only including Black or African American patients.

The multivariable-adjusted HR for combined CHIP and HFpEF was 1.28 (95% CI, 0.93-1.76; P = .13), while for CHIP and HFrEF, it was 0.79 (95% CI, 0.49-1.25; P = .31). Specifically, TET2 CHIP showed a significant association with HFpEF across both cohorts (meta-analyzed HR, 2.35; 95% CI, 1.34-4.11; P = .003), independent of traditional cardiovascular risk factors and CAD. When stratified by C-reactive protein (CRP) levels in the WHI, individuals with CHIP and CRP levels ≥ 2 mg/L had an elevated risk of developing incident HFpEF (HR, 1.94; 95% CI, 1.20-3.15; P = .007), compared with those without CHIP and with a CRP level < 2 mg/L.

Additionally, there were no statistically significant differences observed between participants under 65 years old and those aged 65 or older regarding the associations of CHIP and gene-specific CHIP subtypes with HFpEF and HFrEF, although the number of cases in the younger age group was low. Secondary analyses focusing on large CHIP clones (i.e., CHIP with VAF >10%) found consistent associations for TET2 across all HF subtypes.

While this study used advanced sequencing and rigorous HF event assessment, it had multiple limitations. It lacked power to detect gene-specific associations with HFrEF due to few individuals with certain driver variants like ASXL1 or JAK2, and HF subtype definitions relied solely on ejection fraction, potentially oversimplifying subtype classification. Additionally, despite including racially diverse cohorts, some demographics were underrepresented. Whole-genome sequencing's limited sensitivity to detect small CHIP clones may introduce misclassification bias, although findings align with previous research. Further studies are needed to explore smaller CHIP clones' impact on long-term HF risk using more sensitive approaches.

“Previously reported associations of CHIP with new-onset HF may primarily reflect associations with HFpEF,” the authors concluded. “Further research into the connections between CHIP, inflammation, and HFpEF may have implications for future management of HFpEF, including development of targeted therapies.”

Reference

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