Clonal Hematopoiesis and Incident Heart Failure

Area of Science:

• Cardiovascular Medicine
• Hematology
• Genetics

Background:

• Clonal hematopoiesis of indeterminate potential (CHIP) is an age-related condition involving clonal expansion of hematopoietic cells with preleukemic mutations.
• CHIP has been associated with cardiometabolic diseases, including heart failure (HF), but less common CHIP driver variants and mediating factors remain understudied.

Purpose of the Study:

• To investigate the association between specific CHIP subtypes and incident HF.
• To determine the extent to which CHIP-associated comorbidities mediate the relationship between CHIP and HF.

Main Methods:

• A prospective, population-based cohort study using UK Biobank data from 2006-2020.
• Whole-exome sequencing (WES) was performed on participants without prevalent HF or hematologic malignancy.
• Cox regression models analyzed associations between CHIP/subtypes and incident HF, with mediation analyses for comorbidities (CAD, AF, T2D, CKD).

Main Results:

• Among 417,616 participants, CHIP was associated with increased HF risk (aHR, 1.27).
• Non-DNMT3A CHIP subtypes (TET2, ASXL1, JAK2, spliceosome) showed a stronger association with HF (aHR, 1.52).
• Comorbidities (CAD, AF, T2D, CKD) accounted for 28.2% of the non-DNMT3A CHIP-HF association.

Conclusions:

• CHIP, particularly non-DNMT3A subtypes, is significantly associated with incident heart failure.
• CHIP-associated comorbidities explain only a portion of the CHIP-HF link, indicating CHIP is an independent HF risk factor.
• These findings highlight CHIP as a potential therapeutic target for HF prevention.