Abstract 11: Prospective Association of Tet2 Mediated Clonal Hematoopoiesis and Heart Failure and Its Subtypes in Postmenopausal Women

Abstract

Background: Recent studies have shown that hematopoietic stems cells can undergo clonal expansion secondary to somatic mutations, termed clonal hematopoiesis of indeterminate potential (CHIP). TET2 is frequently mutated in individuals with CHIP and has been associated with coronary heart disease in humans and Heart Failure in mice models. We investigated whether any of the top three somatic mutations ( DNMT3A,TET2, ASXL1) associated with CHIP were prospectively associated with heart failure (HF), heart failure with preserved ejection fraction (HFPEF) or heart failure with reduced ejection fraction (HFrEF) in post menopausal women. Methods: A subcohort of 5214 postmenopausal women in the Women’s Health Intiative were evaluated for CHIP and HF. CHIP was determined at the Broad Institute via whole genome sequencing using the GATK4 MuTect2 somatic variant caller through the NHLBI TOPMed project. Hospitalized heart failure was based upon trained physician record review. HFpEF was defined as an EF > 50% and HFrEF as EF<50% . Cox proportional hazards model were evaluate adjusting for age, race, income, education, cigarette smoking, body mass index, coronary heart disease, atrial fibrillation, diabetes , hypertension, systolic blood pressure, and stroke. Inverse probability weighting was used to account for selection bias associated with the subcohort selection. Results: Of the 5214 postmenopausal women, 597 developed HF, 283 HFpEF and 204 HFrEF. N=408 had CHIP. The top 3 gene mutations associated with CHIP (N=364) were DNMT3A (4.8%), TET2 (1.7%) and ASXL1 (0.5%). Women with CHIP associated with any of the top 3 mutations and with TET2 were associated with HF, HFpEF but not HFrEF. DNMT3A and ASXL1 CHIP mutations were not associated HF, HFpEF or HFrEF (See Table ). Conclusion: CHIP associated with the top 3 somatic mutations and TET2 were prospectively associated with HF and HFpEF consistent with animal models and the concept of HFpEF being associated with pathologic aging. Replication of these findings in other cohorts is warranted.