Background: Recent studies have shown that hematopoietic stems cells can undergo clonal expansion secondary to somatic mutations in leukocytes-related genes, termed clonal hematopeisis of indeterminate potential (CHIP). The epigenetic regulator TET2 is frequently mutated in individuals with CHIP and has been associated with coronary heart disease in humans and Heart Failure in mice models through a mechanism of IL1B/NLRP3 Inflammasome. 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 post menopausal women in the Women’s Health Intiative were evaluated for CHIP and heart failure. CHIP was determined at the Broad Institute via whole genome sequencing using the GATK4 MuTect2 somatic variant caller through the NHLBI TOPMed project. Genotypes DNMT3A, TET2, ASXL1 associated with CHIP were evaluated for a prospective association with HF, HFpEF and HFrEF. Acute decompensated hospitalized heart failure was based upon trained physician record review over 15 years of follow-up. 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 mellitus, hypertension, systolic blood pressure, and stroke. Inverse probability weighting was used to account for selection bias associated with the sub cohort selection.
Results: Of the 5214 post menopausal 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 CIP associated with any of the top 3 mutations and with TET2 were associated with HF, HFpEF but not HFrEF. DNMT3A and ASXL1 CHP mutations were not associated HF, HFpEF or HFrEF (See Table ).
HR and 95% CI HF HFpEF HFrEF
CHIP associated with Any of the Top 3 Gene mutations 1.36 (1.08,1.70) 1.42 (1.03,1.94) 0.84 (0.52,1.37)
DNMT3A 1.07 (0.80,1.44) 1.11 (0.74,1.67) 0.62(0.32,1.21)
TET2 2.07 (1.44,2.97) 2.50 (1.54, 4.06) 0.95 (0.38,2.36)
ASXL1 1.60 (0.80,3.23) 1.04 (0.31,3.56) 2.01 (0.70,5.79)
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.