AHA Scientific Sessions 2026 Abstract · Nov 2, 2026
Clonal Hematopoiesis of Indeterminate Potential as a Cardiovascular Driver - An Umbrella Review of Systematic Reviews and Meta-Analyses
By Mannam R, shabrawi MN, Khalid F et al.
Background: Clonal hematopoiesis of indeterminate potential (CHIP), marked by age-related somatic mutations in hematopoietic stem cells (mostly TET2 and DNMT3A), is a novel cardiovascular risk factor. Affecting approximately 10% of adults aged ≥70, CHIP links aging and cardiovascular pathology by driving systemic "inflammaging" via innate immune activation (NLRP3 inflammasome, IL-1β). This sustained inflammatory signaling promotes macrophage-mediated atherosclerotic plaque instability and mesenchymal calcification in aortic valves. Research Question: How do specific CHIP mutations, predominantly TET2 and DNMT3A, influence the incidence and mortality of cardiovascular diseases? Methods: We systematically searched PubMed, MEDLINE, EMBASE, and the Cochrane Library till Feb 2026 to identify relevant studies. This umbrella review synthesizes meta-analytic and cohort evidence (e.g., UK Biobank, All of Us, WHI) evaluating CHIP-associated cardiovascular endpoints. We focus on mutation-specific hazard ratios (HR) for coronary artery disease, heart failure (HF) subtypes, aortic valve stenosis (AVS), and post-transcatheter aortic valve replacement (TAVR) mortality to map the clinical phenotypes of TET2 and DNMT3A. Results: CHIP carriers exhibit a 1.9-fold increased coronary heart disease risk and a 4-fold early-onset myocardial infarction risk. Phenotypes diverge by mutation: TET2 strongly drives incident HF with preserved ejection fraction (HR=2.50, 95%CI 1.54-4.06) and elevated AVS risk, whereas DNMT3A shows attenuated HF associations (HR=1.11, 95%CI 0.74-1.67). However, combined DNMT3A/TET2 carriers face 3-fold higher post-TAVR mortality (HR=3.1, 95%CI 1.2-8.1) and doubled HF mortality (HR=2.1, 95%CI 1.0-4.2). Mechanistically, TET2 deficiency directly increases IL-1β/IL-6 secretion, while DNMT3A amplifies bone marrow inflammatory signaling to propagate systemic inflammaging. Conclusion: TET2 and DNMT3A mutations drive overlapping cardiovascular morbidities via innate immune activation. CHIP is a targetable inflammatory axis, refining prognostication and highlighting therapeutic avenues (e.g., IL-1β antagonism) for atherosclerosis, HF, and AVS.