Clonal Hematopoiesis and Its Cardiovascular Implications: A Scientific Statement From the American Heart Association

Authors, Journal, Affiliations, Type, DOI

• June-Wha Rhee (City of Hope), Kelly L. Bolton, Dipti Gupta, Lachelle D. Weeks, Alexander G. Bick (Vanderbilt), Alan R. Tall (Columbia), Kenneth Walsh (UVA), José J. Fuster (CNIC, Spain), Pradeep Natarajan (MGH), on behalf of AHA Molecular Determinants of Cardiovascular Health Committee and Cardio-Oncology Committee
• Circulation. 2026;153:e940–e952
• AHA Scientific Statement
• DOI: 10.1161/CIR.0000000000001404

Overview

This 2026 AHA Scientific Statement provides a comprehensive update on clonal hematopoiesis (CH) — the benign clonal expansion of HSCs driven by somatic mutations in leukemia-associated genes — and its cardiovascular implications. CH is effectively ubiquitous after age 70 and confers a 1.7–2× increased ASCVD risk (DNMT3A/TET2/ASXL1), 25% higher HF risk (meta-analysis n=56,597), and worse outcomes after MI, cardiogenic shock, and valve interventions. Gene-specific mechanisms are detailed: TET2 drives IL-1β/NLRP3 inflammasome activation (canakinumab reduces ischemic events in TET2 carriers in CANTOS post-hoc); DNMT3A impairs efferocytosis and raises HB-EGF; JAK2 V617F drives thrombosis via NET formation. Therapy-related CH (TP53/PPM1D after chemotherapy) amplifies late cardiotoxicity. No CH-specific CVD therapy is yet proven, but colchicine, vitamin C (TET2 restoration), and metformin (DNMT3A fitness reduction) are under investigation.

Keywords

Clonal hematopoiesis, CHIP, cardiovascular disease, atherosclerosis, heart failure, atrial fibrillation, inflammasome, IL-1β, TET2, DNMT3A, JAK2, therapy-related CH

Key Takeaways

Evolving Definition and Terminology

• CH (clonal hematopoiesis) is the broad term encompassing all clonal expansion of HSCs without known hematologic cancer. CHIP specifically refers to CH with a leukemia-associated somatic variant at VAF ≥2% plus absence of cytopenias, dysplasia, or neoplasia — a pre-malignant WHO-recognized condition.
• VAF ≥2% corresponds to >4% of circulating blood cells from one clone (heterozygous variant, neutral copy number).
• Error-corrected deep sequencing reveals CH driver variants arise early in life; ~10% of adults >70 years have CHIP at VAF ≥2%; CH with lower VAF is nearly ubiquitous above age 70.
• Clonal cytopenia of undetermined significance: unexplained persistent cytopenias in the context of CHIP variants — also WHO pre-malignant.
• CH risk score stratifies for myeloid malignancy progression: high risk = >50% blood cancer in 10 years; low risk = <1% in 10 years. Post-hoc analyses suggest it also predicts CVD-related death.

Risk Factors for CH

• Dominant risk factor: chronologic age.
• Germline predisposition: TERT variant (OR 1.3, most prominent); ATM (OR 1.46); PARP1 (OR 0.87, protective); RUNX1/CHEK2/TINF2/PTPN11 rare pathogenic variants → 2–10× CH risk. TCL1A promoter variant protects against TET2/ASXL1 CH but predisposes to DNMT3A CH.
• Therapy-related CH (t-CH): Cytotoxic chemotherapy selects for DDR pathway variants (TP53, PPM1D, CHEK2, ATM). Prevalence up to 30% in relatively young cancer survivors. Radiation → 2–4× increased CH risk.
• Toxic exposures: Smoking (ASXL1-CH specifically); particulate matter (WTC first responders); space radiation (emerging concern).
• Chronic inflammation: HIV (IFN-γ activation); premature menopause (estrogen loss); obesity and sleep deprivation (low-grade inflammation); healthy diet is protective.
• Ancestry: CH frequency 1.6-fold lower in Mexico City cohort vs UK Biobank; JAK2-CH especially reduced — whether genetic, environmental, or both is unclear.

CH and Cardiovascular Disease Outcomes

• ASCVD: DNMT3A/TET2/ASXL1 CH → 1.7–2× higher ASCVD risk vs non-carriers. Higher CAC scores in CH carriers. CH enriched 4-fold in early-onset MI. CH worsens outcomes after MI and cardiogenic shock. Relationship with recurrent ASCVD events in established disease is inconsistent. Larger clones (VAF ≥10%) and TET2/JAK2 variants carry the greatest ASCVD risk.
• Heart failure: Meta-analysis of 56,597 individuals → 25% higher HF risk in CH carriers independent of traditional risk factors and CAD. CH not significantly associated with overall HFrEF/HFpEF, but gene-specific analysis: TET2 variants 2.4-fold enriched in HFpEF; ASXL1 associated with modestly reduced EF. CH with HF → higher all-cause mortality and HF-related hospitalisations.
• Broader CVD: CH associated with AF, stroke, PAD, aortopathy, myocarditis, and worse outcomes after aortic valve interventions. JAK2 V617F specifically linked to increased thrombosis (arterial + venous).

Gene-Specific Mechanisms

TET2

• LOF → elevated IL-1β (TET2-deficient macrophages overactivate NLRP3 inflammasome → increased IL-1β secretion; heightened histone acetylation at Il1β promoter).
• Humans with somatic TET2 variants have elevated circulating IL-1β (not seen with other CH variants).
• IL6R D358A germline variant (reduces IL-6 signalling) mitigates elevated CAD risk of TET2-CH carriers.
• CANTOS post-hoc: canakinumab (IL-1β antibody) reduces ischemic events far more in TET2-CH carriers than non-CH. Colchicine mitigates TET2-CH atherosclerosis in mouse models.
• Therapeutic hypothesis: IL-1β–targeted or NLRP3 inhibitor–based therapy specifically beneficial in TET2-CH.

DNMT3A

• LOF → similar but milder proinflammatory cytokine/chemokine effects vs TET2.
• Additional mechanisms: (1) impairs efferocytosis in atherosclerotic plaques → adverse plaque remodeling; (2) increased secretion of HB-EGF → cardiac fibrosis.
• Distinct tissue-resident-like macrophage populations and inflammatory gene expression signatures vs TET2-CH.
• Metformin proposed to reduce DNMT3A-variant clonal fitness.

ASXL1

• Truncating variants (C-terminal exon) → truncated protein (distinct from TET2/DNMT3A LOF).
• Promotes inflammation and cardiac remodelling post-LAD ligation in mice. Accelerates atherosclerosis via enhanced myeloid cell inflammation.
• Gene-specific: ASXL1 CH associated with modestly reduced EF in HF cohort studies.

JAK2 V617F

• Common myeloproliferative neoplasm driver; associated with CVD risk even in the absence of elevated blood cell counts (identified in 3–4% of general European population by droplet digital PCR).
• Mechanisms: increased platelet activation, polycythemia, NETs → venous and arterial thrombosis; myeloid cell and myocardial inflammation → HF; macrophage proliferation, mitochondrial ROS, NLRP3/AIM2 inflammasome activation, impaired efferocytosis → atherosclerosis; thoracic aortic aneurysm in mouse models.

Therapy-Related CH (t-CH: TP53, PPM1D, CHEK2, ATM)

• Selected by cytotoxic chemotherapy via DDR pathway gene fitness advantage under genotoxic stress.
• TP53-CH amplified by doxorubicin → worse anthracycline-induced cardiomyopathy.
• PPM1D-CH → increased IL-1β + myocardial fibrosis after angiotensin II infusion in mice; NLRP3 inhibitor reverses these effects.
• ATM/CHEK2 variants: increased CVD risk in t-CH context; mechanistic data less developed.

Clinical Translation

• No official CH screening guidelines. CH currently identified incidentally (hereditary cancer panels, solid tumour liquid biopsy, haematology panels for abnormal counts).
• CHIP clinics at tertiary centres provide multidisciplinary surveillance (primarily haematologic malignancy; CV risk evaluated by cardio-oncology).
• CVD risk management: Current CVD risk prediction models (PREVENT, SCORE2) do not incorporate CH. Guideline-concordant primary/secondary prevention is the recommended approach until CH-specific CVD therapies are proven.
• Potential therapeutic strategies:
  • Vitamin C: may restore TET2 function
  • Metformin: may reduce DNMT3A-variant clonal fitness
  • Colchicine: mitigates TET2-CH atherosclerosis (preclinical + indirect CANTOS data)
  • Canakinumab/NLRP3 inhibitors: benefit in TET2-CH (post-hoc; no prospective CVD trial)
  • Clone reduction strategies: early stage, not proven

Limitations of the Document

• Most mechanistic data from mouse bone marrow transplant models; relative importance of systemic vs. direct myocardial/plaque effects of variant immune cells unresolved in humans.
• CH-ASCVD risk association is inconsistent in the UK Biobank low-risk population; depends on clone definition, VAF calling, and population risk level.
• Causality of CH for CVD (vs. shared predisposition) not established for all outcomes; bidirectional relationship computationally proposed but longitudinal data favour CH → ASCVD directionality.
• No prospective CVD clinical trials for any CH-targeted therapy yet completed.
• Mosaic chromosomal alterations and CH with unknown drivers: CVD associations largely unclear.

Key Concepts Mentioned

• concepts/Clonal-Hematopoiesis — primary concept page; major update required
• concepts/ASCVD-Risk-Assessment — CH not yet in CVD risk models; future integration
• concepts/Cancer-Therapy-Related-CV-Toxicity — t-CH amplifies anthracycline cardiotoxicity

Key Entities Mentioned

• entities/Heart-Failure — 25% higher HF risk; TET2 2.4× in HFpEF; ASXL1 → reduced EF
• entities/Atrial-Fibrillation — CH associated with AF
• concepts/Cardio-Oncology — CH as emerging cardio-oncology risk factor; CHIP clinics

Wiki Pages Updated

• wiki/sources/ch-aha-2026.md (created)
• wiki/sourceindex.md (updated)
• wiki/wikiindex.md (updated)
• wiki/concepts/Clonal-Hematopoiesis.md (major update)
• wiki/entities/Heart-Failure.md (CH-HF section added)
• wiki/concepts/ASCVD-Risk-Assessment.md (CH as emerging risk factor added)
• wiki/concepts/Cancer-Therapy-Related-CV-Toxicity.md (t-CH section added)
• wiki/concepts/Cardio-Oncology.md (CHIP clinics added)