Blood Cell Mutations May Quietly Fuel Heart Disease and Arterial Plaque Growth

Cardiovascular disease remains the leading cause of death worldwide, and traditional risk factors do not explain all of it. Somatic mutations, acquired DNA changes that accumulate with age, are well known in cancer but are now found in apparently healthy tissues. This review asks whether such mutations in blood and vascular cells help cause cardiovascular disease.

The authors reviewed the literature, focusing on clonal hematopoiesis of indeterminate potential (CHIP). CHIP is defined as myeloid-cancer-associated mutations in blood cells at a variant allele fraction of at least 2%, without overt blood cancer. It is detected by next-generation sequencing. The commonest genes are DNMT3A, TET2 and ASXL1, with JAK2, TP53, PPM1D and SF3B1 less common. The review also covers evidence from mice, human cohorts, and plaque and vascular tissue sequencing.

CHIP is linked to more than a tenfold higher risk of blood cancer and to atherosclerosis, myocardial infarction, heart failure and coronary calcification. Early small studies reported relative risks above twofold, but larger studies found smaller or no increases. Risk varies by gene. TET2 confers over 1.5-fold higher coronary risk, TP53 over twofold, and JAK2 over twofold for arterial and venous thrombosis, with paradoxically more bleeding. In LDLR-knockout mice, TET2-deficient blood cells increased aortic plaque size by 60% via IL-1β and NLRP3 inflammasome activation. DNMT3A-mutant monocytes raise IL-1β and IL-6 and activate cardiac fibroblasts, promoting fibrosis. In UK Biobank participants with established ASCVD, 5% carried CHIP, and they had higher risks of future events and death, especially with large or multiple clones. Mutations also appear in vascular tissue. JAK2V617F has been found in plaque endothelial cells, and exome sequencing found somatic mutations in 12 of 13 carotid plaques but in none of 11 non-atherosclerotic arteries. Clone VAFs ranged from 1% to 30% and spanned up to 16 mm.

Clinically, CHIP could refine risk stratification and guide therapy. In a post hoc CANTOS analysis, canakinumab appeared to benefit TET2-mutant CHIP carriers more. Colchicine reduced atherosclerosis in TET2-mutant mice, was associated with fewer myocardial infarctions in human TET2 CHIP carriers, and was linked to reduced TET2 clone expansion in a LoDoCo2 post hoc analysis. Metformin may suppress DNMT3A R882H clones.

Important caveats remain. Causality is unresolved: Mendelian randomization supports links to atrial fibrillation but not atherosclerotic events, and inflammation may drive CHIP rather than the reverse. Plaque mutations may reflect infiltrating blood cells or contamination rather than vessel-wall mutations. The evidence for endothelial and smooth-muscle somatic mutation is preliminary, and study methods vary in sequencing depth and VAF thresholds. The therapeutic findings come mostly from post hoc analyses and need prospective validation.