Clonal Haematopoiesis Emerges as a Powerful Cardiovascular Risk Factor and Drug Target

Cardiovascular disease (CVD) remains the world's leading killer, yet substantial residual risk persists even when traditional risk factors like LDL cholesterol and blood pressure are controlled. Biological ageing drives much of this gap, but the molecular mechanisms have been poorly understood. Clonal haematopoiesis (CH) — the age-related clonal expansion of mutated blood stem cells — is now recognised as a potent, largely overlooked cardiovascular risk factor that may help explain this residual risk.

CH of indeterminate potential (CHIP), defined as a myeloid leukaemia-associated somatic mutation detected at ≥2% variant allele frequency in the absence of blood disorder, affects roughly 10% of people aged 70 and rises to 20% or more beyond that age. The three most common driver genes — DNMT3A, TET2, and ASXL1 — account for 65–80% of all CHIP mutations, with additional contributions from JAK2, TP53, PPM1D, SF3B1, and SRSF2. Crucially, population-based studies show CHIP raises all-cause mortality by 30–50%, and cause-specific analyses reveal this excess mortality is driven primarily by cardiovascular — not cancer — deaths.

Epidemiological evidence strongly links CHIP to atherosclerotic CVD. An early landmark analysis of four case-control studies found CHIP carriers faced nearly twice the risk of coronary artery disease and approximately four times the risk of myocardial infarction. Associations extend to stroke, peripheral artery disease, and angiographic coronary phenotypes. Gene-specific analyses reveal important heterogeneity: TET2, JAK2, and spliceosome/DNA-damage-repair gene mutations carry the strongest atherosclerotic risk, while DNMT3A mutations show attenuated or null associations in multiple large cohorts. Beyond atherosclerosis, CHIP is also independently associated with incident heart failure, adverse cardiac remodelling, atrial fibrillation, and worsened outcomes after cardiac interventions. Mosaic loss of the Y chromosome, the most common chromosomal form of CH in men, has additionally been linked to cardiac fibrosis and heart failure.

Mechanistically, experimental animal models — primarily using bone marrow transplantation to create chimeric mice with Tet2- or Dnmt3a-mutant haematopoietic cells — confirm causal roles for CHIP mutations in accelerating atherosclerosis and heart failure. Key pathways include amplified NLRP3 inflammasome activation, excessive IL-1β and IL-6 production, impaired efferocytosis in plaques, enhanced macrophage infiltration into cardiac tissue, and epigenetic dysregulation of inflammatory gene programmes. These findings have direct therapeutic implications: clinical trials of anti-inflammatory agents such as IL-6 inhibitors (ziltivekimab) and IL-1β blockers are underway with CHIP status as a stratifying variable.

The authors propose that CHIP screening could enable cardiovascular precision medicine — identifying high-risk individuals for intensified monitoring or preferential enrolment in anti-inflammatory trials. Important caveats include the technical limitations of standard whole-exome/genome sequencing in detecting low-VAF variants, inconsistent associations across studies due to heterogeneous CHIP definitions, and the lack of randomised clinical trial data specifically targeting CHIP carriers. The field is rapidly evolving, and prospective CHIP-focused intervention trials will be needed to confirm whether treating CH directly translates to reduced cardiovascular events.