Association of clonal hematopoiesis of indeterminate potential with cardiovascular mortality in cardiovascular-kidney-metabolic syndrome: a large prospective cohort study.
Zhao Z, Ma C, et al. • Frontiers in endocrinology • 2026
CHIP is an independent risk factor for cardiovascular mortality across all stages of CKM syndrome, and it exacerbates this outcome primarily by driving systemic inflammation, immune dysregulation, and aberrant tissue remodeling.
Key Findings
Results
Large CHIP was independently associated with higher cardiovascular mortality among UK Biobank participants with CKM syndrome stages 1-4.
The analysis included 288,384 participants across CKM stages 1-4, with 6,515 cardiovascular deaths over a median follow-up of 16.5 years.
After multivariable adjustment, Large CHIP had a hazard ratio of 1.24 (95% CI, 1.09-1.40) for cardiovascular mortality compared with non-CHIP.
Analyses used Kaplan-Meier curves and multivariable Cox proportional hazards models.
Results
Individuals with Large CHIP had a significantly higher unadjusted risk of cardiovascular mortality than non-CHIP individuals at every CKM stage.
Kaplan-Meier analyses showed higher cardiovascular mortality in the Large CHIP group across all CKM stages (all log-rank P < 0.05).
Results
The association between Large CHIP and cardiovascular mortality was consistent across subgroups, regardless of CKM stage or established cardiometabolic and renal diseases.
Subgroup analyses confirmed consistent effects across CKM stages and across the presence of established cardiometabolic and renal diseases.
Sensitivity analyses were conducted to assess the robustness of the results.
Results
Proteomic analysis in the UKB Pharma Proteomics Project indicated that the excess cardiovascular mortality risk associated with CHIP involves immune-inflammatory dysregulation and tissue structural remodeling.
Circulating proteins jointly associated with CHIP and cardiovascular mortality were identified within UKB-PPP.
Functional enrichment analysis of these proteins pointed to immune-inflammatory and tissue remodeling pathways.
Results
Specific circulating proteins mediated substantial proportions of the CHIP-related cardiovascular mortality risk.
DSC2, a structural component, mediated 34.3% of the risk.
VSIG4, an immune-regulatory receptor, mediated 33.1%.
CD300C, an immune-regulatory receptor, mediated 29.2%.
These were identified through mediation analyses.
What This Means
This study used data from the UK Biobank to examine whether clonal hematopoiesis of indeterminate potential (CHIP) is linked to death from cardiovascular causes in people with cardiovascular-kidney-metabolic (CKM) syndrome. CHIP is a condition in which blood stem cells acquire gene mutations and form expanded clones. CKM syndrome describes the interconnected health problems of the heart, kidneys, and metabolism. The study followed 288,384 people across CKM stages 1-4 for a median of 16.5 years, during which 6,515 died of cardiovascular causes.
People with a large CHIP clone had about a 24% higher risk of cardiovascular death than those without CHIP, after accounting for other factors (hazard ratio 1.24). The higher risk appeared at every CKM stage and was consistent regardless of whether people already had cardiometabolic or kidney disease.
The researchers also analyzed blood proteins and found that the excess risk seemed to involve inflammation, immune system dysregulation, and changes in tissue structure. Three proteins (DSC2, VSIG4, and CD300C) each accounted for roughly 29-34% of the statistical link between CHIP and cardiovascular death. This research suggests that CHIP may be a useful marker of cardiovascular risk in people with CKM syndrome and points to biological pathways that could be studied further. As an observational study, it shows association rather than proof of cause.
Zhao Z, Ma C, Zhao L, Zhao X, Li Q, Ding Y, et al.. (2026). Association of clonal hematopoiesis of indeterminate potential with cardiovascular mortality in cardiovascular-kidney-metabolic syndrome: a large prospective cohort study.. Frontiers in endocrinology. https://doi.org/10.3389/fendo.2026.1910361