Association of clonal hematopoiesis of indeterminate potential with cardiovascular mortality in cardiovascular-kidney-metabolic syndrome: a large prospective cohort study.

Background: Cardiovascular-kidney-metabolic (CKM) syndrome represents a progressive pathophysiological continuum. While clonal hematopoiesis of indeterminate potential (CHIP) is known to increase the risk of CKM disease onset and adverse prognoses, its overall and stage-specific impacts on cardiovascular mortality within the CKM framework, alongside the circulating proteomic mechanisms mediating this excess risk, remain largely unknown. Methods: Participants from the UK Biobank with available CHIP data across the CKM syndrome continuum were included. The primary outcome was cardiovascular mortality. Kaplan-Meier curves and multivariable Cox proportional hazards models were utilized to evaluate the incremental risk conferred by CHIP. Sensitivity and subgroup analyses were conducted to ascertain result robustness. Within UKB Pharma Proteomics Project (UKB-PPP), circulating proteins jointly associated with CHIP and cardiovascular mortality were identified, followed by functional enrichment and mediation analyses to elucidate the underlying mechanisms. Results: During a median follow-up of 16.5 years, 6,515 cardiovascular deaths were recorded among 288,384 participants across CKM stages 1-4. Across all varying CKM stages, individuals harboring Large CHIP exhibited a significantly higher risk of cardiovascular mortality compared to the non-CHIP group (all log-rank P < 0.05). Following multivariable adjustment, Large CHIP emerged as an independent risk factor for cardiovascular mortality (hazard ratio, 1.24; 95% confidence interval, 1.09-1.40), with subgroup analyses confirming consistent effects regardless of CKM stage or established cardiometabolic and renal diseases. Proteomic profiling, corroborated by UKB-PPP, revealed that the mechanisms driving this excess risk predominantly involve immune-inflammatory dysregulation and tissue structural remodeling. This pathway was highlighted by critical downstream mediators, including the structural component DSC2 (mediating 34.3% of the risk) and key immune-regulatory receptors such as VSIG4 (33.1%) and CD300C (29.2%). Conclusions: CHIP is an independent risk factor for cardiovascular mortality across all stages of CKM syndrome. Mechanistically, CHIP exacerbates this adverse outcome primarily by driving systemic inflammation, immune dysregulation, and aberrant tissue remodeling.