The effect of clonal hematopoiesis on long-term outcomes in patients undergoing coronary artery bypass grafting.

Background: Clonal hematopoiesis of indeterminate potential (CHIP), characterized by age-related somatic mutations in hematopoietic stem and progenitor cells, has been identified as a potential risk factor for cardiovascular events and mortality. However, the significance of CHIP in the context of coronary artery bypass grafting (CABG) remains unexplored. We aim to investigate the potential impact of CHIP on long-term outcomes of patients who underwent CABG.

Methods: We conducted a nested case-control study with 497 patients from the randomized Statin Therapy in Cardiac Surgery (STICS) cohort (ClinicalTrials.gov number NCT01573143). CHIP mutations were identified using ultra-deep sequencing of a targeted panel of 23 genes, with a mean depth of coverage of 16,043x. The relationship between CHIP and major adverse cardiovascular and cerebrovascular events (MACCE), including all-cause death, non-fatal ischemic stroke (IS), and non-fatal myocardial infarction (MI), was analyzed using Cox proportional hazards models and Fine-Gray regression to account for competing risks. We also validated our findings using data from the selected UK Biobank cohort of CABG to assess the generalizability.

Results: CHIP with a variant allele frequency (VAF) ≥ 2% was detected in 91 patients (18.3%), while CHIP with lower VAF (≥ 0.1%) was present in 46.3% of patients. DNMT3A and TET2 were the most frequently mutated genes. Over a median follow-up of 6.0 years (interquartile range [IQR], 3.5-6.5 years), CHIP (VAF ≥ 2%) was not significantly associated with MACCE (adjusted hazard ratio [aHR] 1.23, 95% confidence interval [CI] 0.90-1.70) and non-fatal IS/MI (aHR: 0.96, 95% CI: 0.62-1.49) but was associated with an increased risk of all-cause death (aHR 1.73, 95% CI 1.08-2.78) and cardiovascular death (aHR 2.58, 95% CI 1.47-4.55) compared to their counterparts. However, CHIP with small clones (VAF 0.1%-2%) showed no significant association with any long-term outcomes. In the UK Biobank cohort of CABG, CHIP (VAF ≥ 2%) was also significantly associated with an increased risk of all-cause death (aHR: 2.00, 95% CI: 1.29-3.08) over a median follow-up of 11.1 years (IQR, 9.9-15.4 years).

Conclusions: CHIP mutations are common in CABG patients and are associated with a higher risk of mortality, highlighting their potential role in long-term risk assessment and management.