TET 2-mutant clonal hematopoiesis is associated with peripheral bypass graft occlusion: A multicenter retrospective cohort pilot study.

OBJECTIVE

Clonal hematopoiesis of indeterminate potential (CHIP), defined by somatic mutations in hematopoietic cells, is associated with cardiovascular disease through proinflammatory mechanisms. We investigated whether CHIP, and specifically TET2 mutations, is associated with peripheral bypass graft occlusion in patients with peripheral arterial disease.

METHODS

In this multicenter, retrospective cohort pilot study, 47 patients with peripheral arterial disease who had undergone femoropopliteal or femorocrural bypass grafting were analyzed. CHIP status was assessed from peripheral blood using a 40-gene myeloid sequencing panel. Time-to-event analyses were performed using Kaplan-Meier survival analysis and multivariable Cox proportional hazards regression adjusted for diabetes and smoking status.

RESULTS

Of 47 patients, 33 had bypass graft occlusion and 14 had patent grafts. CHIP was detected in 14 individuals (29.8%). The mutational spectrum differed markedly between groups: in the patent graft group, all CHIP mutations were in DNMT3A, whereas TET2 was the most frequently mutated gene in the occlusion group (7 of 17 mutations; 41%). All five TET2-mutant patients belonged to the occlusion group. Cell sorting revealed CHIP variants predominantly in myeloid cells, natural killer cells, and B lymphocytes, with near-absence in T cells. Cox regression demonstrated a significant association between TET2 mutation and bypass occlusion (hazard ratio, 6.70; 95% confidence interval, 1.96-22.96; P = .003).

CONCLUSIONS

TET2 mutations are associated with peripheral bypass graft occlusion and may represent a novel biomarker for graft failure risk. These findings require validation in larger prospective studies.

CLINICAL RELEVANCE: Clonal hematopoiesis, particularly TET2 mutations, is increasingly recognized as a driver of atherosclerotic cardiovascular disease and peripheral arterial disease (PAD). This pilot study extends that risk to the surgical setting, demonstrating a strong association between TET2 mutations and peripheral bypass graft occlusion (hazard ratio, 6.70). If confirmed in larger prospective cohorts, preoperative TET2 screening could identify a high-risk subgroup of patients with PAD requiring intensified postoperative imaging surveillance, more aggressive antithrombotic regimens, earlier reintervention thresholds, and consideration of targeted anti-inflammatory prophylaxis. Such gene-specific risk stratification could shift bypass care toward individualized, biomarker-guided management of patients with PAD undergoing revascularization.