Spliceosome gene mutations synergize with anthracyclines to amplify atrial fibrillation risk in hematologic malignancies: a multicenter cohort study with discovery and validation

Background Atrial fibrillation (AF) is a life-threatening complication in patients with hematologic malignancies, yet personalized risk stratification for this condition remains highly challenging. Spliceosome gene mutations are key drivers of the initiation and progression of hematologic malignancies. However, their specific role in the pathogenesis of AF, as well as the potential synergistic effects with core chemotherapeutic agents such as anthracyclines, remains largely unclear. Methods This retrospective cohort included a discovery cohort (n = 1321) and a validation cohort (n = 412) of hematologic malignancy patients (male, 53.9%; age, 62 years). Firth penalized Cox, competing risk models, and FDR correction assessed associations between CHIP-related mutations (DTA, spliceosome, DNA damage repair genes) and AF. Sensitivity analyses addressed immortal time bias and mutational burden thresholds. Interaction analysis evaluated spliceosome mutation-anthracycline synergy. Mechanistic validation involved co-culturing human monocytes with atrial fibroblasts and Western Blot (WB) to detect fibrosis-related proteins. Results Spliceosome gene mutations were significantly associated with increased AF risk in the discovery cohort (adjusted HR = 1.59, 95% CI: 1.05–2.42, P  = 0.030), a finding robust to sensitivity analyses and confirmed in the validation cohort (HR = 2.71, 95% CI: 1.24–5.95, P  = 0.013). A significant synergistic interaction between spliceosome mutations and anthracycline exposure was observed in both the discovery cohort (sHR = 2.99, 95% CI: 1.21–7.40, P  = 0.018) and the validation cohort (sHR = 3.78, 95% CI: 1.09–13.14, P  = 0.036). Patients with spliceosome mutations exhibited left atrial enlargement (mediation effect: 26.6%), elevated monocyte counts, and higher levels of IL-6 and TNF-α. In vitro , monocytes from mutation carriers promoted collagen I expression in human atrial fibroblasts. Conclusions Spliceosome gene mutations are a novel, independent predictor of AF in hematologic malignancies and synergistically amplify anthracycline-related AF risk. Myeloid-driven inflammation and atrial structural remodeling appear to be key mediating mechanisms. These findings advocate for enhanced AF surveillance in spliceosome-mutated patients receiving anthracyclines and highlight inflammation as a potential therapeutic target for cardio-protection.