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

Abstract

Abstract Background Atrial fibrillation (AF) is a life‑threatening complication in patients with hematologic malignancies, yet personalized risk stratification remains challenging. Spliceosome gene mutations are key drivers of these malignancies, but their specific role in AF pathogenesis and potential synergy with anthracyclines is unclear. Methods This retrospective cohort study included a discovery cohort ( n = 1160) and a validation cohort ( n = 412). Multivariable Cox regression, Fine‑Gray competing risk models, and false discovery rate (FDR) correction were used to assess the association between clonal hematopoiesis of indeterminate potential (CHIP)-related mutations (DTA, spliceosome, and DNA damage repair genes) and AF. To avoid immortal time bias, anthracycline exposure was treated as a time-dependent covariate. Interaction analysis was used to evaluate the synergistic effect between spliceosome mutations and anthracyclines. Mechanistic exploration was performed using monocyte‑atrial fibroblast co‑culture and western blotting. Results In the discovery cohort, spliceosome mutations were significantly associated with AF (sHR = 1.67, 95% CI: 1.09–2.55, FDR q = 0.029). This association remained robust after sensitivity analyses, and was confirmed in the validation cohort (sHR = 6.26, 95% CI: 1.52–25.8, FDR q = 0.022). A significant synergistic interaction was observed between spliceosome mutations and anthracycline exposure: in the discovery cohort, the time‑dependent competing risk model (adjusted for age, sex, disease subtype) yielded an sHR of 3.68 (95% CI: 1.23–10.9, P = 0.019), with consistent results in the validation cohort (sHR = 5.14, 95% CI: 1.29–20.6, P = 0.021). The interaction remained robust in sensitivity analyses. Exploratory analyses showed that patients with spliceosome mutations had larger left atrial diameter and higher monocyte counts (both FDR q < 0.05), with monocyte counts positively correlated with IL‑6 levels. In vitro, monocytes from mutation carriers promoted COL1A1 and α‑SMA expression in atrial fibroblasts, an effect attenuated by IL‑6 neutralization. Conclusions Spliceosome gene mutations appear to be a novel independent predictor of AF in patients with hematologic malignancies and show a synergistic effect with anthracyclines in increasing AF risk. Myeloid-driven inflammation and atrial remodeling likely contribute to this process. These findings suggest that enhanced AF surveillance could be considered in spliceosome-mutated patients receiving anthracyclines, and that inflammation may represent a potential therapeutic target for cardioprotection.