Breast tumour-secreted ADAM10 mediates atrial fibrogenesis and fibrillation.

Summary

Before any therapy, women with breast cancer had a markedly higher AF prevalence and ECG markers of atrial remodeling than matched controls. Mechanistically, tumor-secreted soluble ADAM10 cleaved EphrinB2 in atrial fibroblasts to drive fibrosis and AF; pharmacologic or genetic inhibition of ADAM10/EphrinB2 signaling attenuated AF in mice.

Key Findings

• AF prevalence was higher in treatment-naïve breast cancer (6.41%) vs controls (0.90%), with more abnormal P-wave terminal force.
• Orthotopic breast cancer and tumor-conditioned media induced atrial fibrosis and increased AF susceptibility in mice.
• Tumor-secreted sADAM10 cleaved EphrinB2 in atrial fibroblasts; inhibiting ADAM10 or knocking down EphrinB2 reduced fibrosis and AF; plasma sADAM10 correlated with sEphrinB2 (R2=0.67).

Clinical Implications

Pre-treatment AF screening and rhythm surveillance should be considered in breast cancer, with potential biomarker risk stratification using sADAM10/sEphrinB2. Targeting sADAM10 could emerge as a cardio-oncology therapeutic strategy.

Limitations

• Observational human data limit causal inference; residual confounding is possible.
• Generalizability beyond breast cancer and to clinical intervention remains unproven.

Future Directions

Prospective AF screening studies in oncology cohorts, validation of sADAM10/sEphrinB2 as risk biomarkers, and early-phase trials of ADAM10 inhibitors to prevent AF.