Ibrutinib-Induced Pulmonary ACE Activation Promotes Atrial Fibrillation in Rats

The molecular mechanism of ibrutinib-induced atrial fibrillation (AF) remains unclear. We here demonstrate that treating rats with ibrutinib for 4 weeks resulted in the development of inducible AF, left atrial enlargement, atrial fibrosis, and downregulation of connexin expression, which were associated with CSK inhibition and Src activation. Ibrutinib upregulated ACE protein expression in HPMECs by inhibiting the PI3K-AKT pathway, subsequently increasing circulating Ang II levels. However, the expression of ACE and Ang II in the left atria was not affected. Importantly, we observed that perindopril significantly mitigated ibrutinib-induced left atrial remodeling and AF promotion by inhibiting the activation of the ACE and its downstream CSK-Src signaling pathway. These findings indicate that Ibrutinib-induced activation of the ACE contributes to AF development and could serve as a novel target for potential prevention strategies.