Background
The Bruton's Tyrosine Kinase Inhibitor ibrutinib is associated with ventricular arrhythmia (VA) and sudden death. However, the pro-arrhythmic electrophysiological dysregulation that
Conclusions
Ibrutinib-induced VA is associated with old age in SHR. Acute dysregulation of calcium and repolarization dynamics play important roles in ibrutinib-induced VF.
Methods
Langendorff-perfused hearts of young (10 to 14 weeks) and old (10 to 14 months) SHRs were treated with ibrutinib (0.1 μmol/l) or vehicle for 30 min. Simultaneously, LV epicardial action potential and cytosolic calcium transients were optically mapped following an incremental pacing protocol. Calcium and action potential dynamics parameters were analyzed. VA vulnerability was assessed by electrically inducing ventricular fibrillations (VFs) in each heart. Western blot analysis was performed on LV tissues.
Results
Ibrutinib treatment resulted in higher vulnerability to VF in old SHR hearts (27.5 ± 7.5% vs. 5.7 ± 3.7%; p = 0.026) but not in young SHR hearts (8.0 ± 4.9% vs. 0%; p = 0.193). In old SHR hearts, following ibrutinib treatment, action potential duration (APD) alternans (p = 0.008) and APD alternans spatial discordance (p = 0.027) were more prominent. Moreover, calcium transient duration 50 was longer (p = 0.032), calcium amplitude alternans ratio was significantly lower (p = 0.001), and time-to-peak of calcium amplitude was shorter (p = 0.037). In young SHR hearts, there were no differences in calcium and APD dynamics. Conclusions: Ibrutinib-induced VA is associated with old age in SHR. Acute dysregulation of calcium and repolarization dynamics play important roles in ibrutinib-induced VF.