Acute Effects of Ibrutinib on Ventricular Arrhythmia in Spontaneously Hypertensive Rats.

BACKGROUND

The Bruton's Tyrosine Kinase Inhibitor ibrutinib is associated with ventricular arrhythmia (VA) and sudden death. However, the pro-arrhythmic electrophysiological dysregulation that results from ibrutinib with age and cardiovascular disease is unknown.

OBJECTIVES

This study sought to investigate the acute effects of ibrutinib on left ventricular (LV) VA vulnerability, cytosolic calcium dynamics, and membrane electrophysiology in old and young spontaneous hypertensive rats (SHRs).

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.