Impaired Cardiac AMPK (5′‐Adenosine Monophosphate‐Activated Protein Kinase) and Ca2+‐Handling, and Action Potential Duration Heterogeneity in Ibrutinib‐Induced Ventricular Arrhythmia Vulnerability

Abstract

Background We recently demonstrated that acute administration of ibrutinib, a Bruton's tyrosine kinase inhibitor used in chemotherapy for blood malignancies, increases ventricular arrhythmia (VA) vulnerability. A pathway of ibrutinib‐induced vulnerability to VA that can be modulated for cardioprotection remains unclear. Methods and Results The effects of ibrutinib on cardiac electrical activity and Ca2+ dynamics were investigated in Langendorff‐perfused hearts using optical mapping. We also conducted Western blotting analysis to evaluate the impact of ibrutinib on various regulatory and Ca2+‐handling proteins in rat cardiac tissues. Treatment with ibrutinib (10 mg/kg per day) for 4 weeks was associated with an increased VA inducibility (72.2%±6.3% versus 38.9±7.0% in controls, P<0.002) and shorter action potential durations during pacing at various frequencies (P<0.05). Ibrutinib also decreased heart rate thresholds for beat–to–beat duration alternans of the cardiac action potential (P<0.05). Significant changes in myocardial Ca2+ transients included lower amplitude alternans ratios (P<0.05), longer times‐to‐peak (P<0.05), and greater spontaneous intracellular Ca2+ elevations (P<0.01). We also found lower abundance and phosphorylation of myocardial AMPK (5′‐adenosine monophosphate‐activated protein kinase), indicating reduced AMPK activity in hearts after ibrutinib treatment. An acute treatment with the AMPK activator 5‐aminoimidazole‐4‐carboxamide‐1‐β‐D‐ribofuranoside ameliorated abnormalities in action potential and Ca2+ dynamics, and significantly reduced VA inducibility (37.1%±13.4% versus 72.2%±6.3% in the absence of 5‐aminoimidazole‐4‐carboxamide‐1‐β‐D‐ribofuranoside, P<0.05) in hearts from ibrutinib‐treated rats. Conclusions VA vulnerability inflicted by ibrutinib may be mediated in part by an impairment of myocardial AMPK activity. Pharmacological activation of AMPK may be a protective strategy against ibrutinib‐induced cardiotoxicity.

Keywords

• action potential
• AMPK
• calcium handling
• ibrutinib
• ventricular arrhythmias