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

• Published in: Journal of the American Heart Association 2024-06, Vol.13 (12), p.e032357
• Main Authors: Zhao, Yanan, Du, Beibei, Chakraborty, Praloy, Denham, Nathan, Massé, Stéphane, Lai, Patrick F H, Azam, Mohammed Ali, Billia, Filio, Thavendiranathan, Paaladinesh, Abdel-Qadir, Husam, Lopaschuk, Gary D, Nanthakumar, Kumaraswamy
• Format: Article
• Language: English
• Subjects: action potential; AMPK; calcium handling; ibrutinib; Original Research; ventricular arrhythmias
• ISSN: 2047-9980; 2047-9980
• DOI: 10.1161/JAHA.123.032357

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.BACKGROUNDWe 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.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