Abstract 811: The Role of Mitochondrial Stress and the Late Sodium Current in Ibrutinib-Mediated Atrial Fibrillation

Abstract

Background: Ibrutinib (a Bruton’s tyrosine kinase inhibitor, BTKI) is rapidly becoming the treatment of choice for many B-cell malignancies, but its proarrhythmic effects may limit its widespread use. GWAS have consistently identified an AF risk locus on chromosome (chr) 4q25, and the nearest gene Pitx2c has been implicated in AF development as evidenced by increased AF in Pitx2c +/- mice which serve as an experimental model for clinical AF. Objective: To assess the role of the late cardiac Na current (I Na,L ) and oxidative stress in mediating increased susceptibility to AF in Pitx2c +/- mice which are genetically prone to developing AF as well as in atrial human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) exposed to ibrutinib. Method: Pitx2c +/- mice were administered ibrutinib (30mg/kg/day IP) for 14 days while atrial hiPSC-CMs were exposed to ibrutinib for 48 hrs. Results: There was a graded increase in AF episodes and burden with the number of days the Pitx2c +/- mice were exposed to ibrutinib versus controls ( Fig. 1A ). The action potential duration at 90% repolarization and the I Na-L were markedly prolonged ( Fig. 1B-C ). Furthermore, we observed a significant increase in mitochondrial fragmentation ( Fig. 1D-E ) and superoxide production ( Fig. 1F-G ) in ibrutinib treated atrial hiPSC-CMs versus controls. Conclusion: We showed in Pitx2c +/- mice and atrial hiPSC-CMs that ibrutinib-mediated AF may in part be related to enhanced I Na-L and mitochondrial dysfunction leading to increased oxidative stress. Patients undergoing ibrutinib treatment may benefit from novel therapies which target mitochondrial dysfunction or the late cardiac sodium current.