Abstract 17405: Chronic Treatment of Ibrutinib Reduces PI3K Activation and Causes Increased Mitochondrial Oxidative Stress Leading to Heightened AF in Pitx2c +/- Mice

Abstract

Background: Ibrutinib, a Bruton’s tyrosine kinase inhibitor which is currently used as first line treatment to various B-cell malignancies is known to cause proarrhythmic effects in patients thus limiting its continual use. Ibrutinib treated patients have been shown to be at a 4-fold increased risk of developing atrial fibrillation (AF), but the underlying molecular mechanisms remain unclear. Studies have shown that Pitx2 , the nearest gene to the 4q25 locus has been implicated in AF pathology and thus can serve as an experimental model for clinical AF. Objective: The goal of this study is to assess the role of the late cardiac Na current (I Na,L ), PI3K activation, and oxidative stress in mediating the increased susceptibility to AF in Pitx2c +/- mice and atrial human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) exposed to ibrutinib. Method: Pitx2c +/- mice were administered ibrutinib (30mg/kg/day IP) for 23 days after which their AF burden were assessed using transesophageal rapid pacing (TErP) along with their weight, BP, and plasma glucose. Atrial hiPSC-CMs were exposed to ibrutinib for 48 hrs. ELISA, IHC, Western blotting, cellular patch clamping and, qPCR studies were performed. Results: Pitx2c +/- mice were exposed to ibrutinib showed a graded increase in AF burden. ( Fig. 1A-C ). There was a decreased activation of the PI3K pathway and pAkt leading to overall decrease in SERCA2a expression ( Fig. 1D-F ). There was a significant increase in mitochondrial fragmentation and superoxide production in ibrutinib treated atrial hiPSC-CMs ( Fig G ) and the action potential duration at 90% repolarization and the I Na-L were markedly prolonged after ibrutinib exposure( Fig H ). Conclusion: We showed in Pitx2c +/- mice and atrial hiPSC-CMs that ibrutinib-mediated AF may in part be related to enhanced I Na-L , decreased activation of PI3K and SERCA2a and increased fibrosis leading to mitochondrial fragmentation and increased oxidative stress.