Pavel Zhabyeyev1, Brent McLean2, Xueyi Chen1, Bart Vanhaesebroeck3, Gavin Y Oudit4. 1. Department of Medicine, University of Alberta, Edmonton, Canada; Mazankowski Alberta Heart Institute, University of Alberta, Edmonton, Canada. 2. Department of Medicine, University of Alberta, Edmonton, Canada; Department of Physiology, University of Alberta, Edmonton, Canada; Mazankowski Alberta Heart Institute, University of Alberta, Edmonton, Canada. 3. UCL Cancer Institute, London, UK. 4. Department of Medicine, University of Alberta, Edmonton, Canada; Mazankowski Alberta Heart Institute, University of Alberta, Edmonton, Canada. Electronic address: gavin.oudit@ualberta.ca.
Abstract
BACKGROUND: Phosphoinositide 3-kinase α (PI3Kα) is a proto-oncogene with high activity in the heart. BYL719 (BYL) is a PI3Kα-selective small molecule inhibitor and a prospective drug for advanced solid tumors. We investigated whether acute pharmacological inhibition of PI3Kα has pro-arrhythmic effects. METHODS & RESULTS: In isolated wild-type (WT) cardiomyocytes, pharmacological inhibition of PI3Kα (BYL719) increased contractility by 28%, Ca2+ release by 20%, and prolonged action potential (AP) repolarization by 10-15%. These effects of BYL719 were abolished by inhibition of reverse-mode Na+/Ca2+ exchanger (NCX) (KB-R7943) or by inhibition of late Na+ current (INa-L) (ranolazine). BYL719 had no effect on PI3Kα-deficient cardiomyocytes, suggesting BYL719 effects were PI3Kα-dependent and mediated via NCX and INa-L. INa-L was suppressed by activation of PI3Kα, application of exogenous intracellular PIP3, or ranolazine. Investigation of AP and Ca2+ release in whole heart preparations using epicardial optical mapping showed that inhibition of PI3Kα similarly led to prolongation of AP and enhancement of Ca2+ release. In hearts of PI3Kα-deficient mice, β-adrenergic stimulation in the presence of high Ca2+ concentrations and 12-Hz burst pacing led to delayed afterdepolarizations and ventricular fibrillation. In vivo, administration of BYL719 prolonged QT interval [QTcF (Fridericia) increased by 15%] in WT, but not in PI3Kα-deficient mice. CONCLUSIONS: Pharmacological inhibition of PI3Kα is arrhythmogenic due to activation of INa-L leading to increased sarcoplasmic reticulum Ca2+ load and prolonged QT interval. Therefore, monitoring of cardiac electrical activity in patients receiving PI3K inhibitors may provide further insights into the arrhythmogenic potential of PI3Ka inhibition.
BACKGROUND: Phosphoinositide 3-kinase α (PI3Kα) is a proto-oncogene with high activity in the heart. BYL719 (BYL) is a PI3Kα-selective small molecule inhibitor and a prospective drug for advanced solid tumors. We investigated whether acute pharmacological inhibition of PI3Kα has pro-arrhythmic effects. METHODS & RESULTS: In isolated wild-type (WT) cardiomyocytes, pharmacological inhibition of PI3Kα (BYL719) increased contractility by 28%, Ca2+ release by 20%, and prolonged action potential (AP) repolarization by 10-15%. These effects of BYL719 were abolished by inhibition of reverse-mode Na+/Ca2+ exchanger (NCX) (KB-R7943) or by inhibition of late Na+ current (INa-L) (ranolazine). BYL719 had no effect on PI3Kα-deficient cardiomyocytes, suggesting BYL719 effects were PI3Kα-dependent and mediated via NCX and INa-L. INa-L was suppressed by activation of PI3Kα, application of exogenous intracellular PIP3, or ranolazine. Investigation of AP and Ca2+ release in whole heart preparations using epicardial optical mapping showed that inhibition of PI3Kα similarly led to prolongation of AP and enhancement of Ca2+ release. In hearts of PI3Kα-deficient mice, β-adrenergic stimulation in the presence of high Ca2+ concentrations and 12-Hz burst pacing led to delayed afterdepolarizations and ventricular fibrillation. In vivo, administration of BYL719 prolonged QT interval [QTcF (Fridericia) increased by 15%] in WT, but not in PI3Kα-deficient mice. CONCLUSIONS: Pharmacological inhibition of PI3Kα is arrhythmogenic due to activation of INa-L leading to increased sarcoplasmic reticulum Ca2+ load and prolonged QT interval. Therefore, monitoring of cardiac electrical activity in patients receiving PI3K inhibitors may provide further insights into the arrhythmogenic potential of PI3Ka inhibition.
Authors: Phu N Tran; Jiansong Sheng; Aaron L Randolph; Claudia Alvarez Baron; Nicolas Thiebaud; Ming Ren; Min Wu; Lars Johannesen; Donna A Volpe; Dakshesh Patel; Ksenia Blinova; David G Strauss; Wendy W Wu Journal: PLoS One Date: 2020-11-06 Impact factor: 3.240
Authors: K Lockhart Jamieson; Ahmed M Darwesh; Deanna K Sosnowski; Hao Zhang; Saumya Shah; Pavel Zhabyeyev; Jun Yang; Bruce D Hammock; Matthew L Edin; Darryl C Zeldin; Gavin Y Oudit; Zamaneh Kassiri; John M Seubert Journal: Int J Mol Sci Date: 2021-02-08 Impact factor: 5.923