Inhibition of PI3Kinase-α is pro-arrhythmic and associated with enhanced late Na+ current, contractility, and Ca2+ release in murine hearts

Pavel Zhabyeyev; Brent McLean; Xueyi Chen; Bart Vanhaesebroeck; Gavin Y Oudit

doi:10.1016/j.yjmcc.2019.05.008

Inhibition of PI3Kinase-α is pro-arrhythmic and associated with enhanced late Na⁺ current, contractility, and Ca²⁺ release in murine hearts

J Mol Cell Cardiol. 2019 Jul:132:98-109. doi: 10.1016/j.yjmcc.2019.05.008. Epub 2019 May 13.

Authors

Pavel Zhabyeyev¹, Brent McLean², Xueyi Chen¹, Bart Vanhaesebroeck³, Gavin Y Oudit⁴

Affiliations

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.

PMID: 31095940
DOI: 10.1016/j.yjmcc.2019.05.008

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 (I_Na-L) (ranolazine). BYL719 had no effect on PI3Kα-deficient cardiomyocytes, suggesting BYL719 effects were PI3Kα-dependent and mediated via NCX and I_Na-L. I_Na-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 [QT_cF (Fridericia) increased by 15%] in WT, but not in PI3Kα-deficient mice.

Conclusions: Pharmacological inhibition of PI3Kα is arrhythmogenic due to activation of I_Na-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.

Keywords: Adrenergic stimulation; Afterdepolarization; Arrhythmias; Long QT; PI3Kα.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Action Potentials*
Animals
Arrhythmias, Cardiac / etiology*
Arrhythmias, Cardiac / metabolism
Arrhythmias, Cardiac / pathology
Calcium / metabolism*
Male
Mice
Mice, Inbred C57BL
Myocytes, Cardiac / metabolism
Myocytes, Cardiac / pathology*
Phosphatidylinositol 3-Kinases / chemistry*
Phosphatidylinositol 3-Kinases / genetics
Phosphatidylinositol 3-Kinases / metabolism
Sodium / metabolism*
Sodium Channel Blockers / pharmacology
Sodium-Calcium Exchanger / metabolism
Thiazoles / pharmacology*

Substances

Sodium Channel Blockers
Sodium-Calcium Exchanger
Thiazoles
Alpelisib
Sodium
Calcium

Grants and funding

CIHR/Canada