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

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%, Ca release by 20%, and prolonged action potential (AP) repolarization by 10-15%. These effects of BYL719 were abolished by inhibition of reverse-mode Na/Ca exchanger (NCX) (KB-R7943) or by inhibition of late Na current (I) (ranolazine). BYL719 had no effect on PI3Kα-deficient cardiomyocytes, suggesting BYL719 effects were PI3Kα-dependent and mediated via NCX and I. I was suppressed by activation of PI3Kα, application of exogenous intracellular PIP3, or ranolazine. Investigation of AP and Ca release in whole heart preparations using epicardial optical mapping showed that inhibition of PI3Kα similarly led to prolongation of AP and enhancement of Ca release. In hearts of PI3Kα-deficient mice, β-adrenergic stimulation in the presence of high Ca concentrations and 12-Hz burst pacing led to delayed afterdepolarizations and ventricular fibrillation. In vivo, administration of BYL719 prolonged QT interval [QT (Fridericia) increased by 15%] in WT, but not in PI3Kα-deficient mice.

CONCLUSIONS

Pharmacological inhibition of PI3Kα is arrhythmogenic due to activation of I leading to increased sarcoplasmic reticulum Ca 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.