Abstract 15697: Acute Pharmacological Inhibition of PI3Kα by the Novel Cancer Drug, BYL-719, Has a Pro-arrhythmic Effect
Introduction: Phosphatidylinositol-3-kinase α (PI3Kα) is an oncogene with high activity in the heart. BYL-719 (BYL) is a specific PI3Kα inhibitor and a prospective cancer drug for advanced solid tumors.
Hypothesis: Acute pharmacological inhibition of PI3Kα can mediate adverse effects on heart function.
Methods: In isolated murine cardiomyocytes, contractility was assessed by sarcomere tracking, Ca2+ release was measured using fluorescence (FURA 2), and electrical activity was recorded using patch-clamp techniques. In excised hearts, electrical activity and Ca2+ release were visualized by epicardial optical mapping (voltage RH237 and Ca2+ Rhod-2). In vivo cardiac electrical activity was assessed by ECG. Cardiomyocyte-specific PI3Kα-deficient mice (αMHC-Cre-p110αflx/flx) were used as a negative control.
Results: In isolated cardiomyocytes, BYL (10 nM - 1 μM) increased contractility in a dose-dependent manner. BYL (100 nM) failed to increase contractility in PI3Kα-deficient cardiomyocytes or in the presence of a specific reverse-mode Na+/Ca2+ exchanger (NCX) blocker (KB-R7943) or ranolazine, which blocks both reverse mode NCX and late Na+ current (INa,L) suggesting a PI3Kα-dependent effect mediated via NCX with possible INa,L involvement. BYL increased Ca2+ release by 21±6%. This increase was absent in PI3Kα-deficient cardiomyocytes and was blocked by ranolazine. BYL prolonged action potential at 20, 50, and 90% of repolarization by 11±3%, 16±2%, and 11±2% respectively, which was blocked by ranolazine and was absent in PI3Kα-deficient cardiomyocytes. BYL did not affect K+ currents, but inhibited L-type Ca2+ current, and activated INa,L in PI3Kα-dependent manner. In whole heart preparations, action potential was prolonged and Ca2+ release was increased similarly to isolated cardiomyocytes. Administration of BYL for 4 days prolonged QT interval (QTcF (Fridericia) increased by 19±4%) in wildtype mice, but not in PI3Kα-deficient mice.
Conclusions: Acute pharmacological inhibition of PI3Kα activity has pro-arrhythmic effects due to activation of INa,L leading to increased Ca2+ load and prolongation of the QT interval. Clinical application of PI3Kα inhibitors should proceed with caution due to the potential for adverse arrhythmias.
- Arrhythmias, treatment of
- Long QT syndrome
- Sodium channel
- Excitation-contraction coupling (ECC)
Author Disclosures: P. Zhabyeyev: None. B. McLean: None. B. Vanhaesebroeck: None. G.Y. Oudit: None.
- © 2016 by American Heart Association, Inc.