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

Abstract

Background: Phosphoinositide 3-kinase  (PI3K) is a proto-oncogene with high activity in the heart. BYL719 (BYL) is a PI3K-selective small molecule inhibitor and a prospective drug for advanced solid tumors. We investigated whether acute pharmacological inhibition of PI3K has pro-arrhythmic effects. Methods & Results: In isolated wild-type (WT) cardiomyocytes, pharmacological inhibition of PI3K (BYL719) increased contractility by 28%, Ca 2+ 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 2+ exchanger (NCX) (KB-R7943) or by inhibition of late Na + current (INa-L) (ranolazine). BYL719 had no effect on PI3K-deficient cardiomyocytes, suggesting BYL719 effects were PI3K-dependent and mediated via NCX and INa-L. INa-L was suppressed by activation of PI3K, application of exogenous intracellular PIP3, or ranolazine. Investigation of AP and Ca 2+ release in whole heart preparations using epicardial optical mapping showed that inhibition of PI3K similarly led to prolongation of AP and enhancement of Ca 2+ release. In hearts of PI3K-deficient mice, -adrenergic stimulation in the presence of high Ca 2+ 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 PI3K-deficient mice. Conclusions: Pharmacological inhibition of PI3K is arrhythmogenic due to activation of INa-L leading to increased sarcoplasmic reticulum Ca 2+ 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 PI3K inhibition.

Soluble Epoxide Hydrolase in Aged Female Mice and Human Explanted Hearts Following Ischemic Injury

“…Tissue doppler taken at the mitral annulus was used to describe LV filling pressure described by E', E'/A', and E/E'. An electrocardiogram (ECG) was obtained using telemetry in mice at baseline, 7 days, and 28 days post-MI while under anesthesia, as previously described [52].…”

Mechanisms of QT prolongation by buprenorphine cannot be explained by direct hERG channel block

“…Examples of drugs that prolong the QT C interval yet are associated with low TdP risk (i.e., ranolazine, amiodarone, and verapamil) suggest that concomitant inhibition of late Na + (I NaL ) [4] and/or L-type Ca 2+ current (I CaL ) [5,6] could offset the TdP risk imposed by hERG channel block. Though less common, some drugs prolong the QT C interval by increasing I NaL [7,8]. Basic science studies also show that delayed repolarization and ventricular arrhythmias can occur by pharmacologically enhancing I CaL [9].…”

PI3K inhibitors in thrombosis and cardiovascular disease

“…Indeed, at present the predominant focus of PI3K inhibitor development is cancer, with small molecules targeting all Class I PI3K isoforms (either individually or non‐selectively) currently in clinical trials, and Class II and Class III PI3K inhibitors being considered for future promise in this setting. From the discussion above, it is clear that PI3K inhibition has the potential to lead to unwanted cardiovascular events, including arrhythmia and cardiac remodelling [198, 210–215]. In some scenarios, the benefits may outweigh the risks, and cardiotoxicity may not apply to all PI3K inhibitors or dosing regimes, but careful cardiovascular monitoring of patients on PI3K‐targeted therapy should be in place, particularly for compromised individuals.…”