Ranolazine for Congenital and Acquired Late INa -Linked Arrhythmias In Silico Pharmacological Screening

Rationale: The antianginal ranolazine blocks the human ether-a-go-go-related gene-based current I-Kr at therapeutic concentrations and causes QT interval prolongation. Thus, ranolazine is contraindicated for patients with preexisting long-QT and those with repolarization abnormalities. However, with its preferential targeting of late I-Na (I-NaL), patients with disease resulting from increased I-NaL from inherited defects (eg, long-QT syndrome type 3 or disease-induced electric remodeling (eg, ischemic heart failure) might be exactly the ones to benefit most from the presumed antiarrhythmic properties of ranolazine. Objective: We developed a computational model to predict if therapeutic effects of pharmacological targeting of I-NaL by ranolazine prevailed over the off-target block of I-Kr in the setting of inherited long-QT syndrome type 3 and heart failure. Methods and Results: We developed computational models describing the kinetics and the interaction of ranolazine with cardiac Na+ channels in the setting of normal physiology, long-QT syndrome type 3-linked KPQ mutation, and heart failure. We then simulated clinically relevant concentrations of ranolazine and predicted the combined effects of Na+ channel and I-Kr blockade by both the parent compound ranolazine and its active metabolites, which have shown potent blocking effects in the therapeutically relevant range. Our simulations suggest that ranolazine is effective at normalizing arrhythmia triggers in bradycardia-dependent arrhythmias in long-QT syndrome type 3 as well tachyarrhythmogenic triggers arising from heart failure-induced remodeling. Conclusions: Our model predictions suggest that acute targeting of I-NaL with ranolazine may be an effective therapeutic strategy in diverse arrhythmia-provoking situations that arise from a common pathway of increased pathological I-NaL.