Ranolazine for Congenital and Acquired Late INa Linked Arrhythmias: In Silico Pharmacologic Screening
Rationale: The antianginal ranolazine blocks the hERG-based current IKr 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 INa(INaL), patients with disease resulting from increased INaL from inherited defects (e.g. Long QT syndrome type-3, LQT3), or disease induced electrical remodeling (e.g., ischemic heart failure), might be exactly the ones to most benefit from the presumed antiarrhythmic properties of ranolazine.
Objective: We developed a computational model to predict if therapeutic effects of pharmacological targeting of late INa by ranolazine prevailed over the off-target block of hERG in the setting of inherited LQT3 and heart failure.
Methods and Results: We developed computational models describing the kinetics the interaction of ranolazine with cardiac Na+ channels in the setting of normal physiology, LQT3 linked ΔKPQ mutation, and heart failure. We then simulated clinically relevant concentrations of ranolazine and predicted the combined effects of Na+ channel and hERG 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 LQT3 as well tachyarrhythmogenic triggers arising from heart failure-induced remodeling.
Conclusions:Our model predictions suggest that acute targeting of late INa with ranolazine may be an effective therapeutic strategy in diverse arrhythmia provoking situations that arise from a common pathway of increased pathologic late INa.
- computational model
- late INa
- arrhythmia (mechanisms)
- antiarrhythmic drug
- long QT syndrome
- heart failure
- HERG arrhythmia
- Received June 6, 2013.
- Revision received July 16, 2013.
- Accepted July 18, 2013.