Ranolazine for congenital and acquired late iNa-linked arrhythmias: In silico pharmacological screening Journal Article


Authors: Moreno, J. D.; Yang, P. C.; Bankston, J. R.; Grandi, E.; Bers, D. M.; Kass, R. S.; Clancy, C. E.
Article Title: Ranolazine for congenital and acquired late iNa-linked arrhythmias: In silico pharmacological screening
Abstract: RATIONALE:: The antianginal ranolazine blocks the human ether-a-go-go-related gene-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 (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 INaL by ranolazine prevailed over the off-target block of IKr 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 ΔKPQ mutation, and heart failure. We then simulated clinically relevant concentrations of ranolazine and predicted the combined effects of Na channel and IKr 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 INaL with ranolazine may be an effective therapeutic strategy in diverse arrhythmia-provoking situations that arise from a common pathway of increased pathological INaL. © 2013 American Heart Association, Inc.
Keywords: controlled study; human cell; drug efficacy; phenotype; low drug dose; steady state; genotype; bradycardia; drug screening; heart failure; drug metabolism; heart arrhythmia; computer model; heart muscle cell; oxidative phosphorylation; drug binding; concentration response; sodium channel; heart repolarization; cyclic amp dependent protein kinase; calcium calmodulin dependent protein kinase ii; ranolazine; membrane potential; sodium current; computational model; late ina; long-qt syndrome type 3; heart depolarization; long qt syndrome 3
Journal Title: Circulation Research
Volume: 113
Issue: 7
ISSN: 0009-7330
Publisher: Lippincott Williams & Wilkins  
Date Published: 2013-09-01
Start Page: e50
End Page: e61
Language: English
DOI: 10.1161/circresaha.113.301971
PROVIDER: scopus
PUBMED: 23897695
PMCID: PMC3896218
DOI/URL:
Notes: --- - "Export Date: 1 November 2013" - "CODEN: CIRUA" - "Source: Scopus"
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  1. Jonathan D Moreno
    5 Moreno