Ranolazine protects ventricular fibroblast from failing human heart against dronedarone-induced toxicity



Dronedarone (DR), a new antiarrhythmic drug designed to reduce amiodarone’s extracardiac toxicity, was associated with increased heart failure (HF) and mortality in patients with atrial fibrillation (AF) and left ventricular dysfunction. Reducing DR’s negative effect on failing heart can improve the safety of this drug. Ranolazine (RZ), an antianginal drug, was shown to improve the antiarrythmic efficacy of low DR dose; however, it is not known if RZ reduces the adverse cardiac effects of DR.


The effect of RZ pretreatment (3µM) on DR (0-30µM) mediated impairment of mitochondrial oxidative phosphorylation (XF96 Extracellular Flux Analyzer), oxidative stress (MitoSOX Red fluorescence) and susceptibility to cell death (lactate dehydrogenase assay, LDH) was determined in ventricular fibroblasts from patients with advanced HF undergoing left ventricular assist device implantation.


DR dose-dependently reduced cell viability inducing 50% of cell death (Panel A) and inhibited mitochondrial oxygen consumption rate (OCR) (Panel B) with increase in mitochondrial superoxide production (Panel C). RZ significantly reduced DR toxicity with rightward shift in a dose response curve for cell viability (A) with preservation of mitochondrial OCR (B) and reduced superoxide production (C).


RZ reduced DR-induced cellular toxicity by improving mitochondrial OCR and reducing superoxide production and could be a novel strategy to improve safety of DR in HF patients.

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