Ranolazine Prevents Phenotype Development in a Mouse Model of Hypertrophic Cardiomyopathy

Abstract

Background: Current therapies are ineffective in preventing the development of cardiac phenotype in young carriers of mutations associated with hypertrophic cardiomyopathy (HCM). Ranolazine, a late Na⁺ current blocker, reduced the electromechanical dysfunction of human HCM myocardium in vitro.

Methods and results: To test whether long-term treatment prevents cardiomyopathy in vivo, transgenic mice harboring the R92Q troponin-T mutation and wild-type littermates received an oral lifelong treatment with ranolazine and were compared with age-matched vehicle-treated animals. In 12-months-old male R92Q mice, ranolazine at therapeutic plasma concentrations prevented the development of HCM-related cardiac phenotype, including thickening of the interventricular septum, left ventricular volume reduction, left ventricular hypercontractility, diastolic dysfunction, left-atrial enlargement and left ventricular fibrosis, as evaluated in vivo using echocardiography and magnetic resonance. Left ventricular cardiomyocytes from vehicle-treated R92Q mice showed marked excitation-contraction coupling abnormalities, including increased diastolic [Ca²⁺] and Ca²⁺ waves, whereas cells from treated mutants were undistinguishable from those from wild-type mice. Intact trabeculae from vehicle-treated mutants displayed inotropic insufficiency, increased diastolic tension, and premature contractions; ranolazine treatment counteracted the development of myocardial mechanical abnormalities. In mutant myocytes, ranolazine inhibited the enhanced late Na⁺ current and reduced intracellular [Na⁺] and diastolic [Ca²⁺], ultimately preventing the pathological increase of calmodulin kinase activity in treated mice.

Conclusions: Owing to the sustained reduction of intracellular Ca²⁺ and calmodulin kinase activity, ranolazine prevented the development of morphological and functional cardiac phenotype in mice carrying a clinically relevant HCM-related mutation. Pharmacological inhibitors of late Na⁺ current are promising candidates for an early preventive therapy in young phenotype-negative subjects carrying high-risk HCM-related mutations.

Keywords: arrhythmias; calcium; cardiomyocyte; drug therapy; prevention; remodeling; sodium.