Ranolazine Prevents Phenotype Development in a Mouse Model of Hypertrophic Cardiomyopathy

• Published in: Circulation. Heart failure Vol. 10; no. 3
• Main Authors: Coppini, Raffaele, Mazzoni, Luca, Ferrantini, Cecilia, Gentile, Francesca, Pioner, Josè Manuel, Laurino, Annunziatina, Santini, Lorenzo, Bargelli, Valentina, Rotellini, Matteo, Bartolucci, Gianluca, Crocini, Claudia, Sacconi, Leonardo, Tesi, Chiara, Belardinelli, Luiz, Tardiff, Jil, Mugelli, Alessandro, Olivotto, Iacopo, Cerbai, Elisabetta, Poggesi, Corrado
• Format: Journal Article
• Language: English
• Published: United States 01.03.2017
• Subjects: Animals; Blotting, Western; Calcium-Calmodulin-Dependent Protein Kinases - metabolism; Cardiomyopathy, Hypertrophic - genetics; Cardiomyopathy, Hypertrophic - metabolism; Cardiomyopathy, Hypertrophic - physiopathology; Cardiomyopathy, Hypertrophic - prevention & control; Disease Models, Animal; Echocardiography, Doppler; Excitation Contraction Coupling - drug effects; Genetic Predisposition to Disease; Heart Rate; Hypertrophy, Left Ventricular - genetics; Hypertrophy, Left Ventricular - metabolism; Hypertrophy, Left Ventricular - prevention & control; Magnetic Resonance Imaging; Male; Membrane Potentials; Mice, Inbred C57BL; Mice, Transgenic; Microscopy, Confocal; Mutation; Myocardial Contraction - drug effects; Myocytes, Cardiac - drug effects; Myocytes, Cardiac - metabolism; Myocytes, Cardiac - pathology; Phenotype; Ranolazine - pharmacology; Sodium - metabolism; Sodium Channel Blockers - pharmacology; Time Factors; Troponin T - genetics; Ventricular Dysfunction, Left - genetics; Ventricular Dysfunction, Left - metabolism; Ventricular Dysfunction, Left - prevention & control; Ventricular Function, Left - drug effects; sodium; remodeling; calcium; drug therapy; arrhythmias; cardiomyocyte; prevention
• ISSN: 1941-3289; 1941-3297; 1941-3297
• DOI: 10.1161/CIRCHEARTFAILURE.116.003565

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. 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 [Ca ] and Ca 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 [Ca ], ultimately preventing the pathological increase of calmodulin kinase activity in treated mice. Owing to the sustained reduction of intracellular Ca 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.