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.

Ranolazine prevents phenotype development in a mouse model of hypertrophic cardiomyopathy / Coppini, Raffaele; Mazzoni, Luca; Ferrantini, Cecilia; Gentile, Francesca; Pioner, Josè Manuel; Laurino, Annunziatina; Santini, Lorenzo; Bargelli, Valentina; Rotellini, Matteo; Bartolucci, Gian Luca; Crocini, Claudia; Sacconi, Leonardo; Tesi, Chiara; Belardinelli, Luiz; Tardiff, Jil; Mugelli, Alessandro; Olivotto, Iacopo; Cerbai, Elisabetta; Poggesi, Corrado. - In: CIRCULATION. HEART FAILURE. - ISSN 1941-3289. - ELETTRONICO. - 10:(2017), pp. 10:e003565-10:e003565. [10.1161/CIRCHEARTFAILURE.116.003565]

Ranolazine prevents phenotype development in a mouse model of hypertrophic cardiomyopathy

Coppini, Raffaele;Mazzoni, Luca;Ferrantini, Cecilia;Gentile, Francesca;Pioner, Josè Manuel;Laurino, Annunziatina;Santini, Lorenzo;Rotellini, Matteo;Bartolucci, Gian Luca;Tesi, Chiara;Mugelli, Alessandro;Olivotto, Iacopo;Cerbai, Elisabetta;Poggesi, Corrado
2017

Abstract

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.
2017
10
10:e003565
10:e003565
Goal 3: Good health and well-being for people
Coppini, Raffaele; Mazzoni, Luca; Ferrantini, Cecilia; Gentile, Francesca; Pioner, Josè Manuel; Laurino, Annunziatina; Santini, Lorenzo; Bargelli, Valentina; Rotellini, Matteo; Bartolucci, Gian Luca; Crocini, Claudia; Sacconi, Leonardo; Tesi, Chiara; Belardinelli, Luiz; Tardiff, Jil; Mugelli, Alessandro; Olivotto, Iacopo; Cerbai, Elisabetta; Poggesi, Corrado
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Utilizza questo identificatore per citare o creare un link a questa risorsa: https://hdl.handle.net/2158/1081254
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