Ranolazine Prevents Phenotype Development in a Mouse Model of Hypertrophic Cardiomyopathy
Authors: Coppini R., Mazzoni L., Ferrantini C., Gentile F., Pioner J. M., Laurino T., Santini L., Bargelli V., Rotellini M., Bartolucci G., Crocini C., Sacconi L., Tesi C., Belardinelli L., Tardiff J., Mugelli A., Olivotto i., Cerbai E., Poggesi C.
Autors Affiliation: Department NeuroFarBa and Department of Experimental and Clinical Medicine, University of Florence, Italy; European Laboratory for Non-linear Spectroscopy (LENS), University of Florence & National Institute of Optics (INO–CNR), Sesto Fiorentino, Italy; Gilead Sciences Inc., Foster City, CA; Department of Cellular and Molecular Medicine University of Arizona at Tucson, USA; and Referral Center for Cardiomyopathies, Careggi University Hospital, Florence, Italy
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.
Journal/Review: CIRCULATION-HEART FAILURE
Volume: 10 (3) Pages from: e003565-1 to: e003565-38
More Information: This work was supported by Telethon Italy (GGP13162), by the EU (STREP Project 241577 BIG HEART, 7th European Framework Program), the Italian Ministry of Health (RF 2010-2313451, RF2013-02356787, and GR-2011-02350583), Regione Toscana (FASSalute 2014, ToRSADE project) and by NIH HL075619.KeyWords: arrhythmias; cardiomyocyte; calcium; drug therapy; preventionDOI: 10.1161/CIRCHEARTFAILURE.116.003565Citations: 43data from “WEB OF SCIENCE” (of Thomson Reuters) are update at: 2021-10-24References taken from IsiWeb of Knowledge: (subscribers only)Connecting to view paper tab on IsiWeb: Click hereConnecting to view citations from IsiWeb: Click here