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Updated: Mar 6, 2026
Isolation, Culture, and Functional Characterization of Adult Mouse Cardiomyoctyes
Published on: September 24, 2013
Ranolazine Prevents Phenotype Development in a Mouse Model of Hypertrophic Cardiomyopathy
Raffaele Coppini1, Luca Mazzoni2, Cecilia Ferrantini2
1From the Department NeuroFarBa (R.C., L.M., T.L., L. Santini, V.B., G.B., A.M., E.C.) and Department of Experimental and Clinical Medicine (C.F., F.G., J.M.P., C.T., C.P.), University of Florence, Italy; European Laboratory for Non-linear Spectroscopy (LENS), University of Florence & National Institute of Optics (INO-CNR), Sesto Fiorentino, Italy (C.C., L. Sacconi); Gilead Sciences Inc., Foster City, CA (L.B.); Department of Cellular and Molecular Medicine University of Arizona at Tucson, USA (J.T.); and Referral Center for Cardiomyopathies, Careggi University Hospital, Florence, Italy (M.R., I.O.). raffaele.coppini@unifi.it.
Insights
Ranolazine, a late Na+ current blocker, prevented hypertrophic cardiomyopathy (HCM) development in mice with HCM mutations. This finding suggests ranolazine may offer a new preventive therapy for individuals at high risk for HCM.
Area of Science:
- Cardiovascular Research
- Pharmacology
- Genetics
Background:
- Current hypertrophic cardiomyopathy (HCM) therapies are ineffective in preventing cardiac phenotype development in young mutation carriers.
- Ranolazine, a blocker of the late sodium current, demonstrated efficacy in reducing electromechanical dysfunction in human HCM myocardium in vitro.
Purpose of the Study:
- To investigate the long-term efficacy of ranolazine in preventing cardiomyopathy development in vivo.
- To evaluate ranolazine's effects on cardiac structure, function, and cellular mechanisms in a mouse model of HCM.
Main Methods:
- Lifelong oral ranolazine treatment was administered to transgenic mice with the R92Q troponin-T mutation and wild-type littermates.
- Cardiac phenotype, including interventricular septum thickness and left ventricular function, was assessed using echocardiography and magnetic resonance imaging.
- Excitation-contraction coupling, intracellular calcium handling, and late sodium current were analyzed in cardiomyocytes and myocardial tissue.
Main Results:
- Ranolazine treatment prevented the development of HCM-related cardiac phenotype in 12-month-old male R92Q mice.
- Treated mutant mice showed normalized cardiomyocyte excitation-contraction coupling, reduced intracellular calcium, and inhibited late sodium current.
- Ranolazine counteracted myocardial mechanical abnormalities, including inotropic insufficiency and increased diastolic tension, in mutant mice.
Conclusions:
- Sustained reduction of intracellular calcium and calmodulin kinase activity by ranolazine prevented morphological and functional cardiac phenotype in mice with an HCM mutation.
- Pharmacological inhibition of the late sodium current represents a promising strategy for early preventive therapy in individuals at high risk for HCM.
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.
