title: Ranolazine Prevents Phenotype Development in a Mouse Model of Hypertrophic Cardiomyopathy.
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.
  
  
  
  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.
  
  
  
  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.
authors.affiliation: From 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.
authors.forename: Raffaele
authors.initials: R
authors.lastname: Coppini
authors.affiliation: From 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.).
authors.forename: Luca
authors.initials: L
authors.lastname: Mazzoni
authors.affiliation: From 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.).
authors.forename: Cecilia
authors.initials: C
authors.lastname: Ferrantini
authors.affiliation: From 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.).
authors.forename: Francesca
authors.initials: F
authors.lastname: Gentile
authors.affiliation: From 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.).
authors.forename: Josè Manuel
authors.initials: JM
authors.lastname: Pioner
authors.affiliation: From 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.).
authors.forename: Annunziatina
authors.initials: A
authors.lastname: Laurino
authors.affiliation: From 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.).
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Santini
authors.affiliation: From 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.).
authors.forename: Valentina
authors.initials: V
authors.lastname: Bargelli
authors.affiliation: From 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.).
authors.forename: Matteo
authors.initials: M
authors.lastname: Rotellini
authors.affiliation: From 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.).
authors.forename: Gianluca
authors.initials: G
authors.lastname: Bartolucci
authors.affiliation: From 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.).
authors.forename: Claudia
authors.initials: C
authors.lastname: Crocini
authors.affiliation: From 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.).
authors.forename: Leonardo
authors.initials: L
authors.lastname: Sacconi
authors.affiliation: From 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.).
authors.forename: Chiara
authors.initials: C
authors.lastname: Tesi
authors.affiliation: From 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.).
authors.forename: Luiz
authors.initials: L
authors.lastname: Belardinelli
authors.affiliation: From 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.).
authors.forename: Jil
authors.initials: J
authors.lastname: Tardiff
authors.affiliation: From 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.).
authors.forename: Alessandro
authors.initials: A
authors.lastname: Mugelli
authors.affiliation: From 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.).
authors.forename: Iacopo
authors.initials: I
authors.lastname: Olivotto
authors.affiliation: From 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.).
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Cerbai
authors.affiliation: From 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.).
authors.forename: Corrado
authors.initials: C
authors.lastname: Poggesi
mesh_terms: D000818:Animals; D015153:Blotting, Western; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism; D002312:Cardiomyopathy, Hypertrophic / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control*; D004195:Disease Models, Animal; D015150:Echocardiography, Doppler; D056966:Excitation Contraction Coupling / Q000187:drug effects; D020022:Genetic Predisposition to Disease; D006339:Heart Rate; D017379:Hypertrophy, Left Ventricular / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control; D008279:Magnetic Resonance Imaging; D008297:Male; D008564:Membrane Potentials; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D018613:Microscopy, Confocal; D009154:Mutation; D009200:Myocardial Contraction / Q000187:drug effects; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D010641:Phenotype; D000069458:Ranolazine / Q000494:pharmacology*; D012964:Sodium / Q000378:metabolism*; D026941:Sodium Channel Blockers / Q000494:pharmacology*; D013997:Time Factors; D020107:Troponin T / Q000235:genetics; D018487:Ventricular Dysfunction, Left / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control; D016277:Ventricular Function, Left / Q000187:drug effects
chemical_list: D026941:Sodium Channel Blockers; D020107:Troponin T; D012964:Sodium; D000069458:Ranolazine; D017871:Calcium-Calmodulin-Dependent Protein Kinases
keywords: arrhythmias; calcium; cardiomyocyte; drug therapy; prevention; remodeling; sodium