Iacopo Olivotto1, Paolo G Camici1, Piera Angelica Merlini1, Claudio Rapezzi1, Monica Patten1, Vicent Climent1, Gianfranco Sinagra1, Benedetta Tomberli2, Francisco Marin1, Philipp Ehlermann1, Lars S Maier1, Alessandra Fornaro1, Claudius Jacobshagen1, Antonello Ganau1, Luciano Moretti1, Antonio Hernandez Madrid1, Raffaele Coppini1, Giorgio Reggiardo1, Corrado Poggesi1, Francesco Fattirolli1, Luiz Belardinelli1, Gianfranco Gensini1, Alessandro Mugelli1. 1. >From the Cardiomyopathy Unit, Careggi University Hospital, Florence, Italy (I.O., B.T., A.F.); Vita Salute University and Scientific Institute San Raffaele, Milan, Italy (P.G.C.); Dipartimento Cardiotoracovascolare, Ospedale Niguarda, Milan, Italy (P.A.M.); Ospedale S. Orsola Malpighi, Bologna, Italy (C.R.); Clinic of General and Interventional Cardiology, University Heart Center, Hamburg, Germany (M.P.); Cardiology Department, Hospital General Universitario de Alicante, ISABIAL - FISABIO, Alicante, Spain (V.C.); Cardiovascular Department, Ospedale di Cattinara, Trieste, Italy (G.S.); Hospital Universitario Virgen de la Arrixaca, IMIB-Arrixaca, Murcia, Spain (F.M.); University Hospital, Heidelberg, Germany (P.E.); University Hospital Regensburg, Germany (L.S.M.); Herz zentrum Georg-August-Universitaet, Göttingen, Germany (C.J.); Department of Clinical and Experimental Medicine, Cardiology, Sassari Hospital, Sassari, Italy (A.G.); Ospedale Mazzoni, Ascoli Piceno, Italy (L.M.); Hospital Ramòn y Cajal, Alcalá University, Madrid, Spain (A.H.M.); Department Neurofarba, University of Florence, Italy (R.C., A.M.); Medi Service, Genoa, Italy (G.R.); Department of Experimental and Clinical Medicine, University of Florence, Italy (C.P., F.F.); Gilead Sciences, Foster City, CA (L.B.); and CESMAV, Florence, Italy (G.G.). 2. >From the Cardiomyopathy Unit, Careggi University Hospital, Florence, Italy (I.O., B.T., A.F.); Vita Salute University and Scientific Institute San Raffaele, Milan, Italy (P.G.C.); Dipartimento Cardiotoracovascolare, Ospedale Niguarda, Milan, Italy (P.A.M.); Ospedale S. Orsola Malpighi, Bologna, Italy (C.R.); Clinic of General and Interventional Cardiology, University Heart Center, Hamburg, Germany (M.P.); Cardiology Department, Hospital General Universitario de Alicante, ISABIAL - FISABIO, Alicante, Spain (V.C.); Cardiovascular Department, Ospedale di Cattinara, Trieste, Italy (G.S.); Hospital Universitario Virgen de la Arrixaca, IMIB-Arrixaca, Murcia, Spain (F.M.); University Hospital, Heidelberg, Germany (P.E.); University Hospital Regensburg, Germany (L.S.M.); Herz zentrum Georg-August-Universitaet, Göttingen, Germany (C.J.); Department of Clinical and Experimental Medicine, Cardiology, Sassari Hospital, Sassari, Italy (A.G.); Ospedale Mazzoni, Ascoli Piceno, Italy (L.M.); Hospital Ramòn y Cajal, Alcalá University, Madrid, Spain (A.H.M.); Department Neurofarba, University of Florence, Italy (R.C., A.M.); Medi Service, Genoa, Italy (G.R.); Department of Experimental and Clinical Medicine, University of Florence, Italy (C.P., F.F.); Gilead Sciences, Foster City, CA (L.B.); and CESMAV, Florence, Italy (G.G.). benedetta.tomberli@gmail.com.
Abstract
BACKGROUND: The late sodium current inhibitor ranolazine reverses the main electrophysiological and mechanical abnormalities of human hypertrophic cardiomyopathy (HCM) cardiomyocytes in vitro, suggesting potential clinical benefit. We aimed to assess the effect of ranolazine on functional capacity, symptomatic status, diastolic function, and arrhythmias in HCM. METHODS AND RESULTS: In this multicenter, double-blind, phase 2 study, 80 adult patients with nonobstructive HCM (age 53±14 years, 34 women) were randomly assigned to placebo (n=40) or ranolazine 1000 mg bid (n=40) for 5 months. The primary end point was change in peak VO2 compared with baseline using cardiopulmonary exercise test. Echocardiographic lateral and septalE/E' ratio, prohormone brain natriuretic peptide levels, 24-hour Holter arrhythmic profile, andquality of life were assessed. Ranolazine was safe and well tolerated. Overall, there was no significant difference in VO2 peak change at 5 months in the ranolazine versus placebo group (delta 0.15±3.96 versus -0.02±4.25 mL/kg per minute; P=0.832). Ranolazine treatment was associated with a reduction in 24-hour burden of premature ventricular complexes compared with placebo (>50% reduction versus baseline in 61% versus 31%, respectively; P=0.042). However, changes in prohormone brain natriuretic peptide levels did not differ in the ranolazine compared with the placebo group (geometric mean median [interquartile range], -3 pg/mL [-107, 142 pg/mL] versus 78 pg/mL [-71, 242 pg/mL]; P=0.251). Furthermore, E/E' ratio and quality of life scores showed no significant difference. CONCLUSIONS: In patients with nonobstructive HCM, ranolazine showed no overall effect on exercise performance, plasma prohormone brain natriuretic peptide levels, diastolic function, or quality of life. The drug showed an excellent safety profile and was associated with reduced premature ventricular complex burden. Late sodium current inhibition does not seem to improve functional capacity in HCM. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrialsregister.eu. Unique identifier: 2011-004507-20.
RCT Entities:
BACKGROUND: The late sodium current inhibitor ranolazine reverses the main electrophysiological and mechanical abnormalities of human hypertrophic cardiomyopathy (HCM) cardiomyocytes in vitro, suggesting potential clinical benefit. We aimed to assess the effect of ranolazine on functional capacity, symptomatic status, diastolic function, and arrhythmias in HCM. METHODS AND RESULTS: In this multicenter, double-blind, phase 2 study, 80 adult patients with nonobstructive HCM (age 53±14 years, 34 women) were randomly assigned to placebo (n=40) or ranolazine 1000 mg bid (n=40) for 5 months. The primary end point was change in peak VO2 compared with baseline using cardiopulmonary exercise test. Echocardiographic lateral and septal E/E' ratio, prohormone brain natriuretic peptide levels, 24-hour Holter arrhythmic profile, and quality of life were assessed. Ranolazine was safe and well tolerated. Overall, there was no significant difference in VO2 peak change at 5 months in the ranolazine versus placebo group (delta 0.15±3.96 versus -0.02±4.25 mL/kg per minute; P=0.832). Ranolazine treatment was associated with a reduction in 24-hour burden of premature ventricular complexes compared with placebo (>50% reduction versus baseline in 61% versus 31%, respectively; P=0.042). However, changes in prohormone brain natriuretic peptide levels did not differ in the ranolazine compared with the placebo group (geometric mean median [interquartile range], -3 pg/mL [-107, 142 pg/mL] versus 78 pg/mL [-71, 242 pg/mL]; P=0.251). Furthermore, E/E' ratio and quality of life scores showed no significant difference. CONCLUSIONS: In patients with nonobstructive HCM, ranolazine showed no overall effect on exercise performance, plasma prohormone brain natriuretic peptide levels, diastolic function, or quality of life. The drug showed an excellent safety profile and was associated with reduced premature ventricular complex burden. Late sodium current inhibition does not seem to improve functional capacity in HCM. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrialsregister.eu. Unique identifier: 2011-004507-20.
Authors: Caroline J Coats; Menelaos Pavlou; Oliver T Watkinson; Alexandros Protonotarios; Linda Moss; Rebecca Hyland; Khadija Rantell; Antonis A Pantazis; Maite Tome; William J McKenna; Michael P Frenneaux; Rumana Omar; Perry M Elliott Journal: JAMA Cardiol Date: 2019-03-01 Impact factor: 14.676
Authors: Jiali Nie; Quanlu Duan; Mengying He; Xianqing Li; Bei Wang; Chi Zhou; Lujin Wu; Zheng Wen; Chen Chen; Dao Wu Wang; Katherina M Alsina; Xander H T Wehrens; Dao Wen Wang; Li Ni Journal: J Cell Physiol Date: 2018-11-29 Impact factor: 6.384