Author + information
- Received April 15, 2019
- Revision received June 7, 2019
- Accepted June 7, 2019
- Published online November 25, 2019.
- Raffaele Coppini, MD, PhDa,∗ (, )
- Cecilia Ferrantini, MD, PhDb,c,
- Josè Manuel Pioner, PhDb,
- Lorenzo Santini, MSa,
- Zhinuo J. Wang, PhDd,
- Chiara Palandri, MSa,
- Marina Scardigli, PhDe,
- Giulia Vitale, MSb,
- Leonardo Sacconi, PhDe,
- Pierluigi Stefàno, MDb,c,
- Laura Flink, MDf,
- Katherine Riedy, MDg,
- Francesco Saverio Pavone, PhDe,
- Elisabetta Cerbai, PhDa,
- Corrado Poggesi, MDb,
- Alessandro Mugelli, MDa,
- Alfonso Bueno-Orovio, PhDd,
- Iacopo Olivotto, MDb,c and
- Mark V. Sherrid, MDg
- aDepartment NeuroFarBa, University of Florence, Florence, Italy
- bDepartment of Experimental and Clinical Medicine, University of Florence, Florence, Italy
- cCardiomyopathy Unit, Careggi University Hospital, Florence, Italy
- dDepartment of Computer Sciences, University of Oxford, Oxford, United Kingdom
- eEuropean Laboratory for Nonlinear Spectroscopy (LENS), University of Florence, Sesto Fiorentino, Italy and National Institute of Optics, National Research Council, Florence, Italy
- fDivision of Cardiology, San Francisco Veterans Affairs Medical Center and University of California-San Francisco, San Francisco, California
- gHypertrophic Cardiomyopathy Program, New York University Langone Health, New York, New York
- ↵∗Address for correspondence:
Dr. Raffaele Coppini, Department NeuroFarBa, University of Florence, Viale G. Pieraccini 6, 50139 Firenze, Italy.
• In patients with HCM and symptomatic LVOT-obstruction, first treatment with disopyramide leads to a marked reduction of LVOT gradients, with a slight decrease of resting ejection fraction and a modest increase of corrected QT interval, highlighting high efficacy and safety.
• In single cardiomyocytes and intact trabeculae from surgical samples of patients with obstructive HCM, in vitro treatment with 5 μmol/l disopyramide lowered force and Ca2+ transients while reducing action potential duration and the rate of arrhythmic afterdepolarizations.
• These effects are mediated by the combined inhibition of peak and late Na+ currents, L-type Ca2+ current, delayed-rectifier K+ current, and ryanodine receptors.
• In addition to the negative inotropic effect of disopyramide, in vitro results suggest additional antiarrhythmic actions.
Disopyramide is effective and safe in patients with obstructive hypertrophic cardiomyopathy. However, its cellular and molecular mechanisms of action are unknown. We tested disopyramide in cardiomyocytes from the septum of surgical myectomy patients: disopyramide inhibits multiple ion channels, leading to lower Ca transients and force, and shortens action potentials, thus reducing cellular arrhythmias. The electrophysiological profile of disopyramide explains the efficient reduction of outflow gradients but also the limited prolongation of the QT interval and the absence of arrhythmic side effects observed in 39 disopyramide-treated patients. In conclusion, our results support the idea that disopyramide is safe for outpatient use in obstructive patients.
Supported by the European Union’s Horizon 2020 Research and Innovation Programme (grant 777204, SILICO-FCM, to Drs. Ferrantini, Pioner, Poggesi, and Olivotto), the Italian Ministry of Health (grants RF-2013-02356787, NET-2011-02347173, and GR-2011-02350583 to Drs. Ferrantini and Olivotto), Regione Toscana (FAS-Salute 2014, project ToRSADE to Drs. Coppini, Santini, and Cerbai), a British Heart Foundation Intermediate Basic Science Research Fellowship (FS/17/22/32644 to Drs. Wang and Bueno-Orovio) and an ARCHER RAP Award. All authors have reported that they have no relationships relevant to the contents of this paper to disclose.
The authors attest they are in compliance with human studies committees and animal welfare regulations of the authors’ institutions and Food and Drug Administration guidelines, including patient consent where appropriate. For more information, visit the JACC: Basic to Translational Science author instructions page.
- Received April 15, 2019.
- Revision received June 7, 2019.
- Accepted June 7, 2019.
- 2019 The Authors