Long-Term Follow-Up Data on Flecainide Use as an Antiarrhythmic in Arrhythmogenic Right Ventricular Cardiomyopathy
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Background Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited cardiomyopathy associated with a high risk of ventricular arrhythmia (VA). Several animal models have been used to postulate a therapeutic role of the inhibition of the ryanodine 2 receptor via the use of flecainide for this disease. Clinical data describing its use are scarce, however, especially in patients without implantable cardioverter-defibrillators or with left ventricular (LV) involvement. Objectives This study sought to report safety and effectiveness long-term, multicenter data on the impact of flecainide therapy on arrhythmic outcomes in patients with a definite diagnosis of ARVC. Methods Patients with definite ARVC receiving flecainide at 12 academic institutions were enrolled in the study. Baseline was defined as the time of flecainide initiation. Premature ventricular complex burdens, nonsustained ventricular tachycardia (NSVT) rates, and sustained VA yearly/rates were collected and compared while on and off flecainide. Side effects and flecainide discontinuation were tracked. Analyses were performed in the overall cohort as well as stratifying for genotype (gene positive vs negative; plakohpillin-2 [PKP-2] vs non PKP-2) and for LV involvement. Results A total of 191 patients (age 37.9 ± 13.7 years; 69.0% male; 89.0% probands; 59.2% having implantable cardioverter-defibrillators; 33.0% with prior VA; 43.5% PKP-2+; LV ejection fraction 55.9 ± 7.3%; right ventricular ejection fraction 44.5 ± 10.5% at baseline) were enrolled, with 66 patients (34.6%) showing LV involvement. The median dose of flecainide was 200 mg/d [150-200 mg/d], with 166 patients (86.9%) also taking a beta-blocker. The median follow-up time on flecainide was 4.2 years [1.9-6.3 years]. Flecainide was well tolerated, with a low (7.9%) discontinuation rate. After flecainide initiation, a significant reduction in the 24-hour premature ventricular complex burden and in the rate of nonsustained ventricular tachycardia was observed (2,190 vs 418; P < 0.001; 35.1% vs 21.5%; P = 0.003). For patients with prior VA events, a significant reduction in the amount of VA episodes/y (1.1 [0.4-1.6] episodes/y vs 0 [0-0.3] episodes/y; P < 0.001) was observed. These safety and effectiveness findings were consistent across genotype subgroups, as well as in patients with and without LV involvement. Conclusions Flecainide use had a favorable safety profile and was associated with an observed to a significant reduction in arrhythmic burden in patients with ARVC, irrespective of the underlying genotype or LV involvement.
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Flecainide has shown promising anti-inflammatory and antiarrhythmic properties via RyR2 modulation.
“Flecainide, a sodium channel blocker, has also shown promising anti-inflammatory and antiarrhythmic properties via RyR2 modulation [90,91].”
From A Paradigm Shift: Arrhythmogenic Cardiomyopathy Is an Inflammatory Disease (2026) · cites this paper as [91]
Controlling inflammation may represent an adjunctive strategy in ACM-related arrhythmia management, enhancing responsiveness to pharmacological therapy and improving outcomes following catheter ablation but not currently replacing the need for an ICD in high-risk patients.
“Consequently, controlling inflammation may represent an adjunctive strategy in ACM-related arrhythmia management, enhancing responsiveness to pharmacological therapy and improving outcomes following catheter ablation but not currently replacing the need for an ICD in patients at high risk [57,91,107,108].”
From A Paradigm Shift: Arrhythmogenic Cardiomyopathy Is an Inflammatory Disease (2026) · cites this paper as [91]
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- Authors
- Gaine, S., Rolland, T., Asatryan, B., Laredo, M., Sampognaro, J., Carrick, R. T., Peretto, G., Muller, S., Villatore, A., Murray, B., Tichnell, C., te Riele, A. S. J. M., Loh, P., Compagnucci, P., Casella, M., Martini, M., Schiavone, M., Tondo, C., Cappelletto, C., Sinagra, G., Merlo, M., Jankelson, L., Delmar, M., Targetti, M., Pieroni, M., Olivotto, I., Calò, L., Graziosi, M., Biagini, E., Tandri, H., Bauce, B., James, C., Cerrone, M., Calkins, H., Gandjbakhch, E., & Gasperetti, A.
- Affiliations
- Johns Hopkins University (US)
- Sorbonne Université (FR)
- IRCCS Ospedale San Raffaele (IT)
- Utrecht University (NL)
- Azienda Ospedaliero-Universitaria delle Marche (IT)
- Marche Polytechnic University (IT)
- University of Padua (IT)
- Centro Cardiologico Monzino (IT)
- University of Milan (IT)
- University of Trieste (IT)
- New York University (US)
- Azienda Ospedaliero-Universitaria Careggi (IT)
- Policlinico Casilino (IT)
- IRCCS Azienda Ospedliero-Universitaria di Bologna Policlinico di Sant'Orsola (IT)
- Vanderbilt University (US)
- Corresponding author
- Muller, Steven
- Loh, Peter
- Cappelletto, Chiara
- Sinagra, Gianfranco
- Merlo, Marco
- Graziosi, Maddalena
- Biagini, Elena
- Gasperetti, Alessio
- ORCID
- Gaine, Sean
- Rolland, Thomas
- Asatryan, Babken
- Sampognaro, James
- Carrick, Richard T.
- Peretto, Giovanni
- Muller, Steven
- Villatore, Andrea
- Murray, Brittney
- Tichnell, Crystal
- Loh, Peter
- Compagnucci, Paolo
- Casella, Michela
- Martini, Marika
- Schiavone, Marco
- Tondo, Claudio
- Cappelletto, Chiara
- Sinagra, Gianfranco
- Merlo, Marco
- Jankelson, Lior
- Delmar, Mario
- Targetti, Mattia
- Pieroni, Maurizio
- Olivotto, Iacopo
- Calò, Leonardo
- Graziosi, Maddalena
- Biagini, Elena
- Tandri, Harikrishna
- Bauce, Barbara
- James, Cynthia
- Cerrone, Marina
- Calkins, Hugh
- Gandjbakhch, Estelle
- Gasperetti, Alessio
- Venue
- JACC: Clinical Electrophysiology
- Publisher
- Elsevier BV
- Published
- 2025-06
- Volume
- 11
- Issue
- 6
- Pages
- 1159-1170
- ISSN
- 2405-500X (ISSN-L)
- OpenAlex
- W4409486871
- Cited by
- 14
- References
- 37
- Citations by year
- 2026: 10 · 2025: 4
- FWCI
- 9.78
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- JACC. Clinical electrophysiology (publishedVersion)
- PubMed (publishedVersion)
- ArTS Archivio della ricerca di Trieste (University of Trieste https://www.units.it/) (submittedVersion, cc-by-nc-nd)
- Florence Research (University of Florence) (submittedVersion)
- Padua Research Archive (University of Padova) (submittedVersion)
- Topics
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiovascular Effects of Exercise
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiac electrophysiology and arrhythmias
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiomyopathy and Myosin Studies
- Keywords
- arrhythmogenic right ventricular cardiomyopathy, flecainide, antiarrhythmic therapy, ventricular arrhythmias, ryanodine receptor, plakophilin-2, left ventricular involvement, non-sustained ventricular tachycardia, premature ventricular contractions, drug safety, long-term outcomes, beta-blockers, implantable cardioverter-defibrillator
- MeSH terms
- Adult, Anti-Arrhythmia Agents, Female, Flecainide, Follow-Up Studies, Humans, Male, Middle Aged, Treatment Outcome, Tachycardia, Ventricular, Arrhythmogenic Right Ventricular Dysplasia, Young Adult
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