Prognostic Role of Myocarditis-Like Episodes and Their Treatment in Patients With Pathogenic Desmoplakin Variants

Alessio Gasperetti¹, Steven A Muller^{1

2}, Giovanni Peretto³, Babken Asatryan¹, Alexandros Protonotarios⁴, Mikael Laredo⁵, Pierre-Yves Tarlet⁵, Petros Syrris⁴, Richard T Carrick¹, Brittney Murray¹, Crystal Tichnell¹, Paul Scheel¹, Marta Gigli⁶, Sing-Chien Yap⁷, Kalliopi Pilichou⁸, Cristina Basso⁸, Kristen Medo⁹, Max Jason⁹, Valentina A Rossi¹⁰, Ardan M Saguner¹⁰, Firat Duru¹⁰, Dominic Abrams¹¹, Julia Cadrin-Tourigny¹², Mattia Targetti¹³, Maurizio Pieroni^{13

14}, Maddalena Graziosi^{15

16}, Elena Biagini^{15

16}, Philippe Charron⁵, Moniek Cox¹⁷, Michela Casella¹⁸, Claudio Tondo¹⁹, James S Ware²⁰, Sanjay K Prasad²⁰, Leonardo Calò²¹, Eric Smith²², Jodie Ingles²³, Harikrishna Tandri²⁴, Flavie Ader⁵, Stacey Peters²⁵, Dominica Zentner²⁵, Jeremy Russo²⁵, Silvia Ravaro²⁶, Lia Crotti^{26

27}, Svenn Dittmann²⁸, Eric Shulze-Bahr²⁸, Eric D Carruth²⁹, Vikki A Krysov³⁰, Victoria N Parikh³⁰, Giulio Conte³¹, Arthur Wilde^{32

33}, J Peter van Tintelen^{2

34}, Anneline S J M Te Riele², Gianfranco Sinagra⁶, Luisa Mestroni⁹, Matthew Taylor⁹, Marco Merlo⁶, Luigi Adamo¹, Hugh Calkins¹, Barbara Bauce⁸, Elena Arbelo^{35

36

37}, Perry M Elliott⁴, Estelle Gandjbakhch⁵, Neal Lakdawala³⁸, Adam Helms²², Cynthia A James¹, Nisha A Gilotra¹

Affiliations

¹ Department of Medicine, Division of Cardiology, Johns Hopkins University School of Medicine, Baltimore, MD (A.G., S.A.M., B.A., R.T.C., B.M., C. Tichnell, P.S., L.A., H.C., C.A.J., N.A.G.).
² Division of Cardiology, University Medical Center Utrecht, the Netherlands (S.A.M., J.P.v.T., A.S.J.M.t.R.).
³ Multidisciplinary Disease Unit for Myocarditis and Arrhythmogenic Cardiomyopathies, IRCCS San Raffaele Scientific Institute, Milan, Italy (G.P.).
⁴ Inherited Cardiovascular Diseases Unit, St Bartholomew's Hospital, UCL Institute of Cardiovascular Science, London, UK (A.P., P.S., P.M.E.).
⁵ Sorbonne Université, AP-HP, IHU-ICAN, Groupe Hospitalier Pitié-Salpêtrière, Institut de Cardiologie, Paris, France (M.L., P.-Y.T., P.C., F.A., E.G.).
⁶ Cardiothoracovascular Department, Division of Cardiology, Azienda Sanitaria Universitaria Giuliano Isontina and University of Trieste, Italy (M.G., G.S., M.M.).
⁷ Department of Cardiology, Thorax Center, Cardiovascular Institute, Erasmus MC, Rotterdam, the Netherlands (S.-C.Y.).
⁸ Department of Cardiac, Thoracic, Vascular Sciences and Public Health, University of Padua, Italy (K.P., C.B., B.B.).
⁹ University of Colorado Cardiovascular Institute, University of Colorado Anschutz Medical Campus, Aurora (K.M., M.J., L.M., M.T.).
¹⁰ Department of Cardiology, Arrhythmia Unit, University Heart Center, University Hospital Zurich, Switzerland (V.A.R.., A.M.S., F.D.).
¹¹ Center for Cardiovascular Genetics, Boston Children's Hospital and Harvard Medical School, MA (D.A.).
¹² Cardiovascular Genetics Center, Montreal Heart Institute, Université de Montréal, QC, Canada (J.C.-T.).
¹³ Department of Experimental and Clinical Medicine, University of Florence, Meyer Children Hospital and Careggi University Hospital, Italy (M.T., M.P.).
¹⁴ Department of Cardiology, Arezzo University Hospital, Italy (M.P.).
¹⁵ Cardiac Thoracic and Vascular Department, Cardiology Unit, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Italy (M.G., E.B.).
¹⁶ European Reference Network for Rare, Low Prevalence and Complex Diseases of the Heart-ERN GUARD-Heart (M.G., E.B.).
¹⁷ Department of Cardiology, University Medical Centre Groningen, the Netherlands (M. Cox).
¹⁸ Cardiology and Arrhythmology Clinic, University Hospital "Ospedali Riuniti," Department of Clinical, Special and Dental Sciences, Marche Polytechnic University, Ancona, Italy (M. Casella).
¹⁹ Centro Cardiologico Monzino, IRCCS, Department of Clinical Electrophysiology and Cardiac Pacing, Milan, Italy (C. Tondo).
²⁰ National Heart and Lung Institute and MRC London Institute of Medical Sciences, Imperial College London, UK (J.S.W., S.K.P.).
²¹ Department of Cardiology, Policlinico Casilino, Rome, Italy (L. Calò).
²² Department of Internal Medicine, Division of Cardiovascular Medicine, University of Michigan, Ann Arbor (E.S., A.H.).
²³ Genomics and Inherited Disease Program, Garvan Institute of Medical Research, and UNSW Sydney, Australia (J.I.).
²⁴ Department of Medicine, Division of Cardiology, Vanderbilt University Medical Center, Nashville, TN (H.T.).
²⁵ Royal Melbourne Hospital, Melbourne, Victoria, Australia (S.P., D.Z., J.R.).
²⁶ IRCCS, Istituto Auxologico Italiano, Department of Cardiology, Cardiomyopathy Unit, Milan, Italy (S.R., L. Crotti).
²⁷ Department of Medicine and Surgery, Università Milano-Bicocca, Milan, Italy (L. Crotti).
²⁸ Department of Cardiovascular Medicine, Institute for Genetics of Heart Diseases, University Hospital Münster, Germany (S.D., E.-S.B.).
²⁹ Department of Genomic Health, Geisinger, Danville, PA (E.D.C.).
³⁰ Department of Medicine, Division of Cardiovascular Medicine, Stanford Center for Inherited Cardiovascular Disease, Stanford University School of Medicine, CA (V.A.K., V.N.P.).
³¹ Fondazione Cardiocentro Ticino, Department of Cardiology, Lugano, Switzerland (G.C.).
³² Amsterdam UMC location University of Amsterdam, Department of Cardiology, the Netherlands (A.W.).
³³ Amsterdam Cardiovascular Sciences, Heart Failure and Arrhythmias, the Netherlands (A.W.).
³⁴ Department of Genetics, University Medical Center Utrecht, the Netherlands (J.P.v.T.).
³⁵ Cardiology Department, Arrhythmia Section, Hospital Clínic, Universitat de Barcelona, Spain (E.A.).
³⁶ IDIBAPS, Institut d'Investigació August Pi i Sunyer (IDIBAPS), Barcelona, Spain (E.A.).
³⁷ Centro de Investigación Biomédica en Red de Enfermedades Cardiovasculares (CIBERCV), Madrid, Spain (E.A.).
³⁸ Center for Advanced Heart Disease, Brigham and Women's Hospital Cardiovascular Medicine, Boston, MA (N.L.).

PMID: 40832715
DOI: 10.1161/CIRCULATIONAHA.125.073919

Prognostic Role of Myocarditis-Like Episodes and Their Treatment in Patients With Pathogenic Desmoplakin Variants

Alessio Gasperetti et al. Circulation. 2025.

. 2025 Aug 20.

doi: 10.1161/CIRCULATIONAHA.125.073919. Online ahead of print.

Authors

Affiliations

¹ Department of Medicine, Division of Cardiology, Johns Hopkins University School of Medicine, Baltimore, MD (A.G., S.A.M., B.A., R.T.C., B.M., C. Tichnell, P.S., L.A., H.C., C.A.J., N.A.G.).
² Division of Cardiology, University Medical Center Utrecht, the Netherlands (S.A.M., J.P.v.T., A.S.J.M.t.R.).
³ Multidisciplinary Disease Unit for Myocarditis and Arrhythmogenic Cardiomyopathies, IRCCS San Raffaele Scientific Institute, Milan, Italy (G.P.).
⁴ Inherited Cardiovascular Diseases Unit, St Bartholomew's Hospital, UCL Institute of Cardiovascular Science, London, UK (A.P., P.S., P.M.E.).
⁵ Sorbonne Université, AP-HP, IHU-ICAN, Groupe Hospitalier Pitié-Salpêtrière, Institut de Cardiologie, Paris, France (M.L., P.-Y.T., P.C., F.A., E.G.).
⁶ Cardiothoracovascular Department, Division of Cardiology, Azienda Sanitaria Universitaria Giuliano Isontina and University of Trieste, Italy (M.G., G.S., M.M.).
⁷ Department of Cardiology, Thorax Center, Cardiovascular Institute, Erasmus MC, Rotterdam, the Netherlands (S.-C.Y.).
⁸ Department of Cardiac, Thoracic, Vascular Sciences and Public Health, University of Padua, Italy (K.P., C.B., B.B.).
⁹ University of Colorado Cardiovascular Institute, University of Colorado Anschutz Medical Campus, Aurora (K.M., M.J., L.M., M.T.).
¹⁰ Department of Cardiology, Arrhythmia Unit, University Heart Center, University Hospital Zurich, Switzerland (V.A.R.., A.M.S., F.D.).
¹¹ Center for Cardiovascular Genetics, Boston Children's Hospital and Harvard Medical School, MA (D.A.).
¹² Cardiovascular Genetics Center, Montreal Heart Institute, Université de Montréal, QC, Canada (J.C.-T.).
¹³ Department of Experimental and Clinical Medicine, University of Florence, Meyer Children Hospital and Careggi University Hospital, Italy (M.T., M.P.).
¹⁴ Department of Cardiology, Arezzo University Hospital, Italy (M.P.).
¹⁵ Cardiac Thoracic and Vascular Department, Cardiology Unit, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Italy (M.G., E.B.).
¹⁶ European Reference Network for Rare, Low Prevalence and Complex Diseases of the Heart-ERN GUARD-Heart (M.G., E.B.).
¹⁷ Department of Cardiology, University Medical Centre Groningen, the Netherlands (M. Cox).
¹⁸ Cardiology and Arrhythmology Clinic, University Hospital "Ospedali Riuniti," Department of Clinical, Special and Dental Sciences, Marche Polytechnic University, Ancona, Italy (M. Casella).
¹⁹ Centro Cardiologico Monzino, IRCCS, Department of Clinical Electrophysiology and Cardiac Pacing, Milan, Italy (C. Tondo).
²⁰ National Heart and Lung Institute and MRC London Institute of Medical Sciences, Imperial College London, UK (J.S.W., S.K.P.).
²¹ Department of Cardiology, Policlinico Casilino, Rome, Italy (L. Calò).
²² Department of Internal Medicine, Division of Cardiovascular Medicine, University of Michigan, Ann Arbor (E.S., A.H.).
²³ Genomics and Inherited Disease Program, Garvan Institute of Medical Research, and UNSW Sydney, Australia (J.I.).
²⁴ Department of Medicine, Division of Cardiology, Vanderbilt University Medical Center, Nashville, TN (H.T.).
²⁵ Royal Melbourne Hospital, Melbourne, Victoria, Australia (S.P., D.Z., J.R.).
²⁶ IRCCS, Istituto Auxologico Italiano, Department of Cardiology, Cardiomyopathy Unit, Milan, Italy (S.R., L. Crotti).
²⁷ Department of Medicine and Surgery, Università Milano-Bicocca, Milan, Italy (L. Crotti).
²⁸ Department of Cardiovascular Medicine, Institute for Genetics of Heart Diseases, University Hospital Münster, Germany (S.D., E.-S.B.).
²⁹ Department of Genomic Health, Geisinger, Danville, PA (E.D.C.).
³⁰ Department of Medicine, Division of Cardiovascular Medicine, Stanford Center for Inherited Cardiovascular Disease, Stanford University School of Medicine, CA (V.A.K., V.N.P.).
³¹ Fondazione Cardiocentro Ticino, Department of Cardiology, Lugano, Switzerland (G.C.).
³² Amsterdam UMC location University of Amsterdam, Department of Cardiology, the Netherlands (A.W.).
³³ Amsterdam Cardiovascular Sciences, Heart Failure and Arrhythmias, the Netherlands (A.W.).
³⁴ Department of Genetics, University Medical Center Utrecht, the Netherlands (J.P.v.T.).
³⁵ Cardiology Department, Arrhythmia Section, Hospital Clínic, Universitat de Barcelona, Spain (E.A.).
³⁶ IDIBAPS, Institut d'Investigació August Pi i Sunyer (IDIBAPS), Barcelona, Spain (E.A.).
³⁷ Centro de Investigación Biomédica en Red de Enfermedades Cardiovasculares (CIBERCV), Madrid, Spain (E.A.).
³⁸ Center for Advanced Heart Disease, Brigham and Women's Hospital Cardiovascular Medicine, Boston, MA (N.L.).

PMID: 40832715
DOI: 10.1161/CIRCULATIONAHA.125.073919

Abstract

Background: Inflammatory, myocarditis-like episodes precede and are associated with higher risk of sustained ventricular arrhythmias and heart failure in patients with pathogenic or likely pathogenic desmoplakin (DSP) variants. Whether the recurrence and treatment of myocarditis-like episodes influence the outcomes in this population is unknown. This study aimed to assess the prognostic impact of the recurrence and treatment of myocarditis-like episodes in patients with pathogenic or likely pathogenic DSP variants.

Methods: The study was designed as an observational cohort study using all patients with pathogenic or likely pathogenic DSP variants in the DSP-ERADOS Network (Desmopakin Specific Effort for a Rare Disease Outcome Study) enrolled at 31 institutions up until April 30, 2024. Survival from ventricular arrhythmia and heart failure end points and recurrent myocarditis-like episodes was evaluated for both first and recurrent documented myocarditis-like episodes and the impact of immunosuppressive treatment on outcomes assessed.

Results: A total of 1014 patients with pathogenic or likely pathogenic DSP variants (62.4% female; mean age, 40.4±17.4 years; 47.1% probands) were included. Among them, 177 individuals (17.5%) experienced ≥1 documented myocarditis-like episode, with 63 of them (35.6%) receiving immunosuppressive treatment. Immunosuppressive treatment of the first documented myocarditis-like episode was associated with reduced risk of ventricular arrhythmia and heart failure outcomes (hazard ratio, 0.18 [95% CI, 0.07-0.45]; P<0.001; and hazard ratio, 0.09 [95% CI, 0.02-0.39; P=0.001, respectively) over a median follow-up of 6.4 years (95% CI, 4.0-10.5). This risk was comparable to that of patients with no history of myocarditis-like episode but did not correlate with a reduction in recurrent episodes after completion of initial immunosuppression (hazard ratio, 0.85 [95% CI, 0.47-1.54]; P=0.599). In contrast, nonsteroidal anti-inflammatory drugs or colchicine treatment did not influence outcomes.

Conclusions: Immunosuppressive treatment of myocarditis-like episodes in DSP patients was associated with improved combined ventricular arrhythmia or heart failure outcomes, supporting future prospective evaluation in DSP cohorts.

Keywords: arrhythmias, cardiac; cardiomyopathies; death, sudden, cardiac; genetics; inflammation; myocarditis; risk assessment.

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Prognostic Role of Myocarditis-Like Episodes and Their Treatment in Patients With Pathogenic Desmoplakin Variants

Affiliations

Prognostic Role of Myocarditis-Like Episodes and Their Treatment in Patients With Pathogenic Desmoplakin Variants

Authors

Affiliations

Abstract

LinkOut - more resources

Full Text Sources