Multicenter Study

. 2025 Jan 21;46(4):362-376.

doi: 10.1093/eurheartj/ehae571.

Clinical features and outcomes in carriers of pathogenic desmoplakin variants

Alessio Gasperetti^{1

2

3}, Richard T Carrick¹, Alexandros Protonotarios⁴, Brittney Murray¹, Mikael Laredo⁵, Iris van der Schaaf³, Ronald H Lekanne³, Petros Syrris⁴, Douglas Cannie⁴, Crystal Tichnell¹, Chiara Cappelletto⁶, Marta Gigli⁶, Kristen Medo⁷, Ardan M Saguner^{8

9}, Firat Duru^{8

9}, Nisha A Gilotra¹, Stefan Zimmerman¹, Robyn Hylind¹⁰, Dominic J Abrams¹⁰, Neal K Lakdawala¹¹, Julia Cadrin-Tourigny¹², Mattia Targetti¹³, Iacopo Olivotto¹³, Maddalena Graziosi¹⁴, Moniek Cox¹⁵, Elena Biagini¹⁴, Philippe Charron⁵, Michela Casella¹⁶, Claudio Tondo^{17

18}, Momina Yazdani^{19

20}, James S Ware^{19

20}, Sanjay K Prasad^{19

20}, Leonardo Calò²¹, Eric D Smith²², Adam S Helms²², Sophie Hespe²³, Jodie Ingles²³, Harikrishna Tandri¹, Flavie Ader^{24

25}, Giovanni Peretto²⁶, Stacey Peters²⁷, Ari Horton²⁷, Jess Yao²⁷, Sven Dittmann²⁸, Eric Schulze-Bahr²⁸, Maria Qureshi²⁹, Katelyn Young²⁹, Eric D Carruth²⁹, Chris Haggerty^{29

30}, Victoria N Parikh³¹, Matthew Taylor⁷, Luisa Mestroni⁷, Arthur Wilde^{32

33}, Gianfranco Sinagra⁵, Marco Merlo⁶, Estelle Gandjbakhch⁵, J Peter van Tintelen^{2

34}, Anneline S J M Te Riele^{3

34}, Perry M Elliott⁴, Hugh Calkins¹, Cynthia A James¹

Affiliations

¹ Division of Cardiology, Department of Medicine, Johns Hopkins University, 601 North Caroline St., Baltimore, MD 21287, USA.
² Department of Genetics, University Medical Center Utrecht, University of Utrecht, The Netherlands.
³ Department of Medicine, Division of Cardiology, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands.
⁴ UCL Institute of Cardiovascular Science, London, UK.
⁵ Institut de Cardiologie, Sorbonne Université, AP-HP, IHU-ICAN, Groupe Hospitalier Pitié-Salpêtrière, Paris, France.
⁶ Division of Cardiology, Cardiothoracovascular Department, Azienda Sanitaria Universitaria Giuliano Isontina and University of Trieste, Trieste, Italy.
⁷ University of Colorado Cardiovascular Institute, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
⁸ Department of Cardiology, Arrhythmia Unit, University Heart Center, University Hospital Zurich, Zurich, Switzerland.
⁹ Center for Translational and Experimental Cardiology (CTEC), Department of Cardiology, Zurich University Hospital, University of Zurich, 8952 Schlieren, Switzerland.
¹⁰ Center for Cardiovascular Genetics, Boston Children's Hospital and Harvard Medical School, Boston, MA, USA.
¹¹ Brigham and Women's Hospital Cardiovascular Medicine, Boston, MA, USA.
¹² Cardiovascular Genetics Center, Montreal Heart Institute, Université de Montréal, Montréal, QC, Canada.
¹³ Department of Experimental and Clinical Medicine, University of Florence, Meyer Children Hospital and Careggi University Hospital, Florence, Italy.
¹⁴ Cardiology Unit, Cardiac Thoracic and Vascular Department, IRCCS Azienda Ospedaliero-Universitaria di Bologna, European Reference Network for Rare, Low Prevalence and Complex Diseases of the Heart-ERN GUARD-Heart, Italy.
¹⁵ Department of Cardiology, University Medical Centre Groningen, Groningen, The Netherlands.
¹⁶ Department of Clinical, Special and Dental Sciences, Cardiology and Arrhythmology Clinic, University Hospital 'Ospedali Riuniti', Marche Polytechnic University, Ancona, Italy.
¹⁷ Dept. of Clinical Electrophysiology & Cardiac Pacing, Centro Cardiologico Monzino, IRCCS, Milan, Italy.
¹⁸ Dept. of Biomedical, Surgical and Dental Sciences, University of Milan, Milan, Italy.
¹⁹ National Heart and Lung Institute and MRC London Institute of Medical Sciences, Imperial College London, London, UK.
²⁰ Royal Brompton & Harefield Hospitals, Guy's and St. Thomas' NHS Foundation Trust, London, UK.
²¹ Department of Cardiology, Policlinico Casilino, Rome, Italy.
²² Department of Internal Medicine, Division of Cardiovascular Medicine, University of Michigan, Ann Arbor, USA.
²³ Centre for Population Genomics, Garvan Institute of Medical Research, and UNSW Sydney, Sydney, Australia.
²⁴ APHP Sorbonne Université, DMU BioGem, UF de cardiogénétique et myogénétique moléculaire et cellulaire, 75013 Paris, France.
²⁵ Université Paris Cité, UFR de Pharmacie, UP Biochimie, 75006 Paris, France.
²⁶ Department of Cardiac Electrophysiology and Arrhythmology, IRCCS San Raffaele Hospital, Milan, Italy.
²⁷ Royal Melbourne Hospital, Melbourne 3050, Victoria, Australia.
²⁸ Department of Cardiovascular Medicine, Institute for Genetics of Heart Diseases, University Hospital Münster, Münster, Germany.
²⁹ The Heart Institute, Geisinger, Danville, PA, USA.
³⁰ Department of Translational Data Science and Informatics, Geisinger, Danville, PA, USA.
³¹ Stanford Center for Inherited Cardiovascular Disease, Division of Cardiovascular Medicine, Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA.
³² Department of Cardiology, Amsterdam UMC Location University of Amsterdam, Meibergdreef 9, Amsterdam, The Netherlands.
³³ Amsterdam Cardiovascular Sciences, Heart Failure and Arrhythmias, Amsterdam, The Netherlands.
³⁴ Netherlands Heart Institute, Utrecht, The Netherlands.

PMID: 39288222
PMCID: PMC11745529
DOI: 10.1093/eurheartj/ehae571

Multicenter Study

Clinical features and outcomes in carriers of pathogenic desmoplakin variants

Alessio Gasperetti et al. Eur Heart J. 2025.

. 2025 Jan 21;46(4):362-376.

doi: 10.1093/eurheartj/ehae571.

Authors

Affiliations

¹ Division of Cardiology, Department of Medicine, Johns Hopkins University, 601 North Caroline St., Baltimore, MD 21287, USA.
² Department of Genetics, University Medical Center Utrecht, University of Utrecht, The Netherlands.
³ Department of Medicine, Division of Cardiology, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands.
⁴ UCL Institute of Cardiovascular Science, London, UK.
⁵ Institut de Cardiologie, Sorbonne Université, AP-HP, IHU-ICAN, Groupe Hospitalier Pitié-Salpêtrière, Paris, France.
⁶ Division of Cardiology, Cardiothoracovascular Department, Azienda Sanitaria Universitaria Giuliano Isontina and University of Trieste, Trieste, Italy.
⁷ University of Colorado Cardiovascular Institute, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
⁸ Department of Cardiology, Arrhythmia Unit, University Heart Center, University Hospital Zurich, Zurich, Switzerland.
⁹ Center for Translational and Experimental Cardiology (CTEC), Department of Cardiology, Zurich University Hospital, University of Zurich, 8952 Schlieren, Switzerland.
¹⁰ Center for Cardiovascular Genetics, Boston Children's Hospital and Harvard Medical School, Boston, MA, USA.
¹¹ Brigham and Women's Hospital Cardiovascular Medicine, Boston, MA, USA.
¹² Cardiovascular Genetics Center, Montreal Heart Institute, Université de Montréal, Montréal, QC, Canada.
¹³ Department of Experimental and Clinical Medicine, University of Florence, Meyer Children Hospital and Careggi University Hospital, Florence, Italy.
¹⁴ Cardiology Unit, Cardiac Thoracic and Vascular Department, IRCCS Azienda Ospedaliero-Universitaria di Bologna, European Reference Network for Rare, Low Prevalence and Complex Diseases of the Heart-ERN GUARD-Heart, Italy.
¹⁵ Department of Cardiology, University Medical Centre Groningen, Groningen, The Netherlands.
¹⁶ Department of Clinical, Special and Dental Sciences, Cardiology and Arrhythmology Clinic, University Hospital 'Ospedali Riuniti', Marche Polytechnic University, Ancona, Italy.
¹⁷ Dept. of Clinical Electrophysiology & Cardiac Pacing, Centro Cardiologico Monzino, IRCCS, Milan, Italy.
¹⁸ Dept. of Biomedical, Surgical and Dental Sciences, University of Milan, Milan, Italy.
¹⁹ National Heart and Lung Institute and MRC London Institute of Medical Sciences, Imperial College London, London, UK.
²⁰ Royal Brompton & Harefield Hospitals, Guy's and St. Thomas' NHS Foundation Trust, London, UK.
²¹ Department of Cardiology, Policlinico Casilino, Rome, Italy.
²² Department of Internal Medicine, Division of Cardiovascular Medicine, University of Michigan, Ann Arbor, USA.
²³ Centre for Population Genomics, Garvan Institute of Medical Research, and UNSW Sydney, Sydney, Australia.
²⁴ APHP Sorbonne Université, DMU BioGem, UF de cardiogénétique et myogénétique moléculaire et cellulaire, 75013 Paris, France.
²⁵ Université Paris Cité, UFR de Pharmacie, UP Biochimie, 75006 Paris, France.
²⁶ Department of Cardiac Electrophysiology and Arrhythmology, IRCCS San Raffaele Hospital, Milan, Italy.
²⁷ Royal Melbourne Hospital, Melbourne 3050, Victoria, Australia.
²⁸ Department of Cardiovascular Medicine, Institute for Genetics of Heart Diseases, University Hospital Münster, Münster, Germany.
²⁹ The Heart Institute, Geisinger, Danville, PA, USA.
³⁰ Department of Translational Data Science and Informatics, Geisinger, Danville, PA, USA.
³¹ Stanford Center for Inherited Cardiovascular Disease, Division of Cardiovascular Medicine, Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA.
³² Department of Cardiology, Amsterdam UMC Location University of Amsterdam, Meibergdreef 9, Amsterdam, The Netherlands.
³³ Amsterdam Cardiovascular Sciences, Heart Failure and Arrhythmias, Amsterdam, The Netherlands.
³⁴ Netherlands Heart Institute, Utrecht, The Netherlands.

PMID: 39288222
PMCID: PMC11745529
DOI: 10.1093/eurheartj/ehae571

Abstract

Background and aims: Pathogenic variants in the desmoplakin (DSP) gene are associated with the development of a distinct arrhythmogenic cardiomyopathy phenotype not fully captured by either dilated cardiomyopathy (DCM), non-dilated left ventricular cardiomyopathy (NDLVC), or arrhythmogenic right ventricular cardiomyopathy (ARVC). Prior studies have described baseline DSP cardiomyopathy genetic, inflammatory, and structural characteristics. However, cohort sizes have limited full clinical characterization and identification of clinical and demographic predictors of sustained ventricular arrhythmias (VAs), heart failure (HF) hospitalizations, and transplant/death. In particular, the relevance of acute myocarditis-like episodes for subsequent disease course is largely unknown.

Methods: All patients with pathogenic/likely pathogenic (P/LP) DSP variants in the worldwide DSP-ERADOS Network (26 academic institutions across nine countries) were included. The primary outcomes were the development of sustained VA and HF hospitalizations during follow-up. Fine-Gray regressions were used to test association between clinical and instrumental parameters and the development of outcomes.

Results: Eight hundred patients [40.3 ± 17.5 years, 47.5% probands, left ventricular ejection fraction (LVEF) 49.5 ± 13.9%] were included. Over 3.7 [1.4-7.1] years, 139 (17.4%, 3.9%/year) and 72 (9.0%, 1.8%/year) patients experienced sustained VA and HF episodes, respectively. A total of 32.5% of individuals did not fulfil diagnostic criteria for ARVC, DCM, or NDLVC; their VA incidence was 0.5%/year. In multivariable regression, risk features associated with the development of VA were female sex [adjusted hazard ratio (aHR) 1.547; P = .025], prior non-sustained ventricular tachycardia (aHR 1.721; P = .009), prior sustained VA (aHR 1.923; P = .006), and LVEF ≤ 50% (aHR: 1.645; P = .032), while for HF, they were the presence of T-wave inversion in 3+ electrocardiogram leads (aHR 2.036, P = .007) and LVEF ≤ 50% (aHR 3.879; P < .001). Additionally, 70 (8.8%) patients experienced a myocardial injury episode at presentation or during follow-up. These episodes were associated with an increased risk of VA and HF thereafter (HR 2.394; P < .001, and HR 5.064, P < .001, respectively).

Conclusions: Patients with P/LP DSP variants experience high rates of sustained VA and HF hospitalizations. These patients demonstrate a distinct clinical phenotype (DSP cardiomyopathy), whose most prominent risk features associated with adverse clinical outcomes are the presence of prior non-sustained ventricular tachycardia or sustained VA, T-wave inversion in 3+ leads on electrocardiogram, LVEF ≤ 50%, and myocardial injury events.

Keywords: ACM; DSP; DSP cardiomyopathy; Desmoplakin; Hot phases.

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Figures

**Structured Graphical Abstract**
Graphical summary reporting the main findings of the study. Features associated with risk of events include predictors from multivariable models as well as analysis of implications of myocardial injury episodes. aHR, adjusted hazard ratio; ARVC, arrhythmogenic right ventricular cardiomyopathy; DCM, dilated cardiomyopathy; HF, heart failure; HR, hazard ratio; LVEF, left ventricular ejection fraction; NDLVC, non-dilated left ventricular cardiomyopathy; (N)SVT, (non)sustained ventricular tachycardia; PVC, premature ventricular contraction; TFC, 2010 Task Force Criteria; TWI, T-wave inversion; VA, ventricular arrhythmia. Created with BioRender.com.

**Figure 1**
Freedom from sustained VA (left panel) (overall log-rank P < .001) and from HF hospitalizations (right panel) (overall log-rank P < .001) of the study cohort stratified by the cardiomyopathy phenotype that was fulfilled. ARVC, arrhythmogenic right ventricular cardiomyopathy; DCM, dilated cardiomyopathy; HF, heart failure; VA, ventricular arrhythmia

**Figure 2**
Freedom from sustained VA events (upper panel) and from HF hospitalizations (lower panel) from patients for a patient population pre and post the occurrence of myocardial injury events. X axis reports time from first assessment (myocardial injury HR for VA: 2.394 [1.498–3.827], P < .001; for HF hospitalizations: 5.064 [2.847–9.004], P < .001). Number at risk for outcomes (VA events or HF hospitalizations) changes according to the time of occurrence of myocardial injury during follow-up time. HF, heart failure; MI, myocardial injury; VA, ventricular arrhythmia

See this image and copyright information in PMC

References

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Clinical features and outcomes in carriers of pathogenic desmoplakin variants

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Clinical features and outcomes in carriers of pathogenic desmoplakin variants

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