Journal Article Ahead of print
PubMed: 41411472 DOI: 10.1016/j.jacep.2025.10.031
Desmoplakin Cardiomyopathy: Gene Dose-Dependent Myocardial Remodeling, Arrhythmias, and Premature Death.
JACC Clin Electrophysiol
Authors: Anna Guazzo, Induja Perumal Vanaja, Anna Di Bona, Riccardo Bariani, Maria C Disalvo, Mattia Albiero, Nicolas Kuperwasser, Pierre David, Rudy Celeghin, Vittoria Di Mauro, Arianna Scalco, María López-Moreno, Marco Cason, Monica De Gaspari, Mila Della Barbera, Stefania Rizzo, Laura Ventura, Domenico Corrado, Barbara Bauce, Giuseppe Zanotti, Gaetano Thiene, Kalliopi Pilichou, Giovanni Minervini, José Maria Perez Pomares, Mario Pende, Cristina Basso, Marco Mongillo, Tania Zaglia
Affiliations
- Department of Biomedical Sciences, University of Padova, Padova, Italy; Veneto Institute of Molecular Medicine, Padova, Italy.
- Veneto Institute of Molecular Medicine, Padova, Italy; Department of Cardiac, Thoracic, Vascular Sciences and Public Health, University of Padova, Padova, Italy.
- Department of Cardiac, Thoracic, Vascular Sciences and Public Health, University of Padova, Padova, Italy.
- Department of Surgery, Oncology and Gastroenterology, University of Padova, Padova, Italy.
- Structure Fédérative de Recherche Necker, Institut National de la Santé et de la Recherche Médicale US24/Centre National de la Recherche Scientifique Unité d'Appui à la Recherche 3633, Paris, France.
- Institut Imagine, Paris, France.
- Department of Animal Biology, University of Malaga, Malaga, Spain; Instituto de Biomedicina de Malaga-Plataforma en Nanomedicina, Malaga, Spain.
- Department of Statistical Sciences, University of Padova, Padova, Italy.
- Department of Biomedical Sciences, University of Padova, Padova, Italy.
- Université Paris Cité, Centre National de la Recherche Scientifique, Institut National de la Santé et de la Recherche Médicale, Institut Necker Enfants Malades, Paris, France.
- Department of Biomedical Sciences, University of Padova, Padova, Italy; Veneto Institute of Molecular Medicine, Padova, Italy; Department of Cardiac, Thoracic, Vascular Sciences and Public Health, University of Padova, Padova, Italy.
Abstract
BACKGROUND
Pathogenic variants in DSP cause arrhythmogenic cardiomyopathies with variable inheritance pattern. Recessive mutations underlie syndromic forms such as Carvajal syndrome, whereas dominant variants cause DSP cardiomyopathy, a left-dominant arrhythmogenic cardiomyopathy characterized by early electrical instability, inflammation, and fibrosis. The mechanisms driving these phenotypes remain poorly defined.
OBJECTIVES
The authors sought to create a clinically relevant platform to investigate disease mechanisms in Desmoplakin Cardiomyopathy.
METHODS
We generated a knock-in mouse carrying the Dsp S311A mutation, orthologous to the human pathogenic hotspot S299R. Heterozygous and homozygous mice (n ≥6/group) were longitudinally phenotyped by echocardiography, electrocardiographic telemetry, histology, and ultrastructural and molecular analyses. Moderate treadmill exercise was used as a physiological stressor. Outcomes included cardiac function, arrhythmias, fibrosis, apoptosis, inflammation, and desmosomal integrity.
RESULTS
Homozygous Dsp S311A/S311A mice developed early biventricular dysfunction with subepicardial necrosis, replacement fibrosis, myocardial inflammation, spontaneous arrhythmias, and cutaneous defects, recapitulating Carvajal syndrome. Heterozygous Dsp WT/S311A mice exhibited hallmarks of dominant DSP cardiomyopathy: patchy left ventricular fibrosis, apoptosis, inflammation, and electrical instability preceding systolic impairment. Desmosomal remodeling occurred in both genotypes, with connexin-43 mislocalization evident from 1 month, whereas β-catenin nuclear translocation and reduced DSP/DSG2 protein were restricted to homozygotes. Of note, spontaneous arrhythmias and electrical instability were already present in both genotypes, temporally preceding structural remodeling. Exercise accelerated apoptosis, fibrosis, arrhythmias, and premature death.
CONCLUSIONS
This Dsp S311A knock-in model captures key aspects of recessive and dominant DSP cardiomyopathies, uniquely combining spontaneous arrhythmias, inflammation, and extracardiac features. This model provides a unique in vivo platform to dissect DSP-related arrhythmogenic mechanisms and to test therapies aimed at preventing sudden cardiac death.
MeSH
Genes, Fibrosis, Desmoplakins, Cardiovascular Diseases, Genotype, Apoptosis, Mortality, Premature, Mutation, Cardiomyopathies