Desmoplakin Cardiomyopathy

作者：Anna Guazzo, Induja Perumal Vanaja, Anna Di Bona, Riccardo Bariani, MARIA CLAUDIA DISALVO, Mattia Albiero, Nicolas Kuperwasser, Pierre David, Rudy Celeghin, Vittoria Di Mauro, Arianna Scalco, María Fuensanta López-Moreno, Marco Cason, Monica De Gaspari, Mila Della Barbera, Stefania Rizzo, L. Ventura, Domenico Corrado, Barbara Bauce, Giuseppe Zanotti, Gaetano Thiene, Kalliopi Pilichou, Giovanni Minervini, José María Pérez Pomares, Mario Pende, Cristina Basso, Marco Mongillo, Tania Zaglia · 发表于：JACC. Clinical electrophysiology · 年份：2025 · DOI：10.1016/j.jacep.2025.10.031 · 被引用次数：2 · 研究领域：Chemotherapy-induced cardiotoxicity and mitigation、Pericarditis and Cardiac Tamponade、Cardiac electrophysiology and arrhythmias

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: 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: 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 st...