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Desmoplakin Cardiomyopathy: Gene Dose-Dependent Myocardial Remodeling, Arrhythmias, and Premature Death
Anna Guazzo1, Induja Perumal Vanaja2, Anna Di Bona2
1Department of Biomedical Sciences, University of Padova, Padova, Italy; Veneto Institute of Molecular Medicine, Padova, Italy.
Insights
A new mouse model with a Desmoplakin (DSP) mutation mimics both recessive and dominant DSP cardiomyopathies, showing early arrhythmias and inflammation. This model aids in studying arrhythmogenic mechanisms and developing treatments for sudden cardiac death.
Area of Science:
- Cardiovascular Genetics
- Molecular Cardiology
- Disease Modeling
Background:
- Pathogenic variants in DSP gene are linked to arrhythmogenic cardiomyopathies with varied inheritance.
- Recessive DSP mutations cause syndromic forms (e.g., Carvajal syndrome), while dominant variants lead to left-dominant DSP cardiomyopathy.
- Mechanisms underlying DSP cardiomyopathy phenotypes are not fully understood.
Purpose of the Study:
- To develop a clinically relevant in vivo platform for investigating Desmoplakin Cardiomyopathy (DSP) disease mechanisms.
- To model both recessive and dominant forms of DSP cardiomyopathy.
Main Methods:
- Generated a knock-in mouse model with the DspS311A mutation, mimicking a human DSP pathogenic hotspot.
- Phenotyped heterozygous and homozygous mice using echocardiography, ECG telemetry, histology, and molecular analyses.
- Utilized treadmill exercise as a physiological stressor to evaluate outcomes like cardiac function, arrhythmias, and fibrosis.
Main Results:
- Homozygous DspS311A/S311A mice displayed features of Carvajal syndrome, including biventricular dysfunction, inflammation, fibrosis, and cutaneous defects.
- Heterozygous DspWT/S311A mice showed hallmarks of dominant DSP cardiomyopathy, such as left ventricular fibrosis, inflammation, and electrical instability.
- Both genotypes exhibited spontaneous arrhythmias and electrical instability preceding structural cardiac remodeling; exercise exacerbated these phenotypes.
Conclusions:
- The DspS311A knock-in mouse model effectively recapitulates key features of both recessive and dominant DSP cardiomyopathies.
- This model uniquely combines spontaneous arrhythmias, inflammation, and extracardiac manifestations.
- It serves as a valuable in vivo platform for dissecting DSP-related arrhythmogenic mechanisms and for preclinical testing of therapies targeting sudden cardiac death.
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 DspS311A 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 DspS311A/S311A mice developed early biventricular dysfunction with subepicardial necrosis, replacement fibrosis, myocardial inflammation, spontaneous arrhythmias, and cutaneous defects, recapitulating Carvajal syndrome. Heterozygous DspWT/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 DspS311A 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.
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