Abstract
Arrhythmogenic cardiomyopathy has been clinically defined since the 1980s and causes right or biventricular cardiomyopathy associated with ventricular arrhythmia. Although it is a rare cardiac disease, it is responsible for a significant proportion of sudden cardiac deaths, especially in athletes. The majority of patients with arrhythmogenic cardiomyopathy carry one or more genetic variants in desmosomal genes. In the 1990s, several knockout mouse models of genes encoding for desmosomal proteins involved in cell–cell adhesion revealed for the first time embryonic lethality due to cardiac defects. Influenced by these initial discoveries in mice, arrhythmogenic cardiomyopathy received an increasing interest in human cardiovascular genetics, leading to the discovery of mutations initially in desmosomal genes and later on in more than 25 different genes. Of note, even in the clinic, routine genetic diagnostics are important for risk prediction of patients and their relatives with arrhythmogenic cardiomyopathy. Based on improvements in genetic animal engineering, different transgenic, knock-in, or cardiac-specific knockout animal models for desmosomal and nondesmosomal proteins have been generated, leading to important discoveries in this field. Here, we present an overview about the existing animal models of arrhythmogenic cardiomyopathy with a focus on the underlying pathomechanism and its importance for understanding of this disease. Prospectively, novel mechanistic insights gained from the whole animal, organ, tissue, cellular, and molecular levels will lead to the development of efficient personalized therapies for treatment of arrhythmogenic cardiomyopathy.
Highlights
Arrhythmogenic cardiomyopathy (ACM) is a genetic cardiomyopathy characterized by ventricular arrhythmia often leading to sudden cardiac death in young people
The disease was referred to as arrhythmogenic right ventricular cardiomyopathy (ARVC) because the phenotype description was more focused on features of the right ventricle; increasing awareness of left ventricular and biventricular involvement led to the term “ACM” (Sen-Chowdhry et al, 2010)
Because the first disease genes of ACM were discovered more than 20 years ago, a substantial number of in vivo models have been generated and characterized to fill the important gap between the underlying genetic defect and the observed clinical phenotype
Summary
Arrhythmogenic cardiomyopathy (ACM) is a genetic cardiomyopathy characterized by ventricular arrhythmia often leading to sudden cardiac death in young people. In the 1990s, several knockout mouse models of genes encoding for desmosomal proteins involved in cell–cell adhesion revealed for the first time embryonic lethality due to cardiac defects. Different transgenic, knock-in (KI), and conditional cardiac-specific mouse models for the desmosomal genes have been developed to overcome embryonic lethality (Figure 3 and Supplementary Tables 1, 2).
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