Genetic Animal Models for Arrhythmogenic Cardiomyopathy

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.

Hemi- and Homozygous Loss-of-Function Mutations in DSG2 (Desmoglein-2) Cause Recessive Arrhythmogenic Cardiomyopathy with an Early Onset

“…In 2002, Eshkind et al demonstrated that the global homozygous knock-out of Dsg2 in mice is embryonic lethal [ 43 ]. Therefore, different conditional knock-out, knock-in, and transgenic mouse models for Dsg2 leading to murine arrhythmogenic cardiomyopathies have been developed [ 44 , 45 , 46 , 47 , 48 , 49 ]. In spite of this, the first pathogenic DSG2 mutations associated with ACM in humans were found in 2006 [ 37 , 50 ].…”

Toward the Effective Bioengineering of a Pathological Tissue for Cardiovascular Disease Modeling: Old Strategies and New Frontiers for Prevention, Diagnosis, and Therapy

“…Although these mice carry the same mutations observed in boxer dogs and humans, their phenotype is not identical: no fat infiltration is generally observed in the rodent heart myocardium. In addition, transgenesis techniques are more successful in reproducing loss of function than missense mutations ( 73 ).…”

Modifications of Titin Contribute to the Progression of Cardiomyopathy and Represent a Therapeutic Target for Treatment of Heart Failure

“…Animal models are essential for understanding molecular pathways, and several have been utilized to study TTNtv including a mouse model with an A-band truncation mutation, and zebrafish models that have several different truncation variations [ 39 , 40 , 41 , 42 ]. A review of these important models has been recently carried out [ 43 ].…”

“…This is also demonstrated in animal models including a rat knockout of RBM20 [ 60 ]. Further animal models for RBM20 and its targets have been described but are not as well characterized [ 43 ]. The preference for the longer, softer N2BA isoform in RBM20 mutants results in decreased active and passive tension of cardiomyocytes contributing to dilation of the ventricle [ 68 ].…”