Models of arrhythmogenic right ventricular cardiomyopathy/dysplasia

Inherited arrhythmogenic cardiomyopathies are the most common cause of sudden cardiac death (SCD) in patients under 40 years of age. According to a recent expert consensus panel, cardiomyopathies are defined as ‘a heterogeneous group of diseases of the myocardium associated with mechanical and/or electrical dysfunction that usually exhibit inappropriate ventricular hypertrophy or dilatation, and are due to a variety of causes that frequently are genetic’ (Maron et al., 2006). Advances in molecular genetics led to the development of a new classification of cardiomyopathies and the recognition that a subset of inherited cardiomyopathies is associated with lethal ventricular tachyarrhythmias (Maron et al., 2006). The most prototypical of these diseases, arrhythmogenic right ventricular cardiomyopathy/ dysplasia (ARVC/D), commonly presents clinically with ventricular tachyarrhythmias and tends to affect the right ventricle (RV) more than the left ventricle (LV) (MacRae et al., 2006). ARVC/D is typically caused by inherited mutations in desmosomal proteins (Moric-Janiszewska and Markiewicz-Loskot, 2007). Hypertrophic cardiomyopathy (HCM) is characterized by a hypertrophied, nondilated LV in the absence of other systemic or cardiac disease. HCM is most commonly caused by a variety of mutations in genes encoding proteins that are found in the cardiac sarcomere. Familial forms of dilated cardiomyopathy (DCM) are characterized by ventricular enlargement and systolic dysfunction in the absence of LV hypertrophy. DCM is associated frequently with supraventricular arrhythmias and SCD (Boussy et al., 2008), and can be caused by mutations in sarcomeric, cytoskeletal or nuclear envelope proteins. Other forms of cardiomyopathy, including left ventricular noncompaction (LVNC) and restrictive cardiomyopathy (RCM) are less common and are not discussed in this review. Animal models of arrhythmogenic cardiomyopathies have contributed to a better understanding of the pathophysiological processes leading to both cardiomyopathy and an increased susceptibility to cardiac arrhythmias (Awad et al., 2008). A variety of animals have been used to examine the pathological effects of mutations at both the whole organism/organ level and the cellular and molecular level (Berul, 2003). Initial animal models typically involved the serendipitous discovery of an inherited form of cardiomyopathy, followed by a forward genetic approach to identify the defect underlying the disease phenotype (Brink and Lochner, 1967; Kittleson et al., 1999). With the advent of genetically modified mouse models, inherited mutations identified in humans with cardiomyopathy are now modeled in transgenic or knock-in mice that may or may not recapitulate the clinical features of the disease (Berul, 2003). It is important to note that transgenic mouse models may have limitations from unintended alterations in gene expression besides the targeted gene. Likewise, single gene knockout models may introduce compensatory changes in other related structural genes, which may confound phenotypic results. However, animal models of arrhythmogenic cardiomyopathy continue to provide valuable insights into our understanding of the arrhythmogenic substrate, and the confluence of both cardiomyopathic and arrhythmogenic phenotypes. In this review, we will evaluate the current state of animal models of cardiomyopathies that are associated with cardiac arrhythmias, and will briefly discuss the new mechanistic insights obtained from these studies.