The animal models described in this chapter support the notion that ARVC/D is a disease of the desmo-some. Although the only model to date that appears to recapitulate ARVC/D in part is that of desmo-plakin, the cumulative message of these desmosome-mutant mice is that disruption of desmosome func tion leads to cardiomyopathy. The fact that fibrous infiltration is common in all, that there is myocardial thinning in all, and that the desmoplakin model has abnormalities of lipid accumulation in the myocardium, is sufficient to state that these models provide the necessary proof of concept that the "final common pathway" of ARVC/D is desmosomal dysfunction; in other words, ARVC/D is a disease of the desmosome. Future human and animal models will continue to focus on desmosomal and other ad-herens junction proteins and other genes responsible for this disorder is likely to be identified. The next series of important steps in better understanding the paradigm of this disorder include defining the mechanisms responsible for the fatty infiltrative process, the mechanisms responsible for the disruption of the junctions and intercalated disks, and the mechanisms responsible for the development of arrhythmias [49,
50]. Our "final common pathway" hypothesis would suggest that these rhythm disturbances are likely to occur from secondary disruption of ion channel function (cascade events) and we predict that one or more ion channels will be found to be dysfunctional based on abnormal interactions with the desmo-some, intercalated disks, or specific cadherin proteins that probably bind to these important channels . Once determined, these models will enable targeted therapies to be developed, leading to more predictable and better survival of affected individuals.
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