Pathophysiology Beyond Cardiac Myocytes
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In the current issue of the Circulation Research, Karmouch et al1 present a provocative study attributing a pivotal role in the pathogenesis of arrhythmogenic cardiomyopathy (ACM) to the loss of DSP (desmoplakin) gene in a subpopulation of the cells of the conduction system. This hypothesis is in sharp departure from the current view on the disease, and it opens the question on whether the data reported in mice with a selective expression of the genetic defects in the specialized cells of the conduction system replicate the clinical phenotype found in patients.
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ACM is a genetic disease of the heart muscle caused, in most instances, by mutations in genes encoding for desmosomal proteins that is predominantly inherited as an autosomal dominant trait.1 Two syndromic recessive forms of the disease have been described and both present abnormalities in skin2 and heart. Carvajal Syndrome3 presents a striate type of keratoderma, is associated with a cardiomyopathy with preferred involvement of the left ventricle, and is associated with DSP mutations. Occasionally, Carvajal is inherited as a dominant disease that also presents hypodontia.4 Naxos disease5 is associated with mutations in the plakoglobin gene and manifests diffuse keratoderma and right ventricular cardiomyopathy. Occasionally, Naxos disease with dominant inheritance has been reported.
Karmouch et al1 investigate the recessive form of ACM caused by mutations in the DSP gene that manifests with palmo-plantar keratosis, wooly hair, and dilatation of both ventricular chambers with fibro-fatty infiltration and life-threatening arrhythmias.3 There is general consensus that cardiac manifestations of the disease are the consequence of DSP mutations that alter the function of cardiac myocytes (CMs). The assumption that mutations in cardiac genes affect CMs is not unique to ACM; rather, it is the paradigm in the study of most …