Conclusions

The observed abnormalities of cardiomyocytes, in particular at the level of intercellular junctions and cy-toskeleton structure, may explain pathophysiological features in ARVC/D such as the alterations of mechanical and electrical properties that can lead to life-threatening arrhythmias and sudden cardiac death. Typical ultrastructural features of ARVC/D are represented by intracellular lipid droplets and IDs abnormalities, consisting of decreased desmosome number and increased desmosome length, pale desmosomes and abnormal small junctions, and intercellular gap widening in the absence of convolution. These ultrastructural features, together with the growing evidence of desmosome protein-encoding genes mutations, are consistent with a cell-to-cell junction car-diomyopathy. Whether these abnormalities are present in concealed forms as an early diagnostic marker remains to be elucidated in prospective electron microscopy studies. However, at present, we cannot recommend electron microscopy for routine diagnostic purposes.

In summary, based upon our ultrastructural findings and on experimental studies [19,43,44], we believe that disruption of desmosomal integrity is the primum movens leading to the onset of ARVC/D, which results in defective mechanical linkage between myocytes and in abnormal localization of cell-cell adhesion junction proteins with possible subsequent transcriptional changes of related genes and secondary remodeling of gap junctions.We suggest that these defects in the desmosomal "final common pathway" might lead to the ARVC/D phe-notype including cell death, fibrogenesis, adipogen-esis, and arrhythmias.

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