Arrhythmogenic remodeling of the intercalated disk

Abstract

Several structures present in the intercalated disk at the longitudinal ends of the cardiomyocytes are important for propagation of the electrical impulse. Gap junctions, of which Connexin43 (Cx43) is the most important protein in the ventricle, ensure electrical coupling between the cardiomyocytes. Mechanical connection between the cells at the site of the intercalated disk is maintained by desmosomes. Furthermore, the cardiac sodium channel (NaV1.5) ensures excitability of the cells. Obviously, disturbances in expression or function of these structures can decrease cell-cell coupling and thereby smooth conduction, which can lead to severe cardiac arrhythmias. Arrhythmogenic Cardiomyopathy (AC) is a progressive cardiac disease characterized by electrical and structural degeneration, predominantly of the right ventricle, which may eventually also affect the left ventricle and interventricular septum. Patients present with syncope, palpitations, and sudden cardiac death. 60% of the AC cases is associated with mutations in the genes encoding for desmosomal proteins: Plakophilin2 (PKP2), Plakoglobin (PKG), Desmoplakin (DSP), Desmocollin2 (DSC2) and/or Desmoglein2 (DSG2). Prevalence of the disease is 1:2000-1:5000, however (early) diagnosis of the disease is difficult, so many cases can be un- or misdiagnosed. Diagnosis is based on to the revised Task Force Criteria, which are based on global or regional dysfunction and structural alterations, tissue characterization of the ventricular wall, re- and depolarization or conduction abnormalities, arrhythmias, and family history. We have shown in mice that extreme reduction in electrical coupling (Cx43) leads to reduced and heterogeneous NaV1.5 expression and that a 50% reduction of PKP2 leads to reduced excitability but not to decreased electrical coupling. Previous studies have shown that a 50% reduction of NaV1.5 in mice did not cause decreased electrical coupling. Furthermore, a 50% reduction in Cx43 did only slightly reduce conduction velocity, which indicates that probably NaV1.5 was not affected. Influence of disturbances in the mechanical coupling appears to be largest of the three: extreme disturbances of the desmosome lead to reduction in both electrical coupling and excitability, while milder reductions still affect the sodium channel. Disturbances in electrical coupling, however, can induce changes in excitability in extreme cases, but the effect is less pronounced in milder cases while it does not seem to affect mechanical connection. Finally a reduction in excitability of the cell will have less effect on electrical coupling or mechanical connection, but excitability is always affected when one of the other components change. If reductions are relatively small, conduction reserve prevents development of an arrhythmogenic substrate. We have seen various effects of AC on desmosomal protein, NaV1.5, and Cx43 expression and distribution patterns. Penetrance of the disease is not similar in patients with the same mutation, even within a family and also AC patients without identified mutations are described. Probably, external or additional triggers, being genetic background and/or environmental factors, are necessary in that case to induce arrhythmias. Future studies are needed to study the existence and effects of these triggers and to uncover currently unidentified players that participate in the molecular substrate underlying AC.