General Introduction and Thesis Outline | 11 Figure 1. The cardiac desmosome The cardiac desmosome provides mechanical cell-cell contact by connecting the cytoskeletons between cardiac myocytes. The encoded proteins (genes) associated with ARVC are divided into desmosomal (the most common being Plakophilin-2, or PKP2) and non-desmosomal proteins (for instance Phospholamban, or PLN). Pathophysiology The exact pathophysiological mechanism of ARVC is still a matter of debate. Besides the characteristic histopathologic pattern of fibrofatty replacement of myocardium, patchy inflammatory infiltrates are often observed in association with dying myocytes, suggesting that the pathologic process may be immunologically mediated. Wall thinning and aneurysmal dilatation are typically localized in the inflow tract (subtricuspid region) and outflow tract (infundibular region) of the RV.3 While the initial report of ARVC described the RV apex as typical localization for disease manifestation, more recent data showed that the apex is only involved in end-stage disease. On the other hand, the revised “triangle of dysplasia” includes the posterolateral wall of the LV as early affected region.8 It is thought that genetically abnormal desmosomes lead to disruption of intercellular junctions with myocyte detachment and cell death. This process of mechanical uncoupling occurs in reaction to mechanical wall stress and is aggravated by for instance physical exercise.9 The fibrofatty tissue that replaces myocardium forms a substrate for ventricular arrhythmias by slowing intra-ventricular conduction and through scar-related macro-reentry circuits, similar to that in myocardial infarction. Besides mechanical coupling, the desmosome also plays a crucial role in electrical coupling of cardiomyocytes by interacting with gap junctions and the sodium channel complex within the intercalated disc.10 Complex mechanisms operating at this molecular and cellular level may also contribute to occurrence of life-threatening ventricular arrhythmias in ARVC. Clinical presentation The estimated prevalence of ARVC is around 1:2000 to 1:5000 in the general population.9 Inheritance is characterized by incomplete penetrance and varying disease expression. There is age-related penetrance, whereby patients typically become symptomatic between the second and fourth decade of life.6 Clinical presentation of ARVC is variable and may include palpitations, exercise-induced (pre-)syncope, chest pain, and dyspnea. However, life-threatening arrhythmias 1
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