10 | Chapter 1 INTRODUCTION Sudden cardiac death (SCD) resulting from cardiac arrest represents a major public health concern worldwide, accounting for an estimated 15-20% of all deaths.1 Particularly in young, seemingly healthy individuals, it is an event with devastating impact. Families and physicians are left with many unanswered questions: Did we miss any signs? Could it have been prevented? And who else is at risk? It was estimated that in the Netherlands, every three days an individual below the age of 40 dies of SCD.2 While in older patients coronary artery disease is the most common cause of SCD, typical causes in the young are congenital heart disease, heritable electrical disease and heritable cardiomyopathy. Arrhythmogenic right ventricular cardiomyopathy (ARVC), subject of a large part of this thesis, is a relatively common cause of SCD within the latter category. However, both at autopsy and in survivors of sudden cardiac arrest, a substantial amount of cardiac arrests remains unexplained. When no underlying cause is identified after extensive diagnostic testing, patients are diagnosed with idiopathic ventricular fibrillation. This subset of patients is subject of the addendum of this thesis. Arrhythmogenic Right Ventricular Cardiomyopathy ARVC is a genetic cardiomyopathy which is characterized by progressive loss of primarily right ventricular myocardium and its substitution by fibrous and fatty tissue.3 Over the years, several terms were introduced related to this disease. The original term, arrhythmogenic right ventricular dysplasia, refers to the developmental disorder (“dysplasia”) that this disease was thought to be at the time. Later, ARVD was recognized as a progressive disease which develops after birth (“cardiomyopathy”) and after a transition period with the term ARVD/C, it was replaced with ARVC. While the classical and most comprehensively described phenotype primarily affects the right ventricle (RV), a proportion of patients has predominant LV disease. In recent years, the term arrhythmogenic cardiomyopathy (AC) was introduced to cover the whole spectrum of biventricular involvement. In this thesis, the terms AC and ARVC are used interchangeably, but focus is on the classical predominant RV phenotype. Genetic background Early observations of familial disease clustering suggested a genetic basis for ARVC. The Greek physician couple Nikos Protonotarios and Adalena Tsatsopoulou recognized that individuals on the Greek island of Naxos had a form of ARVC in conjunction with a cardiocutaneous syndrome (wooly hair and palmoplantar keratosis).4 In 2000, genetic linkage analysis of patients with socalled Naxos disease started an important breakthrough in defining the genetic background of ARVC.5 The typical phenotype is explained by similar junction structures in myocardial and epidermal tissue. Genetic variants in the gene encoding for plakoglobin were the first disease causing genetic variants identified in patients with ARVC. Plakoglobin is a component of the cardiac desmosome, which is responsible for cell-to-cell adhesion of cardiomyocytes (Figure 1). In subsequent years, more desmosomal variants were linked to ARVC and nowadays likely- (pathogenic) variants are identified in the majority of patients. Most of these disease causing variants in ARVC are inherited in an autosomal dominant pattern. Currently, the most common ARVC-associated gene is plakophilin-2 (PKP2), which was identified in about half of the ARVC patients in the Netherlands and the USA.6 However, also genetic variants in non-desmosomal proteins can cause ARVC, suggesting other pathogenic mechanisms in a final common pathway leading to myocardial fibrosis, fat infiltration and ventricular arrhythmias.7
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