10 Chapter 1 General introduction Background Fabry disease (FD) is a rare, inherited, slowly progressive X-linked lysosomal storage disorder (OMIM 301500). The worldwide prevalence is estimated at 1:40,000 to 1:117,000 in males [1]. The substantial disparity in the reported disease prevalence may be explained by variations in the definition of FD, which in some studies individuals with non-pathogenic variants or variants of unknown significance in the GLA gene are classified as having FD [2]. Mutations in the galactosidase alpha gene (GLA) are the primary cause of FD, leading to a decreased activity of the lysosomal enzyme alpha-galactosidase A (AGAL) (enzyme commission no.3.2.1.22) [3, 4]. This results in intracellular accumulation of the enzymes’ main substrate, globotriaosylceramide (Gb3) in various organs, including the vascular endothelium, kidneys, brain, peripheral nerves and heart [5-8]. Several processes may be set into motion by the increasing cellular accumulation of Gb3 and its derivative Globotriaosylsphingosine (lysoGb3), that ultimate lead to organ damage. Cardiac involvement is common in FD and can manifest as left ventricular hypertrophy (LVH) and myocardial interstitial fibrosis formation. During adulthood, symptomatic cardiac disease in the form of conduction abnormalities, arrhythmias, ischemic heart disease and heart failure may arise, ultimately leading to cardiac death in many patients [9]. Alterations in electrophysiological markers and cardiac morphology and function precede the development of clinical heart disease. Currently, the knowledge on the course of these changes and in which patients do they arise is lacking. Also, data on the age of occurrence, the progression rate and how these clinical markers are linked to clinical outcomes is limited. The main goal of this thesis is to study the cardiac manifestations of FD, the course of cardiac disease as reflected in electrophysiological and echocardiographic features in men and women with FD throughout adult life, and how they differ from the healthy population. Pathophysiology of cardiac involvement in FD Gb3 accumulates in all cardiac cell types and tissues, including myocytes, endothelial and smooth muscle cells of intramyocardial vessels and conduction tissue [10, 11]. Although Gb3 is expected to have direct toxic effects, secondary alterations of cellular processes in response to accumulation of storage material are likely to have significant pathological consequences. This theory was supported by the finding that only 1-2% of the left ventricle volume consisted Gb3 in post-autopsy cardiac material from FD patients [12]. Moreover, despite Gb3 clearance from the vascular endothelium, many patients still develop organ-
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