13 General introduction and thesis outline be aimed at identifying cardiac involvement at an earlier stage of the disease, so that timely preventive therapy can be started. Currently, the most commonly used treatment is enzyme replacement therapy (ERT), which was introduced in 2001 [49]. ERT is an expensive and burdensome treatment. As such, being able to identify which patient needs treatment and at what time point in the development of FD manifestations is essential. These therapy initiation decisions are especially relevant in patients with non-classical FD and women with classical FD given the high disease heterogeneity in these patient groups, as only a subset of patients develops cardiovascular events with a highly variable age of onset [26, 28]. An increasing number of studies showed that initiation of Fabry specific treatment when there is myocardial fibrosis, impaired cardiac function or when clinical complications have already occurred, is less effective in preventing the progression of heart disease compared to earlier treatment initiation [5052]. These findings emphasize the need for identification of cardiac disease markers indicative of early cardiac involvement, at a stage in which structural changes of the heart have not yet occurred. In addition, knowledge of the cardiac disease course may be helpful in monitoring whether or not the progression of FD cardiomyopathy is halted by new FD-specific therapies [53]. The following description is a hypothesized three-stage model for the development of Fabry cardiomyopathy, based on the available literature, emphasizing potential biochemical, electrophysiological and echocardiographic biomarkers. However, this model is mainly based on historical cross-sectional data, where the distinction between classical and non-classical FD is not always made. 1. The accumulation phase: sphingolipids (particularly Gb3) accumulate in the cardiac tissue but clinical signs of cardiac disease are not yet present [11, 54, 55]. At which age this cardiac accumulation starts is unknown, as the youngest patient who underwent an endomyocardial biopsy published in literature was 17 years old [15]. Although the primary substrate of AGAL is Gb3, and it seems obvious that Gb3 could serve as a potential biomarker, Gb3 is often not elevated in men with non-classical FD and women with classical FD, even though these patients may develop significant cardiac pathology [56]. In contrast to Gb3, plasma concentrations of lysoGb3, are increased in all patients with FD and are stable throughout life in an untreated patient (chapter 5) and have a clear correlation with (cardiac) disease severity [25, 57, 58]. Endomyocardial biopsies are too invasive in clinical settings for patients to be used to detect early cardiac involvement. A low native T1 value on cardiac MRI (CMR) is likely a manifestation of myocardial sphingolipid overload [59, 60]. Studies correlating the low T1 values on CMR with the degree of Gb3 accumulation in histopathological examinations are lacking. Low T1 values are found in FD patients, in presence but also in absence of LVH, suggesting 1
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