187 Summary and general discussion usefulness as an individual disease trait. The strongest association observed, was that between plasma lysoGb3 levels and the LVMi on the echocardiogram. The association of plasma lysoGb3 with echocardiographic markers of diastolic (dys)function (RWT, LAVI, Septal e’ and E/e’) was a novel finding. This is particularly relevant since diastolic dysfunction is the major contributor to HF in FD, which we showed to be the leading cause of death in FD patients (this thesis- Chapter 2). Higher plasma lysoGb3 levels were associated with a greater LAVI. For RWT, septal e’ and E/e’, there was a significant association for absolute levels, but no difference was found in slope over time. These results indicate that lysoGb3 does not only have a relationship with altered cardiac morphology (LVMi) but also with cardiac function. Additionally, the plasma lysoGb3 was closely related to markers of renal and cerebral disease. We may conclude that measuring lysoGb3 at the time of diagnosis gives information into the expected natural cardiac and non-cardiac disease course, facilitating rational treatment and follow-up protocols in FD patients. General discussion Fabry cardiomyopathy, towards early diagnosis and rational follow-up The disease course in patients with FD is very heterogeneous. Studies conducted by our team and others have shown significant differences in age at symptom onset and disease progression between men and women and patients with classical and non-classical FD [1-3]. The X-linked inheritance and the variety in mutation severity can account for, at least a large part, of this heterogeneity. Since the disease can also differ between male members of the same family, other factors, such as genetic, epigenetic or environmental factors, must be at play as well [4]. To be able to understand the natural history and the effect of interventions it is crucial to establish criteria to separate particular FD phenotypes with comparable symptoms and severity. Even though there seems to be consensus regarding the criteria used to distinguish the classical and non-classical (sometimes referred to as cardiac variant or late onset) FD phenotypes, many authors still report on FD cohorts as a single patient group [5-7]. This makes the interpretation of treatment outcome data almost impossible, since the difference in symptom free survival between male FD patients with classical FD and non-classically affected males or classically affected females on average is 10 years [1, 2]. We strongly believe that a minimum requirement for FD cohort studies is to optimize the classification between classical and non-classical disease and to distinguish between sexes. Only when this is performed properly, new markers can come and would enable a further differentiation between patients. Thus, in all studies performed within this thesis we consistently distinguished between the sexes and between classical and non6
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