198 Chapter 6 Another outcome may be that carrying a non-classical genetic GLA variant in women only increases the risk of cardiovascular complications in the presence of additional risk factors, e.g. hypertension, dyslipidemia or smoking. In that case, management of general cardiovascular risk factors, with a lower threshold for treatment compares to the general population, may be more important than FD specific treatment. This approach will hopefully prevent the over-medicalization of women with non-classical FD and reduce therapy costs considerably. Also, the lysoGb3 will help clinicians in genetic counselling and discussions about expected disease severity in offspring. Below we propose a follow-up protocol per FD patient group: Patient group Outpatient clinic visit and ECG frequency, every Cardiovascular imaging (echocardiography and CMR) frequency, every** Treated FD patients with FD specific treatment or patients in whom the cardiac disease is too extensive for FD specific treatment 1 year 3 years Untreated patients with plasma lysoGb3: 2,3-40 nmol/L 1 year 2 years, intervals may be increased if no changes are observed Untreated patients with plasma lysoGb3 < 2,3 nmol/L 3 years from age 40§ 5 years from age 50§ ** The frequency at which cardiovascular imaging evaluations are performed can be adjusted individually if there is a reason, based on ECG, medical history and laboratory tests, to carry out the examination earlier, later, or not at all. § The necessity of this recommendation will need to be reassessed once more data become available. Finally, we propose that the current guidelines should be amended to include a composite score for early cardiac disease detection, incorporating electrocardiographic parameters, echocardiographic and plasma LysoGb3. This composite score should ideally be validated for prognosticating clinically relevant cardiac disease in a second cohort of FD patients. Future perspectives An important limitation of the studies in this thesis is that the studied changes in ECG and echocardiographic markers could not predict the occurrence of major adverse cardiovascular events (MACE) because: a) for patients who were diagnosed with FD after their first MACE we did not have ECG or echocardiography data prior to this event, and b) the younger FD patients did not develop a MACE during follow-up. To provide answers to the prognostic value question even longer follow-up in larger international FD cohorts is needed, to
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