197 Summary and general discussion The score would be based on the Z scores of various ECG and echocardiographic parameters, as determined by comparison with a reference range for an age and sex matched control group, using a cut-off of 1.5 as an example. To ensure its validity for prognostication of clinically significant cardiac disease in Fabry patients, it is recommended that the composite score be validated through application to a second cohort of patients with FD. An important area of further research as well is that the investigated ECG and echo markers in this thesis usually remain within standard reference limits, which are the same for adults of all ages. Hence we also discovered that there is a need for improved age and sex specific ECG reference values to be able to detect early changes in Fabry cardiomyopathy and other genetic cardiomyopathies [36]. Although the current thesis provides insight into which parameters can be studied to assess their predictive value for the development of Fabry cardiomyopathy, future studies should focus on developing a prediction model in which a combination of clinical and readily available imaging and electrophysiological data will predict the risk of developing ventricular arrhythmias, heart failure or cardiovascular death in FD patients. This knowledge will help clinicians make better decisions regarding the administration of ERT and future emerging therapies. Fabry cardiomyopathy: revising guidelines for follow-up Given our observations that the rate of change of ECG and echocardiographic markers is low (e.g. increase/decrease of a few milliseconds or millimeters), it is advisable to increase the intervals of cardiac imaging evaluations in order to: 1. Make more accurate statements about the manifestation and progression of cardiac disease; 2. Reduce measurement variation; and 3. Decrease unnecessary frequent examinations, which will result in lowering the pressure on potentially overloaded national healthcare systems. The frequency of ECG evaluations may be higher, as it is a relatively simple, quick and inexpensive examination that can give the clinician an impression of cardiac morphology and function dynamics. Second, assessing the ECG can be used to justify the need for supportive therapies such as the placement of a cardiac device or the intensification of cardiac imaging frequency. Further studies should formally investigate the exact cardiac course of women with non-classic FD. If this is different from the general population, these patients do not require the extensive follow-up or even specific FD treatment, including repeated cardiac imaging, that they are currently receiving. 6
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