133 Echocardiographic changes in Fabry disease relevance as a marker of myocardial dysfunction in FD. IVSd, RWT and E/e’ at baseline were associated with the development of atrial fibrillation later on, showing the relationship of these markers to the development of clinical cardiac disease. It is possible to use the HRs of the Cox regression analysis to estimate the risk of developing AF per decade for each patient subgroup (supplemental table 4). For example, IVSd increases by 1.8 mm per decade in men with FD (table 2), which means that the atrial fibrillation HR for this increase is 1.6 (exp(1.8*0.27)). In addition to evaluating single values of these three parameters, progression over time can also be useful to determine which patients are at risk for the development of clinical cardiac disease later on (see figure 1 and supplemental figure 2). This is especially relevant in female patients, since in contrast to male classical FD patients, they do not all develop symptomatic disease and thus not always require treatment [6, 8]. The European Fabry Working Group recommends starting ERT with an IVSd above 12 mm in women with classical FD [31]. The current study shows that that threshold, based on general reference values, is reached relatively late in the disease development in many women (see figure 2B). Yet when female patients were compared to aged matched control subjects, much lower values for IVSd were significantly different, at a much younger age (figure 2B). In addition, not only abnormal values for IVSd, but also for RWT, as well as the rate of change for LVMi, LAVI and E/e’ (if longitudinal data are available) can be used to detect early cardiac disease development. We therefore suggest to amend the guideline, using a composite score for early cardiac disease, based on the Z scores of the Fabry patients for each parameter when compared to the reference range of the age and sex matched control group (choosing a cut off of for example plus or minus 1.5). In addition to the Z scores for the echocardiography markers, those for ECG parameters could also be included [32]. This composite score should ideally be validated as valid for prognostication of clinically relevant cardiac disease in a second FD patient cohort. The first limitation of the current study is the fact that the data presented in this study come from patients treated with enzyme replacement therapy (92% of the cohort) for at least a part of the follow- up. Though there is clear progression of cardiac disease in this cohort, this may only partially represent the natural disease course. Because of the wide range in patient ages and disease stage at which ERT was initiated in the current patient cohort, the effect of early treatment with ERT cannot be assessed using this data set. However, the current dataset provides a good benchmark for future therapy assessment, for both earlier (e.g. during adolescence) initiation of current therapies in those at risk, as well as for new therapies. One of the major problems with evaluating the effect of treatment on cardiac manifestations in FD is that cardiac complications (e.g. arrhythmia, heart failure) occur relatively late in the disease course. In men with classical FD 4
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