188 Chapter 6 classical FD. First, we used this basic classification for a detailed description of early and late cardiac complications of FD. Next, we looked for widely applicable and easily obtainable clinical markers to diagnose Fabry cardiomyopathy early and identify individual patients who may be at risk of developing cardiac complications. These insights may then become essential to 1) initiate early treatment so that disease progression can be halted through supportive cardiac and non-cardiac interventions (e.g. medication, cardiac implantable devices or tailored physiotherapy programs, etc.) and 2) design rational follow-up practices specific for each patient group to limit unnecessary diagnostics and interventions. Fabry cardiomyopathy and enzyme replacement therapy: knowledge gaps The heart in Fabry disease is the most uniformly affected organ amongst all phenotypes. Left ventricular hypertrophy (LVH) and myocardial fibrosis are the main signs of cardiac involvement in FD. This fibrosis nearly often develops in men with classical FD who also have developed LVH before. It is interesting to note that on cardiovascular imaging, women with classical FD can develop myocardial fibrosis without prior signs of LVH [8], making LVH a less suitable marker for an early diagnosis of Fabry cardiomyopathy in this group. The described early cardiac manifestations of FD in earlier literature includes a shortened PR- interval, higher E/e’ and LAVI [5, 6, 9]. Later on, adults may develop symptoms of cardiac disease such as conduction abnormalities, arrhythmias, ischemic heart disease and HF, which frequently result in cardiac mortality [2]. However, the course and sequence of (early) cardiac biomarkers leading to the development of these cardiac complications remained unknown. Enzyme replacement therapy (ERT) has been authorized for clinical use in patients with FD since 2001 [10]. According to the current clinical recommendations, ERT in men with classical FD (cFD) should be started at the age of 16 years, regardless of the presence of symptoms. However, given the recent insights in the effect of earlier treatment initiation, the start of ERT can be considered from 10 years onwards in male patients with cFD [11]. Thus, although there is some remaining uncertainty about the optimal timing, there is no doubt about the need for FD specific treatment in these patients. While in this group of classically affected males a protective effect on renal function is important, involvement of the kidney is much less relevant in other phenotypes [12]. For the entire cohort of Fabry patients, ERT effects are specifically relevant to improve or prevent cardiac disease. In women with cFD, initiation of ERT in the current clinical practice is contingent upon the manifestation of cardiac disease such as LVH, cardiac events, or subtle myocardial fibrosis [11, 13]. Selecting women with cFD who will benefit from receiving ERT is challenging, as some women display a cardiac disease
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