63 ECG changes in Fabry disease Introduction Fabry disease (FD) is an X-linked lysosomal storage disease with slowly progressive and highly variable clinical expression. The disorder is caused by mutations in the galactosidase alpha (GLA) gene, leading to reduced activity of the lysosomal enzyme alpha-galactosidase A. The enzymes’ substrate globotriaosylceramide (Gb3) and its derivates accumulate in various tissues and organs, including the heart [1, 2]. Over decades, lysosomal dysfunction, disturbed autophagy, inflammatory and fibrotic changes eventually lead to permanent cardiac damage [3-6]. Initially, signs of cardiac involvement may be subtle, such as a low native T1 value on cardiac magnetic resonance imaging (CMR) and a short PR-interval on ECG. At that early stage there are most often no clinical symptoms of cardiac disease and overall cardiac function on echocardiography and CMR is normal [7, 8]. At later disease stages, conduction abnormalities, overt left ventricular hypertrophy (LVH), myocardial fibrosis and eventually symptomatic cardiac disease (heart failure, arrhythmias and sudden cardiac death) occurs [9-12]. Since FD is an X-linked disorder the disease is generally more severe in men. The disease can be classified into an early onset, classical, and a lateronset, non-classical phenotype [9, 10, 13]. A recently conducted observational longitudinal cohort study in 213 FD patients confirmed the heterogeneity of cardiac disease manifestations in FD [14]. Male patients with classical FD (cFD) over the age of 45 years, invariably suffered a cardiovascular event. In contrast, only a subset of females with cFD developed cardiovascular events and with a highly variable age of onset [14]. For male patients with cFD there is no debate about the need for Fabry specific treatment and recent studies suggest that early initiation (specifically of enzyme replacement therapy (ERT) has a better effect on suppressing disease progression) [15, 16]. For women with cFD there is much more uncertainty about the need for treatment of an individual patient (since not all patients will develop complications) and even more about the optimal timing of treatment initiation. Thus, there is a need to identify female patients at risk for symptomatic cardiac disease (and thus in need of intensive monitoring) versus those who are unlikely to develop major cardiac complications. LVH on CMR is a commonly used clinical marker for presence of cardiac manifestation in FD and thus the need to initiate therapy [15]. However, in those that develop LVH this usually occurs in later stages of the disease and some female patients develop cardiac FD complications in the absence of LVH [10, 17]. Hence, identification of biomarkers (other than age, sex and left ventricular mass) that can reliably detect cardiac involvement at an earlier, asymptomatic, disease 3
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