14 Chapter 1 the detection of glycosphingolipid accumulation even prior to the hypertrophy response [59, 61, 62]. In addition to biochemical and imaging markers, early electrocardiogram (ECG) alterations, present in the accumulation phase, have been described in the literature, of which the most important (listed from most to least common) are [24, 45, 63, 64]: - A short PR- interval and P- wave duration; - QRS- and QTc prolongation; - T- wave inversion and meeting the Sokolov-Lyon or Cornell index criteria prior to the onset of LVH on cardiovascular imaging; - Complete bundle branch block, multifocal extra systoles and atrial fibrillation. Symptomatic Fabry cardiomyopathy is characterized by diastolic dysfunction of the left ventricle with normal left ventricular ejection fraction (known as heart failure with preserved ejection fraction, HFpEF) [47, 65]. Pica et al. (2014) described in FD patients with a low T1 and a normal left ventricular mass (suggestive of the accumulation phase), several early LV diastolic function alterations, including an aberrant global longitudinal strain (GLS), higher ratio of early diastolic mitral inflow velocity/ early diastolic septal tissue mitral annulus velocity (E/e’) and a larger left atrial volume index (LAVI) [61]. Abnormal GLS and E/e’ values were associated with the development of adverse cardiac events later on in the disease development [65, 66]. 2. The hypertrophy and fibrosis phase: as Gb3 accumulation progresses, the myocardium will exhibit LVH with interstitial fibrosis formation, detectable by late gadolinium enhancement (LGE) on CMR. The median age at which FD patients develop these features is 40 years for men and 50 years for women (no distinction was made between classical and non-classical patients) [67]. Interestingly, 25% of women with FD without LVH still develop myocardial fibrosis, while fibrosis in men always occurs in the presence of LVH [68]. In other conditions that can lead to cardiac hypertrophy (e.g., aortic stenosis and other genetic hypertrophic cardiomyopathies), sex differences in ventricular hypertrophy are observed, with males again having a greater tendency to develop LVH, thus this sex effect appears to be independent of the underlying pathology [69, 70]. For the FD population, this would mean that 1) the current reference values are too insensitive for the detection of mildly elevated left ventricular mass in women [71] or 2) that we should look for morphological markers of cardiac involvement other than LVH in females with FD. At this disease stage, plasma troponin and N-terminal pro b- type natriuretic peptide (NT-proBNP) also rise and levels are associated with increases in left ventricular mass and the presence of fibrosis. In addition ECG abnormalities, most likely related to LVH and fibrosis, increase (left axis deviation,
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