15 General introduction and thesis outline T-wave inversion and pronounced LVH voltage criteria) [67]. Besides the aforementioned echocardiographic features, HFpEF patients without FD often have elevated Tricuspid regurgitant jet velocity (TR velocity) [72]. However, this marker was found to be normal in a smaller study, including FD patients [73]. 3. The heart failure phase: as the disease progresses, myocardial fibrosis will expand throughout the heart, and the hypertrophic heart tissue will be partly replaced by atrophic tissue with further rising of the plasma troponin and NT-proBNP [67]. Secondary to the extensive cardiac fibrosis, ST-segment alterations [74] and ultimately ventricular arrhythmias [46] can occur. Endstage diastolic heart failure as well as systolic left ventricular dysfunction occur during this stage [65], with heart failure being the most common cause of death [75]. Aims and outline The above mentioned sequence of events is hypothetical and, as said, based primarily on cross- sectional studies describing the cardiac manifestations of FD. Hence the precise longitudinal course of Fabry cardiomyopathy in patient groups stratified by sex and disease phenotype has not been documented. Studying the progression of Fabry cardiomyopathy is crucial for early diagnosis and establishing rational group-specific follow-up protocols to detect complications, but also prevent over- medicalizing patients. The Amsterdam University Medical Centre (AUMC), the national referral centre for patients with FD in the Netherlands has a longitudinal clinical dataset and biobank, which are unique in both their size and the length of systematic follow-up of patients, providing detailed clinical data. To this end, we performed several longitudinal studies at the AUMC, aiming to: 1) Map the course of cardiac manifestations of FD, from pre-symptomatic phase through to complication development, in different FD patient groups (men and women, patients with classical and non-classical FD). 2) Detect electrophysiological, imaging and biochemical characteristics of FD that precede deterioration of cardiac function to be able to detect early cardiac involvement. In Chapter 2, we describe the effect of disease phenotype and sex on the occurrence of cardiac events in FD. In Chapter 3, the evolution of ECG parameters in a large population of adults with classical FD are assessed and compared to those of apparently healthy control subjects. Chapter 4 reports on the development of morphological and functional echocardiographic features 1
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