185 Summary and general discussion The study also aimed to describe the effect of sex and disease phenotype on the occurrence of cardiac events in FD. The risk of major adverse cardiovascular events (MACE) differed significantly between the patient groups classified by phenotype and sex. The risk for developing a MACE was, as expected, the greatest for men with classical FD, intermediate in women with classical FD and men with non- classical FD and even absent in women with non-classical FD. Of note, none of the patients in the latter group developed a MACE. Interestingly, heart failure (HF), not sudden cardiac death, as was indicated in earlier studies, was most often identified as cause of death (42% of all deaths). More than half of the patients who developed sustained ventricular arrhythmias did so in the context of either a ‘structurally’ damaged myocardium (after myocardial infarction) or evident HF. These findings shed new light on the cardiac course of FD within different phenotypes and emphasize the need for diagnostic and therapeutic strategies to detect and treat HF in FD patients. In chapter 3, we sought to identify electrocardiogram (ECG) markers that reflect early cardiac manifestations of FD and markers of disease progression. A total of 1,995 ECGs from 133 patients with classical FD (80% treated with Enzyme replacement therapy (ERT)), spanning 20 years of follow-up, were compared to ECGs from 3,893 apparently healthy individuals from the HELIUS cohort. We assessed how age, FD and sex affected seven ECG parameters (P-wave duration, PR-interval, QRS-duration, QTc, Cornell index, Spatial QRS-T angle and Frontal QRS-axis). Cornell index was greater and frontal QRS-axis more negative in FD patients than in controls before age of 40. For the other ECG parameters, in early adulthood, the rate of change, more than the absolute value, was greater in FD patients compared to controls. From the fifth decade (men) or sixth (women) onwards, absolute values for P-wave duration, QRS-duration, QTc and spatial QRS-T angle were longer and higher in FD patients than controls. The LVMi on CMR was correlated with each of the examined ECG parameters. Additionally, patients with cardiac fibrosis had a longer and higher P- wave duration, QRS-duration, QTc, Cornell index and spatial QRS-T angle than those without fibrosis. These findings demonstrate that the ECG abnormalities indicative of FD vary with age and sex, e.g. higher Cornell index in early adulthood and prolonged QRSduration in late adulthood. Tracking the rate of change in ECG parameters could be a good way to detect disease progression in early adulthood, guiding treatment initiation in those that exhibit significant ECG changes and lack alterations on conventional cardiovascular imaging. In addition, monitoring ECG changes in FD can be 6
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