40 Chapter 2 entire cohort of 213, 19 patients (including the 5 patients described above) had an ICD implanted. The total time the 19 ICDs were in situ was 71 years (range 0.1-9.3 years per patient). Myocardial infarction MI occurred in 22 patients. MI event rate was 5.2 in men with classical FD, 3.1 in women with classical FD and 3.4 in men with non-classical FD. The median eventfree survival was not significantly different between the 3 affected patient groups, although the KM curves do show a similar pattern as seen for the other cardiac events (figure 4D, supplemental figure 6). A classical phenotype increased the risk of MI, but this effect did not hold after correcting for multiple testing (table 3). Group comparisons showed no significant differences in the HRs between the patient groups (table 4). For further MI classification see supplemental table 3. Cardiovascular risk factors (obesity, smoking, hypertension, dyslipidemia and diabetes mellitus) in patients suffering an MI were present in 4 out of 8 men with classical FD (data not available for 2 patients), 8 out of 10 women with classical FD and 4 out of 4 men with non-classical FD (data not shown). Data on other non-major cardiac events can be found in the supplemental results section. Discussion This is the first longitudinal study that describes the prevalence and timing of cardiac events in a large cohort of male and female FD patients, categorized into classical and non-classical patient groups. The results show that these sex- and phenotype-defined patient groups differ substantially in terms of their risk of major cardiac events. The risk for all events showed the same trend: highest in men with a classical FD, intermediate in women with classical and men with non-classical FD and low in women with non-classical FD. For the individual events differences between the groups were not always significant, due to the relative low event rate. In men with classical FD, events occur mainly from the fifth decade of life onwards, resulting in a reduced life expectancy (no men with classical FD in our cohort survived beyond 66 years of age). In women with classical FD and men with non-classical FD events are observed from the sixth decade onwards, with more variability regarding the age of onset. MI is the first major adverse cardiac event observed in 21/38 (55%) of patients with a MACE. Most likely, both macrovascular and microvascular coronary artery disease contribute to the development of ischemia, due to endothelial dysfunction and cardiac hypertrophy in FD [17, 27, 28]. The relative contribution of FD related endothelial pathology and hypertrophy versus that of general risk factors (e.g.
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