41 Cardiac outcomes in Fabry disease smoking) cannot easily be determined, given that the majority of patients had cardiovascular risk factors at the time of MI. Importantly, none of the women with non-classical FD developed a MACE. This variation means that if “cardiac events” is a clinical endpoint in a FD treatment study, men with classical FD should be treated as a separate group, from women with classical FD and men with non-classical FD, and women with non-classical FD should not be included at all. This also means that results from previous clinical trials, in which phenotypic distinction was not made, should be interpreted with caution. Fabry cardiomyopathy is associated with a risk of sudden cardiac death (SCD) and in advanced disease ICD implantation should be considered [15, 29] . The most frequently observed cause of death in the current study was heart failure (42% of all deaths), whereas SCD comprised 17% of all deaths. This finding is in contrast with a recent meta-analysis of Baig et al., that identified SCD as the most common cause of death (62% of all deaths). However, the context of SCD and the Fabry disease phenotype of the included patients were not clear for most studies included in this meta-analysis. In addition, most included studies were performed in small cohorts, with relatively short follow-up duration. In our FD patient cohort SVA rate was low and more than half of the patients developed their first event in the context of either an MI or HF (hospitalization or ejection fraction <35%). An earlier study of Vijapurapu et al. (2019) reported a higher event rate in FD patients with an ICD, however sex and phenotype distribution in this group was not reported. Large multicenter cohort studies are needed to develop a FD SCD risk calculator to guide ICD implantation decision making. Our findings, if confirmed in other longitudinal cohort studies, may change decision-making regarding ICD implantation policy in FD. With the knowledge that HF is the main contributor to death in FD, future studies should aim to detect and treat HF in a much earlier phase of the disease. This highlights the urgent need for biomarkers that predict future development of HF, separating low and high-risk patients, as clearly not all women with classical FD and men with non-classical FD develop HF. A limitation of the current study is its retrospective design, which may lead to under-recording and subsequent underestimation of the event risk, even though we accessed historical files for the majority of patients. Nevertheless, we cannot rule out that for some deceased patients, especially those who died over a decade ago, some cardiac events may have been missed. In addition, the reported age of onset of cardiac manifestations such as systolic dysfunction, LVOT obstruction and heart valve disease depends on the time at which imaging was performed 2
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