28 Chapter 2 Ethics The Medical Ethics Review Committee of the AUMC confirmed that the Medical Research Involving Human Subjects Act (WMO) does not apply to this study (W19-438 # 19.505), because of the retrospective character of this study, using historical data obtained in context of regular patient care. The study was conducted in accordance with the Declaration of Helsinki. Data collection Patients were divided into 4 groups: men with classical FD, men with nonclassical FD, women with classical FD and women with non-classical FD, based on the presence of classical FD symptoms (cornea verticillata, acroparesthesia or angiokeratoma), family history or known mutation-phenotype associations (men and women) and biomarkers and residual alpha-galactosidase A activity (men) [24] (see figure 1 for details). Patients attended the clinic for standardized follow-up visits. Between September 2018 and January 2019, all available patients charts, clinical letters, cardiac imaging reports from birth until the last outpatient clinic visit were investigated to record the following events: cardiovascular death (CVD), HF hospitalization, sustained ventricular arrhythmias (SVA), myocardial infarction (MI), CA, pacemaker or implantable cardiac defibrillator (ICD) implantation, atrial fibrillation (AF), coronary artery disease (CAD), percutaneous coronary intervention (PCI), coronary artery bypass graft (CABG) surgery, systolic dysfunction on cardiac MRI or if unavailable on echocardiography, left ventricular outflow tract (LVOT) obstruction, moderate or severe valve disease and other heart surgery/intervention. The combined endpoint major adverse cardiovascular event (MACE) was defined as the occurrence of at least one of the following events: CVD, HF hospitalization, SVA or MI. SVA included sudden cardiac death (SCD), sudden cardiac arrest, sustained ventricular tachycardia lasting >30 sec, appropriate ICD shock, and ventricular fibrillation. CA were defined as a composite of second-degree atrioventricular block type II, third- degree atrioventricular block, sinusarrest and device implantation for CA. Endpoint definitions are provided in supplemental table 1. Events were adjudicated by a panel of experts consisting of 2 cardiologists (AH and SMB) and 1 metabolic specialist (ML). Statistical analysis For all cardiac events, the event rate per 1000 patient-years was calculated in order to correct for unequal follow-up duration between the different patient groups. The corresponding 95% confidence intervals (CI) were reported for both individual and composite cardiac events, using the Mid-P exact test (table 2, supplemental table 2). For the event rates calculation, follow-up duration from
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