Cardiovascular Morbidity and Mortality in Fabry Disease

Background: Fabry disease (FD) is a rare X-linked lysosomal storage disorder characterized by progressive multisystem involvement, among which cardiac manifestations represent the main determinant of morbidity and mortality. Despite the availability of disease-specific therapies, cardiovascular complications remain frequent and their long-term prognostic determinants are not fully defined. A comprehensive evaluation of cardiovascular outcomes in large, contemporary FD cohorts is therefore essential to improve risk stratification and guide clinical management. Methods: This multicentre, retrospective, longitudinal study included consecutively referred adult patients with a genetically confirmed diagnosis of FD from tertiary referral centres. Clinical, electrocardiographic, echocardiographic, and laboratory data were collected at baseline and during follow-up. The primary endpoint was the occurrence of major adverse cardiovascular events (MACEs), defined as a composite of cardiovascular death, major arrhythmic events, bradyarrhythmias requiring permanent pacemaker implantation, and stroke. Secondary endpoints included the individual components of the primary endpoint. Kaplan– Meier survival analysis and Cox proportional hazards models were used to assess event rates and identify independent predictors of outcomes. Results: A total of 680 patients (mean age 42.3 ± 15.9 years; 41.0% male) were included, of whom 68.7% were receiving enzyme replacement therapy or oral chaperone therapy at baseline or during follow-up. Over a median follow-up of 7.1 years (interquartile range 3.9–11.6), 92 patients (13.5%) experienced a MACE. The estimated 10-year freedom from MACE was 85.1% (95% CI 81.3–88.2) and was significantly lower in males than in females (76.1% vs. 91.3%, p < 0.001). When stratified by sex and GLA variant type, males showed similarly high event rates irrespective of classic or late-onset variants, whereas females with late-onset variants experienced a markedly lower risk compared with those carrying classic variants. 2 On multivariable analysis, increasing age (HR 1.04 per year), lower estimated glomerular filtration rate (HR 0.99 per 1 mL/min/1.73 m²), longer QRS duration (HR 1.02 per 1 ms), and higher left ventricular mass index (HR 1.01 per 1 g/m²) were independently associated with the occurrence of MACEs. Distinct predictors were identified for secondary endpoints, highlighting the heterogeneous mechanisms underlying cardiovascular death, arrhythmic events, conduction disease, and stroke in FD. Conclusions: In this large, multicentre cohort of patients with Fabry disease, cardiovascular events remained frequent despite contemporary disease-specific therapy, particularly in male patients. Simple and widely available clinical markers—such as renal function, ECG conduction parameters, and echocardiographic measures of hypertrophy—were strong and independent predictors of adverse cardiovascular outcomes. These findings underscore the persistent unmet need for improved cardiovascular risk stratification and targeted preventive strategies in Fabry disease, and support a multidisciplinary, longitudinal approach to patient management.