Cardiovascular comorbidities in Anderson-Fabry disease: prevalence and clinical significance

Background: Anderson–Fabry disease (AFD) is a rare X-linked lysosomal storage disorder caused by GLA gene mutations leading to α-galactosidase A deficiency. Enzyme impairment results in systemic accumulation of globotriaosylceramide and related metabolites, causing progressive multi-organ dysfunction. Cardiovascular comorbidities such as arterial hypertension, diabetes mellitus, and dyslipidaemia are major global health issues, but their prevalence and prognostic relevance in AFD remain poorly characterised. Preliminary studies suggested an increased frequency of diabetes among AFD patients, although its prognostic impact is unclear. Aim: To assess the prevalence of cardiovascular comorbidities (hypertension, diabetes, dyslipidaemia) across different AFD phenotypes and sexes, and to determine their impact on clinical outcomes beyond established prognostic indicators. Additionally, to explore the frequency and clinical significance of different diagnostic pathways. Methods: We conducted a national, longitudinal, multicentre, non-interventional observational study including adult patients (≥18 years) with confirmed AFD referred between 2002 and 2024 to ten Italian centres. Exclusion criteria were age < 18 years, likely benign GLA variants, and follow-up < 6 months. Baseline data included demographics, diagnostic pathway, phenotype (classic vs late-onset), and sex. Cardiovascular comorbidities were defined according to current guideline criteria. Echocardiographic parameters (left ventricular [LV] wall thickness, LV mass index, LV volumes and ejection fraction, diastolic indices, left atrial volume, right ventricular [RV] hypertrophy, RV area and systolic function, valvular disease, pulmonary artery systolic pressure) and laboratory markers of renal (serum creatinine, eGFR) and cardiac function (hs-cTnI/T, NT-proBNP) were collected. Cardiac involvement was classified according to the Meucci staging system. The composite endpoint included all-cause death, sustained ventricular tachycardia, aborted sudden cardiac death, ICD activation, ischaemic stroke, or transient ischaemic attack. Data were anonymised and managed through REDCap. All centres obtained local ethics approval and informed consent. Results: A total of 319 patients (median age 44 years; 42% male) were enrolled. At baseline, 78% had at least one cardiovascular risk factor, most frequently arterial hypertension (32%), dyslipidaemia (26%), and type 2 diabetes (4%). During a median follow-up of 3.3 years, 37 patients (12%) experienced the composite cardiac endpoint. Systemic hypertension and diabetes were significantly more prevalent among event-positive patients than among those without events (73% vs 26% and 19% vs 2%, respectively; both p < 0.001); 62% were in Meucci stage 3. In univariate analysis, both systemic hypertension and diabetes were strongly associated with adverse outcomes (HR 6.37, 95% CI 3.03–12.96; HR 4.76, 95% CI 2.09–10.85; p < 0.001 for both). In multivariable models, these associations remained significant, independent of cardiac stage. The combined model including Meucci stage, systemic hypertension, and diabetes showed the best predictive performance (Harrell’s C = 0.765). Moreover, patients diagnosed through cardiological or nephrological pathways exhibited a higher risk of cardiac events. Conclusions: Cardiovascular comorbidities—particularly systemic hypertension and type 2 diabetes—substantially worsen cardiac prognosis in Anderson–Fabry disease. Their coexistence with advanced myocardial involvement markedly increases the risk of adverse outcomes, underscoring the importance of early detection and optimal management of modifiable risk factors. Further pathophysiological and mechanistic studies are warranted to clarify the interplay between metabolic disturbances, vascular dysfunction, and myocardial remodelling in AFD.