Cardiopulmonary exercise test and stress echocardiography in Fabry cardiomyopathy: insights into functional impairment and risk stratification

Background: Cardiopulmonary exercise testing (CPET) evaluates the severity, functional limitations, and risk of heart failure in hypertrophic cardiomyopathy (HCM). It is also used to distinguish HCM from other forms of cardiac hypertrophy, including Anderson-Fabry disease (AFD). In AFD, exercise intolerance may result from multiple systemic factors such as cardiomyopathy, endothelial dysfunction, anaemia, or mitochondrial impairment. However, data on the application of CPET in AFD remain limited. Objective: To compare functional capacity and exercise-induced cardiopulmonary responses between patients with AFD and those with HCM. Methods: We prospectively studied 25 treatment-naïve patients with AFD and cardiac involvement, and 25 patients with non-obstructive HCM matched for age, sex, and cardiovascular risk factors. All subjects underwent CPET with integrated stress echocardiography. Echocardiographic parameters were assessed at rest and peak exercise, and and pulmonary function tests (FVC, FEV₁, MVV) were performed to exclude ventilatory limitations Results: AFD patients had lower peak VO₂ (19.8 vs 21.7 ml/min/kg, p=0.03), earlier anaerobic threshold (p=0.001), higher VE/VCO₂ slope (p=0.017), and greater breathing reserve (p=0.03), despite preserved pulmonary function. Echocardiographically, AFD patients showed lower maximal wall thickness (p=0.01), lower E/e′ at rest and peak (p=0.041 and p=0.004), higher pulmonary artery systolic pressure (PASP) at rest and peak (p=0.017 and p=0.022), and reduced TAPSE/PASP ratio at peak (p=0.026). Conclusions: Although AFD patients presented with less pronounced myocardial hypertrophy compared to HCM, they exhibited significantly greater functional impairment. These findings suggest that exercise intolerance in AFD may be primarily driven by systemic and vascular factors rather than by the degree of cardiac hypertrophy. CPET integrated with stress echocardiography may represent a valuable tool for identifying early extracardiac limitations and stratifying risk in Fabry cardiomyopathy.