Peripheral and cardiac determinants of exercise intolerance in classic Anderson-Fabry disease: insights from cardiopulmonary exercise testing and advanced echocardiography

Abstract Background Exercise intolerance is a common feature of Anderson-Fabry disease (AFD), but its underlying mechanisms remain incompletely understood. Methods and results We studied eighty-eight patients with classical AFD phenotype and preserved ejection fraction. Patients underwent cardiopulmonary exercise testing (CPET), lactate assessment, and advanced echocardiography including myocardial work and atrial strain analysis. Exercise tolerance was reduced across the cohort, with low peak VO2 measured as percent predicted (VO2 %predicted ) and early lactate accumulation. Peak VO2 %predicted declined with worsening left ventricular geometry. Left ventricular diastolic parameters, myocardial work efficiency, and left atrial strain were associated with exercise capacity. In multivariable analysis, left atrial conduit strain emerged as a strong independent predictor. Conclusions Skeletal muscle energetic metabolism alterations primarily drive exercise intolerance in AFD and early cardiac dysfunction, assessed by advanced echocardiography further exacerbated it.