Abstract Background Fabry’s cardiomyopathy patients receiving enzyme replacement therapy (ERT) have no validated cardiac functional biomarkers to evaluate the effect of ERT. Purpose We aimed to investigate functional cardiac biomarkers to assess the response of ERT on the heart and to predict clinical outcomes. Methods Patients with Fabry’s disease having LV wall thickness ≥12mm were prospectively enrolled and treated with Agalsidase beta. The primary endpoint was the change of exercise peak E/e’ by diastolic stress echocardiography (DSE) during ERT; secondary endpoints were changes in conventional echo-Doppler parameters, LV global longitudinal strain (LVGLS), and diastolic reserve (DR25W) by DSE. We compared two groups (stable and progression groups) divided by LVMI change in CMR. Clinical outcomes were defined as a composite of cardiovascular death, aborted sudden cardiac death, and stroke. Results Between March 2015 and January 2021, 20 patients (mean age 46.6±12.8 years, 50.0% women) were enrolled and received Agalsidase beta during 2.0±0.9 years. 13 (65.0%) patients remained stable, and 7 (35.0%) experienced progression during ERT. The annual change of peak exercise E/e’ showed no significant differences between the two groups. However, LVGLS and diastolic reserve (DR25W) significantly improved in the stable group but not in the progression group. The annual change of LVGLS (AUC, 0.84 [95% CI, 0.64–1.00], sensitivity 57.1%, specificity 100.0%, P=0.007) and DR25W (AUC, 0.84 [95% CI, 0.63–1.00], sensitivity 71.4%, specificity 90.9%, P=0.008) had a significant predictive value for LV mass progression in ROC analysis (Figure). Kaplan-Meier analysis revealed that LV mass progression was significantly associated with poor clinical outcomes (Log-rank, P=0.014). Conclusion Cardiac functional imaging biomarkers were useful in predicting the effect of ERT in patients with Fabry’s cardiomyopathy. LV mass progression during ERT was associated with poor clinical outcomes. ROC analysis