Long-term clinical-pathologic results of enzyme replacement therapy in pre-hypertrophic Fabry disease cardiomyopathy

Background Limited ability of ERT in removing Gb-3 from cardiomyocytes is recognized for advanced FDCM. Pre-hypertrophic FDCM is believed to be cured or stabilized by ERT. However, no pathologic confirmation is available. Purpose Long-term clinical-pathologic impact of ERT on pre-hypertrophic FDCM. Methods Fifteen Fabry patients with LVMWT ≤ 10.5 mm at CMR required EMB because of angina and/or ventricular arrhythmias. EMB showed coronary small vessel disease in angina cohort and vacuoles in smooth muscle cells and cardiomyocytes around 20% of cell surface containing myelin bodies at electron microscopy. Patients received α-agalsidase in 8 and β-agalsidase in 7 cases. Both groups referred symptoms improvement except 2 patients treated with α- and β-agalsidase respectively. After ERT administration ranging from 4 and 20 years all patients had control CMR and LVEMB because of persistence of symptoms or patients enquiry on disease resolution. Results In 13 asymptomatic FDCM patients, LVMWT and LV-mass, cardiomyocyte diameter, vacuole surface/cell surface ratio and vessels remained unchanged even after 20 years observation and storage material was still present at electron microscopy. In 2 symptomatic patients, FDCM progressed with larger and more engulfed by Gb-3 myocytes being associated to myocardial virus-negative lymphocytic inflammation. Conclusions ERT stabilizes storage deposits and myocyte dimensions in 87% of patients with pre-hypertrophic FDCM. Gb-3 is never completely removed even after long-term treatment. Immune-mediated myocardial inflammation can overlap limiting ERT activity. Figure legend Long-term ERT effects on FDCM. ERT improves symptoms, stabilizes storage deposits and left ventricular mass index in 87% of patients with pre-hypertrophic FDCM. In 13% of patients there is a progression of the disease in spite of ERT, with a superimposed immune-mediated myocardial inflammation at EMB.