Fabry Cardiomyopathy: Myocardial Fibrosis, Inflammation, and Down-Regulation of Mannose-6-Phosphate Receptors Cause Low Accessibility to Enzyme Replacement Therapy.

Background: The clinical impact of enzyme replacement therapy on advanced Fabry disease cardiomyopathy appears to be limited. The pathologic mechanisms involved are still unclear.

Methods And Results: Ten male patients with advanced Fabry disease cardiomyopathy on enzyme replacement therapy, whose disease progressed from maximal wall thickness of 15.4±2.2 to 19.3±2.1 mm in 8.6±1.4 years of follow-up, underwent left ventricular endomyocardial biopsy before and 4 hours after β-agalsidase infusion (1 mg/kg). Comparative studies between pre- and postinfusion samples included the following: histology, electron microscopy and assessment of myocardial α-galactosidase A activity; immunohistochemistry for α-galactosidase A and semiquantitative evaluation (from 0 to 3) of its cardiomyocyte content; and ultrastructural immunogold analysis with anti-α-galactosidase A ab; and Western blot quantification of mannose-6-phosphate receptors. Controls were surgical biopsies from patients with mitral stenosis. Histologic and ultrastructural evaluation showed myocarditis in 7 of 10 patients, There was no removal of storage material while myocardial fibrosis was 9.8%±6.8% versus 3.8%±2.0% of controls. At ultrastructural immunogold analysis, myocardial α-galactosidase A activity increased in postinfusion samples by overall 1.89-fold. Alpha-galactosidase A immunostaining in cardiomyocytes was absent at baseline in all patients and did not significantly improve in postinfusion samples. Immunogold particles increased by 1.33-fold (17.6±3.6 preinfusion versus 21.5±5.9 postinfusion), remaining far from normal controls (86.9±6.6). Protein analysis showed mannose-6-phosphate receptors to be 81% lower than in a normal heart.

Conclusions: In spite of enzyme delivery to cardiac tissue, our study shows a low accessibility to enzyme replacement therapy of cardiomyocytes affected by advanced Fabry disease cardiomyopathy. It is sustained by myocardial fibrosis, inflammation, and severe down-regulation of mannose-6-phosphate receptors.