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.