title: Vasculopathy in patients with Fabry disease: current controversies and research directions.
abstract: Fabry disease is an X-linked lysosomal storage disorder due to deficiency of the enzyme alpha-galactosidase A. The principal clinical manifestations of Fabry disease consist of cardiovascular complications including cerebrovascular, renal and cardiac disease but the pathophysiology of this specific vasculopathy is unclear. With the development of targeted treatment for Fabry disease, i.e. enzyme replacement therapy, it has become apparent that the removal of stored glycosphingolipid from the endothelial cells does not prevent progression of vascular disease in many patients. The aim of this study is to review the current available literature on vascular function tests, imaging and pathology studies and propose a hypothesis on the evolution of arterial complications in Fabry disease. Clearly, although premature atherosclerosis is suggested to occur, most studies describe absence of characteristic plaque formation. Smooth muscle cell hypertrophy, is probably the earliest feature of a complex vasculopathy, as in females and atypical cardiac variants, who have residual enzyme activity, no endothelial storage of significance is found. Subsequently, processes occur as observed in neo intima formation however with formation of more fibrotic structures. In the presence of a hyperdynamic circulation in combination with a less compliant vascular wall, it is hypothesized that upregulation of local renin angiotensine systems may occur. Angiotensin II is known to increase adhesion molecules, cytokines and chemokines and exerts a pro-inflammatory effect on leucocytes, endothelial cells and vascular smooth muscle cells. This enhances release of pro-thrombotic factors and opposes actions mediated through angiotensin 2 (AT2) receptor, including the release of nitric oxide (NO). A combination of reduced vascular compliance and activation of pro-thrombotic factors can lead to vascular complications in Fabry disease.
authors.affiliation: Department of Endocrinology and Metabolism, Academic Medical Center, Amsterdam, The Netherlands.
authors.forename: S M
authors.initials: SM
authors.lastname: Rombach
authors.forename: Th B
authors.initials: TB
authors.lastname: Twickler
authors.forename: J M F G
authors.initials: JM
authors.lastname: Aerts
authors.forename: G E
authors.initials: GE
authors.lastname: Linthorst
authors.forename: F A
authors.initials: FA
authors.lastname: Wijburg
authors.forename: C E M
authors.initials: CE
authors.lastname: Hollak
mesh_terms: D000328:Adult; D000368:Aged; D035843:Biomedical Research / Q000639:trends*; D001808:Blood Vessels / Q000473:pathology*; D003952:Diagnostic Imaging; D004727:Endothelium / Q000473:pathology; D000795:Fabry Disease / Q000150:complications* / Q000175:diagnosis / Q000473:pathology*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D010641:Phenotype; D013927:Thrombosis / Q000150:complications / Q000473:pathology