the Role of cArdiac Inflammation, endoThelial Dysfunction, and FIbrosis in fabrY Disease

Fabry disease is a rare X-linked lysosomal disorder affecting 1:58,000 in the Danish population (males 1:85,000; females 1:44,000) \[1\]. A mutation in the gene encoding the enzyme alpha-gal A, an essential enzyme in normal lysosomal function, causes progressive cellular accumulation of the glycosphingolipids, especially globotriaosylceramide (Gb3). This leads to a severe disruption of cellular function. Men with a classic phenotype present with no or very low alpha-gal A-activity and develop early multi-organ involvement, especially renal and cardiac disease, resulting in a severely impaired prognosis \[2\]. However, both men and women can be affected in the presence of a disease-bearing mutation \[2,3\]. Females and men with a non-classic phenotype can also present with early organ involvement. However, their presentation is often more heterogeneous. While the classic male phenotype evidently need early initiation of therapy, the need of treatment is less clear in females and in males with a non-classic phenotype \[3\]. Furthermore, the incidence of new genetic variants of uncertain clinical significance, possibly indicating a Fabry diagnosis, has increased due to the general implementation of genetic screening programs \[4-6\]. At present, approximately 100 patients in Denmark are diagnosed with a disease-bearing mutation and followed at the Danish National Fabry Centre at Copenhagen University Hospital - Rigshospitalet. The continuing clinical challenge of who will need and when to initiate treatment necessitates close monitoring of patients at risk and, thus, a continued search for precise, reliable methods able to detect early cardiac involvement. Early initiation of therapy prior to the full manifestation of Fabry disease has shown to impede progression while evidence suggests a late initiation of treatment has reduced effects \[7-10\], further stressing the importance of early detection of Fabry cardiomyopathy and thus, early initiation of treatment.

Cardiomyopathy in Fabry disease In Fabry disease, the complication of greatest prognostic impact is cardiac manifestations, herein including arrhythmias, heart failure and cardiac death \[2,3,11\]. Although, the progressive deposition of Gb3 accounts for a maximum of 5% of total cardiac volume \[12-14\], a disproportionate cardiomyocyte hypertrophy, coronary wall thickening and endothelial dysfunction have been noted as general findings \[12-14\]. Indeed, left ventricular hypertrophy (LVH) has long been a hallmark of Fabry cardiomyopathy \[15\], however, the disproportionate relationship between a relatively small accumulation of Gb3 and the clinical cardiac manifestation of pronounced LVH has led to the proposal of the accumulation of Gb3 per se causes an early disruption of cellular function by pathways involving oxidative stress and inflammation \[14-18\]. The stress induced by Gb3 is believed to exacerbate left ventricular mass increase, cellular apoptosis, and cause the irreversible substitution of functioning tissue with reparative fibrosis. A key site and mechanism of stress and perhaps an early indicator of disease may, therefore, be found investigating changes across the vascular wall. Not only does Gb3 accumulation cause structural changes \[12-14,19\], Gb3 have been shown to induce the production of reactive oxygen species (ROS) through important inflammatory pathways such as transforming growth factor (TGF) β-dependent signaling, a key step in the Fabry-related vasculopathy preceding fibrosis \[18\]. The early structural changes in the endothelium might, therefore, tie directly to early and detrimental dysfunction \[18,19\].