Intraepidermal nerve fiber density as a predictor of cardiac events in Fabry disease

Anderson-Fabry disease (FD) is a rare lysosomal storage disorder with multi-organ involvement. Cardiac manifestations are the major determinant of prognosis, yet reliable predictors of disease progression are lacking. Small fiber neuropathy can emerge in various aetiologies of hypertrophic cardiomyopathy, but its correlation remains unclear. Intraepidermal nerve fiber density (IENFD) from skin punch biopsy provides an established tool of measuring small fiber dysfunction. Clinically, we observed that FD patients with severe cardiac phenotypes often show markedly reduced IENFD without presentation of typical neurological symptoms matching small fiber neuropathy.

FD patients with available skin biopsy samples evaluated between 2006 and 2022 were included. Patients were divided by median IENFD for clinical evaluation. Subsequent subgroup analysis for two predefined cardiac endpoints (development of late gadolinium enhancement (LGE) on cardiac MRI and cardiac device implantation) were done. Multivariable Cox regression analysis assessed the prognostic value of IENFD. A total of 170 patients (47% men) were analysed. Median IENFD was 3.8 fibers/mm. Patients with reduced IENFD showed more frequent cardiac (85% vs. 41%), renal (54% vs. 21%), and cerebrovascular (27% vs. 7%) involvement (all P < 0.001). FD cardiomyopathy was more advanced in those with low IENFD (IVSd: 12.5 ± 3.3 vs. 9.6 ± 2.3 mm, P < 0.001). In the conducted subgroup analysis IENFD < 4.2 fibers/mm independently predicted LGE (HR: 5.26, 95% CI: 1.53-18.06, P = 0.008, n = 55 patients included), while IENFD < 1 fiber/mm predicted device implantation (HR: 3.72, 95% CI: 1.00-13.78, P = 0.05, n = 124 patients included).

IENFD was identified as independent risk factor for developing two major cardiac endpoints (LGE in MRI/device implantation) associated with poor cardiac outcome in FD.

NCT03362164.