Pathophysiology of Geographic Atrophy in AMD: Role of Choroidal Vascular Dropout

Abstract

Purpose : Geographic atrophy (GA) is a severe, blinding complication of age-related macular degeneration. The pathogenesis of GA is incompletely understood. While photoreceptor cells, RPE and choriocapillaris all degenerate in GA, the health of the choroid in GA eyes has not been comprehensively examined. In this report we evaluated the vascular density of the choroid in both human donor eyes and in patients with GA, and assessed a marker of hypoxia in the retina as a function of choroidal vascularity.

Methods : Macular sections were collected from human donor eyes and were labeled with the UEA-I lectin to quantify the vascular endothelium of the choroid. Eyes with GA (n = 11 eyes from 11 donors) or non-GA eyes (n = 25 eyes from 20 donors) were assessed. Choriocapillaris density, choroidal area, and vascular lumen cross sectional areas were determined, and the ratio of lumen to total area was determined as a single value for each eye. Five living patients with GA and 4 controls were similarly evaluated using three-dimensional SD OCT analysis, in which the areas of non-reflective choroidal large vessel volumes were measured and divided by the entire choroidal volume to generate the lumen to stroma ratio. Eyes with varying choriocapillaris densities were employed for retinal VEGF ELISA analysis.

Results : The lumen to stroma ratio did not differ significantly in healthy eyes with the thickest and thinnest choroids (p=0.49). GA eyes, however, showed significantly reduced lumen to stroma ratios compared to controls (0.19 vs. 0.28, corrected p<0.05). The lumen to stroma ratio was also lower in living GA patients (0.13, 95%CI 0.12–0.14) than controls (0.27, 95%CI, 0.25–0.29). Histologically, GA eyes also showed significant loss of choriocapillaris (corrected p<0.01) especially in regions of RPE degeneration (p<0.05). In ELISA analyses, retinas overlying choroids with degenerative choriocapillaris showed upregulated VEGF protein (r2 for trend = 0.66).

Conclusions : The choroid undergoes thinning during normal aging with consistent ratios of choroidal vasculature to total area. In GA, vascular loss occurs in both large vessels and in the choriocapillaris. This vascular dropout is associated with increased VEGF synthesis in the overlying retina, consistent with ischemic injury. Protecting the choroid from vascular loss may be an important avenue for treatment and prevention of GA.

This is an abstract that was submitted for the 2016 ARVO Annual Meeting, held in Seattle, Wash., May 1-5, 2016.

 

Example of vascular quantification.