Arterial and Venous Density during Early NPDR by Fractal Dimension: Association with Loss of Protective RAS

Abstract

Purpose : Vascular damage and altered repair are implicated in the pathogenesis of diabetic retinopathy (DR). The renin-angiotensin system (RAS) has been associated with accelerated vascular damage and altered repair, and specifically with the dysfunction of circulating angiogenic cells (CACs), a critical bone marrow-derived population involved in vascular remodeling. For this prospective study, we are testing the hypothesis that retinal vascular density increases during early-stage nonproliferative DR (NPDR), based on previous results from a small retrospective study (IOVS 51(1):498).

Methods : Vascular patterns were extracted from Heidelberg Spectralis^® FA-OCT images of 13 control, 7 mild NPDR and 5 moderate NPDR retinas as a significant study expansion beyond the ARVO 2016 report. Automated unsupervised (image segmentation) and supervised (e.g., deep learning) machine learning methods are replacing previous semi-automated vessel extraction. Vascular branching was mapped and quantified by NASA’s VESsel GENeration Analysis (VESGEN) software that includes calculation of the fractal dimension (D_f) from skeletonized vascular images by the box-counting method. D_f, a sensitive measure of vascular space-filling pattern, varies between the limiting Euclidean dimensions of 1 and 2. For this NPDR cohort, we assessed changes in the migratory function of CACs and gene expression of Mas, the receptor for Ang-(1-7) and a key component of vascular-protective RAS, to determine whether changes were associated with retinal vascular remodeling.

Results : By D_f (mean ± SD), venous and arterial densities were 1.37 ± 0.02 and 1.32 ± 0.03 for mild NPDR, and 1.37 ± 0.02 and 1.33 ± 0.03 for moderate NPDR, compared to 1.32 ± 0.02 and 1.31 ± 0.03 for controls. A significant increase in veins and lesser increase in arteries during early NPDR is demonstrated. Migratory dysfunction of CACs correlated with severity of DR. Compared to controls, Mas receptor mRNA in CACs of diabetics without DR was increased. However, levels were reduced with NPDR onset, indicating possible loss of compensation of protective RAS in early DR.

Conclusions : As assessed by the fractal dimension, the space-filling capacity of both veins and arteries was greater in early NPDR than in controls. Results suggest that loss of the protective RAS axis within diabetic CACs is associated with increased vascular damage and remodeling during DR.

This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.