Abstract
An explanatory computational model is developed of the contiguous areas of retinal capillary loss which play a large role in diabetic maculapathy and diabetic retinal neovascularization. Strictly random leukocyte mediated capillary occlusion cannot explain the occurrence of large contiguous areas of retinal ischemia. Therefore occlusion of an individual capillary must increase the probability of occlusion of surrounding capillaries. A retinal perifoveal vascular sector as well as a peripheral retinal capillary network and a deleted hexagonal capillary network are modelled using Compucell3D. The perifoveal modelling produces a pattern of spreading capillary loss with associated macular edema. In the peripheral network, spreading ischemia results from the progressive loss of the ladder capillaries which connect peripheral arterioles and venules. System blood flow was elevated in the macular model before a later reduction in flow in cases with progression of capillary occlusions. Simulations differing only in initial vascular network structures but with identical dynamics for oxygen, growth factors and vascular occlusions, replicate key clinical observations of ischemia and macular edema in the posterior pole and ischemia in the retinal periphery. The simulation results also seem consistent with quantitative data on macular blood flow and qualitative data on venous oxygenation. One computational model applied to distinct capillary networks in different retinal regions yielded results comparable to clinical observations in those regions.
Highlights
Diabetes mellitus is a group of metabolic diseases characterized by hyperglycemia, or elevated blood glucose
Capillaries near the foveal avascular zone (FAZ) carried a relatively small blood flow, and had a higher probability of occlusion based on the assumed occlusion mechanism
This corresponds to a slight elevation of vascular endothelial growth factor (VEGF) above the basal non-diabetic state; an elevation sufficient to induce the presence of a low level of intercellular adhesion molecules (ICAMs) allowing diabetes induced leukostasis
Summary
Diabetes mellitus is a group of metabolic diseases characterized by hyperglycemia, or elevated blood glucose. By 2030, diabetes mellitus is projected to be the 7th leading cause of death worldwide [3]. Type 2 diabetes is the most common form of diabetes and includes 90% of people with diabetes worldwide Both types of diabetes produce similar complications [4]. Diabetes causes 1% of worldwide blindness and diabetic retinopathy is the leading cause of blindness in people 20–64 years of age in the U.S [4, 10]. Its early clinically visible manifestations are damage to the smallest blood vessels, the capillaries, in the retina with resultant microaneurysms, hemorrhages, edema, and nerve fiber layer infarcts [4]. The major cause of decreased visual acuity is diabetic maculopathy which reduces visual acuity largely as a consequence of macular edema, fluid accumulation in the macula due to leakage from abnormal capillaries (Fig 1A). Most affected patients will have areas of abnormal leaking capillaries with surrounding edema and adjacent areas of capillary occlusion often seen as enlargement of the foveal avascular zone (FAZ) [11,12,13,14]
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