Differentiating Microaneurysm Pathophysiology in Diabetic Retinopathy Through Objective Analysis of Capillary Nonperfusion, Inflammation and Pericytes

Microaneurysms are biomarkers of microvascular injury in diabetic retinopathy (DR). Impaired retinal capillary perfusion is a critical pathogenic mechanism in the development of microvascular abnormalities. Targeting fundamental molecular disturbances due to capillary nonperfusion, such as increased vascular endothelial growth factor expression, does not always reverse the anatomic complications of DR suggesting that other pathogenic mechanisms independent of perfusion also play a role. We stratify the effects of capillary nonperfusion, inflammation and pericyte loss on microaneurysm size and leakage in DR through three-dimensional analysis of 636 microaneurysms using high-resolution confocal scanning-laser microscopy. Capillary nonperfusion, pericyte loss and inflammatory cells were found to be independent predictors of microaneurysm size. Nonperfusion alone without pericyte loss or inflammation was not a significant predictor of microaneurysm leakage. Microaneurysms found in regions without nonperfusion were significantly smaller than those found in regions with nonperfusion, and their size was not associated with pericyte loss or inflammation. In addition, microaneurysm size was a significant predictor of leakage in regions with nonperfusion only. This report refines our understanding of the disparate pathophysiologic mechanisms in DR and provides a histologic rationale for understanding treatment failure of microvascular complications in DR.