Aqueous levels of angiopoietin-like 4 and semaphorin 3e correlate with nonperfusion area and macular volume in diabetic retinopathy

Objective To investigate the aqueous levels of angiopoietin-like 4 (ANGPTL4), semaphorin 3E (Sema3E), and vascular endothelial growth factor (VEGF) in patients with diabetic retinopathy and to ascertain their association with diabetic retinopathy phenotypes. Design Prospective, nonrandomized, comparative case series. Participants Of all 104 consecutive patients (104 eyes) who had intravitreal anti-VEGF injections from April 2012 through April 2013 for diabetic macular edema (DME), 51 had severe nonproliferative diabetic retinopathy (NPDR) and 53 had proliferative diabetic retinopathy (PDR). The controls were 54 consecutive nondiabetic patients who had undergone cataract surgery (54 eyes) during the same period. Methods The ANGPTL4, Sema3E, and VEGF levels in aqueous humor samples obtained before intravitreal injections were measured by enzyme-linked immunosorbent assay. Capillary nonperfusion area (NPA) was calculated from encircled angiography using the 7 standard field images described in the Early Treatment Diabetic Retinopathy Study protocol. Total macular volume (TMV) was measured by spectral-domain optical coherence tomography. Main Outcome Measures Aqueous ANGPTL4, Sema3E, and VEGF levels in severe NPDR, PDR, and control groups and their correlations with each other, NPA, and TMV. Results The severe NPDR and PDR groups had higher aqueous levels of ANGPTL4 and VEGF than the control group (all P < 0.001). The PDR group had higher ANGPTL4 and VEGF levels than the severe NPDR group (both P < 0.001). The aqueous ANGPTL4 levels of all diabetic retinopathy patients correlated positively with NPA (r = 0.820, P = 0.003) and TMV (r = 0.824, P < 0.001). The control group had higher aqueous Sema3E levels than the NPDR and PDR groups (both P < 0.001). Aqueous Sema3E levels correlated negatively with VEGF levels in all subjects (r = -0.57, P = 0.025). Conclusions The ANGPTL4 may be a candidate target in DME treatment and a biomarker of ischemic-induced retinopathy, including diabetic retinopathy.