Altered Functionality of Lipoprotein(a) Impacts on Angiogenesis in Diabetic Retinopathy.

Purpose: Diabetic retinopathy (DR) is a complication of type 2 diabetes mellitus (T2DM). Lipoprotein(a) (Lp(a)) contributes to the progression of DR, but how is unclear. In homeostasis of the retinal microvasculature, myeloid-derived pro-angiogenic cells (PACs) also play a pivotal role, and fail to function properly in diabetic conditions. Here, we explored the putative contribution of Lp(a) from patients with T2DM with/without DR and healthy controls on inflammation and angiogenesis of retinal endothelial cells (RECs), and on PAC differentiation. Subsequently, we compared the lipid composition of Lp(a) from patients to that from healthy controls. Methods: Lp(a)/LDL obtained from patients and healthy controls were added to TNF-alpha-activated RECs. Expression of VCAM-1/ICAM-1 was measured using flowcytometry. Angiogenesis was determined in REC-pericyte co-cultures stimulated by pro-angiogenic growth factors. PAC differentiation from peripheral blood mononuclear cells was determined by measuring expression of PAC markers. The lipoprotein lipid composition was quantified using detailed lipidomics analysis. Results: Lp(a) from patients with DR (DR-Lp(a)) failed to block TNF-alpha-induced expression of VCAM-1/ICAM-1 in REC whereas Lp(a) from healthy controls (healthy control [HC]-Lp(a)) did. DR-Lp(a) increased REC angiogenesis more than HC-Lp(a) did. Lp(a) from patients without DR showed intermediate profiles. HC-Lp(a) reduced the expression of CD16 and CD105 in PAC, but T2DM-Lp(a) did not. Phosphatidylethanolamine content was lower in T2DM-Lp(a) than in HC-Lp(a). Conclusions: DR-Lp(a) does not show the anti-inflammatory capacity seen with HC-Lp(a), but increases REC angiogenesis, and affects PAC differentiation less than HC-Lp(a). These functional differences in Lp(a) in T2DM-related retinopathy are associated with alterations in the lipid composition as compared to healthy conditions.

Intra- and Intergrader Agreement for Detection of OCT Angiographic Characteristics Associated With Type 3 Neovascularization.

Purpose: To examine the intra- and intergrader agreement on morphologic characteristics of type 3 neovascularization on optical coherence tomography angiography (OCT-A). Methods: OCT-A images of 22 eyes from 21 patients with a new-onset, treatment-naive type 3 neovascularization were included in this cross-sectional retrospective agreement study. Each image was graded three times by two independent medical retina specialists to assess intra- and intergrader agreement. The graders scored the presence or absence of the following vascular and structural features: intraretinal neovascularization (IRN), subretinal neovascularization, sub-retinal pigment epithelium (RPE) neovascularization (SRPEN), retinal choroidal anastomosis (RCA), intraretinal cysts, subretinal fluid, and pigment epithelial detachment. Agreement was analyzed for each feature using Gwet's AC1, к statistics, and percentage of agreement. Results: The best agreement (AC1) was found for intraretinal neovascularization (withingrader1: 0.94; withingrader2: 0.93 and between: 1.00) and intraretinal cysts (withingrader1, 1.00; withingrader2, 0.97 and between, 1.00). The poorest intragrader agreements were observed for SRPEN (withingrader1, 0.54 and withingrader2, 0.36) and RCA (withingrader1, 0.45 and withingrader2, 0.52), and the poorest intergrader agreement was found for SRPEN, RCA, and pigment epithelial detachment (0.18, 0.37, and 0.15, respectively). Conclusions: Although the agreement values were high for intraretinal features, considerable grader variability was found for the vascular and structural features in the deeper retina or under the RPE. Clinicians should be careful to base therapeutic decisions on qualitative OCT-A assessment, because even well-trained specialists show a considerable grader variation in their subjective evaluation. Translational Relevance: The clinical value of OCT-A imaging largely depends on the agreement of subjective evaluations by ophthalmologists.

Detailed optical coherence tomography angiographic short-term response of type 3 neovascularization to combined treatment with photodynamic therapy and intravitreal bevacizumab.

PURPOSE: To explore the short-term vascular and structural changes of type 3 neovascularization using optical coherence tomography angiography (OCT-A) when treated with a combination of photodynamic therapy (PDT) and intravitreal bevacizumab (IVB), and to evaluate the course of different sequences of the combined therapies. METHODS: Thirty eyes of 29 treatment-naïve patients with a type 3 neovascularization were included in this prospective observational cohort study. They were all treated with PDT and IVB 2 weeks apart, starting either with PDT (PDT-first group) or IVB (IVB-first group). Optical coherence tomography angiography (OCT-A) imaging was performed at week 0, 2, 4 and 18, and best corrected visual acuity (BCVA) at week 0 and 18. Vascular, structural and functional features were graded and analysed over time. RESULTS: In all patients, at all follow-up visits, vascular and structural features were significantly more often decreased or resolved than unchanged or increased. Best corrected visual acuity (BCVA) significantly improved at 18 weeks. Vascular, structural and functional outcomes were all slightly better in the PDT-first group compared to the IVB-first group, although not statistically significant. CONCLUSION: Combined treatment of PDT and IVB is effective in short-term for type 3 neovascularization based on vascular and structural features. Initial treatment with PDT tended to be more effective than with IVB.