Retinal vascular geometry and its relationships to diabetes and diabetic retinopathy

Abstract

© 2012 Dr. Sasongko, Muhammad BayuPURPOSE: Diabetic retinopathy (DR) is a major cause of visual disability worldwide. Retinal vessel diameter, measured from fundus photographs, has been shown to be predictive of DR. However, other parameters reflecting the geometry of the retinal vasculature (e.g. vessel tortuosity, branching angle) in DR are unexplored. This doctoral work presents the associations between traditional DR risk factors and retinal vascular geometry (aim 1), associations of retinal vascular geometry with DR (aim 2), and with novel markers of DR including the relative contribution of these markers and retinal vascular geometry to DR (aim 3). METHODS: This study used two specific clinical samples of children and adolescents (aged 12 to 20 years) with type 1 diabetes (N=1200) and adults (aged 18 to 70 years) with type 1 and 2 diabetes (N=244). Retinal vascular geometric parameters (tortuosity, branching angle, length to diameter ratio, optimality deviation) were measured from disc-centred fundus photographs using semi-automated computer software following standardized protocol. DR was also assessed from fundus photographs (7-field for the children sample and 2-field for the adult sample), according to modified Airlie House Classification, and categorized into mild, moderate, and vision-threatening DR (VTDR, including severe non-proliferative and proliferative DR, with or without clinically significant macular oedema). Detailed clinical characteristics (e.g. duration of diabetes, blood pressure, body mass index [BMI], the use of insulin and other medications, history of cardiovascular or other diseases) were obtained via interview with a specific questionnaire and clinical examinations. Traditional and novel biomarkers were assessed from fasting blood sample, including concurrent HbA1c level, fasting blood glucose, cholesterol and other lipid profiles, serum creatinine, apolipoprotein (Apo) AI and B, high sensitivity C-reactive proteins [CRP], soluble e-selectin, inter-cellular adhesion molecule-1 [ICAM-1], vascular adhesion molecule-1 [VCAM-1], total nitrite, and endothelin-1 [ET-1] levels. Measures of dynamic retinal and skin microvascular function were also obtained using dynamic retinal vessel analyser and skin iontophoresis. Associations of traditional and novel risk factors with retinal vascular geometry were assessed using analysis of covariance and generalized linear models. Associations of retinal vascular geometry with DR and DR severity were assessed using binary, ordinal, and multinomial logistic regression models. RESULTS: Aim 1: Associations between traditional DR risk factors and retinal vascular geometry Longer diabetes duration was associated with larger arteriolar branching angle and increased arteriolar optimality deviation; higher HbA1c was associated with increased arteriolar tortuosity; higher SBP was associated with decreased arteriolar LDR; and higher total cholesterol levels was associated with increased arteriolar LDR and decreased venular optimality deviation in the children sample. In the adult sample, longer diabetes duration was associated with increased arteriolar tortuosity. Aim 2: Associations of retinal vascular geometry with DR DR was present in 170 (18%) of the children, and in 114 (44%) of the adults. Retinal arteriolar tortuosity showed significant associations with DR, in both children (odds ratio [OR] 1.42, 95% confidence interval [CI] 1.11 – 1.83; P=0.005; per standard deviation [SD] increase in arteriolar tortuosity) and adults (OR for mild DR 1.53, 1.03 – 2.05; P=0.014; OR for moderate DR 1.67, 1.10 – 2.55; P=0.016; per SD increase). Aim 3: Associations of novel markers for DR with retinal vascular geometry and the relative contribution of retinal vascular geometry to DR Among the adults, ApoAI level was inversely associated with DR (OR 0.76, 95% CI 0.59–0.98; per SD increase), while ApoB and ApoB/AI (OR 1.31, 1.02–1.68 and OR 1.48, 1.13–1.95; per SD increase in ApoB and ApoB/AI respectively) were positively associated with DR. Increasing CRP levels were positively associated only with the presence of VTDR (OR 1.38, 1.07–1.68, per SD increase), which was more pronounced in subjects with BMI≥30 kg/m2 (OR 2.9; P=0.019 for interaction). Per SD increase in ApoAI level was inversely (mean difference in arteriolar tortuosity -2.83 x 10-5 ; P=0.044), while ApoB was positively (mean difference 1.75 x 10-5; P=0.050) associated with arteriolar tortuosity. Reduced flicker-light induced retinal vasodilation was related to more tortuous arterioles and venules (mean difference in arteriolar tortuosity 5.62 x 10-5, 4.50 – 6.72 x 10-5; P<0.001 and in venules 5.94 x 10-5, 3.33 – 8.55 x 10-5; P<0.001; comparing highest vs. lowest tertile of flicker-light vasodilation). Finally, diabetes duration contributed the most (51%) to the risk of DR, followed by ApoAI (16%), SBP (13%), retinal arteriolar tortuosity (8%), and flicker-light induced venular and arteriolar dilation (3% and 0.5% respectively). CONCLUSIONS: Key diabetes-related factors (e.g. duration of diabetes, HbA1c level) are associated with retinal microvascular geometry, mainly arteriolar tortuosity. In line with this, increased arteriolar tortuosity is also consistently associated with early stages of DR in both study samples. Furthermore, we demonstrate relationships between retinal arteriolar tortuosity and a number of novel risk markers for DR found in this study (serum ApoAI and ApoB) and also to novel markers for DR found in other studies (flicker-light induced retinal vascular function). Retinal arteriolar tortuosity and ApoAI is shown to have considerable contribution to DR risk and substantially improved the clinical performance of DR prediction model in terms of the specificity, independent of traditional risk markers. These findings provide novel evidence that variations in retinal vascular tortuosity may be markers of diabetes-related vascular damage due to adverse exposure of diabetic milieu, reflecting increased person’s susceptibility to DR