Retinal Hemodynamics in Early Diabetic Macular Edema

Discussion

To the best of our knowledge, this is the first study to investigate retinal arteriolar hemodynamics and relate the findings to systemic measures of control in a defined cohort of patients at increasing risk for the development of DME. The defined groups represent a relatively early form of diabetic retinopathy and are classified based on identified risk factors for the development of DME. Bidirectional laser Doppler velocimetry combined with a simultaneous measurement of vessel diameter is the only method to truly quantify volumetric blood flow in absolute units. This new technique has provided valuable insight into the early hemodynamic disturbances in diabetic retinopathy (20,29–31). This study characterizes early retinal hemodynamic disturbances and systemic correlates in diabetic patients with increasing risk for the development of DME.

In our cohort, we found a clear increase in the maximum-to-minimum velocity ratio with increasing risk for the development of DME. Groups 3 and 4, those with visible retinopathy and macular edema, respectively, had significantly higher maximum-to-minimum velocity ratios compared with normal control subjects. The univariate correlations of systolic and diastolic blood pressure, IOP, serum potassium, and pulse rate on the maximum-to-minimum velocity ratio were not apparent in a multivariate analysis. However, age and duration of diabetes remained significantly related to the maximum-to-minimum velocity ratio using multivariate analysis. Although age and duration of disease are often correlated to each other, they were not in our cohort of patients, which supports their independent relation to the maximum-to-minimum velocity ratio. The positive correlations of maximum-to-minimum velocity ratio to age and duration of diabetes suggest a loss of compliance of the arterial circulation. The site of the decreased compliance could be up- or downstream from the point of retinal hemodynamic assessment. Work is currently being undertaken in our lab to determine whether the increase of vessel rigidity is at the point of measurement of retinal hemodynamics. With decreased compliance of the arterial circulation, an increase in the pulsatility of blood is expected due to a lack of dampening of the pulse wave. An effect of increased arterial rigidity with diabetes, hypertension, and age is well documented in the macrovasculature (32–35), with possible resulting detrimental effects on the retinal microvasculature.^[36–39]

One previous study^[20] using laser Doppler velocimetry in a small number of subjects showed an increase in the maximum-to-minimum velocity ratio with increasing severity of retinopathy, although there was a decrease in the maximum-to-minimum velocity ratio compared with control subjects. A more recent study^[40] in patients with age-related macular degeneration showed a clear increase in the maximum-to-minimum velocity ratio with increasing disease severity. It was also shown that the maximum-to-minimum velocity ratio was decreased after panretinal photocoagulation, suggesting that an increased maximum-to-minimum velocity ratio was detrimental in the progression to proliferative retinopathy.^[41] Using Doppler sonography, Kawagishi et al.^[42] found an increase in resistance index in the central retinal artery of patients with type 1 diabetes before the development of retinopathy. It was hypothesized that the increased resistance index resulted from a combination of increased vessel rigidity and peripheral vascular resistance. However, Dimitrova et al.^[43] did not find an increased resistive index in the central retinal artery in patients with progressive retinopathy using color Doppler imaging. In their relatively small sample, Dimitrova et al. found an increased resistive index in the central retinal vein only. It has been shown by Polska et al.^[44] that resistive index, as assessed by color Doppler imaging of the retrobulbar circulation, and retinal vascular resistance, as assessed by laser Doppler velocimetry, do not always correlate. In agreement with our study, Ino-ue et al.^[45] found increased pulsatility indexes in the ophthalmic artery using color Doppler imaging in patients with background and proliferative retinopathy. In animal models of diabetes, the basement membrane of both arteries and veins are thickened.^[46] This basement membrane thickening is aggravated by the presence of hypertension.^[47] An accelerated arteriosclerosis within the retinal arterioles may represent one of the earliest changes associated with the development of diabetic retinopathy.

A prevailing theory in the pathogenesis of diabetic retinopathy is that of hyperperfusion.^[16] Kohner et al.^[16] suggested that increased blood flow led to increased shear stress on the vessel wall. Support for this was found in a number of studies that showed decreased blood flow with insulin treatment to lower blood glucose^[48] and increased blood flow with advancement of retinopathy.^[20,49] However, the nature of the blood flow alteration is far from conclusive, even when only considering data published by the same authors. Grunwald et al.^[30] found no significant changes in retinal blood flow in any of his untreated diabetic groups. Others, using fluorescein angiographic techniques, have found a decrease in retinal blood flow in patients with diabetes and no retinopathy at the level of the arterioles^[14] and capillaries.^[50] Konno et al.^[51] found an initial decrease in blood flow and then an increase as duration of diabetes increased in a prospective series of patients. Our cross-sectional study showed similar nonsignificant trends (Fig. 2C). A review of the retinal hemodynamic alterations in diabetes shows much controversy, but there is some indication that retinal arterioles are dilated before visible retinopathy and that a hyperperfusion of the retina occurs.^[17] In our sample, diameter, velocity, and flow values were independently related to age. Velocity was also independently related to systolic blood pressure and mean arterial blood pressure. However, we did not find any significant alterations in retinal arteriolar diameter, velocity, or flow across the groups with respect to the development of DME. Our sample represents a relatively early stage of the pathogenesis of diabetic retinopathy due to the fact that we excluded patients with moderate-to-severe nonproliferative and proliferative retinopathy.

Our study showed that systolic blood pressure and mean arterial blood pressure were elevated in those with retinopathy and DME compared with control subjects. Duration of diabetes was longer and A1C was higher in those with retinopathy and DME compared with those without retinopathy. The effects of hypertension and elevated A1C are well-documented risk factors for the development of DME.^[52–55] Duration of diabetes is an established risk factor for retinopathy^[56,57] and more specifically for macular edema.^[52] Our study grouped patients with DME together regardless of severity, and this group clearly had decreased vascular compliance as assessed by the maximum-to-minimum velocity ratio. It is not surprising that a significant correlation exists between the maximum-to-minimum velocity ratio and duration of disease, given that macular edema occurs more frequently as the duration of disease increases. Pulse rate was elevated in all diabetic groups compared with control subjects. In the Cardiovascular Health Study^[34], elevated pulse rate was a strong predictor of aortic stiffness in men and women. Elevated pulse rates also predict incident DME, but this effect was not independent of hypertension.^[58] The urinary albumin-to-creatinine ratio was higher in those with retinopathy and DME compared with those without retinopathy. Increased urinary albumin-to-creatinine ratio with increasing risk of DME reflects a decline in renal function and a shift in the osmotic balance of blood that might favor the development of DME.^[59,60]

These results establish the baseline characteristics of a cohort of patients with diabetes at increasing risk for DME. These patients are being followed prospectively to confirm the factors that alter retinal hemodynamics and to determine the impact of changes in retinal hemodynamics in the development of DME. Cross-sectionally, we found an increase in the maximum-to-minimum velocity ratio with increasing risk of DME. This finding suggests an increase of vascular rigidity in the arterial circulation and may indicate accelerated arteriosclerosis early in the development of diabetic retinopathy.

We acknowledge the staff of the Toronto Western Hospital Eye Clinic and the Retina Research Group for their support in the recruitment and follow-up of patients. The authors thank Erin Harvey in Department of Statistics and Actuarial Science, University of Waterloo, for her assistance with the statistical analysis.

Diabetes. 2006;55(3):813-818. © 2006  American Diabetes Association, Inc.

Aspects of this work were presented at the 2004 Annual Meeting of the Association for Research in Vision and Ophthalmology.

Cite this: Retinal Hemodynamics in Early Diabetic Macular Edema - Medscape - Mar 01, 2006.