Hemma Resch

Reduced response of retinal vessel diameters to flicker stimulation in patients with diabetes

Background/aim: Stimulation of the retina with flickering light increases retinal arterial and venous diameters in animals and humans, indicating a tight coupling between neural activity and blood flow. The aim of the present study was to investigate whether this response is altered in patients with insulin dependent diabetes mellitus. Methods: 26 patients with diabetes mellitus with no or mild non-proliferative retinopathy and 26 age and sex matched healthy volunteers were included in the study. Retinal vessel diameters were measured continuously with the Zeiss retinal vessel analyser. During these measurements three episodes of square wave flicker stimulation periods (16, 32, and 64 seconds; 8 Hz) were applied through the illumination pathway of the vessel analyser. Results: In retinal arteries, the response to stimulation with diffuse luminance flicker was significantly diminished in diabetic patients compared to healthy volunteers (ANOVA, p<0.0031). In non-diabetic controls flicker stimulation increased retinal arterial diameters by +1.6% (1.8%) (mean, p<0.001 v baseline), +2.8% (SD 2.2%) (p<0.001) and +2.8% (1.6%) (p<0.001) during 16, 32, and 64 seconds of flicker stimulation, respectively. In diabetic patients flicker had no effect on arterial vessel diameters: +0.1% (3.1%) (16 seconds, p = 0.9), +1.1% (2.7%) (32 seconds, p = 0.07), +1.0% (2.8%) (64 seconds, p = 0.1). In retinal veins, the response to flicker light was not significantly different in both groups. Retinal venous vessel diameters increased by +0.7% (1.6%) (16 seconds, p<0.05), +1.9% (2.3%) (32 seconds, p<0.001) and 1.7% (1.8%) (64 seconds, p<0.001) in controls during flicker stimulation. Again, no increase was observed in the patients group: +0.6% (2.4%), +0.5% (1.5%), and +1.2% (3.1%) (16, 32, and 64 seconds, respectively). Conclusion: Flicker responses of retinal arteries and veins are abnormally reduced in patients with IDDM with no or mild non-proliferative retinopathy. Whether this diminished response can be attributed to altered retinal vascular reactivity or to decreased neural activity has yet to be clarified.

Endothelial dysfunction in glaucoma

Glaucoma is a group of ocular diseases characterized by optic neuropathy associated with loss of the retinal nerve fibre layer and re‐modelling of the optic nerve head, and a subsequent particular pattern of visual field loss. Increased intraocular pressure is the most important risk factor for the disease, but the pathogenesis of glaucoma is not monofactorial. Among other factors, ischaemia and vascular dysregulation have been implicated in the mechanisms underlying glaucoma. The vascular endothelium plays an important role in the regulation of ocular blood flow and pathological alterations of vascular endothelial cells may induce ischaemia and dysregulation. The present review summarizes our current evidence of endothelial dysfunction in glaucoma. This is of interest because endothelial dysfunction is a good prognostic factor for progression in several diseases. Although such data are lacking for glaucoma, endothelial dysfunction may provide an attractive target for therapeutic intervention in open‐angle glaucoma and other vascular disorders of the eye.

Response of Retinal Vessel Diameters to Flicker Stimulation in Patients with Early Open Angle Glaucoma

Introduction:Diffuse luminance flicker increases retinal vessel diameters in animals and humans, indicating the ability of the retina to adapt to different metabolic demands. The current study seeks to clarify whether flicker-induced vasodilatation of retinal vessels is diminished in glaucoma patients. Methods:Thirty-one patients with early stage glaucoma (washout for antiglaucoma medication) and 31 age- and sex- matched healthy volunteers were included in the study. Retinal vessel diameters were measured continuously with a Retinal Vessel Analyzer. During these measurements three episodes of square wave flicker stimulation periods (16, 32, and 64 secs; 8 Hz) were applied through the illumination pathway of the retinal vessel analyser. Results:Flicker-induced vasodilatation in retinal veins was significantly diminished in glaucoma patients as compared with healthy volunteers (ANOVA, P < 0.01). In healthy volunteers, retinal venous vessel diameters increased by 1.1 ± 1.8% (16 seconds, P < 0.001), 2.0 ± 2.6 (32 seconds, P < 0.001), and 2.1 ± 2.1% (64 seconds, P < 0.001) during flicker stimulation. In glaucoma patients, venous vessel diameters increased by 0.2 ± 1.7% (16 seconds, P < 0.6), 1.1 ± 2.1% (32 seconds, P < 0.01), and 0.8 ± 2.5 (64 seconds, P < 0.09). In retinal arteries, no significant difference in flicker response was noticed between the two groups (ANOVA, P < 0.6). In healthy controls, flicker stimulation increased retinal arterial vessel diameters by 1.0 ± 2.4% (P < 0.03), 1.6 ± 3.2% (P < 0.004) and 2.4 ± 2.6% (P < 0.001) during 16, 32, and 64 seconds of flicker, respectively. In glaucoma patients, flickering light changed arterial vessel diameters by 0.3 ± 2.6% (16 seconds, P = 0.4), 1.3 ± 3.1% (32 seconds, P = 0.03), and 1.8 ± 3.8% (64 seconds, P = 0.005). Conclusion:Flicker-induced vasodilatation of retinal veins is significantly diminished in patients with glaucoma compared with healthy volunteers. This indicates that regulation of retinal vascular tone is impaired in patients with early glaucoma, independently of antiglaucoma medication.

Estimation of Ocular Rigidity Based on Measurement of Pulse Amplitude Using Pneumotonometry and Fundus Pulse Using Laser Interferometry in Glaucoma

PURPOSE There is evidence from theoretical models and animal studies that the biomechanical properties of the optic nerve head and the sclera play a role in the pathophysiology of glaucoma. There are, however, only a few data available that demonstrate such biomechanical alterations in vivo. In this study, the hypothesis was that patients with primary open-angle glaucoma (POAG) have an abnormal ocular structural stiffness based on measurements of intraocular pressure amplitude and ocular fundus pulsation amplitude (FPA). METHODS Seventy patients with POAG and 70 healthy control subjects matched for age, sex, intraocular pressure and systemic blood pressure were included. The ocular PA and pulsatile ocular blood flow were assessed with pneumotonometry. The FPA was measured by using laser interferometry. Based on the Friedenwald equation, a coefficient of ocular rigidity (E1) was calculated relating PA to FPA. RESULTS There was no difference in systemic blood pressure, intraocular pressure, and ocular perfusion pressure (OPP) between the patients with glaucoma and the healthy control subjects. Both, FPA and PA were lower in the patients with glaucoma than in the control subjects. The calculated factor E1 was significantly higher in the patients with POAG (0.0454 +/- 0.0085 AU) than in the control subjects (0.0427 +/- 0.0058 AU, P = 0.03). Multiple regression analysis revealed that E1 was independent of age and sex, and correlated only slightly with OPP. CONCLUSIONS The present study indicates increased ocular rigidity in patients with POAG. This is compatible with a number of previous animal experiments and supports the concepts that the biomechanical properties of ocular tissues play a role in the diseases process.

Reduced Retinal Vessel Response to Flicker Stimulation but Not to Exogenous Nitric Oxide in Type 1 Diabetes

PURPOSE Various studies have shown that retinal vessels in patients with diabetes mellitus have a reduced capacity to adapt to changes in perfusion pressure and to stimulation with flickering light. Structural and functional changes in retinal vessels in diabetes could lead to a general reduction of vasodilator and/or vasoconstrictor capacity. To gain more insight into this topic, we compared the response of retinal vessel diameters to systemic glyceryl trinitrate (GTN) and stimulation with diffuse luminance flicker in patients with diabetes and healthy control subjects. METHODS Twenty patients with type 1 diabetes mellitus featuring no or mild nonproliferative diabetic retinopathy and 20 healthy, age-matched subjects were included in this study. A vessel analyzer was used for measurement of diameters of retinal arteries and veins. The response of diameters was measured continuously during stimulation with flickering light, as well as immediately after sublingual application of 0.8 mg GTN. RESULTS The response of retinal vessels to flickering light was significantly reduced in the patients with diabetes (arteries: 2.9% in diabetes versus 7.0% in control subjects, P < 0.002; veins: 4.6% in diabetes versus 6.8% in control subjects, P = 0.020). GTN-induced vasodilatation was not different between the patients with diabetes and the healthy control subjects (P >or= 0.70). CONCLUSIONS The present study confirmed reduced response of retinal vessels to stimulation with flickering light in diabetes. The response of retinal vessels to a direct NO-donor, however, was maintained. This result indicates that abnormal flicker-induced vasodilatation in diabetes is not a consequence of generally reduced retinal vascular reactivity (ClinicalTrials.gov number, NCT00432029).

Effect of Dual Endothelin Receptor Blockade on Ocular Blood Flow in Patients with Glaucoma and Healthy Subjects

PURPOSE Several lines of evidence indicate that altered blood flow regulation may contribute to the pathogenesis of glaucomatous optic neuropathy. Recent data support the hypothesis that the endothelin system is involved in the processes that lead to vascular dysregulation in glaucoma. This study was conducted to test the hypothesis that bosentan, a dual endothelin receptor antagonist, increases ocular blood flow in patients with glaucoma. METHODS Fourteen patients with primary open-angle glaucoma and 14 sex- and age-matched healthy volunteers were included. Both groups received bosentan 500 mg daily for 8 days. Ocular hemodynamics were assessed at baseline and on the last study day. Retinal vessel diameters and retinal red blood cell velocity were recorded with a retinal vessel analyser and laser Doppler velocimetry, respectively. Choroidal and optic nerve head blood flow were measured with laser Doppler flowmetry. RESULTS Retinal arteries and veins showed a significant dilatation after administration of bosentan in both groups (+5%-8%). Retinal blood velocity and retinal blood flow increased up to +45% after administration of bosentan in both patients and healthy subjects. Administration of bosentan increased choroidal (+12%-17%) and optic nerve head blood flow (+11%-24%) in both groups. The effect of bosentan on ocular blood flow parameters was comparable between the two groups. CONCLUSIONS The data from the present study indicate that dual inhibition of endothelin receptors increases ocular blood flow in patients with glaucoma and healthy subjects. Further studies are needed to study the dose-response relationship of this effect and to characterize the role of endothelin receptor subtypes.

Effect of regular smoking on flicker induced retinal vasodilatation in healthy subjects.

BACKGROUND Habitual smoking is a risk factor for a variety of vascular diseases, including ocular pathologies. In the current study, we set out to investigate whether the regulation of retinal vascular tone is impaired in habitual smokers. For this purpose, vascular reactivity was tested during flicker light induced vasodilatation in smokers and in a non-smoking control group. METHODS In this prospective, balanced, parallel group study 24 chronic smokers (28.1 ± 3.3 years) and 24 age-matched never-smoking volunteers (28.2 ± 4.0 years) were included. Flicker induced vasodilatation was measured in major retinal arteries and veins using a retinal vessel analyzer and flicker induced changes in retinal blood velocities were assessed in retinal veins by laser Doppler velocimetry. Three flicker periods of 60s were scheduled. Blood cotinine concentration was determined and a Fagerstrom questionnaire was performed to evaluate nicotine dependency. RESULTS In non-smoking subjects, stimulation with flicker light increased retinal venous diameter by +7.7 ± 3.1%, +6.9 ± 2.9% and +7.1 ± 2.8% during the three flicker periods, respectively. Flicker induced vasodilatation in veins was significantly diminished in chronic smokers (+4.9 ± 2.4%, +6.3 ± 3.1% and +5.7 ± 3.4%, ANOVA between groups, p=0.032) as compared to the non-smoking control group. Calculated retinal blood flow in the measured veins increased by a maximum of +54 ± 21%, +43 ± 18% and +46 ± 19% during the three stimulation periods in the non-smoking subjects, respectively. The flicker induced increase in retinal blood flow as assessed in the veins was significantly reduced in chronic smokers as compared to the non-smoking control group (+19 ± 16%, +26 ± 14%, +24 ± 13%, ANOVA between groups, p=0.013). In retinal arteries, flicker stimulation increased retinal arterial diameters by 5.2 ± 3.8%, 5.8 ± 4.8% and 5.5 ± 5.6% during the three flicker periods in the non-smoking group. In smokers, the flicker induced arterial vasodilatation was not significantly different compared to non-smokers (4.6 ± 4.1%, 3.8 ± 3.7% and 4.8 ± 3.4%, ANOVA between groups, p=0.4). CONCLUSION Our data indicate that the flicker induced hemodynamic response of retinal veins is reduced in chronic smokers as compared to age matched healthy volunteers. This supports the hypothesis that chronic smoking leads to vascular dysfunction in the eye.

Correlation of optic disc morphology and ocular perfusion parameters in patients with primary open angle glaucoma

Purpose:  Little information is available about the relationship between glaucomatous visual field defects, morphological changes of the optic disc and ocular blood flow. In this study, ocular blood flow parameters were correlated with parameters of optic nerve head (ONH) morphology and visual field performance in a cross‐sectional study.

Role of Adenosine in the Control of Choroidal Blood Flow during Changes in Ocular Perfusion Pressure

PURPOSE The purpose of the present study was to investigate whether the nucleoside adenosine is involved in the regulatory processes of choroidal blood flow (ChBF) during an experimental decrease in ocular perfusion pressure (OPP). METHODS In this randomized, double-masked, placebo-controlled, two-way crossover study, 14 subjects received either intravenous adenosine or placebo on two different study days. The suction cup method was used for a stepwise increase in intraocular pressure (IOP). Subfoveal ChBF was measured by laser Doppler flowmetry. Mean arterial pressure (MAP) and IOP were measured noninvasively. Ocular perfusion pressure was calculated as OPP = 2/3MAP - IOP. RESULTS Adenosine increased ChBF significantly versus placebo before application of the suction cup (P < 0.05). When the suction cup was applied, a significant decrease in OPP was observed. This effect was comparable on all study days. The decrease in OPP was paralleled by a significant decrease in ChBF (maximum between -43% and -52%) which was less pronounced than the decrease in OPP (maximum between -62% and -64%). Neither placebo nor adenosine influenced the ChBF increase during suction cup-induced changes in OPP. CONCLUSIONS The data of the present study confirm that the human choroid shows some regulatory capacity during a decrease in OPP. Adenosine influences basal vascular tone in the choroid but is not involved in the regulatory mechanisms during an increase in IOP. (ClinicalTrials.gov number, NCT00712764.).

Effect of latanoprost on choroidal blood flow regulation in healthy subjects.

PURPOSE The present study tested the hypothesis that human choroidal blood flow (ChBF) regulation in the face of changes in ocular perfusion pressure (OPP) may be modified by a drug-induced decrease in intraocular pressure (IOP). METHODS This hypothesis was tested in a double-masked, randomized, placebo-controlled, parallel-group trial in 24 healthy volunteers. OPP was manipulated by 6 minutes of squatting and a subsequent period of artificial increase in IOP induced with a suction cup. These interventions were repeated after 14 days of treatment with either latanoprost or placebo. ChBF was measured continuously with a portable laser Doppler flowmeter. RESULTS As expected, latanoprost significantly reduced IOP compared with placebo (P = 0.008). The relative increases in OPP during squatting (P = 0.97) and an artificial IOP increase (P = 0.75), however, were comparable after placebo and latanoprost. The response of ChBF was, in contrast, different between the two treatment groups. During the squatting-induced elevation of OPP, ChBF increased less after latanoprost than after placebo treatment (P = 0.049). During the suction cup-induced increase in IOP, the decrease in ChBF was less pronounced after latanoprost than after placebo (P = 0.026). Latanoprost, however, did not modify baseline ChBF at rest (P = 0.30). CONCLUSIONS The data indicate that latanoprost improves ChBF regulation during both an increase and a decrease in OPP. Since latanoprost did not affect baseline ChBF, the authors assume that this effect is related to the decrease in IOP. This finding has important implications for understanding the relation between IOP and vascular factors in glaucoma, because it indicates that a reduction in IOP itself improves ChBF regulation.