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Retinal capillary perfusion: Spatial and temporal heterogeneity.
Yu, DY, Cringle, SJ, Yu, PK, Balaratnasingam, C, Mehnert, A, Sarunic, MV, An, D, Su, EN
Progress in retinal and eye research. 2019;:23-54
Abstract
The central role of the cardiovascular system is to maintain adequate capillary perfusion. The spatially and temporally heterogeneous nature of capillary perfusion has been reported in some organs. However, such heterogeneous perfusion properties have not been sufficiently explored in the retina. Arguably, spatial and temporal heterogeneity of capillary perfusion could be more predominant in the retina than that in other organs. This is because the retina is one of the highest metabolic demand neural tissues yet it has a limited blood supply due to optical requirements. In addition, the unique heterogeneous distribution of retinal neural cells within different layers and regions, and the significant heterogeneity of intraretinal oxygen distribution and consumption add to the complexity. Retinal blood flow distribution must match consumption of nutrients such as oxygen and glucose within the retina at the cellular level in order to effectively maintain cell survival and function. Sophisticated local blood flow control in the microcirculation is likely required to control the retinal capillary perfusion to supply local retinal tissue and accommodate temporal and spatial variations in metabolic supply and demand. The authors would like to update the knowledge of the retinal microvessel and capillary network and retinal oxidative metabolism from their own studies and the work of others. The coupling between blood supply and energy demands in the retina is particularly interesting. We will mostly describe information regarding the retinal microvessel network and retinal oxidative metabolism relevant to the spatial and temporal heterogeneity of capillary perfusion. We believe that there is significant and necessary spatial and temporal heterogeneity and active regulation of retinal blood flow in the retina, particularly in the macular region. Recently, retinal optical coherence tomography angiography (OCTA) has been widely used in ophthalmology, both experimentally and clinically. OCTA could be a valuable tool for examining retinal microvessel and capillary network structurally and has potential for determining retinal capillary perfusion and its control. We have demonstrated spatial and temporal heterogeneity of capillary perfusion in the retina both experimentally and clinically. We have also found close relationships between the smallest arterioles and capillaries within paired arterioles and venules and determined the distribution of smooth muscle cell contraction proteins in these vessels. Spatial and temporal heterogeneity of retinal capillary perfusion could be a useful parameter to determine retinal microvessel regulatory capability as an early assay for retinal vascular diseases. This topic will be of great interest, not only for the eye but also other organs. The retina could be the best model for such investigations. Unlike cerebral vessels, retinal vessels can be seen even at the capillary level. The purpose of this manuscript is to share our current understanding with the readers and encourage more researchers and clinicians to investigate this field. We begin by reviewing the general principles of microcirculation properties and the spatial and temporal heterogeneity of the capillary perfusion in other organs, before considering the special requirements of the retina. The local heterogeneity of oxygen supply and demand in the retina and the need to have a limited and well-regulated retinal circulation to preserve the transparency of the retina is discussed. We then consider how such a delicate balance of metabolic supply and consumption is achieved. Finally we discuss how new imaging methodologies such as optical coherence tomography angiography may be able to detect the presence of spatial and temporal heterogeneity of capillary perfusion in a clinical setting. We also provide some new information of the control role of very small arterioles in the modulation of retinal capillary perfusion which could be an interesting topic for further investigation.
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Evaluation of Foveal Avascular Zone and Capillary Plexuses in Diabetic Patients by Optical Coherence Tomography Angiography.
Ciloglu, E, Unal, F, Sukgen, EA, Koçluk, Y
Korean journal of ophthalmology : KJO. 2019;(4):359-365
Abstract
PURPOSE To investigate the foveal avascular zone (AVZ), superficial and deep foveal and parafoveal vessel density (VD) changes related to diabetic retinopathy. METHODS Forty-nine type 2 diabetes mellitus (DM) and 45 healthy control subjects were included in this study. The demographic data (age and sex), disease duration, and level of glycated hemoglobin were collected. Superficial VD (%), superficial AVZ area (mm²), deep VD (%) and deep AVZ area (mm²) were evaluated via optic coherence tomography angiography. RESULTS Superficial AVZ was 0.438 ± 0.05 mm² in the DM group, 0.246 ± 0.022 mm² in the control group (p < 0.001). Deep AVZ was 0.732 ± 0.06 mm² in the DM group, and 0.342 ± 0.022 mm² in the control group (p < 0.001). Superficial foveal VD was 29.45 ± 0.76 mm² in the DM group, and 34.86 ± 0.75 mm² in the control group (p < 0.001). Deep foveal VD was 24.85 ± 1.08 mm² in the DM group, and 33.47 ± 0.56 mm² in the control group (p < 0.001). CONCLUSIONS In this study, we demonstrated an enlargement in the foveal AVZ along with a reduction in the vascular density of the superficial and deep capillary network in the foveal and parafoveal area using optic coherence tomography angiography in patients with nonproliferative diabetic retinopathy. This technique can be used to monitor the progression of the disease and to evaluate the response to treatment.
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Optical coherence tomography angiography analysis of the choriocapillary layer in treatment-naïve diabetic eyes.
Yang, J, Wang, E, Zhao, X, Xia, S, Yuan, M, Chen, H, Zhang, X, Chen, Y
Graefe's archive for clinical and experimental ophthalmology = Albrecht von Graefes Archiv fur klinische und experimentelle Ophthalmologie. 2019;(7):1393-1399
Abstract
PURPOSE To evaluate the capillary flow density (CFD) of choriocapillary (CC) microvasculature using optical coherence tomography angiography (OCT-A) in diabetic eyes and the association of CFD and systemic and metabolic factors. METHODS Cross-sectional study. This study enrolled 282 eyes of 146 subjects, including 43 healthy control eyes, 56 diabetic eyes without diabetic retinopathy (DR), 43 eyes with mild nonproliferative DR (NPDR), 54 eyes with moderate NPDR, 38 eyes with severe NPDR, and 48 eyes with proliferative DR (PDR). CFD was measured in the CC layer. Clinical data were collected. Multiple linear regression analyses were performed to identify associated clinical variables. RESULTS CFD in the CC layer presented a downward trend with DR progression. Comparisons of CFD in the CC layer between adjacent stages of DR revealed significant differences between severe NPDR and PDR using both 3-mm and 6-mm scan patterns (P = 0.003, P = 0.001). CFD in the CC layer in DR with diabetic macular edema (DME) was less than that in DR without DME using both 3-mm and 6-mm scan patterns (P < 0.001, P < 0.001). Coronary artery disease and atherosclerosis in other locations, estimated glomerular filtration rate, and increased HbA1c were associated with CFD in the CC layer using both 3-mm and 6-mm scan patterns (all P values < 0.05). CONCLUSIONS OCT-A revealed decreased CFD in the CC layer in the PDR stage and the presence of DME. Diabetic patients with apparently decreased CFD should be assessed carefully under general conditions.
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DECREASED RETINAL CAPILLARY DENSITY IS ASSOCIATED WITH A HIGHER RISK OF DIABETIC RETINOPATHY IN PATIENTS WITH DIABETES.
Czakó, C, Sándor, G, Ecsedy, M, Récsán, Z, Horváth, H, Szepessy, Z, Nagy, ZZ, Kovács, I
Retina (Philadelphia, Pa.). 2019;(9):1710-1719
Abstract
PURPOSE To quantify retinal microvascular alterations using optical coherence tomography angiography in diabetic patients, and to evaluate the accuracy of decreased vessel density (VD) in predicting early diabetic retinopathy (DR). METHODS One hundred and two eyes of 51 diabetic patients and 92 eyes of 46 individuals without diabetes were examined. Duration of diabetes, insulin therapy, blood pressure, HbA1C, dyslipidemia, axial length, and the presence of DR were recorded. Retinal VD was measured using optical coherence tomography angiography. The effect of risk factors on VD and on DR was assessed using multivariable regression analyzes. RESULTS Compared with controls, VD was lower in diabetic patients (P < 0.05) and correlated with diabetes duration (P = 0.02). Decreased VD was associated with a higher risk of DR (odds ratio: 1.24, P = 0.009) after controlling for systemic and ocular confounding variables. Eyes with a VD of <50% had an odds ratio of 4.55 (P = 0.003) for DR and an odds ratio of 3.22 (P = 0.03) for decreased visual acuity (<20/25) after controlling for systemic and ocular confounding factors. CONCLUSION The risk of DR and vision loss is substantially higher in eyes with lower VD, suggesting that optical coherence tomography angiography metrics may serve as prognostic biomarkers for the prediction of early onset DR.
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Effects of Rosuvastatin and Aspirin on Retinal Vascular Structures in Hypercholesterolemic Patients with Low-to-Moderate Risk of Coronary Artery Disease.
Li, L, Wang, S, Huang, H, Cai, Y, Xi, Y, Bai, Y, Ma, C
American journal of cardiovascular drugs : drugs, devices, and other interventions. 2019;(4):415-420
Abstract
INTRODUCTION Atherosclerosis erodes large elastic arteries and damages peripheral small vessels. Evaluating retinal vessel caliber enables exploration of the effect of improving microcirculation with statins. OBJECTIVE We investigated whether rosuvastatin therapy improves retinal vasculature in hypercholesterolemic patients with a low-to-moderate risk of coronary artery disease (CAD). METHODS This was a prospective, open-label, randomized study in which 127 patients were enrolled and randomized (ratio 1:1) into rosuvastatin and control groups. RESULTS Rosuvastatin increased retinal arteriolar calibers by 3.560 µm at 12 months, decreased retinal venular calibers by 3.110 µm at 6 months and by 5.860 µm at 12 months, and increased the artery-vein ratio (AVR) by 2.68% at 6 months and by 5.90% at 12 months. Meanwhile, in the control group, retinal arteriolar calibers decreased by 1.110 µm at 12 months, retinal venular calibers increased by 1.020 µm at 6 months and by 1.04 µm at 12 months, and AVR decreased by 1.12% at 6 months and by 1.73% at 12 months. All the above parameters were statistically significant between groups, but there was no significant change in retinal arteriolar calibers at 6 months. The increased AVR correlated significantly with decreased C-reactive protein (CRP) at 6 months and decreased low-density lipoprotein and CRP at 12 months. DISCUSSION For patients with a low-to-moderate risk of CAD, we found a significant effect of rosuvastatin on retinal microvasculature, including AVR increase, venular constriction, and arteriolar dilation after 6-12 months of treatment. CLINICAL TRIAL REGISTRATION Chinese Clinical Trial Registry identifier number ChiCTR-IOR-15006664.
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Topical Treatment With Brimonidine and Somatostatin Causes Retinal Vascular Dilation in Patients With Early Diabetic Retinopathy From the EUROCONDOR.
Grauslund, J, Frydkjaer-Olsen, U, Peto, T, Fernández-Carneado, J, Ponsati, B, Hernández, C, Cunha-Vaz, J, Simó, R, ,
Investigative ophthalmology & visual science. 2019;(6):2257-2262
Abstract
PURPOSE Structural retinal microvascular changes have been identified as risk markers of diabetic retinopathy (DR). In order to estimate the retinal response of neuroprotective eye drops, we aimed to evaluate the effect of topical retinal neuroprotection on retinal microvascular changes in early DR. METHODS Patients with type 2 diabetes with no or early DR were randomized 1:1:1 to topical treatment with placebo, brimonidine, or somatostatin in a 96-week prospective, phase II to III, European multicenter trial. Retinal vascular calibers were measured semiautomatically in digital fundus images by certified graders at baseline and follow-up and summarized as central retinal arteriolar and venular equivalent (CRAE and CRVE). RESULTS Of 449 patients originally included, 297 completed the study with gradable retinal images. Median age and duration of diabetes was 64.5 and 9.9 years, and 65.7% were male. At baseline, Early Treatment Diabetic Retinopathy Study levels were 10 (no DR, 42.8%), 20 (minimal DR, 28.3%), and 35 (mild DR, 29.0%), and CRAE and CRVE did not differ between groups. As opposed to patients with no or minimal DR at baseline, patients with mild DR in the active groups developed a larger retinal arteriolar (brimonidine: +6.2 μm, P = 0.006; somatostatin: +7.2 μm, P = 0.006) and venular (brimonidine: +13.9 μm, P = 0.01; somatostatin: +14.3 μm, P = 0.0001) caliber in contrast to those in the placebo group. CONCLUSIONS Topical treatment with brimonidine and somatostatin causes retinal arteriolar and venular dilation in patients with type 2 diabetes and preexisting early DR. Upcoming studies should elaborate on the potential of these findings in arresting early DR.
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Macular vessels density in diabetic retinopathy: quantitative assessment using optical coherence tomography angiography.
AttaAllah, HR, Mohamed, AAM, Ali, MA
International ophthalmology. 2019;(8):1845-1859
Abstract
PURPOSE The aim of this study was to evaluate macular perfusion using OCTA automated software algorithms; vessel area density (VD) and non-flow tool to measure FAZ area in treatment-naïve diabetic eyes with moderate or severe NPDR and having macular edema, and correlate these parameters with LogMAR (logarithm of the minimum angle of resolution) visual acuity. Diabetic eyes without macular edema were included, to detect and define differences within the parameters between diabetic eyes with and without macular edema. METHODS Forty-five diabetic eyes with diabetic macular edema, forty diabetic eyes without macular edema, and forty eyes of healthy controls were examined using OCTA (RTVue-XR Avanti; Optovue, Inc, Fremont, CA). The macular vessel area density (VD) and foveal avascular zone (FAZ) area were assessed and statistically compared between the three groups and also correlated with the foveal thickness and visual acuity. Data were entered and analyzed by SPSS 19. Quantitative data were presented as mean and standard deviation, and qualitative data presented as frequency distribution; independent samples t test, Chi square test and Pearson correlation were done. RESULTS Mean whole image VD was 44.4 ± 3.6 in diabetic eyes with DME, 45.6 ± 4.2 in diabetics without DME, and 49 ± 3.9 in control eyes (P = 0.001). Diabetic eyes with DME had significantly lower vessels density values at the level of the deep retinal plexus (in the parafoveal, superior hemi, inferior hemi, temporal, superior, and nasal areas), when compared with diabetic eyes without DME. In diabetic eyes with DME, significant fair negative correlation was found between whole image vessels density at the level of the superficial retinal plexus and LogMAR VA (r = - 0.313, P = 0.036). Also, a significant fair positive correlation was found between FAZ area (at both the superficial and deep retinal plexus) and LogMAR visual acuity, in diabetic eyes with DME, where eyes with larger FAZ area had worse vision (P = 0.005 and P = 0.016, respectively). Diabetic eyes with DME had significantly larger FAZ area at the level of the superficial capillary plexus (mean superficial FAZ ± SD 0.55 ± 0.25) than diabetic eyes without edema (mean superficial FAZ ± SD 0.41 ± 0.12) and control subjects (mean superficial FAZ ± SD 0.35 ± 0.09). CONCLUSION Using OCTA machine with AngioAnalytics parameters (vessel area density and non-flow area) helped in objective quantification of macular perfusion and accurately measuring the FAZ area in diabetic eyes with macular edema. Both parameters were significantly correlated with visual function in treatment-naïve diabetic eyes with edema. These OCTA biomarkers could be used to predict visual function in such eyes, to monitor response to treatment.
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Theobromine consumption does not improve fasting and postprandial vascular function in overweight and obese subjects.
Smolders, L, Mensink, RP, van den Driessche, JJ, Joris, PJ, Plat, J
European journal of nutrition. 2019;(3):981-987
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Abstract
BACKGOUND Theobromine, a component of cocoa, may favorably affect conventional lipid-related cardiovascular risk markers, but effects on flow-mediated dilation (FMD) and other vascular function markers are not known. OBJECTIVE To evaluate the effects of 4-week theobromine consumption (500 mg/day) on fasting and postprandial vascular function markers. DESIGN In a randomized, double-blind crossover study, 44 apparently healthy overweight (N = 30) and obese (N = 14) men and women with low HDL-C concentrations, consumed daily 500 mg theobromine or placebo for 4 weeks. After 4 weeks, FMD, peripheral arterial tonometry (PAT), augmentation index (AIx), pulse wave velocity (PWV), blood pressure (BP) and retinal microvasculature measurements were performed. These measurements were carried out under fasting conditions and 2.5 h after a high-fat mixed meal challenge. RESULTS 4-week theobromine consumption did not change fasting vascular function markers, except for a decrease in central AIx (cAIx, - 1.7 pp, P = 0.037) and a trend towards smaller venular calibers (- 2 µm, P = 0.074). Consuming a high-fat mixed meal decreased FMD (0.89 pp, P = 0.002), reactive hyperemia index (RHI, - 0.30, P < 0.001), peripheral systolic BP (SBP, - 3 mmHg, P ≤ 0.001), peripheral diastolic BP (DBP, - 2 mmHg, P ≤ 0.001), central SBP (- 6 mmHg, P ≤ 0.001) and central DBP (- 2 mmHg, P ≤ 0.001), but increased heart rate (HR, 2 bpm, P < 0.001). Theobromine did not modify these postprandial effects, but increased postprandially the brachial artery diameter (0.03 cm, P = 0.015), and decreased the cAIx corrected for a HR of 75 (cAIx75, - 5.0 pp, P = 0.004) and peripheral AIx (pAIx, - 6.3 pp, P = 0.017). CONCLUSION Theobromine consumption did not improve fasting and postprandial endothelial function, but increased postprandial peripheral arterial diameters and decreased the AIx. These findings do not suggest that theobromine alone contributes to the proposed cardioprotective effects of cocoa. This trial was registered on clinicaltrials.gov under study number NCT02209025.
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Implication of Deep-Vascular-Layer Alteration Detected by Optical Coherence Tomography Angiography for the Pathogenesis of Diabetic Retinopathy.
Dimitrova, G, Chihara, E
Ophthalmologica. Journal international d'ophtalmologie. International journal of ophthalmology. Zeitschrift fur Augenheilkunde. 2019;(4):179-182
Abstract
The aim of this narrative mini review is to analyze optical coherence tomography angiography (OCTA) parameters from reports that involved both superficial and deep vascular layers in patients with diabetes and to assess their relevance for the pathogenesis of diabetic retinopathy (DR). Papers published from January 2015 to August 2018 describing the use of OCTA in diabetes were identified and reviewed through a Medline/PubMed search. OCTA studies suggest that parameters are altered in patients with diabetes in all retinal vascular layers. From all included studies that evaluated both the superficial and the deep vascular layer, a number of studies suggested that the deep vascular layer was affected at an earlier stage of DR. OCTA parameter alterations were more prominent in the deep vascular layer than in the superficial vascular layer in patients with DR, and deep-vascular-layer alterations were most evident in patients with diabetic macular edema. Regarding that retinal venules originate from the deep vascular layer of the retina, alteration of OCTA parameters at the deep vascular layer in diabetic patients may imply a predominant affection of the venous side of the retinal vascular system in the pathogenesis of DR.
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Longitudinal Wide-Field Swept-Source OCT Angiography of Neovascularization in Proliferative Diabetic Retinopathy after Panretinal Photocoagulation.
Russell, JF, Shi, Y, Hinkle, JW, Scott, NL, Fan, KC, Lyu, C, Gregori, G, Rosenfeld, PJ
Ophthalmology. Retina. 2019;(4):350-361
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PURPOSE Wide-field swept-source (SS) OCT angiography (OCTA) was compared with ultrawide-field (UWF) fluorescein angiography (FA) for evaluating neovascularization (NV) before and after panretinal photocoagulation (PRP) in eyes with treatment-naive proliferative diabetic retinopathy (PDR). DESIGN Prospective, observational, consecutive case series. PARTICIPANTS Patients with treatment-naive PDR. METHODS Patients were imaged using the SS OCTA 12 × 12-mm field of view (PLEX Elite 9000; Carl Zeiss Meditec, Inc, Dublin, CA) at baseline and at 1 week, 1 month, and 3 months after PRP. Select eyes were imaged with 5 SS OCTA 12 × 12-mm scans to create posterior pole montages. Ultrawide-field fundus photography and UWF FA were obtained at baseline and 3 months after PRP. MAIN OUTCOME MEASURES Neovascularization visualized using wide-field SS OCTA and UWF FA. RESULTS From January through May 2018, wide-field SS OCTA was performed on 20 eyes with treatment-naive PDR from 15 patients. The en face SS OCTA 12 × 12-mm vitreoretinal interface (VRI) slab images showed NV at baseline in 18 of 20 eyes (90%). Of the remaining 2 eyes, the posterior pole montage captured peripheral NV in one eye, and in the other eye, no evidence of NV was detected with either UWF FA or SS OCTA. After PRP, both SS OCTA and FA demonstrated similar progression or regression of NV, but SS OCTA provided more detailed visualization of the vascular changes. CONCLUSIONS Neovascularization in PDR can be identified at baseline and imaged serially after PRP using wide-field SS OCTA. In patients with a high clinical suspicion for PDR, wide-field SS OCTA likely will be the only imaging method needed for diagnosis and longitudinal evaluation of NV.