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Purpose We aimed to explore the velocity waveform characteristics of the retinal artery associated with age and the cardio-ankle vascular index (CAVI) as a conventional arterial stiffness marker by applying the Doppler optical coherence tomography (DOCT) flowmeter. Methods In this cross-sectional study, DOCT flowmeter imaging was performed in 66 participants aged 21 to 83 years (17 men, 49 women) with no history of eye diseases and no systemic diseases, except for hypertension. Retinal blood velocity waveform was analyzed where several parameters in time (upstroke time, T1, T2, T3, and T4) and area under the waveform (area elevation, area declination, A1, A2, A3, and A4) were extracted. Systolic blood pressure-adjusted Pearson's coefficients were calculated to determine the correlations of each parameter with age or CAVI. Results Corrected upstroke time (UTc) was the waveform parameter most positively correlated with age (r = 0.497, P < 0.001). Area declination was the waveform parameter most negatively correlated with age (r = -0.682, P < 0.001) and CAVI (r = -0.601, P < 0.001). Conclusions We extracted the waveform parameters associated with the risks of arterial stiffening. The velocity waveform analysis of the retinal artery with DOCT flowmeter potentially could become a new method for arterial stiffness identification. Translational Relevance DOCT flowmeter could evaluate arterial stiffening in a different way from the conventional method of measuring arterial stiffening using pressure waveform. Because the DOCT flowmeter can easily, quickly, and noninvasively provide a retinal blood velocity waveform, this system could be useful as a routine medical examination for arterial stiffening.

Purpose It has been reported that peripapillary loops develop after central retinal artery occlusion (CRAO). Although cilioretinal anastomoses have been shown by fluorescein angiography (FA) and indocyanine green angiography, these examinations cannot confirm the structural continuity between the retinal arteries and the posterior ciliary arteries. In the current report, we followed a patient with iatrogenic CRAO in which circumpapillary collaterals formed and assessed the connection between these two vascular systems using optical coherence tomography angiography (OCTA). Observation Iatrogenic CRAO developed in the left eye of a 30-year-old woman during preoperative embolization of a convexity meningioma. FA and OCTA showed complete impairment of the retinal circulation. Two weeks after this event, OCTA images showed flow in the retinal vessels and the beginning of collateral vessel development on the optic disc margin. Six months later, OCTA images showed that these circumpapillary collaterals connected branches of the retinal arteries with the vessels supplying the optic disc, which originate from the posterior ciliary arteries. Conclusion and importance OCTA aided our understanding of the three-dimensional configuration of the circumpapillary collaterals that developed after iatrogenic CRAO, which included anastomosis of the retinal and posterior ciliary artery systems. OCTA is useful for noninvasively monitoring the status of retinal circulatory dynamics after iatrogenic CRAO.

The current study aimed to address whether ripasudil, a Rho-associated coiled-coil containing protein kinase (ROCK) inhibitor developed to treat glaucoma and ocular hypertension (OH), improves diabetic macular edema (DME) since it is known that ROCK upregulates vascular endothelial growth factor. We retrospectively investigated the foveal thickness (FT) measured by spectral-domain optical coherence tomography, visual acuity (VA), and intraocular pressure (IOP) in 12 eyes with DME that received ripasudil treatment for primary open-angle glaucoma or OH and compared them with 14 eyes that received no treatment. One month after ripasudil therapy, the mean FT decreased significantly from 439 ± 72 µm to 395 ± 62 µm (P = 0.003); this change was significantly different from that in the controls, in which the mean FT increased by 1 ± 39 µm (P = 0.01). Ripasudil also caused a significant decrease in IOP from 17.3 ± 5.2 mmHg to 14.6 ± 4.0 mmHg (P = 0.02); this change was significantly greater than that in the controls, in which IOP changed by 0.0 ± 1.6 mmHg (P

Purpose We aimed to observe longitudinal changes in retinal blood flow (RBF) and structural transformations in capillaries using Doppler optical coherence tomography (DOCT) and optical coherence tomography angiography (OCTA) in a feline retinal blood occlusion (RVO) model. Methods RVO was induced by argon green laser photocoagulation (PC) in six eyes of six cats. RBF was measured at a first-order retinal artery and vein by a DOCT flowmeter, and structural changes in the capillaries around the occluded vessels (12 × 12 and 3 × 3 mm) were assessed by OCTA before (at baseline); immediately after PC; and on days 1, 4, 7, and 14 thereafter. Systemic and ocular parameters were monitored during the observation period. Results There were no significant differences in any systemic or ocular parameters before and after PC. Arterial RBF increased significantly on day 1 (160.6 ± 8.6% vs. baseline, P < 0.001) and decreased below baseline after day 1 through 14. Venous RBF decreased immediately after PC (17.4 ± 9.6% vs. baseline, P = 0.001) and then gradually increased afterwards, but did not return to baseline. OCTA showed dilatation of retinal venules immediately after PC to day 1. Collateral vessels began to form on day 4, had matured by day 7, and were pruned on day 14, which formed as mature as normal retinal venule diameters. Conclusions With increasing arterial RBF within 1 day after inducing RVO, venules gradually expanded to form collateral vessels, suggesting that collateral vessels originate from existing capillary networks, not neovascularization.

AimsTo evaluate the associations between retinal blood flow (RBF) and optical coherence tomography (OCT) structural measurements in normal-tension glaucoma (NTG) eyes with single-hemifield visual field (VF) damage by the Doppler OCT.MethodsThe Doppler OCT was used to measure temporal artery (TA) RBF and temporal vein (TV) RBF. Retinal nerve fibre layer thickness (RNFLT) was measured by spectral-domain OCT.ResultsForty-three consecutive eyes of 43 patients with NTG with VF defect confined to a single hemifield and 24 eyes of 24 age-matched healthy subjects were studied. TA and TV RBF and RNFLT were reduced in the damaged hemisphere compared with the normal hemisphere (mean (SD), 3.61 (1.68) vs 5.86 (2.59) µL/min, pConclusionIn NTG eyes with single-hemifield damage, the RBF was significantly reduced in the damaged hemisphere compared with the normal one. The RBF decreased in the normal and damaged hemispheres of NTG eyes compared with the healthy hemisphere independent from RNFLT.

PurposeTo investigate the changes in extracellular matrix (ECM) gene and protein expressions in human trabecular meshwork (HTM) cells in response to mechanical fluid flow stimulation.MethodsHTM cells were cultured on a glass plate and exposed to shear stress (0, 0.2, and 1.0 dyne/cm2) for 12 hours. Changes in gene expressions were evaluated using microarray analysis. The representative genes related to ECM metabolism underwent real-time reverse-transcriptase polymerase chain reaction. Fibronectin (FN) and collagen (COL) IV levels in the supernatant were evaluated using immunoassays. Rho-associated coiled-coil-containing protein kinase (ROCK) activity also was investigated.ResultsAfter stimulation, transforming growth factor β2 mRNA levels were significantly (p < 0.01) lower than that of the static control (0 dyne/cm2 for 12 hours). Matrix metalloproteinase 2 mRNA levels were significantly (p < 0.05) higher than the static control. COL type 1 alpha 2 mRNA, COL type 4 alpha 2 mRNA, and COL type 6 alpha 1 mRNA levels were significantly (p < 0.05, < 0.01, and < 0.05, respectively) higher than the static control. The mean ± standard deviation FN levels (ng/mL) in the supernatant after stimulation (0, 0.2, 1.0 dyne/cm2) were 193.7 ± 7.6, 51.5 ± 21.8, and 34.9 ± 23.6, respectively (p < 0.01). The FN and COL IV levels and ROCK activity were significantly (p < 0.01 and < 0.05, respectively) lower than the static control.ConclusionsChanges in gene and protein expressions related to ECM metabolism occurred in HTM cells after stimulation. Specifically, the suppression of FN and COL IV production might explain the importance of mechanical fluid flow stimulation on maintenance of the normal aqueous humor outflow.

This study aimed to evaluate whether long-term insulin treatment is associated with abnormalities in retinal circulation in type 2 diabetic patients. We evaluated 19 eyes of nondiabetic individuals and 68 eyes of type 2 diabetic patients. The eyes of diabetic patients were classified into two groups according to the presence or absence of long-term insulin therapy. We used a Doppler optical coherence tomography flowmeter to measure diameter, velocity, and blood flow in the major temporal retinal artery. The pulsatility ratio (PR) and resistance index (RI), indices of vascular rigidity, were calculated from the blood velocity profile. PR and RI were significantly elevated in type 2 diabetic patients compared with nondiabetic subjects (P < 0.05). In type 2 diabetes patients, PR and RI were significantly higher in patients receiving long-term insulin treatment than in those without (P < 0.01). There was a significant difference in velocity (P < 0.05), but not diameter and blood flow, between nondiabetic subjects and type 2 diabetes patients. No significant difference in diameter, velocity, or blood flow was observed between the groups with and without long-term insulin treatment. Long-term insulin treatment can affect PR and RI, which might be associated with vascular rigidity of the retinal artery in patients with type 2 diabetes.

Purpose To evaluate the repeatability and reproducibility of the measurement of retinal arteriole pulse waveforms using a novel fully-automated Doppler optical coherence tomography (DOCT) flowmeter in healthy subjects. Methods Twenty eyes of 20 healthy subjects were included to test the intrasession repeatability of pulse waveform analysis. DOCT measurements were performed based on a newly developed instantaneous Doppler angle measurement method. Upstroke time (UT), which is the time from the minimum to the maximum retinal blood velocity, and the resistance index (RI) of the retinal arteriole pulse waveform were measured. Coefficients of variation (CVs) and intraclass correlation coefficients (ICCs) were calculated. Interdevice reproducibility between two instruments was assessed in five eyes of five subjects. Results The mean UT was 130.3 ms (range, 110.1-152.1 ms), and the mean RI was 0.66 (range, 0.51-0.82). The respective ICCs of UT and the RI for the intrasession repeatability of assessment were 0.87 and 0.78. The respective CVs of UT and the RI were 6.6 ± 3.3% and 4.7 ± 2.1%. Regarding interdevice reproducibility, there were no significant differences between the measurements derived from the instruments (P > 0.05). Conclusions Pulse waveform measurement in retinal arterioles using a fully-automated DOCT flowmeter exhibited good repeatability and interdevice reproducibility. Translational relevance The above-described improved DOCT flowmeter system provides reasonably repeatable measurements of retinal arteriole pulse waveforms, potentially facilitating systemic-circulation abnormality monitoring. The examination of the circulation with the novel device can be potentially useful for evaluating systemic circulation.

PURPOSE: To evaluate the ability of OCT optic nerve head (ONH) and macular parameters to detect disease progression in eyes with advanced structural glaucomatous damage of the circumpapillary retinal nerve fiber layer (cRNFL). DESIGN: Longitudinal study. PARTICIPANTS: Forty-four eyes from 37 subjects with advanced average cRNFL damage (≤60 μm) followed for an average period of 4.0 years. METHODS: All subjects were examined with spectral-domain optical coherence tomography (SD-OCT) and visual field (VF) during at least 4 visits. MAIN OUTCOME MEASUREMENTS: Visual field (VF) mean deviation (MD) and visual field index (VFI). OCT cRNFL (average, superior and inferior quadrants), ganglion cell/inner plexiform layer (GCIPL) (average, superior and inferior), rim area, cup volume, average cup-to-disc (C/D) ratio, vertical C/D ratio. RESULTS: At baseline, subjects had a median VF mean deviation (MD) of −10.18 dB and mean cRNFL of 54.55±3.42 μm. The rate of change for MD and VFI were significant. No significant rate of change was noted for cRNFL, while significant (p

To use a Doppler optical coherence tomography (DOCT) flowmeter to investigate segmental retinal blood flow (RBF) and sum of the segmental RBFs (SRBF) changes after panretinal photocoagulation (PRP) was used to treat type 2 diabetes mellitus with severe diabetic retinopathy (DR). Data from five patients with proliferative DR (PDR) (mean age 51.9 ± 10.5 years) was analyzed. The vessel diameter (D), average velocity (V), and retinal blood flow (RBF) in veins were measured using a DOCT flowmeter before and four weeks after PRP. Segmental RBF from inferotemporal (IT), superotemporal (ST), inferonasal (IN), and superonasal (SN) veins were measured, and SRBF was defined as the sum of these measurements. All data were analyzed by Wilcoxson test. After PRP, there were statistically significant decreases in the every segmental D, V, RBF (P0.05). The DOCT flowmeter has the potential to be a clinically useful tool to noninvasively evaluate the changes in retinal circulation during PRP in patients with PDR.

Copper electrodeposits annealed at 80 °C were investigated by electrical resistance measurement, X-ray diffraction and electron backscattered diffraction analyses. The decrease of electrical resistivity had a linear relationship with the re-crystallized area. Interestingly, the texture coefficient of (200) orientation increased as the re-crystallization occurred. Such appearance of (200) texture during annealing seemed to be related to the residual strain in the copper electrodeposits. It is possible to evaluate the progress of grain growth by measuring the electrical resistivity or texture coefficient in copper electrodeposits. †(Received July 23, 2013)

PURPOSE To study retinal blood flow (RBF) measurement reproducibility using segmental-scanning Doppler optical coherence tomography (DOCT) in vitro in glass capillaries and in vivo in anesthetized cats. METHODS As a preliminary study, the flow rates of human blood through glass capillaries were changed by using an infusion pump and measured at 13 preset velocities by DOCT. For in vivo measurement, the cats were anesthetized using sevoflurane. The flow in the parent vessel was compared with the sum of the flow values in the two daughter vessels. The RBF was measured using two different instruments: bidirectional laser Doppler velocimetry (LDV) and DOCT. The reproducibility of the measurements was assessed by calculating the coefficients of variation (CVs) for repeated measurements of RBF at the superior retinal arterioles and venules. RESULTS In vitro, the flow velocities measured by DOCT agreed well with the preset velocities. In vivo, the flow in the parent vessel agreed with the sum of the flow values in the two daughter vessels. In addition, there were no significant differences in the mean averaged CVs of the RBF in both the arterioles and venules between LDV and DOCT. CONCLUSIONS The newly developed segmental-scanning DOCT revealed the accuracy of the measurement in in vitro glass capillaries and reproducibility of the measurements of blood velocity in both the retinal arterioles and venules in anesthetized cats.

PURPOSE: To investigate how glial cells participate in retinal circulation during flicker stimulation in cats. METHODS: Using laser Doppler velocimetry, we measured the vessel diameter and blood velocity simultaneously and calculated the retinal blood flow (RBF) in feline first-order retinal arterioles. Twenty-four hours after intravitreal injections of L-2-aminoadipic acid (LAA), a gliotoxic compound, and the solvent of 0.01 N hydrochloric acid as a control, we examined the changes in RBF in response to 16-Hz flicker stimulation for 3 minutes. We also measured the changes in RBF 2 hours after intravitreal injection of Nω-propyl-L-arginine (L-NPA), a selective neuronal nitric oxide synthase inhibitor, in LAA-treated eyes. To evaluate the effects of LAA on retinal neuronal function, ERGs were monitored. Immunohistochemical examinations were performed. RESULTS: In LAA-treated eyes, histologic changes selectively occurred in retinal glial cells. There were no significant reductions in amplitude or elongation of implicit time in ERG after LAA injections compared with controls. In control eyes, the RBF gradually increased and reached the maximal level (53.5% ± 2.5% increase from baseline) after 2 to 3 minutes of flicker stimulation. In LAA-treated eyes, the increases in RBF during flicker stimulation were attenuated significantly compared with controls. In LAA-treated eyes 2 hours after injection of L-NPA, flicker-evoked increases in RBF decreased significantly compared with LAA-treated eyes. CONCLUSIONS: The current results suggested that increases in RBF in response to flicker stimulation were regulated partly by retinal glial cells.

Purpose To investigate how neuronal nitric oxide synthase (nNOS) contributes to regulation of the retinal circulation during rest and flicker stimulation in cats. Methods Using laser Doppler velocimetry, we measured the vessel diameter and blood velocity simultaneously and calculated the retinal blood flow (RBF) in feline first-order retinal arterioles. After intravitreal injections of Nω-Nitro-L-arginine methyl ester (L-NAME), a nonselective NOS inhibitor, and Nω-propyl-L-arginine (L-NPA), a selective nNOS inhibitor, we continuously monitored the retinal circulation without any perturbations for 2 hours. We then examined the changes in the RBF in response to 16-Hz flicker stimuli for 3 minutes at 2 hours after intravitreal injection of phosphate-buffered saline (PBS) as a control, L-NAME, L-NPA, and thromboxane A2 (TXA2) analogue U46619 as a basal tone-adjusted control. Results After intravitreal injection of L-NAME and L-NPA, the baseline RBF decreased gradually in a dose-dependent manner. In the PBS group, the RBF increased gradually and reached a maximal level after 2 to 3 minutes of flicker stimuli. After 3 minutes of 16-Hz flicker stimuli, the RBF increased by 53.5% ± 3.4% compared with baseline. In the L-NAME and L-NPA groups, the increases in RBF during flicker stimulation were attenuated significantly compared with the PBS group. In the TXA2 group, the reduction in the flicker-induced increase in RBF was comparable to that in the PBS group. Conclusions The current results suggested that increased RBF in response to flicker stimulation may be mediated by nitric oxide (NO) production via nNOS activation.

We report a case of hypertensive choroidopathy with detailed retinal images obtained using spectral-domain optical coherence tomography (SD-OCT).A 19-year-old pregnant woman with no history of high blood pressure had an eclamptic seizure at the 39th week of pregnancy; the baby was delivered by emergency Caesarean section. Six days later, she presented with bilateral blurred vision (best-corrected visual acuity [VA], 0.5, right eye; 0.3, left eye). Bilateral extensive, punctate, pale-yellow Elschnig's spots were present in the posterior fundus. SD-OCT showed a serous retinal detachment (SRD) and retinal pigment epithelium detachment (PED) representing a waveform retinal pigment epithelium (RPE) layer in each eye. The reflective intensity decreased partly at the waveform RPE. A wavy structure suggestive of fibrin was present in both foveas between the photoreceptor ellipsoid zone and the RPE-outer segment line. Four weeks after delivery and oral antihypertensive treatment, the SRDs, PEDs and wavy structure resolved and the VA recovered.SD-OCT visualized SRDs, PEDs, wavy structures under the photoreceptor ellipsoid zone, and areas of low intensity RPE layer in hypertensive choroidopathy.

This work is licensed under a Creative Commons Attribution 4.0 International License., Purpose: To investigate the role of endothelin-1 (ET-1) in retinal glial cells in regulating retinal blood flow (RBF) during hyperoxia in cats. Methods: We measured the vessel diameter (D), blood velocity (V), and blood flow (F) simultaneously in first-order retinal arterioles using a laser Doppler velocimetry system. The animals were under general anesthesia during hyperoxia (100% oxygen) for 10 minutes 24 hours after intravitreal injection of L-2-aminoadipic acid (LAA), a gliotoxic compound, or diluted hydrochloric acid (0.01 N) used as the vehicle control. We also measured the changes in the RBF after intravitreal injection of BQ-123, a specific ET type A receptor antagonist, in LAA-treated eyes. To examine if endothelin-converting enzyme-1 (ECE-1), as an ET-1-generating enzyme located in retinal glial cells, immunohistochemical examinations with costaining of antiglial fibrillary acidic protein (GFAP) antibody and anti-ECE-1 antibody were performed in whole-mount retinas. Results: During hyperoxia, the decreases in D, V, and F in response to hyperoxia were attenuated significantly (P < 0.01 for all comparisons) in the LAA-treated eyes compared with the vehicle control (LAA, D, -8.5 ± 1.5%; V, -13.8 ± 1.5%; F, -27.8 ± 3.0% versus vehicle control, D, -16.8 ± 1.3%; V, -26.3 ± 2.0%; F, -48.9 ± 2.4%). In LAA-treated eyes, intravitreal injections of BQ-123 did not change the rate of hyperoxia-induced RBF compared to LAA-treated eyes. The anti-ECE-1 antibody was costained with anti-GFAP antibody in the whole-mount retinas. Conclusions: The current findings suggest that retinal glial ET-1 may play an important role in regulating RBF during hyperoxia in cats.