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Purpose: Phenylephrine has been shown to affect intraocular pressure (IOP) but the mechanism of action is poorly understood. However, its action as a vasoconstrictor suggests possible effects on episcleral venous pressure (EVP). In this study, we evaluated the effect of phenylephrine on EVP and IOP in healthy subjects., Methods: Forty eyes of 20 subjects were included. Each subject received 3 drops of phenylephrine 2.5% in one eye at 1-minute intervals. The fellow eye served as control. Blood pressure, heart rate, and IOP and EVP of both eyes were measured at baseline, 15 minutes, and 60 minutes after instillation of phenylephrine. IOP was measured by pneumatonometry. EVP was assessed by using a computer-controlled episcleral venomanometer. Changes in IOP, EVP, blood pressure, and heart rate at 15 and 60 minutes were analyzed by paired t-tests., Results: IOP increased 15 minutes after instillation of phenylephrine in both treated (P = 0.001) and control eyes (P = 0.01) and returned to baseline at 60 minutes. The change in IOP at 15 minutes was not significantly different between the 2 groups. EVP in treated eyes was unchanged at 15 minutes (P = 0.8) but decreased significantly at 60 minutes (P < 0.001). In control eyes, there was no change in EVP at any time (P > 0.6). There were no significant changes from baseline in systolic and diastolic blood pressure and heart rate after instillation of phenylephrine., Conclusions: IOP elevation associated with topical phenylephrine is not caused by an increase in EVP in healthy subjects. Instead, EVP decreases with phenylephrine, but the mechanism remains to be determined.

Purpose: Sex hormones may be associated with primary open-angle glaucoma (POAG), although the mechanisms are unclear. We previously observed that gene variants involved with estrogen metabolism were collectively associated with POAG in women but not men; here we assessed gene variants related to testosterone metabolism collectively and POAG risk., Methods: We used two datasets: one from the United States (3853 cases and 33,480 controls) and another from Australia (1155 cases and 1992 controls). Both datasets contained densely called genotypes imputed to the 1000 Genomes reference panel. We used pathway- and gene-based approaches with Pathway Analysis by Randomization Incorporating Structure (PARIS) software to assess the overall association between a panel of single nucleotide polymorphisms (SNPs) in testosterone metabolism genes and POAG. In sex-stratified analyses, we evaluated POAG overall and POAG subtypes defined by maximum IOP (high-tension [HTG] or normal tension glaucoma [NTG])., Results: In the US dataset, the SNP panel was not associated with POAG (permuted P = 0.77), although there was an association in the Australian sample (permuted P = 0.018). In both datasets, the SNP panel was associated with POAG in men (permuted P ≤ 0.033) and not women (permuted P ≥ 0.42), but in gene-based analyses, there was no consistency on the main genes responsible for these findings. In both datasets, the testosterone pathway association with HTG was significant (permuted P ≤ 0.011), but again, gene-based analyses showed no consistent driver gene associations., Conclusions: Collectively, testosterone metabolism pathway SNPs were consistently associated with the high-tension subtype of POAG in two datasets.

Purpose: The mechanism of IOP change during a body position change is poorly understood. In this study, we investigated changes in episcleral venous pressure (EVP) between two body positions, sitting and inclined, and compared this with changes in IOP., Methods: This study was a prospective, comparative case series of 43 eyes of 24 healthy volunteers. IOP was measured using a pneumatonometer in the seated position. EVP was then measured in a selected episcleral vein by using an automated, slit-lamp-mounted venomanometer. Thirty minutes later, the subject was placed in an inclined position with the neck extended and the head resting on the chin rest of the slit lamp. After 5 minutes, IOP and EVP in the same vein were remeasured. EVP in the inclined position was compared with EVP in the seated position, and the change in IOP was compared with the change in EVP. Statistical significance was determined using generalized estimating equation models., Results: Mean IOP increased from 11.4 ± 3.0 mm Hg (mean ± SD) in the sitting position to 13.1 ± 3.4 mm Hg in the inclined position (P < 0.001). Mean EVP increased from 6.4 ± 1.4 mm Hg in the sitting position to 7.8 ± 1.7 mm Hg in the inclined position (P < 0.001). The postural rise in IOP was not different from the rise in EVP (P = 0.18)., Conclusions: In the inclined position, IOP and EVP are higher than they are in the sitting position. The posture-induced rise in IOP can be attributed to an increase in EVP.

Purpose: It is not known if outflow facilities measured by pneumatonography and Schiøtz tonography are interchangeable. In this study we compared outflow facility measured by pneumatonography to outflow facility measured by digital Schiøtz tonography., Methods: Fifty-six eyes from 28 healthy participants, ages 41 to 68 years, were included. Intraocular pressure (IOP) was measured in the sitting and supine positions with a pneumatonometer. With the subject in the supine position, IOP was recorded for 2 minutes by using a pneumatonometer with a 10-g weight and for 4 minutes by using a custom digital Schiøtz tonometer. Outflow facility was determined from the changes in pressure and intraocular volume and a standard assumed ocular rigidity coefficient for each instrument, respectively, and by using an ocular rigidity coefficient calculated by measuring pressure without and with a weight added to the pneumatonometer tip., Results: The outflow facility was 0.29 ± 0.09 μL/min/mm Hg by Schiøtz tonography and 0.24 ± 0.08 μL/min/mm Hg by pneumatonography (P < 0.001) when using the standard assumed constant ocular rigidity coefficient. Mean calculated ocular rigidity coefficient was 0.028 ± 0.01 μL-1, and outflow facility determined by using this coefficient was 0.23 ± 0.08 μL/min/mm Hg by Schiøtz tonography and 0.21 ± 0.07 μL/min/mm Hg by pneumatonography (P = 0.003). Outflow facilities measured by the two devices were correlated when the ocular rigidity was assumed (r = 0.60, P < 0.001) or calculated (r = 0.70, P < 0.001)., Conclusions: Outflow facilities measured by pneumatonography were correlated with those measured by Schiøtz tonography, but Schiøtz tonography reported approximately 10% to 20% higher facilities when using the standard method. When ocular rigidity was determined for each eye, differences were smaller. Measurements from these devices cannot be compared directly.

Purpose: Recent studies indicate that mitochondrial proteins may contribute to the pathogenesis of primary open-angle glaucoma (POAG). In this study, we examined the association between POAG and common variations in gene-encoding mitochondrial proteins., Methods: We examined genetic data from 3430 POAG cases and 3108 controls derived from the combination of the GLAUGEN and NEIGHBOR studies. We constructed biological-system coherent mitochondrial nuclear-encoded protein gene-sets by intersecting the MitoCarta database with the Kyoto Encyclopedia of Genes and Genomes (KEGG) database. We examined the mitochondrial gene-sets for association with POAG and with normal-tension glaucoma (NTG) and high-tension glaucoma (HTG) subsets using Pathway Analysis by Randomization Incorporating Structure., Results: We identified 22 KEGG pathways with significant mitochondrial protein-encoding gene enrichment, belonging to six general biological classes. Among the pathway classes, mitochondrial lipid metabolism was associated with POAG overall (P = 0.013) and with NTG (P = 0.0006), and mitochondrial carbohydrate metabolism was associated with NTG (P = 0.030). Examining the individual KEGG pathway mitochondrial gene-sets, fatty acid elongation and synthesis and degradation of ketone bodies, both lipid metabolism pathways, were significantly associated with POAG (P = 0.005 and P = 0.002, respectively) and NTG (P = 0.0004 and P < 0.0001, respectively). Butanoate metabolism, a carbohydrate metabolism pathway, was significantly associated with POAG (P = 0.004), NTG (P = 0.001), and HTG (P = 0.010)., Conclusions: We present an effective approach for assessing the contributions of mitochondrial genetic variation to open-angle glaucoma. Our findings support a role for mitochondria in POAG pathogenesis and specifically point to lipid and carbohydrate metabolism pathways as being important.

Purpose: Noncoding microRNAs (miRNAs) have been implicated in the pathogenesis of glaucoma. We aimed to identify common variants in miRNA coding genes (MIR) associated with primary open-angle glaucoma (POAG)., Methods: Using the NEIGHBORHOOD data set (3853 cases/33,480 controls with European ancestry), we first assessed the relation between 85 variants in 76 MIR genes and overall POAG. Subtype-specific analyses were performed in high-tension glaucoma (HTG) and normal-tension glaucoma subsets. Second, we examined the expression of miR-182, which was associated with POAG, in postmortem human ocular tissues (ciliary body, cornea, retina, and trabecular meshwork [TM]), using miRNA sequencing (miRNA-Seq) and droplet digital PCR (ddPCR). Third, miR-182 expression was also examined in human aqueous humor (AH) by using miRNA-Seq. Fourth, exosomes secreted from primary human TM cells were examined for miR-182 expression by using miRNA-Seq. Fifth, using ddPCR we compared miR-182 expression in AH between five HTG cases and five controls., Results: Only rs76481776 in MIR182 gene was associated with POAG after adjustment for multiple comparisons (odds ratio [OR] = 1.23, 95% confidence interval [CI]: 1.11-1.42, P = 0.0002). Subtype analysis indicated that the association was primarily in the HTG subset (OR = 1.26, 95% CI: 1.08-1.47, P = 0.004). The risk allele T has been associated with elevated miR-182 expression in vitro. Data from ddPCR and miRNA-Seq confirmed miR-182 expression in all examined ocular tissues and TM-derived exosomes. Interestingly, miR-182 expression in AH was 2-fold higher in HTG patients than nonglaucoma controls (P = 0.03) without controlling for medication treatment., Conclusions: Our integrative study is the first to associate rs76481776 with POAG via elevated miR-182 expression.

Purpose: Topical anesthetics can reduce episcleral venous pressure (EVP) and IOP in rabbits. In this study, we investigated the effect of topical anesthesia on EVP in normal human subjects., Methods: We included in this study 30 eyes of 15 healthy volunteers who were habitual soft contact lens wearers. The EVP was measured before and at 5 and 10 minutes after instillation of topical proparacaine 0.5% in one eye. The EVP was measured by using a custom objective venomanometer. We compared EVP at 5 and 10 minutes after proparacaine to EVP before instilling proparacaine., Results: There was no significant difference between EVP in eyes receiving topical anesthetic at 5 or 10 minutes (7.2 ± 2.2 and 7.6 ± 2.7 mm Hg, respectively; mean ± SD) compared to contralateral eyes (6.9 ± 2.5 and 7.3 ± 2.6 mm Hg, respectively; P > 0.10). As well, EVP was not significantly different 5 or 10 minutes after topical anesthesia compared to baseline in either the eyes receiving anesthetic or the contralateral eyes (all P > 0.10; minimum detectable difference, 1.4-1.9 mm Hg, α = 0.05, β = 0.20, n = 30 eyes)., Conclusions: The EVP in human eyes is not affected significantly by topical anesthetics.

Purpose: We examined the role of DNA copy number variants (CNVs) of known glaucoma genes in relation to primary open angle glaucoma (POAG)., Methods: Our study included DNA samples from two studies (NEIGHBOR and GLAUGEN). All the samples were genotyped with the Illumina Human660W&#95;Quad&#95;v1 BeadChip. After removing non-blood-derived and amplified DNA samples, we applied quality control steps based on the mean Log R Ratio and the mean B allele frequency. Subsequently, data from 3057 DNA samples (1599 cases and 1458 controls) were analyzed with PennCNV software. We defined CNVs as those ≥5 kilobases (kb) in size and interrogated by ≥5 consecutive probes. We further limited our investigation to CNVs in known POAG-related genes, including CDKN2B-AS1, TMCO1, SIX1/SIX6, CAV1/CAV2, the LRP12-ZFPM2 region, GAS7, ATOH7, FNDC3B, CYP1B1, MYOC, OPTN, WDR36, SRBD1, TBK1, and GALC., Results: Genomic duplications of CDKN2B-AS1 and TMCO1 were each found in a single case. Two cases carried duplications in the GAS7 region. Genomic deletions of SIX6 and ATOH7 were each identified in one case. One case carried a TBK1 deletion and another case carried a TBK1 duplication. No controls had duplications or deletions in these six genes. A single control had a duplication in the MYOC region. Deletions of GALC were observed in five cases and two controls., Conclusions: The CNV analysis of a large set of cases and controls revealed the presence of rare CNVs in known POAG susceptibility genes. Our data suggest that these rare CNVs may contribute to POAG pathogenesis and merit functional evaluation., (Copyright 2014 The Association for Research in Vision and Ophthalmology, Inc.)

Purpose: Intraocular pressure in the sitting position changes minimally during sleep, although aqueous humor flow decreases by 50% or more at night. The explanation for this apparent discrepancy has been unclear. This study investigated the roles of outflow facility, episcleral venous pressure (EVP), and uveoscleral outflow in maintaining IOP at night., Methods: Forty-two eyes of 21 healthy subjects (age 47-76 years, mean 59 years) were studied. Aqueous humor flow rate, IOP in the sitting position, outflow facility, and EVP were measured in each eye during the middiurnal period (2:00-4:00 PM). Uveoscleral flow was calculated from the other variables by using the modified Goldmann equation. These variables were remeasured during the midnocturnal period (2:00-4:00 AM) and compared with those measured during the diurnal period by using generalized estimating equation models., Results: Intraocular pressure did not change from the middiurnal period (13.9 ± 3.0 mm Hg) to the midnocturnal period (13.0 ± 1.8 mm Hg, mean ± SD, P = 0.07), although aqueous humor flow rate decreased from 2.48 ± 0.96 μL/min to 1.27 ± 0.63 μL/min (P < 0.001). Outflow facility decreased from 0.23 ± 0.06 μL/min/mm Hg to 0.20 ± 0.06 μL/min/mm Hg (P = 0.004), and EVP was unchanged from the middiurnal period (7.4 ± 1.8 mm Hg) to the midnocturnal period (7.4 ± 2.2 mm Hg, P = 0.95). Uveoscleral outflow decreased 93%, from 0.94 ± 1.26 μL/min during the middiurnal period to 0.07 ± 0.78 μL/min (P = 0.008) during the midnocturnal period., Conclusions: The nocturnal decrease in aqueous humor flow rate in older, healthy subjects is compensated by a small decrease in outflow facility and a large decrease in uveoscleral outflow to maintain a stable IOP.

Purpose: Intraocular pressure (IOP) varies with body position and previous research has indicated that most, but not all, of the variation in IOP is due to changes in episcleral venous pressure (EVP). Positional changes in other aqueous humor dynamic parameters may contribute to the change in IOP. The purpose of this study was to investigate the variation of aqueous humor outflow facility with body position changes., Methods: Healthy volunteers, aged 24 to 45 years old, were recruited for this study. Constant weight tonography was performed using a modified electronic Schiotz tonometer in two positions: seated position, 70 degrees from horizontal with neck extended until the cornea was level with floor; and supine position. A minimum of 30 minutes was allowed between the two measurements. Tonography data were fitted to second order polynomials and values for the initial steady state IOP and the outflow facility were determined using standard tables and normograms. IOP was measured using pneumatonometry., Results: Forty-two eyes from 21 subjects were studied. IOP in the sitting and supine positions were 17.8 +/- 1.7 mm Hg and 19.9 +/- 1.6 mm Hg, respectively, and were significantly different (P < 0.001). The mean outflow facility in the sitting and supine positions were 0.30 +/- 0.31 microL/mL/mm Hg and 0.28 +/- 0.09 microL/mL/mm Hg, respectively, and were not significantly different (P = 0.37)., Conclusions: Aqueous humor outflow facility measured with electronic Schiotz tonography does not vary significantly between the supine and sitting positions.

Purpose: Recent research indicates that intraocular pressure (IOP) does not decrease significantly during the nocturnal period, although aqueous humor flow decreases by 50% or more at night. This study was undertaken to investigate whether changes in outflow facility, episcleral venous pressure, or uveoscleral flow at night could account for the nocturnal IOP., Methods: Sixty-eight eyes of 34 healthy subjects (age, 18-44 years; mean, 29) were studied. Aqueous humor flow rate, IOP, and outflow facility were measured with pneumatonometry, anterior chamber fluorophotometry, and Schiotz tonography respectively, in each eye during the mid-diurnal (2-4 PM) and mid-nocturnal (2-4 AM) periods. Nocturnal IOP, flow rate, and outflow facility were compared to the same variables during the diurnal period. Mathematical models based on the modified Goldmann equation were used to assess the conditions under which these results could be reconciled., Results: Supine IOP decreased slightly from 18.9 +/- 2.7 mm Hg in the mid-diurnal period to 17.8 +/- 2.5 mm Hg in the mid-nocturnal period (mean +/- SD, P = 0.001). Aqueous flow rate decreased from 2.26 +/- 0.73 to 1.12 +/- 0.75 microL/min (mean +/- SD, P < 0.001). There was a nonsignificant trend toward a nocturnal decrease of outflow facility (diurnal, 0.27 +/- 0.11 microL/min/mm Hg; nocturnal, 0.25 +/- 0.08 microL/min/mm Hg; mean +/- SD, P = 0.13)., Conclusions: Outflow facility measured by tonography does not decrease enough during the nocturnal period to compensate for the decreased aqueous humor flow rate. Modeling results indicate that the experimental results could be reconciled only if nocturnal changes in episcleral venous pressure and/or uveoscleral flow occurred.

Purpose: It has been reported that fixation conditions significantly influence the apparent pore density in the inner-wall endothelium of Schlemm's canal. In the present study, the manner in which fixation conditions affect the two subtypes of inner-wall pores, intracellular pores and intercellular (or border) pores, was investigated., Methods: Outflow facility was measured in enucleated human eyes. Eyes were fixed under constant flow" or constant pressure conditions, microdissected to expose the inner wall of Schlemm's canal, and prepared for scanning electron microscopy. The density and diameter of the two subtypes of pores in the inner wall were measured., Results: Intracellular pore density decreased with increasing postmortem time (P < 0.001) and increased with increasing volume of fixative passed through the outflow pathway (P < 0.001), whereas border pore density showed no dependence on these parameters (P > 0.25 and P > 0.15, respectively). Border pore density increased with increasing fixation pressure (P < 0.005), even though intracellular pore density showed no such dependence (P > 0.4). No correlation was found between outflow facility and the predictions of Poiseuille's law, Sampson's law, or the funneling theory for the hydraulic conductivity of the intracellular pores (P > 0.35) or the border pores (P > 0.1)., Conclusions: The intracellular and border pores form two morphologically and functionally distinct populations in the inner wall of Schlemm's canal. The dependence of intracellular pore density on postmortem time and on volume of fixative passed through the outflow pathway suggests that these pores are artifacts of tissue fixation or processing conditions. That border pores do not depend on such conditions and that their presence is correlative with perfusion pressure suggests that this population may be nonartifactual. New histologic techniques for examining the inner wall of Schlemm's canal are necessary to determine the in vivo state of inner-wall pores and how they influence outflow facility.

Purpose: A linear relationship between the density of pores in the inner wall of Schlemm's canal and aqueous outflow facility has been reported previously in a study in which investigators examined only eyes fixed at constant pressure, so that fixative flow rates differed from eye to eye. Because pores may form as a function of flow rate, the purpose in the current study was to verify the previous findings, using constant flow perfusions., Methods: Outflow facility was measured in enucleated human eyes. Eyes were fixed under either constant flow or constant pressure conditions, microdissected to expose the inner wall of Schlemm's canal, and prepared for scanning electron microscopy. The density and diameter of pores in the inner wall were measured., Results: Statistical analysis showed no correlation between outflow facility and either the density or the diameter of pores. Pore density decreased significantly during the hours after death. Examining only eyes for which experimentation was started within 20 hours of death, we found that pore density increased significantly with the volume of fixative that had been perfused through the outflow pathway., Conclusions: The correlation found by Allingham et al between outflow facility and pore density in the inner wall endothelium was not confirmed. However, the relationship between pore density and volume of fixative perfused is consistent with and may be responsible for the finding in the previous study. Because fixation conditions can influence the apparent pore density in the inner wall endothelium significantly, the conclusion reached previously, that pores contribute only 10% of the aqueous outflow resistance, may require reevaluation.