Rhythm of 24-h Intraocular and Perfusion Pressure in Patients With Ocular Hypertension

the of and pressure (OPP) in BP of that individual. BP (SBP) by > 10 mm Hg if the diastolic BP (DBP) differed by > 5 mm Hg. The median of the 3 readings was then considered to be the BP of that individual. A non-contact tonometer (Nidek Co., Ltd.) was used to take IOP measurements. IOP and BP were recorded at 1:00, 3:00, 5:00, 7:00, 9:00, 11:00, 13:00, 15:00, 17:00, 19:00, 21:00 and 23:00 h. The IOP measurement was taken in a sitting position, the IOP value was taken from the right eye measurement value, and the average value of 3 readings was recorded. Mean arterial pressure (MAP) = diastolic BP + 1/3 (systolic BP - diastolic BP); mean ocular perfusion pressure (MOPP) = 2/3 MAP - IOP; systolic ocular perfusion pressure (SOPP) = systolic BP - IOP; diastolic ocular perfusion pressure (DOPP) = diastolic BP - IOP. All monitoring was performed by professionals in the inpatient Department of Ophthalmology.


Introduction
The prevalence of ocular hypertension (OHTN) is between 1.37 and 5.40%, and the prevalence of OHTN among those > 40 years old is higher than in those with primary open angle glaucoma (POAG) [1][2][3] . The proportion of patients with untreated OHTN that progress to POAG is 0.5-2.0% each year [4,5] ; a study reported that up to 25% of patients with OHTN developed POAG within a 10-year period [6] , which resulted in irreversible blindness. The progression of OHTN is insidious, and identifying patients with OHTN who may progress to glaucoma is an important challenge in clinical diagnosis and treatment.

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The blood ow theory is an important factor for the pathogenesis of POAG. Several epidemiological studies have con rmed that low systolic ocular perfusion pressure (SOPP) and/or diastolic ocular perfusion pressure (DOPP) are important risk factors for the development of glaucoma [7][8][9] . Furthermore, there are numerous studies reporting the 24-h IOP rhythm and OPP uctuations of primary open-angle glaucoma (POAG). However, there are currently few reports on the rhythm of IOP and OPP uctuations in those with OHTN.
The aim of the present study was to compare the characteristics of IOP and OPP uctuations between patients with OHTN and healthy subjects, to highlight the OPP changes during patient follow-up, and to provide guidance for diagnosis, identi cation of high-risk individuals, and individualized preventive treatment. These observations aim to reduce the risk of disease, and provide a reference for the standardized, scienti c diagnosis and treatment of OHTN.

Patients And Methods
The present study was approved by the Ethics Committee of Tongji Hospital (Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China) and performed in accordance with the Declaration of Helsinki. Written informed consent was obtained from each subject prior to the start of the study.
General information. The OHTN group included 107 patients (107 eyes) diagnosed with OHTN in Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology between January 2016 and October 2019. The diagnostic criteria were based on the GDG (Guideline Development Group) guidelines [10] which include examinations of corneal thickness, IOP, visual eld and fundus. As such, the inclusion criteria were as follows: i) The angle of the anterior chamber was checked under the anterior goinoscope chamber, ensuring that it was open and with a wide angle; ii) central corneal thickness was measured, and the IOP measured using a Goldmann tonometer was > 21 mmHg at least twice in the rst outpatient clinic visit without medication; iii) No obvious visual eld defects, loss of optic nerve ber layer, and/or change to the glaucoma optic papilla; and iv) no cataracts, ocular fundus lesions and/or other eye lesions, or a history of eye surgery. The control group included 71 healthy volunteers (71 eyes). The central corneal thickness was measured and the IOP corrected, and the IOP measurement was in the normal range. The anterior chamber angle was open and with a wide angle, and the optic disc structure and visual eld detection were normal.
The exclusion criteria were as follows: i) History of eye surgery; ii) history of diabetes and/or heart disease; iii) history of hormone therapy; iv) presence of ocular conditions affecting ocular pressure measurement; and v) use of vasoactive drugs such as beta blockers.
The OHTN group (107 patients) including 53 males and 54 females, with an average age of 22.93 ± 12.40 years. The control group included 71 healthy volunteers (36 male and 35 female) with an average age of 22.79 ± 6.64 years. There were no signi cant differences in sex and age between the two groups.
Methods. All research subjects remained in hospital for 24-h IOP and blood pressure (BP) measurements. BP was determined using a blood pressure monitor (model, HEM-907; OMRON Corporation). After lying at for 5 min, the patient was returned to the sitting position and BP was measured using the right arm; BP measurements were taken twice, 5 min apart, and the mean of the 2 readings was then considered as the BP of that individual. A third measurement was taken if the systolic BP (SBP) differed by > 10 mm Hg or if the diastolic BP (DBP) differed by > 5 mm Hg. The median of the 3 readings was then considered to be the BP of that individual. A non-contact tonometer (Nidek Co., Ltd.) was used to take IOP measurements. IOP and BP were recorded at 1:00, 3:00, 5:00, 7:00, 9:00, 11:00, 13:00, 15:00, 17:00, 19:00, 21:00 and 23:00 h. The IOP measurement was taken in a sitting position, the IOP value was taken from the right eye measurement value, and the average value of 3 readings was recorded. Mean arterial pressure (MAP) = diastolic BP + 1/3 (systolic BP -diastolic BP); mean ocular perfusion pressure (MOPP) = 2/3 MAP -IOP; systolic ocular perfusion pressure (SOPP) = systolic BP -IOP; diastolic ocular perfusion pressure (DOPP) = diastolic BP -IOP. All monitoring was performed by professionals in the inpatient Department of Ophthalmology.
Observational indicators. The following indicators were observed; i) IOP peak value, trough value, mean average value of 12 measurements, and uctuation value (the difference between the peak and trough values from 12 measurements); ii) the maximum, minimum, mean and uctuation mean arterial pressure (MAP) values of 12 measurements; and iii) the maximum, minimum, mean and uctuation values for MOPP, SOPP and DOPP.
Statistical Analysis. Statistical analysis was performed using SPSS 22.0 (IBM, Corp). Continuous variables are expressed as the mean ± SD where appropriate, and were compared using the independent samples t-test. P < 0.05 was considered to indicate a statistically signi cant difference.

Results
Comparison of 24-h IOP and OPP peak, trough, mean and uctuation values between the OHTN and healthy control groups. The mean 24-h IOP of the OHTN group (22.85 ± 2.82 mmHg) was higher than that of the healthy control group (15.81 ± 1.60 mmHg; t=-19.103; P < 0.01). The 24-h IOP diurnal and nocturnal uctuation difference was higher in the OHTN group (8.91 ± 3.07 mmHg) than in the healthy control group (5.89 ± 0.86 mmHg; t=-8.085; P < 0.01) ( Table 1).  OHTN and healthy control group 24-h IOP, MOPP, SOPP and DOPP uctuation curves. The mean and standard deviation values for the IOP, MOPP, SOPP and DOPP of the two groups were plotted at 12 timepoints ( Fig. 1-4). In the OHTN group, the peak IOP time was at 5:00-9:00 h, and the trough time was at19:00-23:00 h; the peak IOP time in the healthy control group was at 5:00-9:00 h, and the trough time was between 17:00-23:00 h. The peak and trough IOP times of the two groups coincided. The peak MOPP time in the OHTN group was at 17:00-23:00 h, and the trough time was at 1:00-5:00 h. In the healthy control group, the peak MOPP time was at 19:00-23:00 h, while the trough time was between 3:00 and 7:00 h. Furthermore, the peak SOPP time of in the OHTN group was between 17:00 and 21:00 h, with a trough time at 1:00-5:00 h. The peak SOPP time in the healthy control group was at 17:00-23:00 h, and the trough time was between 3:00 and 7:00 h.  . 5-7).

Discussion
The aim of the present study was to comprehensively observe the changes in IOP and OPP in patients with OHTN over a 24-h period. The maximum, minimum and mean IOP were signi cantly higher, and the maximum, minimum and mean MOPP were signi cantly lower in patients with OHTN than in healthy control subjects (P < 0.05). The minimum and mean SOPP and DOPP values in the OHTN group were lower than those in the healthy controls (P < 0.05). The IOP, MOPP, SOPP and DOPP diurnal and nocturnal uctuation values were signi cantly larger in the OHTN group than in the healthy control group (P < 0.05). Furthermore, the peak and trough IOP timepoints were similar in both groups, with a trend towards low values during the day and higher values at night. The peak and trough MOPP and SOPP times for the two groups also overlapped, with higher daytime values which declined at night. The 24-h DOPP in the healthy control group tended to be high during the day and low at night, with peak values between 19:00 and 23:00 h and trough values between 3:00 and 7:00 h. No obvious changes were observed in the OHTN group from day to night. Over the 24-h timeframe, the top three times with the greatest frequency of peak IOP counts were 1:00, 5:00 and 11:00 h in the OHTN group, while those in the healthy control group were 7:00, 3:00 and 5:00 h. The top three times at which the highest frequency distribution of MOPP trough values occurred were 1:00, 3:00 and 5:00 h in the OHTN group, and 3:00, 7:00 and 5:00 in the healthy control group.
There are various methods for conducting tonometry, including the use of, for example, the Schiotz tonometer, the Goldmann applanation tonometer, the Ton-Pen tonometer and the non-contact tonometer.
Each tonometer has its own advantages and disadvantages. The Goldmann applanation tonometer method is the internationally recognized gold standard for IOP measurement, but its clinical application is more cumbersome. The non-contact tonometer (NCT) method is non-invasive, requires no anesthetic and is easy to perform. It is widely used in the clinic and is more suitable for repeated IOP measurements within a 24-h period, the accuracy of which has been con rmed in previous studies. Additional methods were adopted in the present study, which included sitting in the daytime and sitting immediately after waking up at night; these factors minimize the in uence of higher suprascleral vein pressure and BP on the IOP results during the nocturnal position (lying at). Therefore, the sitting position was uniformly adopted and the comparison standard was uni ed.
In the current study, the overall IOP of the OHTN group was increased, the mean IOP was higher, and the uctuation amplitude of the diurnal and nocturnal IOP (8.91 ± 3.07 mmHg) was signi cantly higher than that of the healthy control group (5.89 ± 0.86 mmHg). Xu et al [11] studied the repeatability of 24-h IOP monitoring in OHTN, and found that the two 24-h IOP uctuation values were 8.94 ± 3.03 mmHg and 9.06 ± 3.19 mmHg, which is similar to the results of the current study (8.91 ± 3.07 mmHg). At the same time, Xu et al reported that the peak IOP occurred at 6:00 h, and that the trough IOP was observed at 20:00 h, which is similar to the results of the current study. Grippo et al [12] revealed that in habitual positions (diurnal sitting and nocturnal supine), the peak IOP occurred at 11:30 − 5:30 h, and the trough at 5:30 − 21:30 h; while in the supine position, the peak IOP was primarily observed at 7:30 − 3:30 h, and the trough occurred at 17:30 − 23:30 h. In the present study, a sitting position was adopted. Although the IOP peak time was at 9:00 h in patients with OHTN, the peak IOP occurred most frequently at 1:00 and 5:00 h, which is not consistent with the results of the aforementioned studies. The IOP value can be in uenced by various random factors, such as light, activity or uid intake, in addition to the habitual activities of the subject during the day, which may increase IOP variability. A large number of studies have con rmed that elevated IOP and higher IOP diurnal and nocturnal uctuations are important risk factors for POAG [13,14] , but that OHTN does not result in glaucoma-associated optic nerve damage. In recent years, scholars have discovered that the pressure difference across the sieve plate, which is the difference between IOP and intracranial cerebrospinal uid pressure, is an important factors for the pathogenesis of glaucoma. It is speculated that patients with OHTN may experience high intracranial pressure resulting in low-pressure differences across the sieve plate, such that glaucoma-associated optic nerve injury does not occur [15] .
A large number of studies have con rmed that the vascular mechanism is an in uencing factor for the pathogenesis of glaucomatous optic nerve injury. Insu cient or unstable blood supply to the eye can cause optic nerve and axon ischemia and/or reperfusion injury. OPP is an important factor in determining blood ow in the eye. Using the OPP calculation formula, it can be seen that an increase in IOP or a decrease in BP results in a decrease in OPP, which may cause hypoxia and ischemia in the optic nerve, initiating or aggravating visual eld defects in patients with POAG.
A Handan Eye Study revealed that the SOPP, DOPP and MOPP of patients with POAG were consistently lower than those of suspected POAG patients, indicating that OPP plays an important role in the development of glaucoma [3] . An epidemiological study in Singapore indicated that lower MOPP, SOPP and DOPP were independent risk factors for POAG [9] . Early research in Barbados demonstrated that DOPP was decreased by 20% and that the incidence of glaucoma was increased by 3.3 times in patients with POAG. After a 9-year follow-up study, low SOPP, low DOPP and low MOPP were con rmed to be risk factors for glaucoma [16] . Additionally, Topouzis et al [17] suggested that DOPP was more highly correlated with the progression of POAG than SOPP.
Low perfusion pressure and vascular autoregulatory dysfunction are important factors in the pathogenesis of glaucoma. Choi et al [8] assessed patients with normal tension glaucoma for > 6 years, and found that the progression of visual eld defects was closely associated with the uctuation amplitude of the 24-h OPP. Moreover, Sung et al [14] followed 101 patients with normal-tension glaucoma for > 4 years and found that the 24-h MOPP uctuations of those with progressive visual eld damage were signi cantly greater than those without progression.
Sehi et al [18] revealed that the daily percentage reduction in MOPP of untreated POAG patients was signi cantly higher than that of normal subjects, indicating that relative diurnal changes in MOPP may be a risk factor for POAG. These ndings suggest that the alterations in OPP are closely associated with the occurrence and development of glaucoma. Although countless individuals experience low OPP, they do not develop glaucoma due to a normal self-adjusting ability which compensates for the low blood supply caused by low OPP. In the capillary bed of these individuals, and in the range of automatic adjustment ability, a change in perfusion pressure will not cause a change in blood ow [19,20] . When the posture changes, IOP increases or blood pressure decreases, and the vascular autoregulation mechanism is required to maintain OPP stability. OHTN may be due to the normal automatic adjustment ability, which can compensate for the low blood supply resulting from low OPP, thus glaucoma does not develop.
In the present study, the MOPP trough times were between 1:00 and 3:00 h, which are considered to be non-working hours. This suggests that it is best to monitor changes in the 24-h OPP when observing the OHTN perfusion pressure, and to pay particular attention to the occurrence of low OPP at night. The average and uctuating DOPP values in OHTN subjects were signi cantly higher than those in the healthy control group. Furthermore, compared with MOPP and SOPP, no signi cant change in trend was observed, suggesting that changes in DOPP are more sensitive indicators of OHTN than those in MOPP and SOPP. These ndings are consistent with the results of Topouzis et al [17] , suggesting that DOPP is more highly correlated with POAG progression than SOPP. Therefore, for the future diagnosis and treatment of OHTN, more attention should be paid to changes in DOPP.
There are some shortcomings to the present study. Firstly, the study was conducted over a 1-year period; seasonal changes in temperature may in uence IOP and BP, which require further research in the future. Secondly, the traditional posture was adopted, and the IOP at night was measured after waking. At this time, the subject's physiological status, such as hormone levels and the effect of the eyelids, may change, and may cause differences from the IOP measured in the lying position. Thirdly, taking measurements every 2 h cannot fully re ect these physiological changes, and measurements at night will inevitably be affected by other factors, such as exposure to light. In future studies, measurements may be taken using a 24-h tonometer [21] , or a simpler tool might be developed to allow measurements to be taken in the patients' home. Ultimately, carrying out day and night IOP and OPP monitoring will help to improve our understanding of IOP and OPP uctuations to guide the treatment of those with OHTN.