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(1988)
Response of blood flow to warm and cold in normal and low tension glaucoma patients, 105
(2004)
Vasospasm in the pathogenesis of glaucomatous optic neuropathy (in Russian), 2
(2012)
Cardiac autonomic dysfunction in patients with normal tension glaucoma: 24-h heart rate and blood pressure variability analysis, 96
(2008)
Retinal blood flow response to posture change in glaucoma patients compared with healthy subjects, 115
(1996)
Standards of measurement, physiological interpretation, Сlinical use. Task Force of the European Society of Cardiology and the North American Society of Pacing and Electrophysiology, 17
(1985)
Migraine and low tension glaucoma. A case-control study, 25
(1996)
Reproducibility of heart rate variability indices during exercise stress testing and inotrope infusion in chronic heart failure patients, 91
(2008)
Clinical clues of vascular dysregulation and its association with glaucoma, 43
(2010)
Autonomic dysfunction in normal tension glaucoma: the short-term heart rate variability analysis, 19
(2012)
Diastolic double-product: a new entity to consider in normal-tension glaucoma patients, 14
(2007)
Circadian fluctuation of mean ocular perfusion pressure is a consistent risk factor for normal-tension glaucoma, 48
(1994)
Species differences in choroidal vasodilative innervation: evidence for specific intrinsic nitregic and VIP-positive neurons in the human eye, 35
(2010)
Vascular reactivity of optic nerve head and retinal blood vessels in glaucoma—a review, 17
(2014)
Flammer syndrome, 5
(2004)
Abnormal systemic and ocular vascular response to temperature provocation in primary open-angle glaucoma patients: a case for autonomic failure?, 45
(1999)
A study of changes in the status of autonomic nervous system in primary open angle glaucoma cases, 53
(2002)
Impaired cardiovascular responses to baroreflex stimulation in open angle and normal-pressure glaucoma, 102
(2009)
Ocular perfusion pressure and glaucoma: clinical trial and epidemiologic findings, 20
(2003)
Autonomic system activity and 24-hour blood pressure variations in subjects with normal and high tension glaucoma, 12
(2012)
Chronic stress, but not hypercaloric diet, impairs vascular function in rats, 15
(2007)
EMGT Predictors of long term progression in the early manifest glaucoma trial, 114
(2015)
Venous ocular blood flow in primary open angle glaucoma, 3
(2008)
Autoregulation, a balancing act between supply and demand, 43
(2007)
Interactions among higher trait anxiety, sympathetic activity, and endothelial function in the elderly, 41
(2010)
Heart-rate variability in women during 40-hour prolonged wakefulness, 27
(2006)
24-h blood pressure monitoring in normal tension glaucoma: night-time blood pressure variability, 20
(2014)
Central visual field progression in normal tension glaucoma patients with autonomic dysfunction, 55
(1988)
Classification and diagnostic criteria for headache disorders, cranial neuralgias and facial pain, 8
(1986)
Systemic autonomic neuropathy in open-angle glaucoma, 64
Methods for checking and self-checking an output of the cardiovascular system and a checking device
Primary vascular dysregulation (PVD) is believed to be a main cause of local vasospasm and impaired autoregulation as a possible contributing factor in the pathogenesis of normal tension glaucoma (NTG). Subjects with PVD respond stronger to psychological stress. Autonomic dysfunction is another reason of instable ocular blood flow and may be studied by means of assessment of heart rate variability (HRV) especially during a hand-cold provocation test (CPT). To compare the shift of HRV parameters in NTG and healthy subjects after a cold provocation test and to assess the relation between structural damage, circulatory parameters and autonomic dysfunction in NTG. HRV was studied using CPT in 78 NTG patients and 60 health control matches. The ocular blood flow was measured using color Doppler imaging (CDI). The 24 hours blood pressure (BP) monitoring was carried out. The cardiovascular fitness assessment was made to all patients before and after CPT. Mean group difference of HRV parameters was compared between NTG and healthy subjects using the Euclidean metric. The mean ocular perfusion pressure (MOPP) was measured. Optic nerve head and retinal nerve fiber layer (RNFL) were evaluated using spectral-domain optic coherence tomography (SD-OCT). The relation between HRV, CDI, and SD-OCT-parameters was assessed. In contrast to healthy subjects, a predominance of the sympathetic activity after the CPT was revealed in the NTG group. The end diastolic velocity (EDV) in central retinal artery (CRA) and short posterior ciliary artery (SPCA) was significantly reduced in NTG compared to healthy eyes. In NTG, the main HRV parameter characterizing the total effect of autonomic blood circulation regulation (SDNN) correlated with MOPP (0.75, P=.035), SPCA EDV (0.93, P<.001), and CRA EDV (0.9, P<.001). The average daily diastolic BP correlated with RNFL (0.67, P=.009). The NTG patients have the disturbance of the autonomic nervous system, which increases in response to stress provocation and is related to ocular blood flow and structural damage. Abbreviations: ANS = autonomic nervous system, ARI = autonomic regulation index, BP = blood pressure, CDI = color Doppler imaging, CPT = cold provocation test, CRA = central retinal artery, CRV = central retinal vein, EDV = end-diastolic velocity, FLV = focal loss volume, FR = functional reserves, FS = functional status, GCC = ganglion cell complex, GLV = global loss volume, HF = high-frequency range, HRV = heart-rate variability, ILM = internal limiting membrane, IOP = intraocular pressure, LF = low-frequency range, LF/HF = low/high-frequency ratio, MD = mean deviation, MOPP = mean ocular perfusion pressure, NTG = normal tension glaucoma, OA = ophthalmic artery, OCT = optical coherence tomography, ONH = optic nerve head, OPP = ocular perfusion pressure, PI = pulsatility index, pNN50 = number of pairs of consecutive NN-intervals, POAG = primary open-angle glaucoma, PSD = pattern standard deviation, PSV = peak systolic velocity, PVD = primary vascular dysregulation, RI = resistive index, RMSSD = root mean square of the successive differences, RNFL = retinal nerve fiber layer, RPE = retinal pigment epithelium, SAP = standard automated perimetry, SDNN = standard deviation of the NN intervals, SD-OCT = spectral-domain optical coherence tomography, SNA = sympathetic neural activity, SPCA = short posterior ciliary artery, TINN = triangular interpolation of NN, TP = total spectral power, TPCA = temporal short posterior ciliary artery, VF = visual field. Keywords: heart rate variability, normal tension glaucoma, ocular blood flow, ocular perfusion pressure 1. Introduction Editor: Antonio Palazón-Bru. The authors did not receive funding for the research and writing of the article. One of the most recognized current cause of normal tension [1] glaucoma (NTG) is an instable ocular blood flow of optic disc, The authors have no conflicts of interest to disclose. which may be the result of primary vascular dysregulation (PVD) Ophthalmological Department of the Federal Medical and Biological Agency of the Russian Federation, Science Center of Radiation and Chemical Safety and and therefore the impaired autoregulation of retinal blood [2] Hygiene of the Federal Medical and Biological Agency of the Russian Federation. flow. Excessive activity of the sympathetic link of the Correspondence: Natalia Ivanovna Kurysheva, Head of Consultative and autonomic nervous system (ANS) is one of the possible causes Diagnostic Department (BDO), 15 Gamaleya Street, 123098, Moscow leading both to disturbance of blood supply to the ONH and to a (e-mail: e-natalia@list.ru). decrease in ocular perfusion pressure (OPP) in the vessels of the Copyright © 2018 the Author(s). Published by Wolters Kluwer Health, Inc. [3–5] optic nerve and choroid. Heart rate variability (HRV) is a This is an open access article distributed under the Creative Commons well-known tool that allows studying the autonomic modulation Attribution-NoDerivatives License 4.0, which allows for redistribution, commercial [4] of the heart sympathovagal balance. Systemic parasympathetic and non-commercial, as long as it is passed along unchanged and in whole, with credit to the author. and sympathetic neuropathies have been reported in patients [5–8] Medicine (2018) 97:5(e9744) with primary open-angle glaucoma (POAG) and NTG. Furthermore, it has been revealed that the sympathovagal Received: 20 September 2017 / Received in final form: 29 December 2017 / Accepted: 9 January 2018 balance of the autonomic nervous system (ANS) in patients [9,10] http://dx.doi.org/10.1097/MD.0000000000009744 with NTG is shifted toward sympathetic activity, and the 1 Kurysheva et al. Medicine (2018) 97:5 Medicine sympathetic predominance is responsible for the faster rate of history of chronic ocular or systemic corticosteroid use. The age [11] central visual field (VF) progression in NTG. However, the and race distribution of the healthy subjects matched that of the relation between the autonomic dysfunction and structural glaucoma patients. damage in NTG is not clear. Exclusion criteria were the following: large refractive errors It is believed that patients with an instable ocular blood flow (outside of±6.00 dpt sphere or 2.00 dpt cylinder), pupil diameter respond stronger to psychological stress as it has been described < 3mm, systemic administration of beta-blockers and calcium- [12] in patients with primary vascular dysregulation (PVD). Cold channel blockers, concomitant ocular disease (except for early stimulation is a well-established provocation test used for cataract), chronic autoimmune diseases, diabetes mellitus, acute detecting abnormal vascular reactivity in patients with autonom- circulatory disorders in past medical history, and any concomi- [13] ic failures. tant diseases involving the administration of steroid drugs. A Pathological response to cold in patients with glaucoma has history of ocular arterial or venous obstruction (branch or central [14] been previously demonstrated in our research and we have occlusion) and systemic conditions associated with venous described a significant reduction of retrobulbor blood flow in congestion (e.g., heart failure) were also considered as exclusion [15] NTG. Recently, some authors studied the peripheral blood criteria. The patients were instructed to avoid caffeine intake, [1] flow in glaucoma patients after a cold provocation test (CPT) smoking, and exercise for 5hours prior to the study visit. [16] and as a response to posture change. Meanwhile, there is no If both eyes of a patient were eligible, 1 eye was randomly literature data concerning the influence of CPT on HRV in NTG chosen. compared to healthy subjects. Those patients, who previously used antiglaucoma drops, were The objective of this study is to compare the shift of HRV asked to discontinue the drug for a period of 21 days (drug parameters in NTG and healthy subjects after CPT and to assess washout period), while others were newly diagnosed glaucoma the relation between the structural damage, circulatory param- cases. The medical histories of all patients were carefully obtained eters, and autonomic dysfunction in NTG. with special attention paid to the signs of primary or secondary cardiovascular dysregulation (migraine, vasospasm, and neuro- [17] circulatory dystonia). 2. Materials and methods All patients underwent Doppler ultrasound scanning to 2.1. Study design exclude pathology of the brachiocephalic vessels and were referred to the therapeutic outpatient clinic of the Department of The study was approved by the Ethical Committee (Institutional A.I. Burnazyan Federal Medical and Biophysical Center of Review Board) at the Institution of the Federal Medical and FMBA, Moscow, Russia, where they followed the physical Biological Agency of the Russian Federation and was conducted examinations of their health status, including, clinical chemistry, in accordance with Good Clinical Practice within the tenets of the the hematological and urine analysis, hepatitis, and human Declaration of Helsinki. Each patient/healthy subject was immunodeficiency virus serology. required to sign an informed consent form before being enrolled in the study and prior to any measurements being taken. 2.3. Study examinations 2.2. Study subjects All participants underwent complete ophthalmologic examina- Around 138 eyes of 138 subjects (78 patients with early and tions including best corrected acuity, slit lamp examination, IOP moderate NTG and 60 age-matched healthy subjects) were measurement using analyzer of biomechanical properties of eyes included into this study. The patients were recruited from April, (Ocular Response Analyzer, ORA, Reichert Ophthalmic Instru- 2015 up to January, 2016. All patients were Caucasian. ments Inc., Depew, NY), gonioscopy, anterior chamber angle NTG was diagnosed on the basis of characteristic changes in measurement (Visante OCT, Carl Zeiss, Germany), pachymetry the optic disc detected by ophthalmoscopy, which was performed (SP-100, Tomey GmbH, Germany), dilated fundus biomicro- by one glaucoma specialist (NK) and confirmed by 2 other scopy using 78-diopter lens, stereoscopic optic disc photography, glaucoma specialists. The inclusion criteria included pathological and standard automated perimetry (SAP) using a Humphrey deviation from the normal neuroretinal rim, glaucomatous optic Field Analyzer (HFA, Carl Zeiss Meditec Inc., Dublin, CA) with disc cupping, peripapillary atrophy, wedge-shaped defects of the SITA. Only reliable SAP results, which were defined as false- retinal nerve fiber layer (RNFL) adjacent to the optic disc edge, negative and false-positive responses of < 33% and fixation loss hemorrhages at the optic disc boundary, glaucomatous VF loss of < 20%, were eligible for the study. Glaucomatous VF defects on at least 2 consecutive tests, an open angle on gonioscopy (not were determined as having a cluster of 3 or more nonedge points less than 30°), ametropia 0.5 dpt, intraocular pressure (IOP) of with P < .05 and at least 1 point with P < .01 in the pattern 21mm Hg or lower (without topical treatment) in repeated deviation probability plot, PSD of less than 5%; or glaucoma measurements on different days, follow-up at our clinic for at hemifield test results outside normal limits. Both the glaucoma least 4 years with visits at 3- to 5-month intervals, and no ocular patients and the healthy subjects underwent SAP at least twice pathology other than glaucoma. before this study. The healthy participants were recruited from the people The study included 24-hour blood pressure (BP) monitoring or accompanying the patients and had IOP of <21mm Hg for both automated measurement of BP for 24hours at fixed intervals eyes, a normal Humphrey Swedish Interactive Threshold according to a preset program. Measurements were made on an Algorithm (SITA) 24-2 standard visual field with mean deviation outpatient basis in the conditions of normal patient activity. The (MD), and pattern standard deviation (PSD) within 95% limits of device measured heart rate, systolic, and diastolic BP at set the normal reference. They also had a glaucoma hemifield test intervals using the oscillometric method, that is, by analyzing within 97% limits, a central corneal thickness ≥ 500mm, a pulse phenomena in a blood pressure cuff. normal-appearing optic nerve head (ONH), a normal RNFL, an Mean ocular perfusion pressure (MOPP) was calculated on the open anterior chamber angle as observed by gonioscopy, and no basis of IOP and arterial BP measurements immediately before 2 Kurysheva et al. Medicine (2018) 97:5 www.md-journal.com the optical coherence tomography (OCT) scanning and investi- into cold water (+4°C) with small pieces of ice; moreover, the gation of retrobulbar blood flow, after a 10-minute resting period hand was covered with plastic ice bags for 30seconds. The in the sitting position. Systemic BP was measured using the Riva registration of RR-intervals was made at the end of the CPT. Rocci technique. MOPP was calculated using the formula: The following characteristics were taken into account in [19] MOPP=(2/3 diastolic BP + 1/3 systolic BP) 2/ 3 – IOP. accordance with the international standard: BP was measured at rest in the sitting position. When Standard deviation of NN-interval (SDNN): the parameter of measuring BP in the sitting position, a back had a support, HRV characterizing the total effect of autonomic blood and the middle shoulder point was at the heart level (the fourth circulation regulation. A reduction in SDNN reflects low intercostal space). The measurement was made using Adyutor HRV indicating a high tone of heart sympathetic activity. The mechanical tonometer. decrease in SDNN reflects a decrease in HRV, which indicates an increase in the tone of heart sympathetic activity. 2.4. OCT image acquisition and processing The parameter of parasympathetic autonomic regulation activity (RMSSD). All subjects also underwent optic disc area measurement at Total spectral power (TP): the parameter of the absolute RTVue XR Avanti SD-OCT (Optovue, Inc., Fremont, CA) using activity level of regulatory systems. the traditional ONH scan. This scan consists of 12 radial scans of Power in the high-frequency range (HF): the parameter of the 3.4mm in length and 6 concentric ring scans ranging from 2.5 to spectral power of heart rate respiratory undulations reflecting 4.0mm in diameter, all centered on the optic disc. The retinal the activity level of respiratory center. The high- frequency pigment epithelium (RPE) tips are automatically detected by the band reflects fast changes in beat-to-beat variability due to software and are joined to delineate the optic disc margin and to parasympathetic activity. calculate the disc area. All the examinations for a particular Power in the low-frequency range (LF): The low-frequency subject were performed on the same day. OCT was performed in band is considered to be a fair approximation of sympathetic the macular area as well. The tracking mode was used. activity. The very low-frequency band reflects mostly sympa- The ganglion cell complex (GCC) scan mode measured thetic stimulation. macular inner retinal layer thickness from the internal limiting The low/high-frequency ratio is defined as a ratio of low- membrane (ILM) to the inner nuclear layer—Avg.GCC. The frequency to high- frequency power (LF/HF). A higher ratio GCC scan was centered on the fovea and covered a square grid on indicates increased sympathetic activity or reduced parasym- the central macula of 7.07.0mm. The GCC thickness was pathetic activity. determined with the GCC scanning protocol, which consists of The number of pairs of consecutive NN-intervals: the 15 vertical line scans covering a 7.07.0mm area centered about parameter of predominance degree of parasympathetic regula- 1mm temporal to the fovea. The GCC scanning protocol also tion over sympathetic one (pNN50). included a central horizontal line scan for registration of vertical Autonomic regulation index (ARI): the parameter used to scans and fovea center searching. The characteristics of GCC evaluate the activity of ANS. The increased ARI shows the (global loss volume—GLV, focal loss volume—FLV) were also activation of sympathetic regulation, but the decreased ARI measured. shows the activation of parasympathetic regulation. Variation range characterizing the degree of HRV (TINN). 2.5. HRV assessment The cardiovascular fitness assessment was made to all patients 2.6. Color Doppler imaging before and after CPT using Rhythm-MET hardware–software complex developed by the Federal State Unitary Enterprise Ocular and retrobulbar blood flow was registered by means of “Science Center of Radiation and Chemical Safety and Hygiene color Doppler imaging (CDI) and impulse Doppler sonography of the Medical and Biological Agency of the Russian Federation” (multifunctional VOLUSON 730 Pro System, General Electric according to the previously described method. Medical Systems, Germany) using a 10 to 15MHz linear Rhythm-MET hardware–software complex was used in the transducer. The methodology has been described earlier. Blood present study. The method of its work is based on a flow was studied in the ophthalmic artery (OA), central retinal comprehensive analysis of HRV, systemic hemodynamics, and artery (CRA), central retinal vein (CRV), lateral, and medial vegetative regulation. Photoplethysmograms recorded from a short posterior ciliary arteries (SPCA). We registered the Doppler [18] phalanx with an infrared sensor, located in the microproces- frequency shift and obtained quantitative blood flow parameters: sor module of data input and processing, were used as the source peak systolic blood flow velocity (PSV), end diastolic blood flow of data on HRV and peripheral blood flow. Cardiointervals velocity (EDV), mean blood flow velocity (V ), and the mean obtained from photoplethysmograms were processed in accor- resistivity index (RI). dance with the recommendations for assessment of HRV parameters and their subsequent generalization, including 3. Statistical analysis hemodynamics parameters, as well as for the assessment of functional status (FS) and functional reserves (FR) of the Statistical processing and analysis of the results related to HRV cardiovascular system according to the results of the examination parameters were aimed at identifying of those parameters of the at rest and after conducting CPT in order to form groups that are NTG group that would have statistically significant differences homogeneous in FS and FB. CPT also analyzed the parameters of from the mean group values at the comparison of the results time dependence of the amplitude of photoplethysmogram and related both to CPT (А ) and to a rest period (А before the cold rest recovery time after the test. test). The same calculation was made for the control group. The A generally accepted CPT was used as a provocation test. The mean group difference of the considered parameter was testing procedure was the following: a patient’s hand was dipped determined by averaging of the individual values of differences 3 Kurysheva et al. Medicine (2018) 97:5 Medicine statistics—Wilcoxon test, Mann–Whitney U test, implemented in Table 1 the corresponding statistics packages (IBM SPSS Statistics version Characteristics of healthy subjects and patients with normal 21, StatPlus). tension glaucoma. Parameters with the P < .05 were considered statistically Parameter NTG eyes Healthy eyes P significant. Since a number of parameters (GCC, GLV, systolic Age, years 64.2 (8.3) 65.2 (7.3) .613 BP, and MOPP) are depended on the anterior–posterior axis and Systolic BP, mm Hg 136.6 (9.6) 127.2 (10.1) .020 the age of the subjects, we carried out an adjustment for these Diastolic BP, mm Hg 76.3 (9.3) 80.8 (5.1) .03 parameters on the basis of the linear regression model. Minimum daily diastolic BP, mm Hg 28.0± 8.1 36.0± 4.1 .002 Corneal compensated IOP, mm Hg 13.5 (2.5) 14.4 (3.2) .140 MOPP, mm Hg 51.2 (8.3) 61.5 (5.3) .041 4. Results MD, dB 6.6 (3.3) 0.5 (1.09) .001 The patient characteristics are given in Table 1. PSD, dB 4.89 (1.65) 1.10 (0.81) .005 RNFL, mm 85.6 (6.1) 101.8 (6.1) .001 Table 1 shows the median of data and standard deviation (in Savg, mm 91.8 (7.3) 120.1 (7.3) .003 parentheses), the exact Mann–Whitney U test (P ) between the Iavg, mm 99.5 (8.1) 123.1 (9.2) .02 healthy eyes (control group) and NTG. GCC, mm 79.3 (5.2) 98.3 (7.1) .006 MOPP was significantly lower in the patients with NTG than FLV, % 3.48 (1.08) 0.17 (0.1) .003 in the control patients. The daily BP fluctuations in the study GLV, % 8.41 (1.96) 1.54 (1.74) .009 group ranged widely: from 75 to 145mm Hg for systolic BP Axial length, mm 23.2 (1.6) 23.0 (1.2) .673 and from 38 to 95mm Hg for diastolic BP. However, we used Corneal thickness, mm 535 (26.6) 533.5 (21.2) .891 the values of BP at the time of HRV study and IOP BP= blood pressure, FLV= focal loss volume, GCC= ganglion cell complex, GLV= global loss volume, measurement to calculate MOPP. According to the results of IOP= intraocular pressure, MD= mean deviation, MOPP= mean ocular perfusion pressure, NTG= 24-hour BP monitoring, the average systolic and diastolic BP normal tension glaucoma, PSD= pattern standard deviation, RNFL= retinal nerve fiber layer. was significantly lower in the patients with NTG than in the control patients. The same result was obtained with respect to of this parameter determined for each person in the compared the minimum daily diastolic BP. A significant difference in night groups. pulse pressure was also observed: it amounted to 37.0±5.1 1 The Euclidean distance from the experimental point i with the mm Hg in the NTG patients and 48.0±9.1mm Hg in the up to cold cold coordinates ðA ; A Þto the centre of the coordinates of control group (P=.04). i i planeðA ; A Þ was used as a measure of difference. At the HRV parameters in the studied groups and their shifts after the col up to col same time, the coordinates of “experimental points” relating to CPT are shown in Table 2. The Euclidean metric is applied. The the rest conditions (before the test) have the following exact Mann–Whitney U test (P ) between the NTG and healthy cold coordinates:ð0; A Þ. Since the samples are dependent (the same eyes (control group) before a cold test: P=.003; P=.02. composition of subjects), the Wilcoxon signed-ranks test for Table 2 shows that there are statistically significant differences matched pairs was used. The essence of this method is that instead between the studied parameters before and after the CPT both for of estimating the difference of distributions at one-dimensional the NTG group and healthy subjects. At the same time, when the scale of the considered parameter we estimated the distance (the CPT revealed the difference between the NTG group and healthy modulus of a vector) of each of the experimental points from subjects, it was established that only 2 parameters as HF and the natural mathematical object—the center of coordinates—in pNN50 did not significantly differ, so they should be less the space of 2 variables. The resulting set of the moduli of vectors important in case of their further use. is one-dimensional and, therefore, standard statistical processing Quantitative and qualitative representation of the preferred methods may be applied. direction of the shift in vegetative regulation in the NTG group We used standard methods of descriptive statistics: calculation and healthy subjects after the CPT is given in Table 3, where the of mean, standard deviations, T-tests, methods of nonparametric values of the shift in parameters (A) are presented in relative units Table 2 The average heart-rate variability parameters in the patients with normal tension glaucoma and healthy subjects before and after the cold provocation test. NTG Mean values±s Healthy subjects Mean values±s Level of significance of distinction Average values Indicators Before CPT After CPT Before CPT After CPT Indicators columns 2, 3 Indicators columns 4, 5 Indicators columns 3, 5 1 2 3 4 5 678 SDNN 0.034± 0.012 0.050± 0.012 0.042± 0.017 0.066 ± 0.024 0.003 0.0005 0.005 RMSSD 0.033± 0.011 0.050± 0.016 0.032± 0.015 0.054± 0.021 0.004 0.0002 0.018 TINN 0.195± 0.057 0.269± 0.053 0.230± 0.078 0.345± 0.109 0.0001 0.0001 0.010 TP 1082± 929 1570± 899 1773± 1542 3092± 502 0.008 0.02 0.007 LF 233± 134 375± 172 743± 1013 1085± 1253 0.009 0.0001 0.025 HF 256± 169 390± 222 307± 323. 317± 326 0.034 0.025 0.079 pNN50 5.9± 4.4 9.7 ± 6.5 5.7± 6.6 11.6± 9.0 0.08 0.005 0.58 ARI 309± 157 492± 223 249± 169 316± 192 0.009 0.002 0.011 LF/HF 1.14± 0.78 2.2± 2.0 2.92± 2.52 3.6± 0.7 0.003 0.002 0.036 The difference between mean group values in columns 2 and 4 is not significant and not shown in the table. ARI= autonomic regulation index, CPT= cold provocation test, HF= high-frequency range, LF/HF= low/high-frequency ratio, LF= low frequency range, NTG= normal tension glaucoma, pNN50= number of pairs of consecutive NN-intervals, RMSSD (Root Mean Square of the Successive Differences)—parameter of parasympathetic autonomic regulation activity, SDNN= standard deviation of NN-interval, TINN (triangular interpolation of NN)—variation range characterizing the degree of HRV, TP= total spectral power. 4 Kurysheva et al. Medicine (2018) 97:5 www.md-journal.com Table 3 The relative change in heart-rate variability parameter after the cold provocation test. Relative shift Relative shift in Parameters in NTG, dA healthy controls, dA Interpretation of the relative shift of the parameter after the CPT SDNN 47.1% 57.1% The change in parasympathetic regulation in the NTG group is less than in the healthy subjects that may reflect the activity of sympathetic regulation. RMSSD 51.5% 68.8% The change in parasympathetic regulation in the NTG group is less than in the healthy subjects TINN 37.9% 50.0% The change in parasympathetic regulation in the NTG group is less than in the healthy subjects LF 60.9% 46.0% The change of the parameter reflects the prevalence of sympathetic regulation in NTG HF 52.3% 3.3% Not statistically significant pNN50 64.4% 103.5% The change in parasympathetic regulation in the NTG group is less than in the healthy subjects ARI 59.2% 26.9% The change of the parameter reflects the prevalence of sympathetic regulation in NTG LF/HF 93.0% 23.3% The change of the parameter reflects the prevalence of sympathetic regulation in NTG ARI= autonomic regulation index, CPT= cold provocation test, HF= high-frequency range, LF/HF= low/high-frequency ratio, LF= low-frequency range, NTG= normal tension glaucoma, pNN50= number of pairs of consecutive NN-intervals, RMSSD= Root Mean Square of the Successive Differences—parameter of parasympathetic autonomic regulation activity, SDNN= standard deviation of NN-interval, TINN= triangular interpolation of NN—variation range characterizing the degree of HRV. with the ratiodA ¼ðA A Þ=A 100%, and the Table 4 shows the mean group values and the standard after before before qualitative conclusion is built on the analysis of the following deviation, the exact Mann–Whitney U test (P ) between the inequation A < A ; or A > A taking into ac- healthy eyes (control group) and early POAG. after before after before count the accepted physiological interpretation of the considered High correlation between the average pulse BP and OCT parameter. parameters was found out: with cup volume: r=0.65, P=.002, The analysis of relative shifts in the HRV parameters given in with rim volume: r=0.574, P=.008 and with lin. cup/disc ratio: Table 3 and the weighted sum of the individual conclusions on r=0.756, P=.009. High correlation was also found out these parameters provide the basis for the conclusion that CPT between the average daily diastolic BP and RNFL thickness (Avg. has a more pronounced sympathetic response of the autonomic RNFL): r=0.668 (P=.009). nervous system in the NTG group compared to the control group. The pronounced correlation between the main parameter of This difference is especially noticeable from the relative shifts in HRV – SDNN – and MOPP and structural parameters are shown such parameters as LF: dLF =61% > dLF =46% and as in Table 5. NTG Heal LF/HF: dLF/HF =93% > dLF/HF =23%. NTG Heal Thus, based on the results of the conducted analysis of the CPT 5. Discussion effect on the HRV parameters, these parameters can be The present study demonstrates a dysfunction of ANS in NTG recommended as additional ones for the diagnosis of NTG. First compared to healthy subjects and the shift of its balance towards of all, this refers to LF and LF/HF and then to SDNN, HF, and ARI. predominance of sympathetic activity in response to CPT. The parameters of retrobulbar blood flow in NTG were also Sympathetic neural activity (SNA) causes an increase of heart decreased in the NTG patients compared to the healthy subjects rate, stroke volume, and vasoconstriction. SNA regulates the (Table 4). circadian variation of BP and is closely related to nocturnal dipping. The present study observes the significant dipping of Table 4 diastolic BP in NTG compared to healthy subjects. This may be a Color Doppler imaging variables of the retrobulbar vessels in the consequence of the activation of the sympathetic innervation. studied groups. Chronic increased SNA can lead to arterial and cardiac Variables NTG Healthy subjects P remodelling, endothelial dysfunction, increased tissue oxygen CRA PSV, cm/s 11.3± 3.4 14.1± 1.8 .032 demand and subsequent decreasing of the ischamia threshold in CRA EDV, cm/s 2.7± 1.7 3.7± 0.9 .04 all organs, including the eye. CRA V , cm/s 5.8± 2.0 7.0± 1.3 .003 mean It is known that the regulation of ocular hemodynamics is CRA RI 0.78± 0.13 0.74± 0.04 .24 carried out at different levels: organ, tissue, and local (autor- SPCA lat. PSV, cm/s 12.1± 2.6 14.4± 1.8 .002 egulatory). Cell, membrane, and neurohumoral mechanisms play SPCA lat. EDV, cm/s 3.6± 1.6 5.2± 1.2 .03 SPCA lat. V , cm/s 6.8± 1.6 8.5± 1.3 .024 mean SPCA lat. RI 0.71± 0.12 0.63± 0.07 .04 SPCA lat. PI 1.3± 0.42 1.09± 0.2 .032 Table 5 SPCA med. PSV, cm/s 11.5± 2.6 13.8± 2.2 .015 Correlations between standard deviation of NN-interval, mean SPCA med. EDV, cm/s 3.6± 1.8 4.7± 1.0 .004 ocular perfusion pressure and circulatory parameters in studied SPCA med. V , cm/s 6.3± 1.7 8.2± 1.6 .002 mean groups. SPCA med. RI 0.69± 0.14 0.65± 0.06 .24 Variables MOPP SPCA lat. EDV SPCA RI CRA EDV OA PSV, cm/s 34.4± 6.2 39.3± 6.2 .056 OA EDV, cm/s 9.6± 3.1 9.3± 3.7 .06 SDNN 0.75 0.93 0.75 0.9 NTG OA V , cm/s 18.5± 4.1 17.2± 4.5 .074 P= .035 P< .001 P< .001 P< .001 mean OA RI 0.76± 0.2 0.77± 0.06 .088 SDNN 0.12 0.23 0.08 0.123 healthy OA PI 1.39± 0.34 1.77± 0.37 .034 P= .27 P= .35 P= .576 P= .12 CRA= central retinal artery, EDV= end-diastolic velocity, MOPP= mean ocular perfusion pressure, CRA= central retinal artery, EDV= end-diastolic velocity, NTG= normal tension glaucoma, OA= RI= resistive index, SDNN= standard deviation of NN-interval, SPCA= short posterior ciliary arteries. ophthalmic artery, PI= pulsatility index, PSV= peak systolic velocity,RI= resistive index, SPCA= The Spearman’s correlations and corresponding P for healthy subjects are given in italics. short posterior ciliary arteries, V = mean velocity. mean 5 Kurysheva et al. Medicine (2018) 97:5 Medicine their own roles. An optic nerve and its vasculature have rich are generally less prone to dilation, keeping tension of a vascular sympathetic (from cervical sympathetic system) and parasympa- wall, then there is no sufficient expansion of arteries at stress [24] thetic (from oculomotor nerve) innervations. There is the evidence tests. This fact explains the instability of ocular perfusion in of presence of the choroidal neuroplexus represented by numerous patients with PVD. internal autonomic ganglia, forming the autonomous perivascular The present study assessed the shift of HRV parameters network around the choroidal vessels. It is believed that it plays in NTG as a response to CPT. This test along with some vasodilatory function aimed at enhancing the ocular blood flow at others (oxygen, isometric exercise, brachial arterial occlusion, or [20] light load. Apparently, the autonomic dysfunction leading to light flicker) was used to examine blood flow regulation in [9,28,29] the failure of optic nerve and retinal blood flow play a significant NTG. [13] role in ocular physiology and pathophysiology in general and, Gherghel et al modified CPT involving immersion of a right [5] particularly, in glaucoma. hand in 40°C warm water followed by 4°C cold water exposure. According to the results of the present study, the significant Glaucoma patients demonstrated a significant decrease in finger reduction in ocular blood flow in the major vessels supplying the and ocular blood flow, while the healthy subjects exhibited optic nerve has been revealed in the NTG patients, and this increases in systolic BP and pulse pressure and a decrease in finger reduction has correlated to HRV. blood flow during cold provocation, but the ocular blood flow It has been recognized that the reduction of MOPP is closely was unchanged. According to the authors, these findings suggest [21,22] connected with glaucoma progression. High direct correla- a systemic autonomic failure and ocular vascular dysregulation in tion of MOPP with SDNN, observed in the present study, POAG patients. However, this group did not examine the NTG logically explains the possibility of ocular perfusion reduction in patients. the conditions of the increased activity of sympathetic blood flow According to the results of our study, the NTG patients have regulation. demonstrated an increase of SNA in response to CPT and this Our results are consistent with the literature data. According to shift was significantly different compared to the healthy subjects. Riccadonna et al, HRV, as well as the nocturnal diastolic BP Park with co-authors studied the NTG patients with different variability, reduced in NTG compared to POAG patients. types of HRV, and reported that VF progression in patients with Furthermore, these differences were more prominent in more sympathetic predominance is faster than in patients with higher severe clinical forms of NTG. The authors suggested a relation HRV. The authors concluded that the autonomic dysfunction, between the extent of autonomic disorder and severity of especially the decrease of SDNNs, was a predictor of central VF [23] [11] glaucoma. It is known that an increase of the sympathetic ANS progression in NTG. in response to the provocation tests is typical for people with In our study, we described the high correlation between HRV PVD. The development of NTG is associated with possible parameters, namely SDNN, and structural parameters: the more [2] PVD. The present study has pointed out to the role of PVD in pronounced SNA is associated with the more severe glaucoma the NTG pathogenesis. It is believed, that the main cause of PVD damage of ONH and RNFL. These results may be explained on is a vascular endotheliopathy and PVD itself does not lead to the the basis of the reduction of the blood supply to ONH and optic disc blood flow deficiency, but it is realized through peripapillary retina. Indeed, according to the CDI data, the [24] autoregulation failures. It can be assumed that the autor- parameters of retrobulbar blood flow in NTG were reduced egulation failure has been the cause of reduced blood flow in the significantly compared to healthy eyes that is in consistent with [15] examined patients in the present study. our previous data. According to the literature, PVD leads to the significant To the best of our knowledge, this is the first study that imbalance of sympathetic and parasympathetic departments of demonstrates the high correlation between local blood flow and [8] ANS, namely, the predominance of sympathetic innervations. HRV parameters in NTG: the more pronounced SNA was [25] Phelps and Corbett indicated for the first time PVD as a associated with the decreased ocular blood flow in OA and possible cause of NTG. They proved this thesis with the fact that SPCA. Based on the results of the conducted studies of the the patients with NTG often suffer from migraine. Later it was effect of CPT on the HRV parameters, they can be [8,21,22,26] confirmed by other authors. Another important risk recommended as additional parameters for the diagnosis of factor for NTG progression is fluctuations of perfusion NTG. First of all, this refers to LF and LF/HF and then to [26] pressure. It is believed that these fluctuations are primarily SDNN, HF, and ARI. determined by the presence of PVD. Although the role of PVD in Our study has several limitations that must be acknowledged. the pathogenesis of glaucomatous optic neuropathy has been First, we did not study the progression pattern of the disease and discussed for many years, only recent studies due to the use of we did not analyze the relation between HRV and functional loss. modern technologies could prove that patients with NTG, but Second, we did not evaluate the changes of circulatory not healthy individuals, suffer from the retinal blood flow parameters in response to CPT. Third, we did not assess test– [27] autoregulation failure in the conditions of provocation tests. retest variability, though it is known that HRV is a moderately to [30] From this point of view, the dysfunction of the autonomic blood fairly good reliable measurement. flow regulation seems to be of high importance and its study However, our study has an advantage over other studies on [9] attracts attention of the researches. Wierzbowska et al studied HRV in NTG as we did not include patients on antihypertensive HRV in NTG and revealed the sympathovagal balance of ANS in medication or topical medications that could influence BP and NTG patients that shifted towards sympathetic activity with no heart rate values. change of 24-hour pattern of BP variability as compared to the In summary, we found out that the NTG patients have the [10] healthy subjects. Na et al also observed significantly decreased disturbance of autonomic nervous system that increases in SDNN values in patients with NTG. response to stress provocation and is related with ocular blood The matter is that ocular blood flow in PVD can be normal in flow and structural damage. normal conditions, but a failure occurs in the conditions of a This finding refers to the NTG pathogenesis and suggests the provocation test, for example, a CPT. As retinal vessels in PVD use of HRV assessment in glaucoma diagnostics and monitoring. 6 Kurysheva et al. Medicine (2018) 97:5 www.md-journal.com [17] Headache Classification Committee of the International Headache References Society. Classification and diagnostic criteria for headache disorders, [1] Nicolela MT. Clinical clues of vascular dysregulation and its association cranial neuralgias and facial pain. Cephalalgia 1988;8:96. with glaucoma. Can J Ophthalmol 2008;43:337–41. [18] Ryabova TY, Shlapak VN, Shkurenko SA. Methods for checking and [2] Konieczka , Ritch R, Traverso C, et al. Flammer syndrome. EPMA J self-checking an output of the cardiovascular system and a checking 2014;5:11. device. PCT Gazette - Section III. International application numbers and [3] Nesher R, Kohen R, Shulman S, et al. Diastolic double-product: a new corresponding international publication numbers, Weekly Indexes entity to consider in normal-tension glaucoma patients. Isr Med Assoc J 19357-19404, Publication Number: WO 01/78598, No. of the 2012;14:240–3. international application: PCT/RU2000/000320, International filing [4] Narita K, Murata T, Hamada T, et al. Interactions among higher trait date: 02.08.2000, Date of publication: 25.10.2001, Priority Date: anxiety, sympathetic activity, and endothelial function in the elderly. J 2000109508 04/18/2000 RU. https://patentscope.wipo.int/search/ru/ Psychiatr Res 2007;41:418–27. detail.jsf?docId=WO2001078598&redirectedID=true [5] Clark CV, Mapstone R. Systemic autonomic neuropathy in open-angle [19] Heart rate variability. Standards of measurement, physiological glaucoma. Ophthalmol 1986;64:179–85. interpretation, Clinical use. Task Force of the European Society of [6] Kumar R, Ahuja VM. A study of changes in the status of autonomic Cardiology and the North American Society of Pacing and Electrophysi- nervous system in primary open angle glaucoma cases. Indian J Med Sci ology. European Heart Journal 1996;17:354–81. 1999;53:529–34. [20] Flugel C, Tamm E, Mayer B, et al. Species differences in choroidal [7] Brown CM, Dutsch M, Michelson G, et al. Impaired cardiovascular vasodilative innervation: evidence for specific intrinsic nitregic and VIP- responses to baroreflex stimulation in open angle and normal-pressure positive neurons in the human eye. Invest Ophthalmol Vis Sci 1994; glaucoma. Clin Sci 2002;102:623–30. 35:592–9. [8] Anders D, Vollenweider S, Cann J, et al. Heart-rate variability in women [21] Leske M, Heijl A, Hyman L. EMGT Predictors of long term progression during 40-hour prolonged wakefulness. Chronobiol Int 2010;27: in the early manifest glaucoma trial. Ophthalmology 2007;114:1965–72. 1609–28. [22] Leske M. Ocular perfusion pressure and glaucoma: clinical trial and [9] Wierzbowska J, Wierzbowski R, Stankiewicz A, et al. Cardiac autonomic epidemiologic findings. Curr Opin Ophthalmol 2009;20:73–8. dysfunction in patients with normal tension glaucoma: 24-h heart rate [23] Riccadonna M, Covi G, Pancera P, et al. Autonomic system activity and and blood pressure variability analysis. Br J Ophthalmol 2012;96:624–8. 24-hour blood pressure variations in subjects with normal and high [10] Na KS, Lee NY, Park SH, et al. Autonomic dysfunction in normal tension tension glaucoma. J Glaucoma 2003;12:156–63. glaucoma: the short-term heart rate variability analysis. J Glaucoma [24] Flammer J, Mozaffarieh M. Autoregulation, a balancing act between 2010;19:377–81. supply and demand. Can J Ophthalmol 2008;43:317–21. [11] Park H-YL , Park S-H, Park CK. Central visual field progression in [25] Phelps CD, Corbett JJ. Migraine and low tension glaucoma. A case- normal tension glaucoma patients with autonomic dysfunction. Invest control study. Invest Ophthalmol Vis Sci 1985;25:1105–8. Ophthalmol Vis Sci 2014;55:2557–63. [26] Choi J, Kim KH, Jeong J, et al. Circadian fluctuation of mean ocular [12] Neves VJ, Moura MJ, Almeida BS, et al. Chronic stress, but not perfusion pressure is a consistent risk factor for normal-tension hypercaloric diet, impairs vascular function in rats. Stress 2012;15: glaucoma. Invest Ophthalmol Vis Sci 2007;48:104–11. 138–48. [27] Drance CM, Douglas DV, Schilzer M. Response of blood flow to warm [13] Gherghel D, Hosking SL, Cunliffe IA. Abnormal systemic and ocular and cold in normal and low tension glaucoma patients. Am J Ophthalmol vascular response to temperature provocation in primary open-angle 1988;105:35–9. glaucoma patients: a case for autonomic failure? Invest Ophthalmol Vis [28] Plange N, Kaup M, Daneljan L, et al. 24-h blood pressure monitoring in Sci 2004;45:3546–54. normal tension glaucoma: night-time blood pressure variability. J Hum [14] Kurysheva NI, Nagornova ND. Vasospasm in the pathogenesis of Hypertens 2006;20:137–42. glaucomatous optic neuropathy (in Russian). Glaucoma 2004;2:18–24. [29] Venkataraman ST, Flanagan JG, Hudson C. Vascular reactivity of optic [15] Kurysheva N, Kiseleva T, Irtegova E, et al. Venous ocular blood flow in nerve head and retinal blood vessels in glaucoma—a review. Microcir- primary open angle glaucoma. Int J Ophthalmol Eye Res 2015;3:1–7. culation 2010;17:568–81. [16] Feke GT, Pasquale LR. Retinal blood flow response to posture change in [30] Piepoli M, Radaelli A, Ponikowski P, et al. Reproducibility of heart rate glaucoma patients compared with healthy subjects. Ophthalmology variability indices during exercise stress testing and inotrope infusion in 2008;115:246–52. chronic heart failure patients. Clin Sci 1996;91:87–8.
Medicine – Wolters Kluwer Health
Published: Feb 1, 2018
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