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  Choroidal Blood Flow Regulation after Posture Changeor Isometric Exercise in Men with Obstructive Sleep Apnea Syndrome  Hafid Khayi, 1,2   Jean-Louis Pepin, 2,3  Martial H. Geiser, 4  Matthieu Tonini, 1,2  Renaud Tamisier, 2,3  Elisabeth Renard, 1,2   Jean-Philippe Baguet, 2,5  Patrick Levy, 2,3   Jean-Paul Romanet, 1 and Christophe Chiquet  1,2 P   URPOSE .  Obstructive sleep apnea (OSA) syndrome generateshypertension, atherosclerosis, and endothelial and autonomicdysfunction, which may mutually interact with ocular vascular regulation. Exercise and posture changes can be used to ma-nipulate blood pressure, ocular perfusion pressure (OPP), or both. It was hypothesized that choroidal vascular reactivity inresponse to isometric exercise and posture changes could bealtered in OSA patients. M ETHODS .  Healthy men were matched 1:1 for body mass index,sex, and age with patients with newly diagnosed OSA withoutcardiovascular comorbidities. All subjects underwent sleepstudies and cardiovascular phenotyping (24-hour blood pres-sure monitoring, arterial stiffness measurements, and cardiacand carotid echography). Choroidal reactivity was assessed by laser Doppler flowmetry, which measured subfoveal choroidalblood flow. R  ESULTS .  During exercise, blood pressure parameters increasedsignificantly within the same range, with a similar profile over time in OSA patients and control subjects. A significant linear relationship (   P     0.0003) was noted between choroidal vas-cular resistance and the OPP changes during exercise in OSA patients and control subjects. From the sitting to the supineposition, a significant decrease in mean arterial pressure oc-curred in both groups (10.9%–13.4%;  P     0.001). In both populations, no significant change in choroidal blood flow or  vascular resistance was found during the posture change. Cho-roidal blood flow responses to exercise and posture changes were unchanged after 6 to 9 months of continuous positiveairway pressure treatment. C ONCLUSIONS .  This study strongly suggests that the regulation of choroidal blood flow, which depends on the orthosympa-thetic and parasympathetic systems, is unaltered in men with OSA who have no comorbidities. (ClinicalTrials.gov number, NCT00874913.) (   Invest Ophthalmol Vis Sci.  2011;52:9489–9496) DOI:10.1167/iovs.11-7936 O bstructive sleep apnea (OSA) is a common disease occur-ring in up to 5% of the general population. 1 The desatu-ration-reoxygenation sequence is nearly systematically associ-ated with apnea, and hypopnea is a detrimental stimulus for the cardiovascular system. OSA has been shown to generatehypertension, 2 atherosclerosis, 3 endothelial dysfunction, and vascular remodeling. 4 OSA can also be responsible for auto-nomic dysfunction with high sympathetic tone, an increase inbaseline heart rate, elevated muscle sympathetic nerve activ-ity, 2,5 and reduced baroreflex sensitivity. 6  All these potential cardiovascular consequences associated with OSA may also interact with ocular vascular regulation, assuggested by the relation between OSA and nonarteritic ante-rior ischemic optic neuropathy, 7 central serous chorioreti-nopathy, 8 and glaucomatous optic neuropathy. 9 Our recentstudy on ocular microcirculation in OSA  10  with laser Doppler flowmetry (LDF) showed that OSA patients without cardiovas-cular comorbidities exhibited normal choroidal vasoreactivity in response to hyperoxia and hypercapnia. These experimentsexplored the mechanisms underlying hypercapnia-induced va-sodilatation explained by a reduction in pH 11 and an increasein nitric oxide (NO) availability. 12 Contrary to the retinal andoptic nerve head vasculature, choroid vessels are also subjectto autonomic regulation. 13–16 Body posture changes and iso-metric exercise are noninvasive methods for modifying bloodflow to the eye, either after modification of gradient pressurebetween the heart and the eye (posture changes) 17 or after anincrease in systemic blood pressure (exercise). 18 Indeed, de-spite variations in systemic blood flow, choroidal blood flow isknown to be autoregulated to maintain stable nutrition in theouter retina and to keep the temperature of the retina constant.However, its ability to autoregulate may be altered in smok-ers 19 and in patients with eye diseases such as age-relatedmacular degeneration, 20 central serous chorioretinopathy, 21 and glaucoma. 22 On the other hand, the abnormal posturalbehavior of intraocular pressure (IOP) changes has been de-scribed in patients with diabetes or systemic hypertension, 23  which are potential complications of OSA.This study examines the hypothesis that sleep apnea pa-tients differ from control subjects in their ability to regulatechoroidal blood flow in response to changes in blood pressure.To this end, we investigated choroidal vascular reactivity re-sponses to exercise and change in body position in OSA pa- From the Departments of   1 Ophthalmology,  5 Cardiology, and  3 Re-habilitation and Physiology and the  2 Laboratory of Hypoxia and Phys-iopathology, University Hospital, Universite´ Joseph Fourier, Grenoble,France; and  4 Haute Ecole Spe´cialise´e de Suisse Occidentale, University of Applied Sciences, Western Switzerland, Switzerland.Supported by Innovation Hospitalie`re (Grenoble University Hos-pital), AGIRADOM Scientific Council, French Hospitals Federation,Ministry of Foreign Affairs (Egide, Germaine de Stae¨l programme), andHaute Ecole Spe´cialise´e de Suisse Occidentale.Submitted for publication May 25, 2011; revised September 2,2011; accepted September 8, 2011.Disclosure:  H. Khayi  , None;  J.-L. Pepin  , None;  M.H. Geiser  ,None;  M. Tonini  , None;  R. Tamisier  , None;  E. Renard  , None;  J.-P.Baguet  , None;  P. Levy  , None;  J.-P. Romanet  , None;  C. Chiquet  ,NoneCorresponding author: Christophe Chiquet, Department of Oph-thalmology, CHU de Grenoble, F38043, University Hospital, Universite´ Joseph Fourier- Grenoble 1, F38041, Grenoble, France;cchiquet@chu-grenoble.fr. Clinical Trials Investigative Ophthalmology & Visual Science, December 2011, Vol. 52, No. 13Copyright 2011 The Association for Research in Vision and Ophthalmology, Inc.  9489  tients without associated comorbidities and in matched healthy control subjects. This investigation was also carried out after continuous positive airway pressure (nCPAP), which may im-prove vascular reactivity in OSA patients. 24 M  ATERIALS AND  M ETHODS Study Population  OSA Patients.  Twenty-one patients with newly diagnosed OSA and no associated comorbidities were included in this prospectivestudy. Fourteen patients participated in the isometric exercise exper-iment and 15 in the posture experiment. The study was conducted inaccordance with the Declaration of Helsinki for research involvinghuman subjects and adhered to Good Clinical Practice guidelines.Informed consent was obtained from the subjects after explanation of the study. The study protocol was approved by the local institutionalreview board (IRB 6705) and was registered on ClinicalTrials.gov (NCT00874913). This study encompasses data not previously reportedbut acquired from subjects who completed the protocol previously described. 10 Inclusion criteria were presence of OSA, defined by an apnea-hypopnea index (AHI) greater than 15/hour (number of episodes of partial [hypopnea] or complete [apnea] upper airway obstruction); age18 to 80 years; and affiliation with the health care system.Exclusion criteria were ocular disease (including cataract or retinaldisease, ametropia greater than 3 diopters, optic neuropathy), diabe-tes, cardiovascular treatment (vasoconstrictors, vasodilators, beta andalpha agonists or antagonists, NO-derived medication), corticosteroids,theophylline, sildenafil, immunosuppressors, neuroleptics, nonsteroi-dal anti-inflammatories, estrogen plus progestin treatment, hypnotics(benzodiazepines), and local treatment for ocular hypertension or glaucoma. CPAP compliance was considered acceptable if the device was used for at least 4 hours per night. 25 Controls.  Control subjects, matched 1:1 with OSA patients for body mass index (BMI), sex, and age, were assessed by a completeovernight polysomnographic study to rule out OSA and then wereincluded. At the screening visit, each subject underwent a generalexamination and cardiovascular and neurologic examinations. A bloodsample was analyzed to characterize the cardiovascular and metabolicprofile (Table 1). Ophthalmic Examination and Intraocular Pressure Measurement  Each patient had a complete ocular examination (visual acuity, slit-lamp examination, IOP, gonioscopy, funduscopy). The eye examina-tion was completed by visual field tests (Humphrey 24-2 and 10-2 SITA standard visual field) and measurements of retinal nerve fiber layer thickness using optical coherence tomography (OCT3; Carl Zeiss,Oberkochen, Germany). Ocular examination results of all OSA patientsand control subjects were normal. Polysomnography  Continuous recordings were taken with electrode positions C3/A2-C4/  A1-Cz/01 of the International 10-20 System of Electrode Placement, eyemovements, chin electromyogram, and ECG with modified V2 lead.Sleep was scored manually according to standard criteria. 26  Air flow  was measured with nasal pressure associated with the sum of buccaland nasal thermistor signals. Respiratory effort was monitored with abdominal and thoracic bands. An additional indicator of respiratory effort (pulse transit time) was recorded concurrently. Oxygen satura-tion was measured using a pulse oximeter (Biox-Ohmeda 3700; Ohm-eda, Liberty Corner, NJ). Respiratory events were scored in line with clinical research recommendations. 26 Cardiovascular Phenotype of OSA Patients and Control Subjects  Ambulatory blood pressure monitoring (ABPM) was carried out with alightweight monitor (Diasys Integra; Novacor SA, Rueil-Malmaison,France) every 15 minutes during daytime and every 30 minutes duringnighttime. The following ABPM parameters were studied: mean sys-tolic blood pressure (SBP), diastolic blood pressure (DBP), mean arte-rial pressure (MAP), and heart rate over 24 hours and throughout thedaytime (7 am–10 pm) and nighttime (10 pm–7 am). 27 Hypertensionand normal nocturnal dipping were defined as previously reported. 28 Echocardiography, as well as carotid intima-media thickness and stiff-ness, were assessed as previously described by our group. 29 Choroidal Blood Flow Measurements The LDF instrument used in this study to measure subfoveal choroidalblood flow (ChBF) has been described previously. 30 The blood flow   T  ABLE  1.  General Characteristics of OSA Patients and Control Subjects Exercise PostureOSA Patients(  n  14)Healthy Controls(  n  14)  P OSA Patients(  n  15)Healthy Controls(  n  15)  P  Anthropometrics Age, y 49.6  2.4 50.5  2.6 0.95 50.1  2.6 50.4  2.6 0.67Body mass index, kg/m 2 26.3  0.5 25.2  0.4 0.04 26.7  0.5 25.3  0.4 0.09Sleep studies AHI, hours of sleep 38.9  4.2 4.1  0.6   0.001 41.6  4.2 4.1  0.6   0.001Mean nocturnal saturation, % 93.9  0.4 94.3  0.3 0.51 93.8  0.3 94.3  0.3 0.70Time spent at SaO 2  90%, min 28.8  9.1 1.1  0.6 0.001 19.9  5.5 1.1  0.7 0.002Cardiovascular phenotypeSystolic blood pressure, mm Hg 123.8  2.8 124.9  1.6 0.73 123.8  2.5 125.5  1.7 0.47Diastolic blood pressure, mm Hg 82.1  1.7 79.5  1.7 0.16 81.2  0.8 79.5  1.7 0.15Mean blood pressure, mm Hg 95.0  1.9 94.6  1.6 0.86 94.3  1.2 94.9  1.6 0.04Nocturnal dipping, no. patients (%) 7 (50) 5 (36) 0.99 5 (33) 6 (40) 0.48 Arterial stiffness, m/s 9.8  0.5 9.1  0.6 0.49 9.8  0.5 8.7  0.5 0.24IMT right carotid,   m 0.65  0.04 0.58  0.02 0.44 0.67  0.04 0.57  0.02 0.17IMT left carotid,   m 0.64  0.04 0.63  0.03 0.65 0.67  0.04 0.62  0.03 0.71Carotid plaque, no. patients (%) 2 (14) 0 3 (20) 0Left ventricular ejection fraction, % 67.4  1.1 67.0  1.2 0.97 68.3  1.1 67.0  1.6 0.77Dyslipidemia, no. patients (%) 1 (7) 1 (7) 0.99 2 (13) 2 (13) 0.99IMT, intima-media thickness. 9490 Khayi et al.  IOVS,  December 2011, Vol. 52, No. 13  measurement is obtained from the choriocapillaris layer behind the fovea,the superficial layer of the choroid with a dense network of capillaries.The instrument uses a coherent near-infrared probing beam (785 nm, 90   W at the cornea) that conforms to the American National StandardsInstitute standard Z 136.1 for laser safety. The beam is focused at thefovea, and the subject is asked to look directly at the beam. Light back-scattered by the tissue in the sampled volume is collected by a bundle of optic fibers and guided to an avalanche photodiode. The output photo-currentissampledatafrequencyof240kHzwitha16-byteresolutionandprocessed with graphical programming software (LabVIEW; National In-struments, Austin, TX) to ascertain the ChBF parameters in real time at arate of 17 Hz using an algorithm based on photon diffusion and probabi-listic theory. These parameters are choroidal velocity (ChBVel [kHz]),choroidal volume (ChBVol, in arbitrary units [AU]), and relative flow (ChBF    ChBVel    ChBVol [AU]) of the red blood cells within thesampled tissue region. The software automatically rejects signals for  which the light intensity (direct current [DC]) is not within  10% of itsmost frequent value or the volume is suddenly too large because of microsaccades, for example. Care was taken to keep the DC signal asconstantaspossibleduringrecording.Twoormorecontinuous30-secondrecordings of the choroidal LDF parameters were obtained for each measurement, and a minimum 12-second valid measurement in each eye was analyzed. Study Protocol  Patients were asked to abstain from alcohol and caffeine for at least 12hours before the trial. LDF was systematically performed on the righteye. Systolic and diastolic blood pressure measurements were obtained(Dinamap; Critikon, Tampa, FL) during LDF measurements. The IOP of the fellow eye was then immediately measured using a tonometer (Tonopen XL; Reichert Technologies, Depew, NY). Mean ocular per-fusion pressure (OPP) was calculated according to the following for-mula 31 : OPP sitting position  (0.74  MAP)  IOP and OPP supine position  (0.84  MAP)  IOP, in which MAP was calculated as: MAP  DBP  1/3(SBP  DBP).The study was conducted after a randomized, double-blind, three- way crossover design. Two types of experiment were conducted:isometric exercise consisting in squatting (for 2 minutes) and a changein body posture from the sitting to the supine position (for 10 minutes;Fig. 1). These experiments took place on a different day than the gasexperiments reported in another paper. 10 Scheduled resting periods for each subject were at least 20 minutes in a sitting position before the study and 30 minutes between each experimental period. Stable baseline con-ditions were established, ensured by repeated measurement of bloodpressure. Three LDF recordings lasting 30 seconds each were made atbaseline and at the end of the recovery period (Figs. 1A, 1B). Duringsquatting, one 30-second LDF recording was made after 1 and 2 minutesof exercise. For the posture change experiment, three 30-second LDFrecordingsweremadefor5and10minutesinthesupineposition(Fig.1).During the supine position, LDF measurements were taken with the laser Doppler flowmeter mounted on a swivel arm, keeping a stable ocular-to-cornea distance. When several measurements were obtained at one time,only one LDF recording was chosen according to the DC stability over the whole experiment (   10%).Similar experiments were conducted for the OSA group of patientsafter 6 to 9 months of nCPAP treatment. Six of 14 patients and 9 of 15patients were included for this analysis during the exercise and posturechange experiments, respectively. Others were excluded because of CPAP not being indicated (  n  2), noncompliance with CPAP (  n  1),or refusal to participate in the second part of the study (  n  5). Statistical Analysis Data are presented as mean  SEM. Normalized data during the exper-iment were calculated according to baseline data. Data analysis wasconducted with statistical analysis and graphics software (NCSS 97[NCSS, Kaysville, UT]; SAS 9.1.3 [SAS Institute, Cary, NC]). Normality  was assessed using skewness and kurtosis tests. To check the ANOVA assumptions, variance equality was also tested using the ModifiedLevene Equal Variance Test. The changes within each group wereanalyzed by a one-way repeated ANOVA measure (repeated measurefactor was time). Paired  t  -tests were then used for post hoc analysis.The  P   value was modified using Bonferroni correction. The corrected  P   value for post hoc analysis was 0.008. A repeated-model ANOVA wasalso used with two repeated factors, the factor group (first model: OSA  versus healthy; second model: before versus after CPAP) and the factor time. We analyzed group and time effects as well as group-time inter-action. The two groups were also compared at baseline for generalparameters (Table 1; paired  t  -test or Wilcoxon test according thenormality for quantitative data, McNemar test for qualitative data). Therelationships between OPP and blood flow and OPP and vascular resistance were studied using the generalized estimating equation.Sensitivity (the minimum statistically significant change in LDFparameters (  S   ) that could be detected) was calculated using the for-mula 18 S   (  t   SD   )/(   n   P  mean  )  100, where  P  mean  is the mean value of all measurements,  SD   is the SD of the difference between thepaired measurement for all subjects, and  t   is the two-tailed value of the t   distribution at a 0.05 significance level for the  n    1 degrees of freedom. In the present experiment, sensitivity for ChBF in OSA pa-tients and control subjects was 9% and 7%, respectively. As described previously, 32  when using LDF to detect a 15% differ -ence in flow with 80% power by means of a paired test, seven subjectsare needed to evaluate changes within one session.For the exercise experiment, to define the pressure-flow relation-ship, OPP data were divided into five groups of eight values. The mean values from these groups were used to determine the OPP at which theChBF significantly deviated from baseline. R  ESULTS Patient and Control Subject Characteristics The control subjects’ and patients’ characteristics are summa-rized in Table 1. As a whole group, OSA patients were middle-aged, lean, and otherwise healthy except for OSA with a F IGURE  1.  Study protocol. ChBF pa-rameters, IOP, and systemic bloodpressure were measured at baseline,after 1 and 2 minutes of isometricexercise (squatting) or 5 and 10 min-utes in the supine position, and after 10 minutes of recovery.  IOVS,  December 2011, Vol. 52, No. 13  Ocular Blood Flow in OSAS 9491  limited amount of oxygen desaturation at night. As cardiovas-cular consequences, OSA patients exhibited at most subclinicallesions of the cardiovascular system, stage 1 hypertension, or both. No patient had diabetes mellitus. The OSA group con-sisted of 14 patients assessed for exercise and 15 patients for posture. In both groups, BMI was within the normal range, with a statistically but not clinically significant difference be-tween control subjects and OSA patients. Exercise Experiment   At baseline, MAP and OPP were similar in both groups (  n  14OSA patients,  n    14 control subjects), whereas IOP washigher in the healthy group (13.6  0.6 mm Hg in OSA pa-tients; 16.2  0.8 mm Hg in control subjects;  P     0.02) but withinthenormalrange.MAPincreasedduringexercise:27%and33% at 1 and 2 minutes in OSA patients (   P   0.001 from baseline)and 23% and 35% in control subjects (   P   0.001 from baseline),respectively. MAP variations were similar in both groups (   P    0.27). A significant increase of approximately 25% to 30% in both SBP and DBP occurred during exercise within a similar range inboth groups. There was no significant difference between groupsfor SBP (   P     0.16) or DBP (   P     0.57). OPP increased duringexercise: 33% and 41% at 1 and 2 minutes in OSA patients (   P   0.004 from baseline) and 28% and 45% at 1 and 2 minutes incontrol subjects (   P     0.001 from baseline), respectively (nodifference between groups;  P   0.32).The relationship between the OPP and ChBF during thesquatting period is shown in Figures 2A and 2B. No statisticalcorrelation was found between ChBF and OPP (   P     0.28) inOSA and control subjects. A significant linear relationship wasnoted between vascular resistance (R) and the OPP changes(OSA subjects,  R  0.83  OPP  8.50; control subjects,  R  0.67    OPP    20.77) during exercise (   P     0.0003), with asimilar slope in OSA and control subjects (   P   0.3). There wasno statistical interaction (   P     0.82) of the relation betweenOPP and ChBF and the group (OSA or healthy). Posture Change Experiment  OSA patients (  n  15) differed from control subjects (  n  15) inthat they had a lower mean IOP (   P     0.003; Table 2). In OSA patientsandcontrolsubjects,asignificantdecrease(   P   0.001)inMAP (Fig. 3) was noted at 5 minutes (respectively, 10.3%, and10.3%) and 10 minutes (respectively, 10.9%, and 13.4%) duringthe supine position. There was no significant difference betweengroups (   P     0.82). In both populations, MAP regained baseline values at the end of the experiment. A significant increase in IOP was noted in the OSA group (   P     0.02). OPP remained stablethroughout the experiment (Fig. 3).In both populations, no significant change in ChBVol, ChBF,and choroidal vascular resistance was found during the posturechange for both groups. A significant increase in ChBVel wasnotedinbothgroups(20.4%vs.9%incontrolsubjects;  P   0.18). F IGURE  2.  ChBF versus OPP duringsquatting, normalized for baseline.Each data point represents an aver-age of eight successive and indepen-dent values of the percentage changeof OPP in (   A   ) OSA patients and (  B  )control subjects. (  C  ) The correlationbetween choroidal blood resistancesand OPP (   P   0.001) in OSA patientsand control subjects (   P     0.3) is il-lustrated. Normalized data were ex-pressed as mean  SEM. 9492 Khayi et al.  IOVS,  December 2011, Vol. 52, No. 13
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