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Citation: Abdessater, L.; Hein, M.;
Rasquin, F. Analysis of Macular
Vascularization Using Optical
Coherence Tomography Angiography
in Patients with Obstructive Sleep
Apnea Syndrome: A Prospective
Clinical Study. Medicina 2024,60, 757.
https://doi.org/10.3390/
medicina60050757
Received: 7 April 2024
Revised: 27 April 2024
Accepted: 28 April 2024
Published: 2 May 2024
Copyright: © 2024 by the authors.
Licensee MDPI, Basel, Switzerland.
This article is an open access article
distributed under the terms and
conditions of the Creative Commons
Attribution (CC BY) license (https://
creativecommons.org/licenses/by/
4.0/).
medicina
Article
Analysis of Macular Vascularization Using Optical Coherence
Tomography Angiography in Patients with Obstructive Sleep
Apnea Syndrome: A Prospective Clinical Study
Laura Abdessater 1, Matthieu Hein 2, 3, * and Florence Rasquin 4
1Hôpital Universitaire de Bruxelles, Service de Médecine Interne, UniversitéLibre de Bruxelles, ULB,
1070 Bruxelles, Belgium; laura.abdessater@hubruxelles.be
2Hôpital Universitaire de Bruxelles, Service de Psychiatrie et Laboratoire du Sommeil, UniversitéLibre de
Bruxelles, ULB, 1070 Bruxelles, Belgium
3Laboratoire de Psychologie Médicale et Addictologie (ULB312), UniversitéLibre de Bruxelles, ULB,
1020 Bruxelles, Belgium
4Hôpital Universitaire de Bruxelles, Service d’Ophtalmologie, UniversitéLibre de Bruxelles, ULB,
1070 Bruxelles, Belgium; florence.rasquin@hubruxelles.be
*Correspondence: matthieu.hein@ulb.be; Tel.: +32-25553741; Fax: +32-25556955
Abstract: Background and Objectives: Given the conflicting data available in the literature, this study
aimed to investigate the impact of obstructive sleep apnea syndrome (OSAS) on the macular vascular
density (VD) and perfusion density (PD). Materials and Methods: Based on the obstructive apnea–
hypopnea index (OAHI), 61 prospectively recruited patients were assigned to either a control group
(n= 12; OAHI < 5/h) or an OSAS group (n= 49; OAHI
≥
5/h). The macular VD and PD of
the superficial and deep capillary plexuses (SCP and DCP, respectively) were measured in the
parafoveolar and perifoveolar areas using Zeiss PLEX Elite 9000 (6
×
6 mm). The values were
compared between the control and OSAS groups. Results: Compared with the control group, the
OSAS group demonstrated an increased VD of the DCP in the parafoveolar and perifoveolar areas
and PD of the DCP in the perifoveolar area. No significant differences in either the macular VD or
PD of the SCP were observed. There was no correlation between the OAHI and macular VD or PD.
Conclusions: This study indicates that collateral vessel formation and possible retinal vasodilation
occur in the DCP of patients with OSAS.
Keywords: obstructive sleep apnea syndrome; vascular density; retinal vascular network; superficial
capillary plexus; deep capillary plexus; optical coherence tomography angiography
1. Introduction
Obstructive sleep apnea syndrome (OSAS) is a major public health issue. The preva-
lence of OSAS in the global population is difficult to assess, as it is underdiagnosed. OSAS
is associated with an increased risk of cardiovascular events and diabetes. If left untreated,
it can result in difficult-to-control high blood pressure, heart rhythm disorders, and blood
hypercoagulability [
1
]. OSAS is also associated with heart failure, pulmonary hypertension,
and chronic kidney disease [
1
]. Risk factors for OSAS include obesity, age, male sex, African
ethnicity, smoking, and certain craniofacial morphologies [2].
OSAS is characterized by repeated episodes of complete (apnea) or partial (hypopnea)
obstruction of the upper airway during sleep, resulting in episodes of oxygen desaturation,
hypercapnia, and micro-arousals that impair sleep quality [
2
,
3
]. It is diagnosed when
polysomnography reveals an obstructive apnea–hypopnea index (OAHI) greater than 5
(i.e., at least five episodes of obstructive apnea/hypopnea per hour of sleep). Intermit-
tent hypoxia induces hyper-activation of the sympathetic nervous system, inflammatory
response, and oxidative stress. These are the primary mechanisms responsible for the
Medicina 2024,60, 757. https://doi.org/10.3390/medicina60050757 https://www.mdpi.com/journal/medicina
Medicina 2024,60, 757 2 of 11
cardiovascular and metabolic consequences associated with OSAS [
4
]. Acute hypoxia also
induces self-regulated retinal vasodilation [5].
Studies have suggested that OSAS is associated with various ophthalmologic con-
ditions, such as non-arteritic anterior ischemic optic neuropathy, retinal vein occlusion,
glaucoma, central serous chorioretinopathy, and severe diabetic macular edema [
6
,
7
]. Sev-
eral studies have assessed choroidal thickness in patients with OSAS; however, these
studies have presented divergent results. One meta-analysis concluded that there was a
significant decrease in choroidal thickness in patients with OSAS [8].
Optical coherence tomography angiography (OCTA) is an imaging technique that
allows visualization of the retinal and choroidal vasculatures without contrast injection.
The retina is irrigated by two vascular networks: retinal and choroidal vascularization.
OCTA highlights the superficial and deep capillary plexuses (SCP and DCP, respectively)
of the retinal vascular network (RVN). Limited studies have investigated the RVN density
using OCTA in patients with OSAS, and the available evidence is inconsistent. For example,
Yu et al., who were among the first to investigate the macular perfusion density (PD)
in patients with OSAS, reported a decrease in the density in the parafoveolar area with
increasing OSAS severity [
9
]. Meanwhile, Moyal et al. reported no significant differences
in the macular PD between their control, mild OSAS, moderate OSAS, and severe OSAS
groups [
10
]. Additionally, while Cai et al. observed a significant increase in the PD in the
parafoveolar and perifoveolar DCP regions in patients with severe OSAS compared with
that in controls, no difference was seen in the PD of the SCP [3].
The Ophthalmology Department of Erasme Hospital in Brussels is equipped with
PLEX Elite 9000. Owing to its powerful algorithm, this equipment allows accurate quanti-
tative analysis of the retinal vascular density in terms of both the PD and total length of
perfused vessels (VD). This study primarily assesses the retinal vascular density and has
the following objectives:
(1)
To assess the macular VD of both the SCP and DCP in patients with OSAS;
(2)
To assess the macular PD of both the SCP and DCP in patients with OSAS;
(3)
To assess the possible correlation between the macular VD and OSAS severity.
2. Materials and Methods
2.1. Methodology
Patients were recruited from the Sleep Laboratory of Erasme Hospital (SLEH). Polyso-
mnography was previously indicated by each patient’s physician. The study was verbally
described to all patients scheduled for polysomnography either on the day of the procedure
or the following day. Written informed consent was obtained from all patients included in
the study. Patient recruitment, data collection, ophthalmologic examination, and ocular
imaging were performed by the same investigator during each patient’s hospitalization.
2.1.1. Study Design and Population
This single-center prospective observational clinical study assessed SLEH patients
between January and March 2021. The inclusion criteria for this study were to sign informed
consent for participation and to stay at the SLEH between January and March 2021 to benefit
from a polysomnographic examination. The exclusion criteria for this study were OSAS
already treated by CPAP; ongoing oxygen therapy; history of retinal surgery, retinopathy
and/or maculopathy, ocular trauma, or glaucoma; best-corrected visual acuity (BCVA) of
≤
7/10 on the Monoyer scale (
≥
0.2 in LogMar) or a spherical equivalent (SE) of <
−
6 diopters
(strong myopes) in both eyes. A control group and a study group were formed on the basis
of the OAHI following the results of polysomnography. Patients with an OAHI of
≥
5 and
<5 were assigned to the OSAS group and the control group, respectively. Ophthalmologic
examinations were performed blind (i.e., the investigator did not know whether a patient
had OSAS or not).
Medicina 2024,60, 757 3 of 11
2.1.2. Data Collection
Age, sex, body mass index, smoking status, and medical history were collected from
all patients included in this study by a physician during the routine admission interview
based on a standardized form specific to the SLHE. The patients underwent an ophthal-
mologic clinical examination, including refractometry, forced-air tonometry, and BCVA
assessment using the Monoyer scale. Each patient then underwent ocular imaging using
a wide-angle fundus imaging software (Zeiss Clarus 500), optical coherence tomography
(OCT, Heidelberg Engineering Spectralis), Enhanced Depth Imaging OCT (OCT-EDI) of the
macular region, and OCTA (Zeiss PLEX Elite 9000, version 1.7, Swept-Source OCTA). Re-
fraction (SE), BCVA, intraocular pressure (IOP) by pulsed air, macular thickness, choroidal
thickness in the foveolar area, and macular VD and PD were measured in both eyes of
each patient. The polysomnography results were reported by the physician in charge of the
SLEH 3 weeks after the examination was performed. The data were collected and managed
via Erasme Hospital’s secure electronic platform, REDCap.
2.1.3. Polysomnography
Polysomnographic examinations were performed at the SLEH in accordance with the
recommendations of the AASM [
11
]. The polysomnographic setup used is described in
Annex S1. Polysomnographic recordings were visually scored by specialized technicians
in accordance with the AASM criteria [
12
]. Annex S1 shows the criteria for obstructive
sleep apnea and hypopnea and the calculation of the OAHI. OSAS was considered absent
when the OAHI was <5/h and present when the OAHI was
≥
5/h. The OSAS group
included mild (OAHI of 5–14), moderate (OAHI of 15–29), and severe (OAHI of
≥
30)
OSAS cases [13].
2.1.4. Ocular Imaging Data Processing
OCT and OCT-EDI
Macular and choroidal thicknesses were measured at the foveola by an experienced
investigator.
OCTA
OCTA enables the three-dimensional visualization of retinal and choroidal vascular
structures without contrast injection or contact. It is based on the principle of detecting the
movements of diffracting particles, such as erythrocytes. Each B-scan is repeated several
consecutive times at the same retinal location to detect moving pixels (i.e., erythrocytes) and
stationary pixels, thus revealing blood vessel flow [
14
], to generate the retinal microvascular
structure images.
PLEX Elite 9000 features an interferometric technique that provides three-dimensional
structural information using backscattered infrared light at a wavelength of 1060 nm and a
speed of 100,000 A-scan/s [
15
]. The axial resolution is 1.95
µ
m, and the lateral resolution is
20 µm [16].
Calibrated 6
×
6 mm retinal captures centered on the fovea were taken. The quality of
the images was evaluated on the basis of two scores automatically generated by the device
and of the visual quality control of each image performed by the investigator (Annex S2).
The data were then exported to the Advanced Retina Imaging Network platform. The
macular VD in the nine areas of the macula were calculated using the latest version of the
Zeiss algorithm (version 0.7.3), as described in the Early Treatment Diabetic Retinopathy
Study (ETDRS grid, Figure 1) [
15
]. The PD in the parafoveolar and perifoveolar areas
was also calculated. All measurements were calculated in the SCP, DCP, and RVN. The
anatomical location of the capillary plexuses is described in Annex S3.
Medicina 2024,60, 757 4 of 11
Medicina 2024, 60, x FOR PEER REVIEW 4 of 11
Figure 1. Segmentation of the macula according to the Early Treatment Diabetic Retinopathy Study
grid. 1: center; 2: nasal (3 mm); 3: superior (3 mm); 4: temporal (3 mm); 5: inferior (3 mm); 6: nasal (6
mm); 7: superior (6 mm); 8: temporal (6 mm); 9: inferior (6 mm); 1–5: disk (3 mm); 2–5: parafoveolar
ring; 6–9: perifoveolar ring; 1–9: disk (6 mm).
2.2. Statistical Analysis
Only one eye of each patient was selected for the statistical analysis. The eye with the
best OCTA image quality was selected when the image quality of both eyes was not iden-
tical. When the image quality of the two eyes was identical, the choice was made ran-
domly. The normality of distribution of the data was checked using histograms, scaer
boxes, and quantile–quantile plots. Equality of variances was verified using Levene’s test.
Categorical variables were described using percentages and numbers, while continuous
variables were described according to their mean (±standard deviation) or median distri-
bution (interquartile range, p25–p75). Normally distributed data were analyzed using un-
paired Student’s t-tests and skewed or dichotomous data using Wilcoxon and chi2 tests.
Spearman correlation tests were used for correlation analyses. Results were considered
significant when the p-value was <0.05. Statistical analyses were performed using Stata
(version 14).
3. Results
3.1. Sample Characteristics
The sample comprised 61 patients divided into two groups according to their OAHI.
The patients without OSAS (OAHI < 5) were assigned to the control group (n = 12) and
those with OSAS (OAHI > 5) to the study group (n = 49). The numbers of mild (n = 17),
moderate (n = 17), and severe (n = 15) OSAS cases were similar. The OSAS and control
groups were compared, and the results are described in Table 1. There were no significant
differences between the groups in terms of age, sex, or cardiovascular risk factors. The
polysomnographic and ophthalmologic variables are described in the second part of Table
1. The sleep period time and sleep efficiency significantly decreased in the OSAS group.
The microarousal index and desaturation index were significantly higher, and the time
below 90% oxygen saturation was significantly longer in the OSAS group than in the con-
trol group. There were no significant differences in the BCVA, SE, macular thickness, or
choroidal thickness between the groups. An increase in the IOP was observed in the OSAS
Figure 1. Segmentation of the macula according to the Early Treatment Diabetic Retinopathy Study
grid. 1: center; 2: nasal (3 mm); 3: superior (3 mm); 4: temporal (3 mm); 5: inferior (3 mm); 6: nasal
(6 mm); 7: superior (6 mm); 8: temporal (6 mm); 9: inferior (6 mm); 1–5: disk (3 mm); 2–5: parafoveolar
ring; 6–9: perifoveolar ring; 1–9: disk (6 mm).
2.2. Statistical Analysis
Only one eye of each patient was selected for the statistical analysis. The eye with
the best OCTA image quality was selected when the image quality of both eyes was not
identical. When the image quality of the two eyes was identical, the choice was made
randomly. The normality of distribution of the data was checked using histograms, scatter
boxes, and quantile–quantile plots. Equality of variances was verified using Levene’s test.
Categorical variables were described using percentages and numbers, while continuous
variables were described according to their mean (
±
standard deviation) or median dis-
tribution (interquartile range, p25–p75). Normally distributed data were analyzed using
unpaired Student’s t-tests and skewed or dichotomous data using Wilcoxon and chi
2
tests.
Spearman correlation tests were used for correlation analyses. Results were considered
significant when the p-value was <0.05. Statistical analyses were performed using Stata
(version 14).
3. Results
3.1. Sample Characteristics
The sample comprised 61 patients divided into two groups according to their OAHI.
The patients without OSAS (OAHI < 5) were assigned to the control group (n= 12) and
those with OSAS (OAHI > 5) to the study group (n= 49). The numbers of mild (n= 17),
moderate (n= 17), and severe (n= 15) OSAS cases were similar. The OSAS and control
groups were compared, and the results are described in Table 1. There were no significant
differences between the groups in terms of age, sex, or cardiovascular risk factors. The
polysomnographic and ophthalmologic variables are described in the second part of Table 1.
The sleep period time and sleep efficiency significantly decreased in the OSAS group. The
microarousal index and desaturation index were significantly higher, and the time below
90% oxygen saturation was significantly longer in the OSAS group than in the control
group. There were no significant differences in the BCVA, SE, macular thickness, or
choroidal thickness between the groups. An increase in the IOP was observed in the OSAS
group. No ophthalmologic pathologies were observed during wide-angle fundus and
OCT examinations.
Medicina 2024,60, 757 5 of 11
Table 1. Description and comparison of study groups.
Control (n= 12) OSAS (n= 49) p-Value
Demographic variables
Age (years) 36.2 ±11.4 43.8 ±13.3 0.071
Sex (M) 50.0% 67.4% 0.262
Body mass index (kg/m2)28.7 ±8.0 31.9 ±7.2 0.172
Smoking 16.7% 24.5% 0.564
Diabetes type 2 0.0% 8.2% 0.306
High blood pressure 8.3% 22.5% 0.270
Hypercholesterolemia 16.7% 16.3% 0.977
Chronic obstructive pulmonary disease 0% 0%
Polysomnographic variables
Sleep latency (min) 64.5 (39.8–90.5) 58.0 (27.0–96.0) 0.935
Sleep period time (min) 472.0 ±73.8 406.6 ±83.3 0.016
Total sleep time (min) 433.2 ±63.7 384.8 ±78.0 0.051
Sleep efficiency (%) 80.2 (76.2–80.9) 70.6 (61.9–79.0) 0.014
Stage 1 (%) 7.3 (5.1–8.2) 8.2 (6.2–10.0) 0.179
Stage 2 (%) 46.3 ±7.7 51.7 ±10.3 0.095
Stage 3 (%) 20.5 ±9.9 10.1 ±8.6 0.001
REM sleep (%) 18.4 ±7.1 13.6 ±6.5 0.028
Arousal (%) 7.6 (4.5–11.5) 11.7 (7.5–22.0) 0.022
Number of arousals 24.1 ±11.9 28.1 ±13.3 0.347
Micro arousal index 5.0 (5.0–11.5) 15.0 (9.0–23.0) 0.002
Desaturation index 3.5 (2.5–8.0) 14.0 (8.0–37.0) <0.001
Time under 90% oxygen saturation (min)
0.0 (0.0–0.0) 9.5 (1.5–46.0) <0.001
Ophthalmologic variables
Visual acuity (LogMar) −0.5 (−1.1–0.38) −0.3 (−1.0–0.38) 0.548
Spherical equivalent −0.5 (−1.1–0.38) −0.3 (−1.0–0.38) 0.548
Macular thickness (µm) 228.2 ±15.2 227.2 ±20.8 0.876
Choroidal thickness (µm) 334.1 ±65.3 315.6 ±81.7 0.469
Intraocular pressure (mmHg) 13.0 ±2.7 15.3 ±3.4 0.039
3.2. VD and PD
The OSAS group demonstrated a significantly increased VD in the parafoveolar and
perifoveolar DCP and PD in the perifoveolar DCP. No significant differences in the VD and
PD of the SCP or RVN were seen (Tables 2–5) (Annex S4).
Table 2. Vascular density (mm−1) of the superficial capillary plexus.
Control (n= 12) OSAS (n= 49) p-Value
SCP DV mean 19.8 ±1.1 20.4 ±0.7 0.339
SCP DV central 11.9 ±2.8 12.7 ±2.7 0.330
SCP DV nasal (3 mm) 20.2 ±0.9 20.4 ±1.3 0.586
SCP DV superior (3 mm) 20.3 ±1.2 20.4 ±1.0 0.688
SCP DV temporal (3 mm) 20.1 ±1.1 20.4 ±0.9 0.412
SCP DV inferior (3 mm) 20.2 ±1.1 20.3 ±1.1 0.792
SCP DV nasal (6 mm) 21.8 ±0.9 22.0 ±0.7 0.286
SCP DV superior (6 mm) 20.1 (18.6–20.7) 20.4 (19.8–21.0) 0.284
SCP DV temporal (6 mm) 19.0 (17.1–20.0) 19.1 (18.2–19.5) 0.828
SCP DV inferior (6 mm) 19.7 (19.1–21.0) 20.5 (20.0–20.9) 0.217
SCP DV parafoveolar ring 20.2 ±1.0 20.4 ±0.9 0.553
SCP DV perifoveolar ring 20.1 (19.2–20.8) 20.6 (20.1–20.8) 0.211
SCP DV disk (3 mm) 19.3 ±1.1 19.5 ±1.0 0.431
SCP DV disk (6 mm) 19.8 ±1.1 20.2 ±0.7 0.192
Medicina 2024,60, 757 6 of 11
Table 3. Vascular density (mm−1) of the deep capillary plexus.
Control (n= 12) OSAS (n= 49) p-Value
DCP DV mean 13.1 ±3.5 15.2 ±2.7 0.027
DCP DV central 0.8 ±1.1 1.3 ±1.5 0.213
DCP DV nasal (3 mm) 13.2 ±4.3 15.2 ±2.9 0.064
DCP DV superior (3 mm) 13.2 (11.0–18.2) 17.0 (14.5–17.7) 0.157
DCP DV temporal (3 mm) 12.3 ±3.6 14.2 ±3.1 0.067
DCP DV inferior (3 mm) 14.0 ±4.3 15.6 ±2.9 0.128
DCP DV nasal (6 mm) 14.2 ±3.8 16.6 ±2.7 0.012
DCP DV superior (6 mm) 13.0 ±3.7 15.1 ±3.2 0.051
DCP DV temporal (6 mm) 13.6 ±3.7 15.5 ±3.1 0.068
DCP DV inferior (6 mm) 13.5 ±4.3 15.8 ±3.1 0.033
DCP DV parafoveolar ring 13.4 ±3.9 15.3 ±2.7 0.049
DCP DV perifoveolar ring 13.6 ±3.7 15.8 ±2.9 0.028
DCP DV disk (3 mm) 12.0 ±3.6 13.7 ±2.4 0.047
DCP DV disk (6 mm) 13.2 ±3.6 15.2 ±2.7 0.029
Table 4. Vascular density (mm−1) of the total retinal vascular network.
Control (n= 12) OSAS (n= 49) p-Value
RVN DV mean 20.7 ±0.9 21.1 ±0.6 0.074
RVN DV central 12.2 ±2.7 13.0 ±2.7 0.374
RVN DV nasal (3 mm) 21.3 ±1.0 21.5 ±1.0 0.598
RVN DV superior (3 mm) 21.0 ±1.2 21.5 ±0.9 0.097
RVN DV temporal (3 mm) 21.3 ±1.0 21.7 ±0.7 0.133
RVN DV inferior (3 mm) 21.3 ±1.0 21.5 ±1.0 0.547
RVN DV nasal (6 mm) 22.0 ±0.8 22.3 ±0.6 0.152
RVN DV superior (6 mm) 21.0 (20.0–21.6) 21.4 (20.8–21.7) 0.204
RVN DV temporal (6 mm) 20.7 ±1.3 20.9 ±1.0 0.456
RVN DV inferior (6 mm) 20.2 (19.8–21.7) 21.6 (21.1–21.8) 0.067
RVN DV parafoveolar ring 21.2 ±0.9 21.5 ±0.7 0.208
RVN DV perifoveolar ring 20.8 (20.5–21.8) 21.6 (21.2–21.9) 0.119
RVN DV disk (3 mm) 20.2 ±1.0 20.6 ±0.8 0.184
RVN DV disk (6 mm) 20.7 (20.2–21.6) 21.4 (21.0–21.7) 0.099
Table 5. Perfusion density (%).
Control (n= 12) OSAS (n= 49) p-Value
SCP DP parafoveolar ring 0.43 ±0.02 0.44 ±0.02 0.321
SCP DP perifoveolar ring 0.45 (0.42–0.46) 0.46 (0.44–0.46) 0.276
DCP DP parafoveolar ring 0.27 ±0.8 0.31 ±0.6 0.056
DCP DP perifoveolar ring 0.27 ±0.8 0.32 ±0.6 0.032
RVN DP parafoveolar ring 0.45 ±0.2 0.46 ±0.2 0.121
RVN DP perifoveolar ring 0.46 (0.45–0.48) 0.47 (0.47–0.48) 0.147
3.3. Correlation between the VD and OSAS Severity
There was no correlation between the VD and OAHI among the patients with OSAS
(Table 6).
Table 6. Correlation between the vascular density and OAHI.
OAHI
SCP DV mean −0.1833
SCP DV central 0.0535
SCP DV nasal (3 mm) −0.2493
SCP DV superior (3 mm) −0.1092
Medicina 2024,60, 757 7 of 11
Table 6. Cont.
OAHI
SCP DV temporal (3 mm) −0.0773
SCP DV inferior (3 mm) −0.2990
SCP DV nasal (6 mm) −0.1198
SCP DV superior (6 mm) −0.0088
SCP DV temporal (6 mm) −0.1960
SCP DV inferior (6 mm) −0.2350
SCP DV parafoveolar ring −0.1791
SCP DV perifoveolar ring −0.1501
SCP DV disk (3 mm) −0.1662
SCP DV disk (6 mm) −0.1428
SCP DV mean −0.1329
SCP DV central −0.0467
DCP DV nasal (3 mm) −0.1342
DCP DV superior (3 mm) −0.1596
DCP DV temporal (3 mm) −0.1594
DCP DV inferior (3 mm) −0.2150
DCP DV nasal (6 mm) −0.0511
DCP DV superior (6 mm) −0.1332
DCP DV temporal (6 mm) −0.1551
DCP DV inferior (6 mm) −0.1500
DCP DV parafoveolar ring −0.1835
DCP DV perifoveolar ring −0.1450
DCP DV disk (3 mm) −0.1812
DCP DV disk (6 mm) −0.1522
RVN DV mean −0.0987
RVN DV central 0.0605
RVN DV nasal (3 mm) −0.2613
RVN DV superior (3 mm) 0.0189
RVN DV temporal (3 mm) −0.1071
RVN DV inferior (3 mm) −0.2943
RVN DV nasal (6 mm) 0.0507
RVN DV superior (6 mm) 0.0015
RVN DV temporal (6 mm) −0.1303
RVN DV inferior (6 mm) −0.1079
RVN DV parafoveolar ring −0.2096
RVN DV perifoveolar ring −0.0570
RVN DV disk (3 mm) −0.1189
RVN DV disk (6 mm) −0.0953
4. Discussion
This study compared the VD and PD between patients with OSAS and control patients.
There were significant increases in the VD and PD of the DCP in the perifoveolar area in
the OSAS group compared with those in the control group. The VD of the DCP in the
parafoveolar area also significantly increased in the OSAS group. There were no significant
differences in the VD and PD of the SCP and RVN. To our knowledge, this study is the first
to analyze the macular vascular density in terms of vessel length in patients with OSAS.
Nevertheless, several studies have previously analyzed the PD in these patients.
The current results are consistent with those of Cai et al., who reported an increase
in the PD in the parafoveolar and perifoveolar DCP in the severe OSAS group compared
with that in the control group [3]. Furthermore, Moyal et al., Cai et al., and Colak et al. all
reported no significant difference in the PD of the SCP between groups [
3
,
10
,
17
]. This is
because the SCP consists of capillaries, arterioles, and venules, whereas the DCP consists of
only capillaries and venules [
16
,
18
]. Therefore, the oxygen supply is more stable in the SCP
owing to the direct connection to the retinal arterioles from the central retinal artery. This
could explain why hypoxia affects the DCP first [17].
Medicina 2024,60, 757 8 of 11
The current results demonstrate some discrepancy with previous reports regarding the
alteration of the PD of the DCP. Colak et al. and Ucak et al. observed a significant decrease
in the PD of the DCP in the parafoveolar area in their OSAS groups [
17
,
19
]. Colak et al.
also observed this phenomenon in the perifoveolar area [
17
]. Similarly, Yu et al. reported a
significant decrease in the PD of the RVN in the parafoveolar and perifoveolar regions [
9
].
This discrepancy in results could be explained by differences in ethnicity, age, and duration
of OSAS symptoms between the study populations. For example, the populations in the
current study and in the study by Cai et al. were younger than the populations studied
by Ucak et al. and Colak et al. Furthermore, differences in the definition of the groups,
particularly the control group, could reduce the relevance of comparisons between these
studies. Moreover, most previous studies used SD RTVue-XR Avanti, which is a less
powerful device in terms of image acquisition and analysis than SS PLEX Elite 9000.
The OAHI is the classic index used to evaluate OSAS severity. The current study
revealed no correlation between the VD and OAHI in the patients with OSAS. Similarly,
Cai et al. and Colak et al. did not report correlations between the PD and OAHI [
3
,
17
].
However, Yu et al. and Ucak et al. reported negative correlations between the OAHI and
PD [
9
,
19
]. Some experts have questioned the definition of OSAS based only on the OAHI,
as the OAHI may not be the most reliable indicator of OSAS severity. A new definition
of OSAS could include the oxygen desaturation index (ODI) [
20
]. Cai et al. supported
the inclusion of the oxygen saturation in the definition of OSAS, as their results showed
a negative correlation between the perifoveolar PD and the lowest hemoglobin oxygen
saturation [
3
]. However, Colak et al. did not report a correlation between the PD of the
SCP and DCP and time spent under 90% oxygen saturation [17].
The pathophysiological mechanisms driving alterations in the VD and PD of patients
with OSAS are not yet well-understood. It is well-established that OSAS-related inter-
mittent hypoxia results in the activation of the orthosympathetic system, which leads to
peripheral vasoconstriction [
4
,
21
]. However, unlike choroidal vessels, retinal vessels lack
autonomic innervation [
5
]. Hypoxia and hypercapnia result in retinal vasodilation via an
autoregulatory mechanism that maintains appropriate blood flow based on metabolic tissue
needs. This autoregulatory mechanism is mediated by local factors, such as vasoactive
molecules released by the endothelium. Nitric oxide (NO), certain prostaglandins (i.e., PGI2
and PGE2), and extracellular lactate are involved in retinal arterial vasodilation in response
to hypoxia and hypercapnia [
4
,
22
]. These physiological mechanisms could explain the
increase in the PD of the DCP in the perifoveolar area observed in the patients with OSAS
in the current study and in the severe OSAS group in the study by Cai et al. [3].
It is speculated that an increase in the VD in terms of vessel length occurs secondary
to hypoxia; however, the exact nature of the vessels (i.e., whether they are neovessels or
collateral vessels) is unknown. The non-anarchic organization of the vessels observed
in OCTA images supports the hypothesis that they are collateral vessels that develop
in response to hypoxia. This phenomenon has been established at the coronary level in
patients with chronic ischemic heart disease [
23
]. One study has suggested that coronary
collateral vessels also develop in patients with OSAS [
24
]. Patients with OSAS have higher
blood levels of vascular endothelial growth factor (VEGF) than individuals without OSAS.
Intermittent hypoxia stimulates VEGF gene transcription via hypoxia-induced factors [
25
].
Oxidative stress may also be involved in the development of collateral vessels [
26
]. The
increased levels of VEGF and oxidative stress present in patients with OSAS are likely
to be the two mechanisms involved in the collateral vessel formation observed in the
current study.
The decrease in the retinal PD described in previous studies could be explained by
endothelial dysfunction and atherosclerosis, which may be associated with long-term
OSAS [
4
,
27
]. According to a recent meta-analysis, severe OSAS is associated with a high
risk of endothelial dysfunction [
27
]. Long-term endothelial dysfunction and oxidative
stress could induce a decrease in NO production, which would decrease vasodilation and,
therefore, macular vascular perfusion in patients with OSAS [
28
,
29
]. The impairment of
Medicina 2024,60, 757 9 of 11
vascular reactivity, regardless of the relation to endothelial dysfunction, would be more
marked in patients experiencing apnea with an oxygen desaturation index of >20 [
30
]. In
the long term, these mechanisms could be responsible for capillary occlusion or destruction
at the origin of a PD-related decrease. Therefore, it would be interesting to continue the
current study to investigate the VD and PD in the included patients for several years to
observe whether a two-step reaction in the retinal vasculature exists in patients with OSAS.
Limitations
Although this study was a prospective controlled study, it involved a single center,
and its power is limited by the number of patients included. In addition, the control
group included only subjects with complaints related to sleep but without sleep disordered
breathing. Therefore, this group may potentially not be representative of the population
without apnea. However, in order to avoid as much as possible any risk of selection
bias during recruitment for this study, all subjects eligible according to the inclusion
and exclusion criteria were invited to participate. Nevertheless, despite this systematic
invitation, only patients who agreed to participate in this study were included, which may
potentially limit the generalizability of our results. Furthermore, it was difficult to estimate
how long the included patients had experienced OSAS symptoms. Studies with longer
follow-up periods are necessary to confirm the pathophysiological hypotheses and clinical
implications of the current results.
5. Conclusions
This study revealed an increase in the VD of the DCP in the parafoveolar and perifove-
olar areas and PD of the DCP in the perifoveolar area in patients with newly diagnosed
OSAS, which suggests that collateral vessel formation and possible retinal vasodilation
occur in the DCP for this particular subpopulation. Moreover, despite its limitations, this
study therefore seems to open new perspectives for better understanding the pathophysiol-
ogy of ophthalmological complications associated with OSAS. In addition, the identification
of these alterations in macular VD and PD related to OSAS could allow the future develop-
ment of new strategies for the prevention and treatment of ophthalmological complications
in patients with OSAS. Finally, studies with long-term follow-up seem to be necessary to
explore and confirm the hypothesis of a two-phase pathophysiological mechanism that
could explain our results and those of previous studies on older patients with OSAS.
Supplementary Materials: The following supporting information can be downloaded at: https://
www.mdpi.com/article/10.3390/medicina60050757/s1, Annex S1: Polysomnography: setup and
definitions; Annex S2: Quality control of PLEX Elite 9000 OCTA images; Annex S3: Anatomical
location of the capillary plexuses; Annex S4: Graphical representations of significant results for
macular vascular density and perfusion density.
Author Contributions: Conceptualization: L.A. and F.R.; Methodology: L.A., M.H. and F.R.; Formal
Analysis: L.A., M.H. and F.R.; Investigation: L.A., M.H. and F.R.; Software: L.A. and F.R.; Data
Curation: L.A., M.H. and F.R; Writing—Original Draft Preparation: L.A., M.H. and F.R.; Supervision:
M.H. and F.R. All authors have read and agreed to the published version of the manuscript.
Funding: This research received no external funding.
Institutional Review Board Statement: The study was conducted according to the guidelines of the
Declaration of Helsinki and approved by the Ethics Committee of Erasme Hospital (P2020/536/CCB
B4062020000207—Approval date 14 December 2020).
Informed Consent Statement: Informed written and verbal consent was obtained from all partici-
pants before enrolment.
Data Availability Statement: The data presented in this study are available on reasonable request
from the corresponding author.
Acknowledgments: This study would not have been possible without the support of the technical
staff from the Erasme Hospital Sleep Laboratory.
Medicina 2024,60, 757 10 of 11
Conflicts of Interest: The authors declare no conflicts of interest.
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