Secondary Logo

Journal Logo

Original Study

OPTICAL COHERENCE TOMOGRAPHY ANGIOGRAPHY FINDINGS OF MICROVASCULAR AND NEURAL CHANGES IN PRIMARY PULMONARY HYPERTENSION

Gu, Simin MD*,†; Li, Zijing MD*,†; Zhang, Yichi MD, PhD*,†; Liu, Yingmei MD, PhD*,†; Zeng, Peng MD*,†; Zeng, Rui MD*,†; Wang, Wenhui MD*,†; Xiao, Jianhui MD, PhD*,†

Author Information
doi: 10.1097/IAE.0000000000002940
  • Open

The sixth World Symposium on Pulmonary Hypertension Task Force proposed that precapillary pulmonary hypertension (precapillary PH) is best defined by the concomitant presence of mean pulmonary artery pressure of >20 mmHg, pulmonary artery wedge pressure of ≤15 mmHg, and pulmonary vascular resistance of ≥3 wood units. Pulmonary hypertension can be classified into different subtypes according to the clinical symptoms, pathological findings, hemodynamic characteristics, and treatment. It may be idiopathic or secondary to other clinical diseases.1

Ocular abnormalities are considered to be strongly associated primary PH (PPH), a subtype that accounts for approximately 10% of PH.2 The increase pressure in pulmonary artery leads to an increase in the superior vena cava venous pressure, which elevates the ocular venous pressure, resulting in ocular venous dilation and choroidal congestion; in turn, this leads to stasis of the ocular capillary network, ultimately resulting in serious ocular complications secondary to PPH, including ocular signs, such as proptosis,3 chemosis, dilated and tortuous episcleral vessels,4 and fundus abnormalities, such as hemorrhage, macular edema, central serous chorioretinopathy-like (CSC-like) changes,5 and secondary glaucoma.6,7 When PPH patients are referred to the clinic, most ocular abnormalities are asymptomatic or nonspecific.8 Traditional ophthalmic examinations, such as determination of the best-corrected visual acuity or intraocular pressure (IOP) and dilated fundus examination, do not have enough power to detect minor changes in the fundus. Fluorescein fundus angiography is one of the most useful examinations for diagnosing and assessing the severity of fundus diseases. However, it is an invasive technique and may not only cause severe anaphylaxis, even in some healthy individuals,9 but also does not allow the quantification of vessels. Optical coherence tomography angiography (OCTA), a noninvasive cross-sectional imaging technique, is frequently applied.10 High-resolution images can be captured and subtle capillary alterations can be distinguished on OCTA, making quantification feasible.11,12 In addition, some subtle changes in the preclinical stage can be detected, and the lesions can be located. However, there have been no reports of ocular abnormality analysis in PPH by OCTA.

The purpose of this hospital-based study was to report the signs of ocular abnormalities in PPH patients and changes in the capillary density (CD) of the retina and optic nerve head (ONH), the retinal nerve fiber layer (RNFL) thickness, and the ganglion cell complex (GCC) thickness between PPH patients and control subjects on OCTA.

Methods

Subjects

This observational clinical cohort study was approved by the research ethics committee of Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University and adhered to the tenets of the Declaration of Helsinki. Forty-four eyes of 22 PPH subjects were included. After a dilated fundus examination by a very experienced ophthalmologist (the examiner and the subjects were double blinded), 4 PPH patients with fundus changes were included in Group 1 and 18 PPH patients without fundus changes were included in Group 2. Another 44 eyes of 22 healthy participants were included in Group 3 as controls. All subjects enrolled were patients at the Sun Yat-Sen Memorial Hospital from July 2017 to January 2019. The whole process was performed in the hospital, and informed consent was obtained from all study participants. The inclusion criteria included a diagnosis of PPH confirmed by a qualified cardiologist from the Sun Yat-Sen Memorial Hospital. All of the subjects enrolled had never used drugs that might induce PH or other known medicines that might influence ocular function. One subject with severe PPH had been treated with sildenafil to control the disease for more than 10 years.

Baseline ophthalmologic examinations could play a significant role in excluding primary ocular region illness. Ophthalmologic examinations, including determination of the best-corrected visual acuity or IOP and slit-lamp and dilated fundus examinations, were performed on the eyes. Color fundus photographs were obtained (7F-ETDRS) (Canon, Inc, Tokyo, Japan), the central corneal thickness, corneal curvature, anterior chamber depth, and axial length were measured using an IOL Master 700R system (Carl Zeiss Meditec AG, Jena, Germany); the visual field was evaluated with a Humphrey Field Analyzer (Central 30-2 Threshold Test), and OCTA was conducted (Optovue, Inc, Fremont, CA). Basic characteristics, including sex, age, medical history, PPH duration, mean pulmonary artery pressure, and treatment, were collected. The exclusion criteria were as follows: (1) primary ocular disease and (2) known systemic or other predictable factors that might result in ocular complications, such as diabetes, hypertension, and autoimmune disease. The healthy controls underwent the same ophthalmic examination process.

Optical Coherence Tomography Angiography Examinations

Optical coherence tomography angiography images were obtained using the RTVue XR Avanti OCTA device (Optovue, Inc) with its prototype AngioVue software 2.0. The device operates at a speed of 70,000 A scans per second, a wavelength of 840 nm, and a frequency bandwidth of 45 nm. The split-spectrum amplitude-decorrelation angiography algorithm allows the OCTA device to detect erythrocyte movement noninvasively in real time. Centered on the fovea, both the 300-µm-wide region and 600-μm-wide region of the macula were scanned. The inner retinal and outer retinal vascular structures were observed in the screening; parameters in the same layer shared the same vascular plexus, and they had interactions with each other. HD Angio Disc 4.5-mm mode was used to capture a 4.5 mm × 4.5 mm area surrounding the optic disk. The area was divided into different sections, and the radial peripapillary capillary (RPC) density in these sections and the peripapillary thickness were automatically calculated by the software AngioVue 2.0. Furthermore, ONH mode was used to assess the images of the macula and the optic nerve fiber. Ganglion cell complex mode was used to measure the thickness of the RNFL, ganglion cell layer, and inner plexiform layer, and all OCTA examinations were performed by two very experienced ophthalmic examiners. The two examiners were doubled blinded to the subjects. Optical coherence tomography angiography images with a scan quality of <6 were excluded.

Results

Patient Characteristics

Forty-four eyes of 22 subjects and 44 eyes of 22 healthy controls were enrolled in this study. There was no statistical significance in age or sex between the PPH and control subjects. Regarding the baseline ophthalmologic examination, there were statistically significant differences in the best-corrected visual acuity and IOP between Group 1 and Groups 2 and 3 (numerical variables were compared among the three groups [Group 1: PPH with fundus changes, Group 2: PPH without fundus changes, and Group 3: healthy controls] by one-way analysis of variance). The characteristics of the participants, including the mean age, sex, corneal thickness, anterior chamber depth, and axial length, were not significantly different among the three groups. There was a significant increase in the mean pulmonary artery pressure in Group 1 compared with Group 2, but there was no significant difference in the PPH duration between the two cohorts. The characteristics of the participants are presented in Table 1.

Table 1. - Patient Characteristics
Items Group 1 Group 2 Group 3 Group 1 Versus Group 2, P Group 2 Versus Group 3, P Group 1 Versus Group 3, P
Eyes (n) 8 36 44 NA NA NA
Mean age, range (years) 42.38 ± 16.58 44.13 ± 16.949 41.75 ± 17.302 0.838 0.782 0.942
Male: female 2:2 7:11 11:11 NA NA NA
PPH duration (years) 5.125 ± 4.324 3.125 ± 2.167 NA 0.066
mPAP (mmHg) 79.125 ± 21.304 53.500 ± 15.464 NA 0.016 NA NA
BCVA (logMAR [Snellen]) 0.363 ± 0.151 (20/33) 0.089 ± 0.135 (20/20) −0.043 ± 0.695 (20/15) 0.000 0.000 0.000
Corneal thickness (μm) 555.13 ± 31.037 573.25 ± 32.849 543.88 ± 20.794 0.221 0.441 0.054
Anterior chamber depth (mm) 3.4038 ± 0.305 3.0313 ± 0.500 3.480 ± 0.605 0.140 0.079 0.757
Axial length (mm) 23.089 ± 0.781 24.266 ± 0.564 23.534 ± 1.728 0.052 0.216 0.445
IOP (mmHg) 28.50 ± 14.162 16.25 ± 2.121 15.00 ± 1.309 0.008 0.776 0.004
BCVA, best-corrected visual acuity; Group 1, PPH with fundus changes; Group 2, PPH without fundus changes; Group 3, control; mPAP, mean pulmonary arterial pressure; logMAR, logarithm of the minimum angle of resolution; NA, not available.
P < 0.05.

The ocular symptoms reported by the PPH patients with fundus changes were nonspecific and included blurred vision, metamorphopsia as a result of macular involvement, severe eye pain resulting from high IOP, and red eyes because of vascular changes.7,13 Anterior segment manifestations, such as chemosis and dilated and tortuous conjunctival and episcleral veins, are common, and they can be observed not only in PPH patients with fundus changes but also occasionally in PPH patients without fundus changes. Other signs, such as corneal edema, could be assessed in Group 1.14 Moreover, fundus abnormalities, including tortuous retinal vessels, retinal hemorrhage, macular edema, and CSC-like changes, were observed during the dilated fundus examination in Group 1 subjects.15 In our cases, the main ocular manifestations are shown in Table 2.

Table 2. - Major Ocular Signs
Ocular Signs N (%)
Intraocular hypertension 11.36% (5/44)
Chemosis 6.82% (3/44)
Dilated and tortuous episcleral vessel 36.36% (16/44)
Fundus abnormality
 Dilated and tortuous retinal vessels 18.18% (8/44)
 Retinal hemorrhage 18.18% (8/44)
 macular edema 2.27% (1/44)
 Macular neuroepithelial detachment 2.27% (1/44)

Optical Coherence Tomography Angiography Findings

The parameters compared among Groups 1, 2, and 3 included the foveal avascular zone, macular-associated vessel density (VD), optic disk–associated CD, GCC thickness, RNFL thickness, focal loss volume (FLV), global loss volume (GLV), subfoveal choroidal thickness, and choriocapillary flow area. Statistical analysis of the OCTA data was performed using SPSS 25.0 (SPSS, Inc, Chicago, IL). The numerical variables were compared among the three groups by one-way analysis of variance, and Least Significant Difference post hoc analysis was performed to evaluate the significant differences.

Regarding the total macular-associated VD, including the superficial and deep retina, the optic disk–associated CD, including that of the whole image, inside the disk, and in the peripapillary region, was significantly reduced in Group 1 compared with Group 3 (superficial total VD: 38.373 ± 6.926% vs. 44.975 ± 4.984%; P = 0.003; deep total VD: 45.1400 ± 3.638% vs. 50.184 ± 3.980%; P = 0.003; CD inside the disk (ring diameter = 4.5 mm): 54.170 ± 11.736 vs. 61.984 ± 3.546%; P = 0.000; peripapillary CD (ring diameter = 4.5 mm) 47.055 ± 6.087 vs. 58.813 ± 2.338%; P = 0.000; whole RPC density: 45.788 ± 5.451 vs. 55.952 ± 2.656; P = 0.000). However, there was no significant difference in the foveal avascular zone or foveal VD (including the superficial and the deep retinal) between the two cohorts (foveal avascular zone: 2.327 ± 0.526 vs. 2.365 ± 0.289; P = 0.880; superficial foveal VD: 12.116 ± 8.409 vs. 14.825 ± 5.738; P = 0.156; deep foveal VD: 23.746 ± 11.246 vs. 29.780 ± 10.104; P = 0.114). The perifoveal VD in the superficial retina and the parafoveal and perifoveal VD in the deep retina were lower in Group 2 than Group 3 (superficial perifoveal VD: 46.548 ± 5.781 vs. 50.242 ± 3.901; P = 0.001; deep parafoveal VD: 52.550 ± 4.332 vs. 53.000 ± 4.102; P = 0.017; deep perifoveal VD: 46.652 ± 6.162 vs. 50.033 ± 7.707; P = 0.035). There was a similar in the RPC and optic disk–associated CD when comparing Groups 2 and 3 (Figure 1).

Fig. 1.
Fig. 1.:
Ganglion cell complex and ONH reports. The GCC consists of three layers: the RNFL, the ganglion cell layer, and the inner plexiform layer. A. (left: GCC report; right: RNFL report): the right eye of a 25-year-old female control subject. B. (left: GCC report; right: RNFL report): the right eye of a 28-year-old female PPH patient without fundus changes. C. (left: GCC report; right: RNFL report): the right eye of a 28-year-old female PPH patient with fundus changes.

The RNFL thickness was significantly reduced in Group 1 compared with Groups 2 and 3 (Group 1 vs. Group 2: 79.42 ± 22.56 vs. 98.491 ± 11.100; P = 0.000; Group 1 vs. Group 3: 79.42 ± 22.56 vs. 101.338 ± 11.249; P = 0.000). Additionally, the GCC thickness was reduced in Group 1 (Group 1 vs. Group 2: 79.349 ± 18.589 vs. 96.609 ± 14.658; P = 0.001; Group 1 vs. Group 3: 79.349 ± 18.589 vs. 97.450 ± 9.370, P = 0.000). Furthermore, the FLV and GLV were increased in Group 1 compared to the other two groups (FLV: Group 1 vs. Group 2: 7.072 ± 5.955 vs. 1.544 ± 2.703, P = 0.000, Group 1 vs. control: 7.072 ± 5.955 vs. 0.972 ± 0.766, P = 0.000; GLV: Group 1 vs. Group 2: 19.632 ± 15.174 vs. 4.590 ± 6.785, P = 0.001, Group 1 vs. control: 19.632 ± 15.174 vs. 3.019 ± 3.934; P = 0.001). Moreover, the differences in the macular-associated VD, optic nerve–associated CD, RNFL thickness, GCC thickness, FLV, and GLV between Groups 1 and 2 were statistically significant. Details are shown in Tables 3 and 4.

Table 3. - Major VD OCTA Measurements in the PPH Patients and Control Subjects
Items Group 1 Group 2 Group 3 Group 1 Versus Group 2, P Group 1 Versus Group 3, P Group 2 Versus Group 3, P
Total VD (%)
 Superficial total VD (ILM-IPL) 38.373 ± 6.926 43.733 ± 6.168 44.975 ± 4.984 0.018 0.003 0.333
  Foveal VD 12.116 ± 8.409 16.291 ± 8.958 14.825 ± 5.738 0.156 0.350 0.385
  Parafoveal VD 41.848 ± 6.691 46.731 ± 6.247 47.950 ± 5.559 0.038 0.009 0.364
   Temporal 34.707 ± 11.050 28.760 ± 15.502 46.766 ± 5.238 0.177 0.006 0.000
   Superior 43.461 ± 6.666 47.279 ± 7.075 49.746 ± 5.713 0.130 0.013 0.091
   Nasal 43.563 ± 7.184 46.182 ± 6.033 46.715 ± 5.830 0.091 0.027 0.179
   Inferior 39.613 ± 8.104 48.083 ± 7.133 49.060 ± 5.729 0.001 0.000 0.509
  Perifoveal VD 39.823 ± 4.995 46.548 ± 5.781 50.242 ± 3.901 0.001 0.000 0.001
   Temporal 39.410 ± 5.483 46.210 ± 6.523 45.917 ± 4.494 0.002 0.003 0.817
   Superior 40.886 ± 6.321 46.510 ± 5.750 50.591 ± 4.175 0.009 0.000 0.001
   Nasal 45.130 ± 5.819 50.394 ± 6.188 54.240 ± 4.112 0.012 0.000 0.002
   Inferior 40.378 ± 6.573 46.912 ± 6.686 50.229 ± 4.072 0.003 0.003 0.010
 Deep total VD (IPL-OPL) 45.1400 ± 3.638 49.510 ± 4.694 50.184 ± 3.980 0.010 0.003 0.010
  Foveal VD 23.746 ± 11.246 29.780 ± 10.104 29.056 ± 6.480 0.104 0.114 0.908
  Parafoveal VD 48.504 ± 4.881 52.550 ± 4.332 53.000 ± 4.102 0.017 0.008 0.017
   Temporal 48.149 ± 7.682 48.148 ± 7.682 53.250 ± 5.625 0.010 0.006 0.799
   Superior 47.328 ± 4.979 47.328 ± 4.980 52.529 ± 4.800 0.015 0.009 0.778
   Nasal 51.185 ± 5.814 51.185 ± 5.814 53.361 ± 4.911 0.264 0.276 0.938
   Inferior 47.436 ± 6.382 51.465 ± 6.160 52.563 ± 4.488 0.060 0.016 0.369
  Perifoveal VD 44.174 ± 5.170 46.652 ± 6.162 50.033 ± 7.707 0.363 0.031 0.035
   Temporal 44.190 ± 7.100 48.546 ± 6.879 52.900 ± 6.200 0.097 0.001 0.005
   Superior 43.868 ± 5.440 46.439 ± 7.083 50.181 ± 8.333 0.392 0.035 0.035
   Nasal 44.966 ± 4.457 45.803 ± 6.897 48.444 ± 8.927 0.786 0.253 0.144
   Inferior 43.945 ± 6.163 45.844 ± 9.193 48.610 ± 8.380 0.533 0.123 0.124
RPC density (%): (ILM-RNFL)
 Whole density (%) 45.788 ± 5.451 54.217 ± 3.606 55.952 ± 2.656 0.000 0.000 0.027
 Whole capillary (%) 39.541 ± 6.725 47.910 ± 3.322 49.544 ± 2.447 0.000 0.000 0.035
 CD inside disk (ring diameter = 4.5 mm) (%) 54.170 ± 11.736 58.926 ± 5.436 61.984 ± 3.546 0.030 0.000 0.017
Peripapillary CD (ring diameter = 4.5 mm) (%) 47.055 ± 6.087 56.492 ± 4.064 58.286 ± 3.149 0.000 0.000 0.045
CCF (mm2) 2.040 ± 0.394 2.002 ± 0.199 2.102 ± 0.100 0.772 0.452 0.641
CD, optic disk–associated capillary density; CCF, choriocapillary flow area; Group 1, PPH with fundus changes; Group 2, PPH without fundus changes; Group 3, control; ILM, internal limiting membrane; IPL, inner plexiform layer; OPL, outer plexiform layer; RPC, radial peripapillary capillaries; VD, macular-associated vessel density.
P < 0.05.

Table 4. - Retinal nerve fiber layer, GCC, FLV, GLV, and SFCT Measurements in the PPH Patients and Control Subjects
Group 1 Group 2 Group 3 Group 1 Versus Group 2, P Group 1 Versus Group 3, P Group 2 Versus Group 3, P
RNFL 79.42 ± 22.559 98.491 ± 11.100 101.338 ± 11.249 0.000 0.000 0.324
GCC 79.349 ± 18.589 96.609 ± 14.658 97.450 ± 9.370 0.001 0.000 0.770
FLV 7.072 ± 5.955 1.544 ± 2.703 0.972 ± 0.766 0.000 0.000 0.314
GLV 19.632 ± 15.174 4.590 ± 6.785 3.019 ± 3.934 0.001 0.001 0.296
SFCT 411.625 ± 91.206 389.130 ± 49.007 289.380 ± 55.666 0.311 0.000 0.000
Group 1, PPH with fundus changes; Group 2, PPH without fundus changes; Group 3, control; SFCT, subfoveal choroidal thickness.
P < 0.05.

Discussion

Pulmonary hypertension ultimately remains a fatal disease if left untreated and could result in progressive right ventricular failure and even death because of the increase in venous pressure. Additionally, the increasing superior vena cava pressure elevates the ocular venous pressure, resulting in ocular venous dilation and choroidal congestion; in turn, this leads to stasis of the ocular capillary network and ultimately results in serious ocular abnormalities secondary to PPH, including ocular signs, such as proptosis, chemosis, dilated and tortuous episcleral vessels, corneal edema, and fundus abnormalities, such as hemorrhage, macular edema, CSC-like changes, and secondary glaucoma. Moreover, ciliary detachment, uveal effusion, exudative retinal detachment, central retinal vein occlusion,7 and branch retinal vein occlusion16 associated with PH have been reported.

Optical coherence tomography angiography, which allows the noninvasive assessment and measurement of vascular structures in the retina and ONH, is now a widely accepted ophthalmic imaging technique for examining the ocular vasculature.11 This tool, with good repeatability and reproducibility, provides useful information in terms of the VD, ocular blood flow, and thickness of the ONH and retina.10,17 Optical coherence tomography angiography enables visualization of the blood flow in the retina and ONH without the intravenous injection of dye, and it may thus be safer and more efficient than other methods.18 Optical coherence tomography angiography can feasibly be used for frequent assessments and screening in the initial stages of PPH in daily clinical practice and to detect changes in the ONH and retina. In our study, significant reductions in the VD of the retina and ONH and the thickness of the GCC and RNFL were observed in PPH, which have not been reported in previous research. Additionally, there have been no OCTA studies quantifying changes in the ONH and retina in PPH.

In our present study, PPH subjects and healthy control subjects were included, and a reduced total VD (including the superficial total VD and the deep total VD) was observed in the PPH patients compared with the control subjects. The parafoveal VD and the perifoveal VD (including superficial and deep) were obviously decreased in Groups 1 and 2 compared with Group 3. The macular-associated VD seemed to be influenced in PPH secondary to the increasing PH. Furthermore, there was a significant difference between Groups 1 and 2. It needs to be emphasized that changes in the macular-associated VD occurred in the preclinical stage before ocular symptoms and signs occur in PPH. Group 1 showed a decrease in the foveal VD in both the superficial and deep layers; unexpectedly, there was a mildly increasing trend in the foveal VD of Group 2 (including superficial and deep) compared with Group 3. In the early stage of the disease, PPH involves peripheral vascular resistance, and the resistance and vascular remodeling in the periphery may cause compensatory changes in other vascular beds, including the vessels in macula,19 to maintain its visual function. However, occlusive disease or possibly pathological changes may signal a future occlusive event and ultimately result in reduced ocular perfusion in the fundus in PPH.20

In our study, the optic disk–associated CD, including the whole RPC density, the CD inside the disk, and the peripapillary CD, was significantly reduced in the PPH group compared with the control group. Furthermore, a significantly decreasing trend in the optic disk–associated CD was also observed in Groups 1 and 2. Therefore, the chronic retinal hypoxia caused by the stasis resulting from the increased pressure in the choroidal circulation that is induced by increasing pulmonary arterial hypertension may not only contribute to vascular dropout and remodeling in the macular area but also affect the capillaries in the disk. Similarly, neural impairment was noted (Figure 2). A significant decrease in the RNFL thickness and the GCC thickness, and an increase in the FLV and GLV were found in the PPH patients (including those in Groups 1 and 2). In our study, five eyes showed intraocular hypertension in Group 1 and were diagnosed with open-angle glaucoma secondary to pulmonary arterial hypertension after inspection (including gonioscopy). It must be stressed that elevations in IOP are mainly caused by blocking of the aqueous humor outflow pathway, and the difference between the IOP and the episcleral venous pressure provides the force to allow the aqueous humor to flow out of the trabecular meshwork.21 In PPH, increased ocular venous pressure secondary to increased pulmonary arterial pressure results in elevated episcleral venous pressure, which blocks the aqueous humor outflow pathway and eventually induces secondary glaucoma.

Fig. 2.
Fig. 2.:
Superficial VD (macular-associated VD) and deep VD (optic disk–associated CD) report: (A): left: the left eye of a 25-year-old female control subject; middle: the left eye of a 28-year-old female PPH patient without fundus changes, right: the left eye of a 28-year-old female PPH patient with fundus changes. B. left: the left eye of a 25-year-old female control subject, middle: the left eye of a 28-year-old female PPH patient without fundus changes, right: the left eye of a 28-year-old female PPH patient with fundus changes.

Many published studies have indicated that the CD inside the disk and the peripapillary region are significantly reduced in open-angle glaucoma and that the RNFL thickness and the GCC thickness are decreased.22,23 Studies have shown that pathological IOP is a major cause of retinal ganglion cell and optic nerve impairment28; increased IOP can not only directly cause retinal ganglion cell death but also lead to optic neuropathy resulting from ischemia.24 However, a trend toward a reduced RNFL and GCC thickness was also observed in Group 2 despite the absence of increased IOP. This suggests that increased IOP may not be a major risk factor for structural changes in the optic nerve in PPH; however, poor circulation in the retina and optic nerve is a main risk factor for structural injury progression. The blood supply of the optic nerve was decreased in the PPH patients, ultimately leading to damage. Therefore, optic nerve impairment started early in PPH even without clinical symptoms, and the ultimate increase in IOP could worsen the optic nerve damage.

In our study, a significantly greater subfoveal choroidal thickness was observed in the PPH subjects. Increased ocular venous pressure is associated with elevated systemic venous pressure, which affects ocular hemodynamics and causes blood stasis, resulting in thickening of the choroid, and an increased choroidal thickness is a risk factor for CSC. Primary pulmonary hypertension patients have an increased choroidal thickness, and the incidence of CSC among these patients is not unusual.25 In addition, sildenafil, a frequently used drug to control PPH, was found to increase the choroidal blood flow and choroidal thickness.26 Central serous chorioretinopathy occurring after receiving treatment with sildenafil has been previously reported.27,28 Thus, PPH patients treated with sildenafil are more likely to develop CSC. In our patients (Group 1: one patient had been treated with sildenafil for more than 10 years), CSC associated with sildenafil was observed. However, some results in our study are somewhat unexpected considering such preconceptions because the choriocapillary flow was not significantly different between the groups. The higher content of melanocyte pigment in the choroid and its location below the retinal pigment epithelium may influence the measurement outcomes of OCTA. Therefore, future studies are needed to clarify the possible mechanism underlying this finding.

In conclusion, preclinical ocular changes in PPH can be detected by OCTA. Parameters such as the macular-associated VD, optic disk–associated CD, RNFL thickness, and GCC thickness may be useful for the early detection of microvascular and neural impairments in PPH patients with or without fundus changes. Moreover, the deep VD, including the parafoveal and perifoveal VD, and the RNFL and GCC thickness, may be sensitive predictors of ocular impairment in PPH patients without fundus abnormities. This is also the first report to quantify and evaluate vascular dropout and neural impairment in PPH patients.

References

1. Simonneau G, Montani D, Celermajer DS, et al. Haemodynamic definitions and updated clinical classification of pulmonary hypertension. Eur Respir J 2019;24:1–13.
2. Ishaq M, Chand S, Shaikh MI, et al. Primary pulmonary hypertension with retinal neovascularization. J Coll Physicians Surg Pak 2010;20:625–626.
3. Faure C, Miocque S, Fleury L, et al. Primary pulmonary arterial hypertension diagnosed via its ophthalmic features in an adult: diagnosis and therapeutic challenges. Br J Ophthalmol 2012;96:459–469.
4. Parikh RS, Desai S, Kothari K. Dilated episcleral veins with secondary open angle glaucoma. Indian J Ophthalmol 2011;59:153–155.
5. David M, Olivier C, Delphine L, et al. Acute serous retinal detachment in idiopathic pulmonary arterial hypertension. Retin Cases Brief Rep 2017;11:261–265.
6. Nancy K, Christine RG, William SR, et al. Exudative retinal detachment and angle closure glaucoma as the presenting signs of primary pulmonary hypertension. Retin Cases Brief Rep 2011;5:108–112.
7. Senthil S, Kaur B, Jalali S, et al. Secondary open-angle glaucoma and central retinal vein occlusion in a patient with primary pulmonary hypertension. Ophthalmic Surg Lasers Imaging 2009;40:50–53.
8. Lewczuk N, Zdebik A, Bogusławska J, et al. Ocular manifestations of pulmonary hypertension. Surv Ophthalmol 2019;64:694–699.
9. Lopez-Saez MP, Ordoqui E, Tornero P, et al. Fluorescein-induced allergic reaction. Ann Allergy Asthma Immunol 1998;81:428–430.
10. Soares M, Neves C, Marques IP, et al. Comparison of diabetic retinopathy classification using fluorescein angiography and optical coherence tomography angiography. Br J Ophthalmol 2007;101:62–68.
11. Spaide RF, Fujimoto JG, Waheed NK, et al. Optical coherence tomography angiography. Prog Retin Eye Res 2018;64:1–55.
12. Li Z, Alzogool M, Xiao J, et al. Optical coherence tomography angiography findings of neurovascular changes in type 2 diabetes mellitus patients without clinical diabetic retinopathy. Acta Diabetol 2018;55:1075–1082.
13. Watanabe M, Makino S, Obata H. Bilaterally dilated episcleral vessels in patients with heritable pulmonary arterial hypertension. J Gen Fam Med 2017;18:464–465.
14. Krohn J, Bjune C. Uveal effusion and angle-closure glaucoma in primary pulmonary hypertension. Am J Opthamol 2003;135:705–706.
15. Feng Z, Dong L, Cao J, et al. A case study of ciliary detachment with primary pulmonary hypertension. Int Ophthalmol 2018;38:375–379.
16. Yang S, Jeong J, Kim JG, et al. Progressive venous stasis retinopathy and open-angle glaucoma associated with primary pulmonary hypertension. Ophthalmic Surg Lasers Imaging 2006;37:230–233.
17. Cao D, Yang D, Yu H, et al. Optic nerve head perfusion changes preceding peripapillary retinal nerve fibre layer thinning in preclinical diabetic retinopathy. Clin Exp Ophthalmol 2019;47:219–225.
18. Lahme L, Marchiori E, Panuccio G, et al. Changes in retinal flow density measured by optical coherence tomography angiography in patients with carotid artery stenosis after carotid endarterectomy. Sci Rep 2018;8:1–6.
19. Cowburn AS, Takeda N, Boutin AT, et al. HIF isoforms in the skin differentially regulate systemic arterial pressure. Proc Natl Acad Sci U S A 2013;110:17570–17575.
20. Genevois O, Paques M, Simonutti M, et al. Microvascular remodeling after occlusion-recanalization of a branch retinal vein in rats. Invest Ophthalmol Vis Sci 2004;45:594–600.
21. Zhang Jing, Ren Lin, Mei Xi, et al. Microstructure visualization of conventional outflow pathway and finite element modeling analysis of trabecular meshwork. Biomed Eng Online 2016;162:324–334.
22. Hollo G. Optical coherence tomography angiography to better understand glaucoma. J Curr Glaucoma Pract 2017;11:35–37.
23. Alnawaiseh M, Lahme L, Müller V, et al. Correlation of flow density, as measured using optical coherence tomography angiography, with structural and functional parameters in glaucoma patients. Graefes Arc Clin Exp Ophthalmol 2018;256:589–597.
24. Findl O, Strenn K, Wolzt M, et al. Effects of changes in intraocular pressure on human ocular haemodynamics. Curr Eye Res 1997;16:1024–1029.
25. Vance SK, Imamura Y, Freund KB. The effects of sildenafil citrate on choroidal thickness as determined by enhanced depth imaging optical coherence tomography. Retina 2011;31:332–335.
26. Fraunfelder FW, Fraunfeldzer FT. Central serous choroidopathy associated with sildenafil. Retina 2008;28:606–609.
27. Quiram P, Dumars S, Parwar B, et al. Viagra-associated serous macular detachment. Graefes Arch Clin Exp Ophthalmol 2005;243:339–344.
28. Aliferis K, Petropoulos IK, Farpour B, et al. Should central serous chorioretinopathy be added to the list of ocular side effects of phosphodiesterase 5 inhibitors? Ophthalmologica 2012;227:85–89.
Keywords:

primary pulmonary hypertension; optical coherence tomography angiography; ocular complications; retina; retinal nerve fiber layer; choroidal thickness

Copyright © 2020 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the Opthalmic Communications Society, Inc.