Retinal Neurovascular and Choroidal Changes in Pediatric Patients with Cyanotic Congenital Heart Disease: A Multimodal Analysis

Retinal Neurovascular and Choroidal Changes in Pediatric Patients with Cyanotic Congenital Heart Disease: A Multimodal Analysis | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Retinal Neurovascular and Choroidal Changes in Pediatric Patients with Cyanotic Congenital Heart Disease: A Multimodal Analysis Kader Kasar, Taner Kasar This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7852414/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 5 You are reading this latest preprint version Abstract Background: To compare retinal capillary density, foveal avascular zone (FAZ) area, and the thicknesses of the peripapillary retinal nerve fiber layer (RNFL), ganglion cell complex (GCC), and choroid between children with cyanotic congenital heart disease (CCHD) and healthy controls using multimodal optical coherence tomography±angiography (OCT/OCTA). We also examined correlations between these ocular metrics and hemoglobin, hematocrit, and oxygen saturation. Methods: This prospective, age- and sex-matched case–control study enrolled 21 children with CCHD and 21 healthy controls. Retinal capillary density in the superficial and deep capillary plexuses (SCP/DCP) and FAZ area were quantified with OCTA. Peripapillary RNFL, GCC, and choroidal thicknesses were measured with spectral-domain OCT (SD-OCT). To avoid inter-eye correlation, only right-eye data were analyzed. Results: Compared with controls, children with CCHD had a thinner choroid subfoveally and at 1,500 µm nasal and temporal to the fovea (all p<0.001), lower global peripapillary RNFL thickness (p=0.018) with a pronounced inferior-sector deficit (p<0.001), and reduced vessel density in both SCP and DCP (p=0.001 and p<0.001, respectively). In correlation analyses, higher oxygen saturation was associated with greater choroidal thickness at all locations (subfovea p<0.001; nasal 1,500 µm p=0.002; temporal 1,500 µm p=0.001), higher global (p=0.033) and inferior-sector (p<0.001) RNFL thickness, and higher vessel density in SCP and DCP (p=0.003 and p<0.001, respectively). Conversely, higher hemoglobin and hematocrit were associated with a thinner choroid (hemoglobin: subfovea p<0.001, nasal p=0.003, temporal p<0.001; hematocrit: subfovea p<0.001, nasal p=0.002, temporal p<0.001), lower global (hemoglobin p=0.017; hematocrit p=0.012) and inferior-sector (both p<0.001) RNFL thickness, and lower vessel density in both plexuses (SCP: hemoglobin p=0.004, hematocrit p<0.001; DCP: both p<0.001). The FAZ area was inversely associated with oxygen saturation (p=0.009) and positively associated with hemoglobin (p=0.048). GCC thickness did not differ between groups. Conclusions: In pediatric CCHD, retinal capillary density is reduced, the choroid is thinner, and peripapillary RNFL thickness is decreased-while GCC is preserved. Oxygen saturation shows positive associations with these ocular measures, whereas hemoglobin and hematocrit show negative associations. These findings indicate that multimodal OCT/OCTA can detect subclinical ocular involvement and may serve as a noninvasive adjunct for longitudinal monitoring. Cyanotic congenital heart disease Optical coherence tomography angiography Retinal vessel density Deep capillary plexus Choroidal thickness Introduction Congenital heart disease (CHD), structural abnormalities of the heart or great vessels,affects ~ 0.8% of live births and is among the most common major congenital malformations [ 1 , 2 ]. Within this spectrum, cyanotic congenital heart diseases (CCHD) represent the most severe forms, characterized by right-to-left shunting that delivers deoxygenated blood to the systemic circulation and results in persistent chronic hypoxemia [ 3 – 5 ]. Sustained hypoxemia increases mortality and morbidity, diminishes quality of life, and adversely affects multiple organ systems, including hematologic, renal, neurologic, and ophthalmic structures [ 6 – 9 ]. The eye particularly the retinal and optic-nerve circulation is highly sensitive to systemic oxygenation and is often regarded as a “window” to the cardiovascular system. In CCHD, reported ophthalmic findings include retinal vascular tortuosity, venous dilation, arteriovenous occlusion, papilledema, optic nerve hypoplasia, and cataract [ 9 , 10 ]. Although retinal microvascular architecture appears to reflect both the severity and duration of hypoxemia, quantitative pediatric data remain limited, especially regarding retinal vessel density (RVD) [ 11 ]. Advances in ocular imaging now enable detailed assessment of hypoxemia-related changes. Spectral-domain optical coherence tomography (SD-OCT) provides high-resolution structural measurements of the retina and choroid and is a reliable method for quantifying choroidal thickness (CT) [ 12 ]. Optical coherence tomography angiography (OCTA) offers a noninvasive means to quantify and visualize the retinal microcirculation, including vascular density and the foveal avascular zone (FAZ) [ 11 ]. Both modalities are well suited to pediatric populations because they are rapid, safe, and yield high-quality images. Accordingly, the present study evaluated retinal microvasculature (RVD in the superficial and deep capillary plexuses and FAZ area), choroidal thickness, and peripapillary retinal nerve fiber layer (RNFL) and ganglion cell complex (GCC) thicknesses in children with CCHD using SD-OCT and OCTA. By delineating the ocular manifestations of chronic hypoxemia and examining their associations with hemoglobin, hematocrit, and oxygen saturation, we sought to clarify the potential of retinal parameters as noninvasive biomarkers of systemic oxygenation in pediatric CCHD. Materials And Methods This single-center, cross-sectional, comparative study was conducted between April and September 2025 at Ordu University Training and Research Hospital. The sample comprised 21 children with echocardiography-confirmed CCHD followed in the Pediatric Cardiology Clinic and 21 age- and sex-matched healthy children with normal cardiological evaluations and no systemic or cardiac disease as controls. Written informed consent was obtained from parents; the study adhered to the Declaration of Helsinki and was approved by the Ordu University Clinical Research Ethics Committee (approval No. 2025/137). Peripheral oxygen saturation (SaO₂) was measured by pulse oximetry (finger or toe probe) after ≥ 5 minutes of seated rest; patients with SaO₂ ≤ 90% were considered cyanotic. Exclusion criteria were a history of ocular surgery or trauma, glaucoma, uveitis, retinal or other fundus disease, intraocular pressure > 21 mmHg, media opacities compromising image quality (e.g., dense cataract), and additional systemic congenital disorders. All participants underwent a comprehensive ophthalmologic examination in the Department of Ophthalmology, including refraction, best-corrected visual acuity, non-contact tonometry, slit-lamp biomicroscopy, and indirect ophthalmoscopy. To avoid inter-eye correlation, only right-eye data were analyzed. Following pharmacologic pupil dilation, SD-OCT and OCTA were performed between 10:00 and 11:00 a.m. using the Optovue system (Optovue Inc., Fremont, CA, USA). Choroidal thickness was measured on SD-OCT using an enhanced-depth imaging technique, perpendicularly from the outer border of Bruch’s membrane to the choroid–sclera interface at the foveal center and at 1,500 µm nasal and temporal to the fovea. Peripapillary RNFL and GCC thicknesses were recorded. OCTA was used to assess the retinal microvasculature, including retinal vessel density in the superficial and deep capillary plexuses and the FAZ area. For image quality control, three scans were acquired per participant, and the image with the highest signal quality was selected for analysis. Scans with signal strength index (SSI) < 45, decentration, segmentation errors, or algorithm failure were excluded. All measurements were performed by an experienced ophthalmologist masked to participants’ clinical diagnoses. Statistical Analysis The normality of the data was tested using the Shapiro-Wilk test. If the data were normally distributed, groups were compared using the Student’s t-test, and descriptive statistics were reported as Mean ± Standard Deviation. If the data were not normally distributed, the Mann-Whitney U test was used, and descriptive statistics were presented as Median (Min-Max). For categorical variables, group comparisons were conducted using the Chi-Square test. The categorical variables were presented as frequency (n) and percentage (%). Spearman correlation coefficient was calculated to assess the correlation between variables. The package of SPSS 29.0.2.0 software was used for the statistical analysis. Statistical significance was set as α = 0.05. Results Twenty-one children with CCHD and 21 age- and sex-matched healthy controls were included. Demographic and baseline clinical characteristics are summarized in Table 1 . There were no statistically significant between-group differences in age (8.66 ± 2.17 vs 8.66 ± 2.41 years; p = 1.000) or sex distribution (47.6% male, 52.4% female; p = 1.000). Systemic oxygen saturation was lower in the CCHD group (median [range], 84% [78–88] vs 98% [96–100]; p < 0.001), whereas hemoglobin (Hb) and hematocrit (Hct) were higher (Hb: 14.80 [12.80–22.80] vs 12.60 [11.30–14.10] g/dL; Hct: 44.70% [37.90–72.50] vs 37.10% [33.50–42.50]; both p 0.05). Table 1 Demographic characteristics of the study and control groups CCHD (n = 21) Control (n = 21) P value Age (years) 8.66 ± 2.17 8.66 ± 2.41 1.000* Gender, n (%) Male Female 10 (47.6%) 11 (52.4%) 10 (47.6%) 11 (52.4%) 1.000*** Body weight (kg). 28.00 (15.50–78.00) 29.00 (18.00–54.00) 0.484** SaO2 (%) 84.00 (78.0–88.0) 98.00 (96.0-100.0) < 0.001** Hb (g/dL) 14.80 (12.80–22.80) 12.60 (11.30–14.10) < 0.001 Htc (%) 44.70 (37.90–72.50) 37.10 (33.50–42.50) < 0.001** Systolic BP (mmHg) 107.00 ± 11.36 108.19 ± 5.94 0.674* Diastolic BP (mmHg) 67.00 (48.0–82.0) 67.00 (60.0–81.0) 0.427** SE (diopters) -0.40 ± 1.01 0.03 ± 1.25 0.219* IOP (mmHg) 11.95 ± 2.03 11.90 ± 2.07 0.940* Axial length (mm) 21.90 (20.10–22.80) 21.10 (20.07–23.26) 0.099** Continuous variables are presented as mean ± standard deviation or median (interquartile range), and categorical variables as n (%). * Student’s t-test, ** Mann-Whitney U test, *** Chi-Square test. Abbreviations: BP, blood pressure; CCHD, cyanotic congenital heart disease; Hb, haemoglobin; HCT, haematocrit; IOP, intraocular pressure; SaO2, oxygen saturation; SE, spherical equivalent. Cardiac diagnoses in the CCHD cohort were heterogeneous (Table 2 ). The most common categories were pulmonary atresia with ventricular septal defect (PA/VSD; 23.8%), double-outlet right ventricle (DORV;19.0%), and tricuspid atresia (19.0%). Unbalanced atrioventricular septal defect (AVSD) and Eisenmenger physiology each accounted for 9.5%. Less frequent entities truncus arteriosus; congenitally corrected transposition of the great arteries (ccTGA) with ventricular septal defect and pulmonary stenosis; hypoplastic left heart syndrome (HLHS); and pulmonary arteriovenous fistula were each observed in 4.8%. Table 2 Primary cardiac diagnoses in the CHD cohort (N = 21). Diagnostic category n (%) VSD + PA (± MAPCAs/PA anomalies) 5 (23.8) DORV spectrum 4 (19.0) Tricuspid atresia (single-ventricle physiology) 4 (19.0) AVSD (unbalanced ventricle) 2 (9.5) Eisenmenger syndrome (late shunt physiology) 2 (9.5) Truncus arteriosus 1 (4.8) ccTGA ± PS with VSD 1 (4.8) HLHS 1 (4.8) Pulmonary arteriovenous fistula 1 (4.8) Notes: Categorization is by predominant anatomical/physiological diagnosis. Associated findings (e.g., dextrocardia, PAPVD, pulmonary artery hypoplasia/absence) and prior/surgical status (Glenn/Fontan, bands, stents) were not used to define the primary category. Abbreviations: AVSD, atrioventricular septal defect; ccTGA, congenitally corrected transposition of the great arteries; DORV, double-outlet right ventricle; HLHS, hypoplastic left heart syndrome; MAPCAs, major aortopulmonary collateral arteries; PA, pulmonary artery; PS, pulmonary stenosis; VSD, ventricular septal defect. Structural and microvascular imaging findings are presented in Table 3 . CT was significantly lower in the CCHD group at all locations: subfovea (285.0 ± 33.9 vs 366.3 ± 47.8 µm; p < 0.001), 1,500 µm nasal (273.0 ± 39.5 vs 337.9 ± 54.8 µm; p < 0.001), and 1,500 µm temporal (302.9 ± 36.9 vs 368.2 ± 44.7 µm; p < 0.001). The absolute mean between-group differences (~ 65–81 µm) corresponded to an approximate 17–22% reduction across locations. Table 3 Comparison of OCT/OCTA parameters between CCHD and control groups Parameter CCHD (n = 21) Control (n = 21) P value Subfoveal CT (µm) 285.02 ± 33.92 366.31 ± 47.76 < 0.001* Nasal 1500 µm CT (µm) 273.04 ± 39.48 337.94 ± 54.77 < 0.001* Temporal 1500 µm CT (µm) 302.97 ± 36.89 368.23 ± 44.72 < 0.001* GCC thickness (µm) 99.81 ± 8.28 102.19 ± 5.10 0.270* Superior GCC thickness (µm) 98.00 ± 7.2250 100.429 ± 3.8932 0.183* Inferior GCC thickness (µm) 101.00 (86.0–117.0) 98.00 (90.0–117.0) 0.295** RNFL thickness (µm) 98.00 (84.0–113.0) 106.00 (95.0–131.0) 0.018** Superior RNFL thickness (µm) 99.00 (86.0–117.0) 100.00 (93.0–134.0) 0.147** Inferior RNFL thickness (µm) 96.09 ± 8.88 111.81 ± 11.93 < 0.001* FAZ area (mm²) 0.30 ± 0.07 0.26 ± 0.05 0.062* SCP vessel density (%) 49.20 (43.40–51.20) 50.90 (47.90–54.20) 0.001** DCP vessel density (%) 49.80 (35.30–54.20) 54.00 (49.50–57.10) < 0.001** Values are presented as mean ± standard deviation or median (range) as appropriate. P values were calculated using independent-samples t-test (*) for variables presented as mean ± SD, and Mann–Whitney U test (**) for variables presented as median (range). Abbreviations: CCHD, cyanotic congenital heart disease; FAZ, foveal avascular zone; RNFL, retinal nerve fiber layer; GCC, ganglion cell complex; CT, choroidal thickness; SCP, superficial capillary plexus; DCP, deep capillary plexus. Table 4 Correlation analysis between systemic parameters (SaO₂, Hb, Hct) and ocular metrics. Ocular Parameters SaO₂ Hb Hct (r, P) (r, P) (r, P) Subfoveal CT, µm 0.61, < 0.001* -0.56, < 0.001* -0.59, < 0.001* Nasal 1500 µm CT (µm) 0.46, 0.002* -0.45, 0.003* -0.46,0.002* Temporal 1500 µm CT (µm) 0.49, 0.001* -0.55, < 0.001* -0.57, < 0.001* GCC thickness, (µm) 0.12, 0.462 -0.24, 0.129 -0.27, 0.079 Superior GCC thickness (µm) -0.15, 0.357 0.04, 0.783 0.02, 0.909 Inferior GCC thickness (µm) 0.14, 0.382 -0.15, 0.336 -0.23, 0.144 RNFL thickness, µm 0.33, 0.033* -0.36, 0.017* -0.38, 0.012* Superior RNFL thickness (µm) 0.27, 0.090 -0.28, 0.077 -0.29, 0.065 Inferior RNFL thickness (µm) 0.57, < 0.001* -0.61, < 0.001* -0.62, < 0.001* FAZ area, (mm²) -0.40, 0.009* 0.31, 0.048* 0.24, 0.117 SCP vessel density, (%) 0.45, 0.003* -0.43, 0.004* -0.53, < 0.001* DCP vessel density, (%) 0.64, < 0.001* -0.60, < 0.001* -0.55, < 0.001* *p < 0.05 is statistically significant. Abbreviations: SaO₂, peripheral oxygen saturation; Hb, hemoglobin; Hct, hematocrit; SCP, superficial capillary plexus; DCP, deep capillary plexus; FAZ, foveal avascular zone; RNFL, retinal nerve fiber layer; GCC, ganglion cell complex. For neural retinal structure, global peripapillary RNFL thickness was lower in CCHD (median 98.0 [84–113] vs 106.0 [95–131] µm; p = 0.018), with a particularly pronounced inferior-sector reduction (96.09 ± 8.88 vs 111.81 ± 11.93 µm; p 0.05). Retinal capillary vessel density was reduced in CCHD. The superficial capillary plexus (SCP) showed lower density (median [range], 49.2% [43.4–51.2] vs 50.9% [47.9–54.2]; p = 0.001), with a more marked reduction in the deep capillary plexus (DCP) (49.8% [35.3–54.2] vs 54.0% [49.5–57.1]; p < 0.001). The FAZ area was larger in CCHD (0.30 ± 0.07 vs 0.26 ± 0.05 mm²) but did not reach statistical significance (p = 0.062). In summary, children with CCHD exhibited diffuse choroidal thinning, reduced SCP vessel density with a more pronounced decrease in the DCP, and a statistically significant inferior-sector RNFL reduction, whereas other RNFL sectors and GCC were comparable between groups. Discussion This study provides a comprehensive retinal and choroidal evaluation in children with CCHD using multimodal OCT/OCTA. We identified diffuse choroidal thinning, a reduction in RVD with a DCP predominant pattern, and predominantly inferior-sector peripapillary RNFL thinning, while GCC thickness remained unchanged. Across metrics, SaO₂ was positively associated and Hb/Hct were inversely associated with structural and microvascular measures, implicating hypoxemia-related hyperviscosity and endothelial dysfunction as potential drivers of ocular microcirculatory compromise. Retinal vessel density was reduced in both the SCP and DCP, with a more pronounced decrement in the DCP consistent with prior observations in congenital heart disease [ 11 ]. The heightened susceptibility of the DCP may relate to its pericyte-rich, small-caliber capillaries, greater distance from arteriolar oxygen sources, and location within a functional watershed zone [ 13 ]. In our cohort, DCP-RVD showed the strongest positive association with SaO₂ and the strongest inverse associations with Hb/Hct among the vascular layers examined. Concordant evidence from adults with dilated cardiomyopathy related heart failure demonstrates reduced DCP and radial peripapillary capillary densities [ 14 ], supporting the concept that the retinal microcirculation is sensitive to systemic hypoxic burden. Moreover, OCTA-based vascular alterations appear to evolve in parallel with cardiac dysfunction, suggesting a potential role for OCTA as a complementary tool for longitudinal cardiac monitoring [ 15 ]. Peripapillary RNFL thickness was globally reduced in CCHD, with a statistically significant decrement in the inferior sector. This pattern parallels adult CCHD data linking RNFL thinning with reduced cerebral white-matter volume [ 16 ]. The inverse association between inferior-sector RNFL and Hb/Hct in our cohort further supports the hypothesis that hyperviscosity-related perfusion stress contributes to subclinical injury at the optic nerve head. Choroidal thickness was significantly lower at subfoveal, nasal, and temporal locations. The positive association between CT and SaO₂, together with inverse associations with Hb/Hct, indicates that chronic hypoxemia and increased blood viscosity may impair choroidal perfusion and tissue metabolic support. Consistently, decreased subfoveal CT has also been reported in chronic heart failure [ 13 ]. Although the FAZ area tended to be larger in CCHD, the between-group difference was not statistically significant. This may reflect greater susceptibility of the FAZ to inter-individual anatomical variation and the relatively later manifestation of hypoxic effects compared with microvascular metrics such as DCP-RVD [ 18 , 19 ]. Accordingly, for clinical follow-up, SCP/DCP vessel-density measures being more dynamic and hypoxia-sensitive may be prioritized. Strengths of this study include assessment of multiple retinal and choroidal compartments within the same pediatric CCHD cohort; single-eye analysis to avoid inter-eye correlation; masked grading; diurnal timing standardization; and stringent image-quality criteria. The cross-sectional design, however, limits inferences regarding disease progression. In conclusion, pediatric CCHD exhibits an ocular phenotype characterized by DCP-weighted microvascular loss, inferior-sector RNFL thinning, and diffuse choroidal thinning changes that likely reflect the ophthalmic imprint of systemic hypoxemia and hyperviscosity. These data support the use of retinal microcirculatory metrics as noninvasive biomarkers of systemic oxygenation and suggest that OCT/OCTA could serve as a complementary adjunct for clinical monitoring in CCHD. Declarations Author Contributions KK designed the study, performed all ophthalmologic imaging procedures (OCT/OCTA), interpreted ocular data, coordinated the methodology, and was primarily responsible for writing the manuscript. TK contributed to manuscript editing, assisted in patient recruitment, and provided clinical support during data collection. Both authors read and approved the final version of the manuscript. Consent for publication All the patients included in this study gave written informed consent for their personal or clinical details along with any identifying images to be published in this study. • Ethics Approval and Consent to Participate This study was approved by the Ordu University Clinical Research Ethics Committee (Approval No: 2025/137). Written informed consent was obtained from the parents or legal guardians of all participants, in accordance with the Declaration of Helsinki. • Consent for Publication Written informed consent for publication of anonymized data and images was obtained from the parents of all participants. • Availability of Data and Materials The datasets used and analyzed during the current study are available from the corresponding author upon reasonable request. • Competing Interests The authors declare no competing interests. • Funding No external funding was received for this study. • Acknowledgements We would like to thank the clinical staff of the Pediatric Cardiology and Ophthalmology departments for their support in data acquisition and coordination. References Van der Linde D, Konings EE, Slager MA, Witsenburg M, Helbing WA, Takkenberg JJ, et al. Birth prevalence of congenital heart disease worldwide: a systematic review and meta-analysis. J Am Coll Cardiol. 2011;58(21):2241-2247. 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Freiberg FJ, Pfau M, Wons J, Wirth MA, Becker MD, Michels S. Optical coherence tomography angiography of the foveal avascular zone in diabetic retinopathy. Graefes Arch Clin Exp Ophthalmol. 2016;254(6):1051-1058. Sun Z, Yang D, Tang Z, Ng DS, Cheung CY. Optical coherence tomography angiography in diabetic retinopathy: an updated review. Eye (Lond). 2021;35(1):149-161. Additional Declarations No competing interests reported. Cite Share Download PDF Status: Under Review Version 1 posted Reviewers invited by journal 10 Nov, 2025 Editor assigned by journal 05 Nov, 2025 Editor invited by journal 15 Oct, 2025 Submission checks completed at journal 14 Oct, 2025 First submitted to journal 14 Oct, 2025 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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Kasar","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA+UlEQVRIiWNgGAWjYDCCA2wMDDwMDAZgzscGEMnYeIBoLYwzGxgkgFQD8VqYecFagIL4dPDdPpb44U3FPWP+/sPPPtvusKnTbT8MtKXGJhqXFslzaYcl55wpNpO4kWY8O/dMmoTZmUSglmNpuQ04tBicYW+Q5m1LsGG4wWDMnNt2WMLsAFALY8NhfFqaf/P+S7CRP3/8M7MlSMv5h4S0sB2T5m1IMDM4kGPMzAjScoOALZJn2NIs5xxLMDa8kVPM2NuWJrntBtCWBDx+4TvDZnzjTU2C4bzzxzcz/Gyz4Tc7n/7wwYcaG5xacIAE0pSPglEwCkbBKEADAGuJY3bqwAM0AAAAAElFTkSuQmCC","orcid":"","institution":"Ordu University Training and Research Hospital","correspondingAuthor":true,"prefix":"","firstName":"Kader","middleName":"","lastName":"Kasar","suffix":""},{"id":531158387,"identity":"6a0f7582-16a1-42cc-bf38-c3b59e43fd22","order_by":1,"name":"Taner Kasar","email":"","orcid":"","institution":"Ordu University Training and Research 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05:19:42","extension":"xml","order_by":3,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":73739,"visible":true,"origin":"","legend":"","description":"","filename":"1adaf1823b3248f9bb914d81842311a61enriched.xml","url":"https://assets-eu.researchsquare.com/files/rs-7852414/v1/a61404fb04b4372a0db67956.xml"},{"id":94162709,"identity":"7a56844b-58dc-4518-8173-cc45464ec366","added_by":"auto","created_at":"2025-10-23 05:19:42","extension":"xml","order_by":4,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":71366,"visible":true,"origin":"","legend":"","description":"","filename":"1adaf1823b3248f9bb914d81842311a61structuring.xml","url":"https://assets-eu.researchsquare.com/files/rs-7852414/v1/f2242cd55aea4b52ff9a247e.xml"},{"id":94162716,"identity":"e897bfd0-d404-4b91-8ad4-4257731c77a8","added_by":"auto","created_at":"2025-10-23 05:19:42","extension":"html","order_by":5,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":77242,"visible":true,"origin":"","legend":"","description":"","filename":"earlyproof.html","url":"https://assets-eu.researchsquare.com/files/rs-7852414/v1/07ba178efcf476da4c7e8d45.html"},{"id":94163229,"identity":"b34b0f33-00d6-4dbc-8e74-bf6bc5911b0f","added_by":"auto","created_at":"2025-10-23 05:27:47","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":526771,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7852414/v1/d93c19e4-ca72-443b-9971-6535bc5015f0.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Retinal Neurovascular and Choroidal Changes in Pediatric Patients with Cyanotic Congenital Heart Disease: A Multimodal Analysis","fulltext":[{"header":"Introduction","content":"\u003cp\u003eCongenital heart disease (CHD), structural abnormalities of the heart or great vessels,affects\u0026thinsp;~\u0026thinsp;0.8% of live births and is among the most common major congenital malformations [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. Within this spectrum, cyanotic congenital heart diseases (CCHD) represent the most severe forms, characterized by right-to-left shunting that delivers deoxygenated blood to the systemic circulation and results in persistent chronic hypoxemia [\u003cspan additionalcitationids=\"CR4\" citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. Sustained hypoxemia increases mortality and morbidity, diminishes quality of life, and adversely affects multiple organ systems, including hematologic, renal, neurologic, and ophthalmic structures [\u003cspan additionalcitationids=\"CR7 CR8\" citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eThe eye particularly the retinal and optic-nerve circulation is highly sensitive to systemic oxygenation and is often regarded as a \u0026ldquo;window\u0026rdquo; to the cardiovascular system. In CCHD, reported ophthalmic findings include retinal vascular tortuosity, venous dilation, arteriovenous occlusion, papilledema, optic nerve hypoplasia, and cataract [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. Although retinal microvascular architecture appears to reflect both the severity and duration of hypoxemia, quantitative pediatric data remain limited, especially regarding retinal vessel density (RVD) [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eAdvances in ocular imaging now enable detailed assessment of hypoxemia-related changes. Spectral-domain optical coherence tomography (SD-OCT) provides high-resolution structural measurements of the retina and choroid and is a reliable method for quantifying choroidal thickness (CT) [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. Optical coherence tomography angiography (OCTA) offers a noninvasive means to quantify and visualize the retinal microcirculation, including vascular density and the foveal avascular zone (FAZ) [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. Both modalities are well suited to pediatric populations because they are rapid, safe, and yield high-quality images.\u003c/p\u003e\u003cp\u003eAccordingly, the present study evaluated retinal microvasculature (RVD in the superficial and deep capillary plexuses and FAZ area), choroidal thickness, and peripapillary retinal nerve fiber layer (RNFL) and ganglion cell complex (GCC) thicknesses in children with CCHD using SD-OCT and OCTA. By delineating the ocular manifestations of chronic hypoxemia and examining their associations with hemoglobin, hematocrit, and oxygen saturation, we sought to clarify the potential of retinal parameters as noninvasive biomarkers of systemic oxygenation in pediatric CCHD.\u003c/p\u003e"},{"header":"Materials And Methods","content":"\u003cp\u003eThis single-center, cross-sectional, comparative study was conducted between April and September 2025 at Ordu University Training and Research Hospital. The sample comprised 21 children with echocardiography-confirmed CCHD followed in the Pediatric Cardiology Clinic and 21 age- and sex-matched healthy children with normal cardiological evaluations and no systemic or cardiac disease as controls. Written informed consent was obtained from parents; the study adhered to the Declaration of Helsinki and was approved by the Ordu University Clinical Research Ethics Committee (approval No. 2025/137).\u003c/p\u003e\u003cp\u003ePeripheral oxygen saturation (SaO₂) was measured by pulse oximetry (finger or toe probe) after \u0026ge;\u0026thinsp;5 minutes of seated rest; patients with SaO₂ \u0026le; 90% were considered cyanotic. Exclusion criteria were a history of ocular surgery or trauma, glaucoma, uveitis, retinal or other fundus disease, intraocular pressure\u0026thinsp;\u0026gt;\u0026thinsp;21 mmHg, media opacities compromising image quality (e.g., dense cataract), and additional systemic congenital disorders.\u003c/p\u003e\u003cp\u003eAll participants underwent a comprehensive ophthalmologic examination in the Department of Ophthalmology, including refraction, best-corrected visual acuity, non-contact tonometry, slit-lamp biomicroscopy, and indirect ophthalmoscopy. To avoid inter-eye correlation, only right-eye data were analyzed.\u003c/p\u003e\u003cp\u003eFollowing pharmacologic pupil dilation, SD-OCT and OCTA were performed between 10:00 and 11:00 a.m. using the Optovue system (Optovue Inc., Fremont, CA, USA). Choroidal thickness was measured on SD-OCT using an enhanced-depth imaging technique, perpendicularly from the outer border of Bruch\u0026rsquo;s membrane to the choroid\u0026ndash;sclera interface at the foveal center and at 1,500 \u0026micro;m nasal and temporal to the fovea. Peripapillary RNFL and GCC thicknesses were recorded. OCTA was used to assess the retinal microvasculature, including retinal vessel density in the superficial and deep capillary plexuses and the FAZ area.\u003c/p\u003e\u003cp\u003eFor image quality control, three scans were acquired per participant, and the image with the highest signal quality was selected for analysis. Scans with signal strength index (SSI)\u0026thinsp;\u0026lt;\u0026thinsp;45, decentration, segmentation errors, or algorithm failure were excluded. All measurements were performed by an experienced ophthalmologist masked to participants\u0026rsquo; clinical diagnoses.\u003c/p\u003e\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\u003ch2\u003eStatistical Analysis\u003c/h2\u003e\u003cp\u003eThe normality of the data was tested using the Shapiro-Wilk test. If the data were normally distributed, groups were compared using the Student\u0026rsquo;s t-test, and descriptive statistics were reported as Mean\u0026thinsp;\u0026plusmn;\u0026thinsp;Standard Deviation. If the data were not normally distributed, the Mann-Whitney U test was used, and descriptive statistics were presented as Median (Min-Max). For categorical variables, group comparisons were conducted using the Chi-Square test. The categorical variables were presented as frequency (n) and percentage (%). Spearman correlation coefficient was calculated to assess the correlation between variables. The package of SPSS 29.0.2.0 software was used for the statistical analysis. Statistical significance was set as α\u0026thinsp;=\u0026thinsp;0.05.\u003c/p\u003e\u003c/div\u003e"},{"header":"Results","content":"\u003cp\u003eTwenty-one children with CCHD and 21 age- and sex-matched healthy controls were included. Demographic and baseline clinical characteristics are summarized in Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e. There were no statistically significant between-group differences in age (8.66\u0026thinsp;\u0026plusmn;\u0026thinsp;2.17 vs 8.66\u0026thinsp;\u0026plusmn;\u0026thinsp;2.41 years; p\u0026thinsp;=\u0026thinsp;1.000) or sex distribution (47.6% male, 52.4% female; p\u0026thinsp;=\u0026thinsp;1.000). Systemic oxygen saturation was lower in the CCHD group (median [range], 84% [78\u0026ndash;88] vs 98% [96\u0026ndash;100]; p\u0026thinsp;\u0026lt;\u0026thinsp;0.001), whereas hemoglobin (Hb) and hematocrit (Hct) were higher (Hb: 14.80 [12.80\u0026ndash;22.80] vs 12.60 [11.30\u0026ndash;14.10] g/dL; Hct: 44.70% [37.90\u0026ndash;72.50] vs 37.10% [33.50\u0026ndash;42.50]; both p\u0026thinsp;\u0026lt;\u0026thinsp;0.001). Body weight, systemic blood pressure (systolic/diastolic), axial length, intraocular pressure, and spherical equivalent did not differ significantly between groups (all p\u0026thinsp;\u0026gt;\u0026thinsp;0.05).\u003c/p\u003e\n\u003cdiv class=\"gridtable\"\u003e\n \u003ctable id=\"Tab1\" border=\"1\"\u003e\n \u003ccaption language=\"En\"\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003eDemographic characteristics of the study and control groups\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\u0026nbsp;\u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eCCHD (n\u0026thinsp;=\u0026thinsp;21)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eControl (n\u0026thinsp;=\u0026thinsp;21)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eP value\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAge (years)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e8.66\u0026thinsp;\u0026plusmn;\u0026thinsp;2.17\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e8.66\u0026thinsp;\u0026plusmn;\u0026thinsp;2.41\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e1.000*\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eGender, n (%)\u003c/p\u003e\n \u003cp\u003eMale\u003c/p\u003e\n \u003cp\u003eFemale\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e10 (47.6%)\u003c/p\u003e\n \u003cp\u003e11 (52.4%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e10 (47.6%)\u003c/p\u003e\n \u003cp\u003e11 (52.4%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.000***\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eBody weight (kg).\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e28.00 (15.50\u0026ndash;78.00)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e29.00 (18.00\u0026ndash;54.00)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.484**\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eSaO2 (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e84.00 (78.0\u0026ndash;88.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e98.00 (96.0-100.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e\u0026lt;\u0026thinsp;0.001**\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eHb (g/dL)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e14.80 (12.80\u0026ndash;22.80)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e12.60 (11.30\u0026ndash;14.10)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eHtc (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e44.70 (37.90\u0026ndash;72.50)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e37.10 (33.50\u0026ndash;42.50)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e\u0026lt;\u0026thinsp;0.001**\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eSystolic BP (mmHg)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e107.00\u0026thinsp;\u0026plusmn;\u0026thinsp;11.36\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e108.19\u0026thinsp;\u0026plusmn;\u0026thinsp;5.94\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.674*\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eDiastolic BP (mmHg)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e67.00 (48.0\u0026ndash;82.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e67.00 (60.0\u0026ndash;81.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.427**\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eSE (diopters)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-0.40\u0026thinsp;\u0026plusmn;\u0026thinsp;1.01\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.03\u0026thinsp;\u0026plusmn;\u0026thinsp;1.25\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.219*\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eIOP (mmHg)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e11.95\u0026thinsp;\u0026plusmn;\u0026thinsp;2.03\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e11.90\u0026thinsp;\u0026plusmn;\u0026thinsp;2.07\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.940*\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAxial length (mm)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e21.90 (20.10\u0026ndash;22.80)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e21.10 (20.07\u0026ndash;23.26)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.099**\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003ctfoot\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"4\"\u003eContinuous variables are presented as mean\u0026thinsp;\u0026plusmn;\u0026thinsp;standard deviation or median (interquartile range), and categorical variables as n (%). * Student\u0026rsquo;s t-test, ** Mann-Whitney U test, *** Chi-Square test. Abbreviations: BP, blood pressure; CCHD, cyanotic congenital heart disease; Hb, haemoglobin; HCT, haematocrit; IOP, intraocular pressure; SaO2, oxygen saturation; SE, spherical equivalent.\u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tfoot\u003e\n \u003c/table\u003e\n\u003c/div\u003e\n\u003cp\u003eCardiac diagnoses in the CCHD cohort were heterogeneous (Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e). The most common categories were pulmonary atresia with ventricular septal defect (PA/VSD; 23.8%), double-outlet right ventricle (DORV;19.0%), and tricuspid atresia (19.0%). Unbalanced atrioventricular septal defect (AVSD) and Eisenmenger physiology each accounted for 9.5%. Less frequent entities truncus arteriosus; congenitally corrected transposition of the great arteries (ccTGA) with ventricular septal defect and pulmonary stenosis; hypoplastic left heart syndrome (HLHS); and pulmonary arteriovenous fistula were each observed in 4.8%.\u003c/p\u003e\n\u003cdiv class=\"gridtable\"\u003e\n \u003ctable id=\"Tab2\" border=\"1\"\u003e\n \u003ccaption language=\"En\"\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003ePrimary cardiac diagnoses in the CHD cohort (N\u0026thinsp;=\u0026thinsp;21).\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eDiagnostic category\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003en (%)\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eVSD\u0026thinsp;+\u0026thinsp;PA (\u0026plusmn;\u0026thinsp;MAPCAs/PA anomalies)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e5 (23.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eDORV spectrum\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e4 (19.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eTricuspid atresia (single-ventricle physiology)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e4 (19.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAVSD (unbalanced ventricle)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e2 (9.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eEisenmenger syndrome (late shunt physiology)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e2 (9.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eTruncus arteriosus\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e1 (4.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eccTGA\u0026thinsp;\u0026plusmn;\u0026thinsp;PS with VSD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e1 (4.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eHLHS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e1 (4.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ePulmonary arteriovenous fistula\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e1 (4.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003ctfoot\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\"\u003eNotes: Categorization is by predominant anatomical/physiological diagnosis. Associated findings (e.g., dextrocardia, PAPVD, pulmonary artery hypoplasia/absence) and prior/surgical status (Glenn/Fontan, bands, stents) were not used to define the primary category.\u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tfoot\u003e\n \u003c/table\u003e\n\u003c/div\u003e\n\u003cp\u003eAbbreviations: AVSD, atrioventricular septal defect; ccTGA, congenitally corrected transposition of the great arteries; DORV, double-outlet right ventricle; HLHS, hypoplastic left heart syndrome; MAPCAs, major aortopulmonary collateral arteries; PA, pulmonary artery; PS, pulmonary stenosis; VSD, ventricular septal defect.\u003c/p\u003e\n\u003cp\u003eStructural and microvascular imaging findings are presented in Table \u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003e. CT was significantly lower in the CCHD group at all locations: subfovea (285.0\u0026thinsp;\u0026plusmn;\u0026thinsp;33.9 vs 366.3\u0026thinsp;\u0026plusmn;\u0026thinsp;47.8 \u0026micro;m; p\u0026thinsp;\u0026lt;\u0026thinsp;0.001), 1,500 \u0026micro;m nasal (273.0\u0026thinsp;\u0026plusmn;\u0026thinsp;39.5 vs 337.9\u0026thinsp;\u0026plusmn;\u0026thinsp;54.8 \u0026micro;m; p\u0026thinsp;\u0026lt;\u0026thinsp;0.001), and 1,500 \u0026micro;m temporal (302.9\u0026thinsp;\u0026plusmn;\u0026thinsp;36.9 vs 368.2\u0026thinsp;\u0026plusmn;\u0026thinsp;44.7 \u0026micro;m; p\u0026thinsp;\u0026lt;\u0026thinsp;0.001). The absolute mean between-group differences (~\u0026thinsp;65\u0026ndash;81 \u0026micro;m) corresponded to an approximate 17\u0026ndash;22% reduction across locations.\u003c/p\u003e\n\u003cdiv class=\"gridtable\"\u003e\n \u003ctable id=\"Tab3\" border=\"1\"\u003e\n \u003ccaption language=\"En\"\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003eComparison of OCT/OCTA parameters between CCHD and control groups\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eParameter\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eCCHD (n\u0026thinsp;=\u0026thinsp;21)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eControl (n\u0026thinsp;=\u0026thinsp;21)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eP value\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eSubfoveal CT (\u0026micro;m)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e285.02\u0026thinsp;\u0026plusmn;\u0026thinsp;33.92\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e366.31\u0026thinsp;\u0026plusmn;\u0026thinsp;47.76\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e\u0026lt;\u0026thinsp;0.001*\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNasal 1500 \u0026micro;m CT (\u0026micro;m)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e273.04\u0026thinsp;\u0026plusmn;\u0026thinsp;39.48\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e337.94\u0026thinsp;\u0026plusmn;\u0026thinsp;54.77\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e\u0026lt;\u0026thinsp;0.001*\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eTemporal 1500 \u0026micro;m CT (\u0026micro;m)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e302.97\u0026thinsp;\u0026plusmn;\u0026thinsp;36.89\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e368.23\u0026thinsp;\u0026plusmn;\u0026thinsp;44.72\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e\u0026lt;\u0026thinsp;0.001*\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eGCC thickness (\u0026micro;m)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e99.81\u0026thinsp;\u0026plusmn;\u0026thinsp;8.28\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e102.19\u0026thinsp;\u0026plusmn;\u0026thinsp;5.10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.270*\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eSuperior GCC thickness (\u0026micro;m)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e98.00\u0026thinsp;\u0026plusmn;\u0026thinsp;7.2250\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e100.429\u0026thinsp;\u0026plusmn;\u0026thinsp;3.8932\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.183*\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eInferior GCC thickness (\u0026micro;m)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e101.00 (86.0\u0026ndash;117.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e98.00 (90.0\u0026ndash;117.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.295**\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eRNFL thickness (\u0026micro;m)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e98.00 (84.0\u0026ndash;113.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e106.00 (95.0\u0026ndash;131.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.018**\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eSuperior RNFL thickness (\u0026micro;m)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e99.00 (86.0\u0026ndash;117.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e100.00 (93.0\u0026ndash;134.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.147**\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eInferior RNFL thickness (\u0026micro;m)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e96.09\u0026thinsp;\u0026plusmn;\u0026thinsp;8.88\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e111.81\u0026thinsp;\u0026plusmn;\u0026thinsp;11.93\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e\u0026lt;\u0026thinsp;0.001*\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eFAZ area (mm\u0026sup2;)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.30\u0026thinsp;\u0026plusmn;\u0026thinsp;0.07\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.26\u0026thinsp;\u0026plusmn;\u0026thinsp;0.05\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.062*\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eSCP vessel density (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e49.20 (43.40\u0026ndash;51.20)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e50.90 (47.90\u0026ndash;54.20)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.001**\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eDCP vessel density (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e49.80 (35.30\u0026ndash;54.20)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e54.00 (49.50\u0026ndash;57.10)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e\u0026lt;\u0026thinsp;0.001**\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003ctfoot\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"4\"\u003eValues are presented as mean\u0026thinsp;\u0026plusmn;\u0026thinsp;standard deviation or median (range) as appropriate. P values were calculated using independent-samples t-test (*) for variables presented as mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD, and Mann\u0026ndash;Whitney U test (**) for variables presented as median (range).\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"4\"\u003eAbbreviations: CCHD, cyanotic congenital heart disease; FAZ, foveal avascular zone; RNFL, retinal nerve fiber layer; GCC, ganglion cell complex; CT, choroidal thickness; SCP, superficial capillary plexus; DCP, deep capillary plexus.\u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tfoot\u003e\n \u003c/table\u003e\n\u003c/div\u003e\n\u003cdiv class=\"gridtable\"\u003e\n \u003cdiv align=\"char\" class=\"colspec\"\u003e\u003cbr\u003e\u003c/div\u003e\n \u003ctable id=\"Tab4\" border=\"1\"\u003e\n \u003ccaption language=\"En\"\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 4\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003eCorrelation analysis between systemic parameters (SaO₂, Hb, Hct) and ocular metrics.\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\" rowspan=\"2\"\u003e\n \u003cp\u003eOcular Parameters\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eSaO₂\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eHb\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eHct\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003e(r, P)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003e(r, P)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003e(r, P)\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eSubfoveal CT, \u0026micro;m\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.61, \u0026lt;\u0026thinsp;0.001*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e-0.56, \u0026lt;\u0026thinsp;0.001*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e-0.59, \u0026lt;\u0026thinsp;0.001*\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNasal 1500 \u0026micro;m CT (\u0026micro;m)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.46, 0.002*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e-0.45, 0.003*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e-0.46,0.002*\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eTemporal 1500 \u0026micro;m CT (\u0026micro;m)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.49, 0.001*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e-0.55, \u0026lt;\u0026thinsp;0.001*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e-0.57, \u0026lt;\u0026thinsp;0.001*\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eGCC thickness, (\u0026micro;m)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.12, 0.462\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e-0.24, 0.129\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e-0.27, 0.079\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eSuperior GCC thickness (\u0026micro;m)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e-0.15, 0.357\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.04, 0.783\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.02, 0.909\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eInferior GCC thickness (\u0026micro;m)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.14, 0.382\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e-0.15, 0.336\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e-0.23, 0.144\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eRNFL thickness, \u0026micro;m\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.33, 0.033*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e-0.36, 0.017*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e-0.38, 0.012*\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eSuperior RNFL thickness (\u0026micro;m)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.27, 0.090\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e-0.28, 0.077\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e-0.29, 0.065\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eInferior RNFL thickness (\u0026micro;m)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.57, \u0026lt;\u0026thinsp;0.001*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e-0.61, \u0026lt;\u0026thinsp;0.001*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e-0.62, \u0026lt;\u0026thinsp;0.001*\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eFAZ area, (mm\u0026sup2;)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e-0.40, 0.009*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.31, 0.048*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.24, 0.117\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eSCP vessel density, (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.45, 0.003*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e-0.43, 0.004*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e-0.53, \u0026lt;\u0026thinsp;0.001*\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eDCP vessel density, (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.64, \u0026lt;\u0026thinsp;0.001*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e-0.60, \u0026lt;\u0026thinsp;0.001*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e-0.55, \u0026lt;\u0026thinsp;0.001*\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003ctfoot\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"4\"\u003e*p\u0026thinsp;\u0026lt;\u0026thinsp;0.05 is statistically significant. Abbreviations: SaO₂, peripheral oxygen saturation; Hb, hemoglobin; Hct, hematocrit; SCP, superficial capillary plexus; DCP, deep capillary plexus; FAZ, foveal avascular zone; RNFL, retinal nerve fiber layer; GCC, ganglion cell complex.\u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tfoot\u003e\n \u003c/table\u003e\n\u003c/div\u003e\n\u003cp\u003eFor neural retinal structure, global peripapillary RNFL thickness was lower in CCHD (median 98.0 [84\u0026ndash;113] vs 106.0 [95\u0026ndash;131] \u0026micro;m; p\u0026thinsp;=\u0026thinsp;0.018), with a particularly pronounced inferior-sector reduction (96.09\u0026thinsp;\u0026plusmn;\u0026thinsp;8.88 vs 111.81\u0026thinsp;\u0026plusmn;\u0026thinsp;11.93 \u0026micro;m; p\u0026thinsp;\u0026lt;\u0026thinsp;0.001). GCC thickness did not differ between groups for the average value or by sector (all p\u0026thinsp;\u0026gt;\u0026thinsp;0.05).\u003c/p\u003e\n\u003cp\u003eRetinal capillary vessel density was reduced in CCHD. The superficial capillary plexus (SCP) showed lower density (median [range], 49.2% [43.4\u0026ndash;51.2] vs 50.9% [47.9\u0026ndash;54.2]; p\u0026thinsp;=\u0026thinsp;0.001), with a more marked reduction in the deep capillary plexus (DCP) (49.8% [35.3\u0026ndash;54.2] vs 54.0% [49.5\u0026ndash;57.1]; p\u0026thinsp;\u0026lt;\u0026thinsp;0.001). The FAZ area was larger in CCHD (0.30\u0026thinsp;\u0026plusmn;\u0026thinsp;0.07 vs 0.26\u0026thinsp;\u0026plusmn;\u0026thinsp;0.05 mm\u0026sup2;) but did not reach statistical significance (p\u0026thinsp;=\u0026thinsp;0.062).\u003c/p\u003e\n\u003cp\u003eIn summary, children with CCHD exhibited diffuse choroidal thinning, reduced SCP vessel density with a more pronounced decrease in the DCP, and a statistically significant inferior-sector RNFL reduction, whereas other RNFL sectors and GCC were comparable between groups.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eThis study provides a comprehensive retinal and choroidal evaluation in children with CCHD using multimodal OCT/OCTA. We identified diffuse choroidal thinning, a reduction in RVD with a DCP predominant pattern, and predominantly inferior-sector peripapillary RNFL thinning, while GCC thickness remained unchanged. Across metrics, SaO₂ was positively associated and Hb/Hct were inversely associated with structural and microvascular measures, implicating hypoxemia-related hyperviscosity and endothelial dysfunction as potential drivers of ocular microcirculatory compromise.\u003c/p\u003e\u003cp\u003eRetinal vessel density was reduced in both the SCP and DCP, with a more pronounced decrement in the DCP consistent with prior observations in congenital heart disease [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. The heightened susceptibility of the DCP may relate to its pericyte-rich, small-caliber capillaries, greater distance from arteriolar oxygen sources, and location within a functional watershed zone [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. In our cohort, DCP-RVD showed the strongest positive association with SaO₂ and the strongest inverse associations with Hb/Hct among the vascular layers examined. Concordant evidence from adults with dilated cardiomyopathy related heart failure demonstrates reduced DCP and radial peripapillary capillary densities [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e], supporting the concept that the retinal microcirculation is sensitive to systemic hypoxic burden. Moreover, OCTA-based vascular alterations appear to evolve in parallel with cardiac dysfunction, suggesting a potential role for OCTA as a complementary tool for longitudinal cardiac monitoring [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e].\u003c/p\u003e\u003cp\u003ePeripapillary RNFL thickness was globally reduced in CCHD, with a statistically significant decrement in the inferior sector. This pattern parallels adult CCHD data linking RNFL thinning with reduced cerebral white-matter volume [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. The inverse association between inferior-sector RNFL and Hb/Hct in our cohort further supports the hypothesis that hyperviscosity-related perfusion stress contributes to subclinical injury at the optic nerve head.\u003c/p\u003e\u003cp\u003eChoroidal thickness was significantly lower at subfoveal, nasal, and temporal locations. The positive association between CT and SaO₂, together with inverse associations with Hb/Hct, indicates that chronic hypoxemia and increased blood viscosity may impair choroidal perfusion and tissue metabolic support. Consistently, decreased subfoveal CT has also been reported in chronic heart failure [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eAlthough the FAZ area tended to be larger in CCHD, the between-group difference was not statistically significant. This may reflect greater susceptibility of the FAZ to inter-individual anatomical variation and the relatively later manifestation of hypoxic effects compared with microvascular metrics such as DCP-RVD [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e, \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. Accordingly, for clinical follow-up, SCP/DCP vessel-density measures being more dynamic and hypoxia-sensitive may be prioritized.\u003c/p\u003e\u003cp\u003eStrengths of this study include assessment of multiple retinal and choroidal compartments within the same pediatric CCHD cohort; single-eye analysis to avoid inter-eye correlation; masked grading; diurnal timing standardization; and stringent image-quality criteria. The cross-sectional design, however, limits inferences regarding disease progression.\u003c/p\u003e\u003cp\u003eIn conclusion, pediatric CCHD exhibits an ocular phenotype characterized by DCP-weighted microvascular loss, inferior-sector RNFL thinning, and diffuse choroidal thinning changes that likely reflect the ophthalmic imprint of systemic hypoxemia and hyperviscosity. These data support the use of retinal microcirculatory metrics as noninvasive biomarkers of systemic oxygenation and suggest that OCT/OCTA could serve as a complementary adjunct for clinical monitoring in CCHD.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003eAuthor Contributions\u003cbr\u003e\u0026nbsp;KK designed the study, performed all ophthalmologic imaging procedures (OCT/OCTA), interpreted ocular data, coordinated the methodology, and was primarily responsible for writing the manuscript.\u003cbr\u003e\u0026nbsp;TK contributed to manuscript editing, assisted in patient recruitment, and provided clinical support during data collection.\u003cbr\u003e\u0026nbsp;Both authors read and approved the final version of the manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll the patients included in this study gave written informed consent for their personal or clinical details along with any identifying images to be published in this study.\u003c/p\u003e\n\u003cp\u003e\u0026bull; Ethics Approval and Consent to Participate\u003cbr\u003e\u0026nbsp; \u0026nbsp;This study was approved by the Ordu University Clinical Research Ethics Committee (Approval No: 2025/137). Written informed consent was obtained from the parents or legal guardians of all participants, in accordance with the Declaration of Helsinki.\u003c/p\u003e\n\u003cp\u003e\u0026bull; \u003cstrong\u003eConsent for Publication\u003c/strong\u003e\u003cbr\u003e\u0026nbsp; \u0026nbsp;Written informed consent for publication of anonymized data and images was obtained from the parents of all participants.\u003c/p\u003e\n\u003cp\u003e\u0026bull; \u003cstrong\u003eAvailability of Data and Materials\u003c/strong\u003e\u003cbr\u003e\u0026nbsp; \u0026nbsp;The datasets used and analyzed during the current study are available from the corresponding author upon reasonable request.\u003c/p\u003e\n\u003cp\u003e\u0026bull; \u003cstrong\u003eCompeting Interests\u003cbr\u003e\u0026nbsp;\u003c/strong\u003e\u0026nbsp; The authors declare no competing interests.\u003c/p\u003e\n\u003cp\u003e\u0026bull; \u003cstrong\u003eFunding\u003cbr\u003e\u0026nbsp;\u003c/strong\u003e\u0026nbsp; No external funding was received for this study.\u003c/p\u003e\n\u003cp\u003e\u0026bull; \u003cstrong\u003eAcknowledgements\u003cbr\u003e\u0026nbsp;\u003c/strong\u003e\u0026nbsp; We would like to thank the clinical staff of the Pediatric Cardiology and Ophthalmology departments for their support in data acquisition and coordination.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n \u003cli\u003eVan der Linde D, Konings EE, Slager MA, Witsenburg M, Helbing WA, Takkenberg JJ, et al. 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Bagcilar Med Bull. 2023 Jun 15;8(2):161-166. doi: 10.4274/BMB.galenos.2023.2022-10-084.\u003c/li\u003e\n \u003cli\u003eWang J, Jiang J, Zhang Y, Qian YW, Zhang JF, Wang ZL. Retinal and choroidal vascular changes in coronary heart disease: an optical coherence tomography angiography study. Biomed Opt Express. 2019;10(4):1532-1544.\u0026nbsp;\u003c/li\u003e\n \u003cli\u003e\u0026nbsp;Cordina R, Leaney J, Golzan M, Grieve S, Celermajer DS, Graham SL. Ophthalmological consequences of cyanotic congenital heart disease: vascular parameters and nerve fibre layer. Clin Exp Ophthalmol. 2015;43(2):115-23.\u0026nbsp;\u003c/li\u003e\n \u003cli\u003eAltinkaynak H, Kara N, Sayın N, G\u0026uuml;neş H, Avşar S, Yazıcı AT. Subfoveal choroidal thickness in patients with chronic heart failure analyzed by spectral-domain optical coherence tomography. Curr Eye Res. 2014;39(11):1123-8.\u0026nbsp;\u003c/li\u003e\n \u003cli\u003eFreiberg FJ, Pfau M, Wons J, Wirth MA, Becker MD, Michels S. Optical coherence tomography angiography of the foveal avascular zone in diabetic retinopathy. Graefes Arch Clin Exp Ophthalmol. 2016;254(6):1051-1058.\u0026nbsp;\u003c/li\u003e\n \u003cli\u003eSun Z, Yang D, Tang Z, Ng DS, Cheung CY. Optical coherence tomography angiography in diabetic retinopathy: an updated review. Eye (Lond). 2021;35(1):149-161.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"bmc-ophthalmology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"boph","sideBox":"Learn more about [BMC Ophthalmology](http://bmcophthalmol.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/boph","title":"BMC Ophthalmology","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Cyanotic congenital heart disease, Optical coherence tomography angiography, Retinal vessel density, Deep capillary plexus, Choroidal thickness","lastPublishedDoi":"10.21203/rs.3.rs-7852414/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7852414/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground:\u003c/strong\u003e To compare retinal capillary density, foveal avascular zone (FAZ) area, and the thicknesses of the peripapillary retinal nerve fiber layer (RNFL), ganglion cell complex (GCC), and choroid between children with cyanotic congenital heart disease (CCHD) and healthy controls using multimodal optical coherence tomography±angiography (OCT/OCTA). We also examined correlations between these ocular metrics and hemoglobin, hematocrit, and oxygen saturation.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods:\u003c/strong\u003e This prospective, age- and sex-matched case–control study enrolled 21 children with CCHD and 21 healthy controls. Retinal capillary density in the superficial and deep capillary plexuses (SCP/DCP) and FAZ area were quantified with OCTA. Peripapillary RNFL, GCC, and choroidal thicknesses were measured with spectral-domain OCT (SD-OCT). To avoid inter-eye correlation, only right-eye data were analyzed.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults:\u003c/strong\u003e Compared with controls, children with CCHD had a thinner choroid subfoveally and at 1,500 µm nasal and temporal to the fovea (all p\u0026lt;0.001), lower global peripapillary RNFL thickness (p=0.018) with a pronounced inferior-sector deficit (p\u0026lt;0.001), and reduced vessel density in both SCP and DCP (p=0.001 and p\u0026lt;0.001, respectively). In correlation analyses, higher oxygen saturation was associated with greater choroidal thickness at all locations (subfovea p\u0026lt;0.001; nasal 1,500 µm p=0.002; temporal 1,500 µm p=0.001), higher global (p=0.033) and inferior-sector (p\u0026lt;0.001) RNFL thickness, and higher vessel density in SCP and DCP (p=0.003 and p\u0026lt;0.001, respectively). Conversely, higher hemoglobin and hematocrit were associated with a thinner choroid (hemoglobin: subfovea p\u0026lt;0.001, nasal p=0.003, temporal p\u0026lt;0.001; hematocrit: subfovea p\u0026lt;0.001, nasal p=0.002, temporal p\u0026lt;0.001), lower global (hemoglobin p=0.017; hematocrit p=0.012) and inferior-sector (both p\u0026lt;0.001) RNFL thickness, and lower vessel density in both plexuses (SCP: hemoglobin p=0.004, hematocrit p\u0026lt;0.001; DCP: both p\u0026lt;0.001). The FAZ area was inversely associated with oxygen saturation (p=0.009) and positively associated with hemoglobin (p=0.048). GCC thickness did not differ between groups.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusions:\u003c/strong\u003e In pediatric CCHD, retinal capillary density is reduced, the choroid is thinner, and peripapillary RNFL thickness is decreased-while GCC is preserved. Oxygen saturation shows positive associations with these ocular measures, whereas hemoglobin and hematocrit show negative associations. These findings indicate that multimodal OCT/OCTA can detect subclinical ocular involvement and may serve as a noninvasive adjunct for longitudinal monitoring.\u003c/p\u003e","manuscriptTitle":"Retinal Neurovascular and Choroidal Changes in Pediatric Patients with Cyanotic Congenital Heart Disease: A Multimodal Analysis","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-10-23 05:19:37","doi":"10.21203/rs.3.rs-7852414/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"reviewersInvited","content":"","date":"2025-11-10T06:04:45+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-11-05T08:03:28+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2025-10-15T10:20:10+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-10-14T17:35:02+00:00","index":"","fulltext":""},{"type":"submitted","content":"BMC Ophthalmology","date":"2025-10-14T17:32:09+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-ophthalmology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"boph","sideBox":"Learn more about [BMC Ophthalmology](http://bmcophthalmol.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/boph","title":"BMC Ophthalmology","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"e91a79b5-20e1-47d9-b35b-189b3d5e7484","owner":[],"postedDate":"October 23rd, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2025-11-10T06:08:28+00:00","versionOfRecord":[],"versionCreatedAt":"2025-10-23 05:19:37","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-7852414","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7852414","identity":"rs-7852414","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}