Plasma metabolomics identifies key metabolites and improves prediction of diabetic retinopathy: development and validation across multi-national cohorts.

PURPOSE: To identify longitudinal metabolomic fingerprints of diabetic retinopathy (DR) and evaluate their utility in predicting DR development and progression. DESIGN: Multicenter, multi-ethnic cohort study. PARTICIPANTS: This study included 17,675 participants with baseline pre-diabetes/diabetes, in accordance with the 2021 American Diabetes Association guideline, and free of baseline DR from the UK Biobank (UKB); and an additional 638 diabetic participants from the Guangzhou Diabetic Eye Study (GDES) for external validation. METHODS: Longitudinal DR metabolomic fingerprints were identified through nuclear magnetic resonance assay in UKB participants. The predictive value of these fingerprints for predicting DR development were assessed in a fully withheld test set. External validation and extrapolation analyses of DR progression and microvascular damage were conducted in the GDES cohort. Model assessments included the C-statistic, net classification improvement (NRI), integrated discrimination improvement (IDI), calibration, and clinical utility in both cohorts. MAIN OUTCOME MEASURES: DR development, progression, and retinal microvascular damage. RESULTS: Of 168 metabolites, 118 were identified as candidate metabolomic fingerprints for future DR development. These fingerprints significantly improved the predictability for DR development beyond traditional indicators (C-statistic: 0.802, 95% CI, 0.760-0.843 vs. 0.751, 95% CI, 0.706-0.796; P = 5.56×10-4). Glucose, lactate, and citrate were among the fingerprints validated in the GDES cohort. Using these parsimonious and replicable fingerprints yielded similar improvements for predicting DR development (C-statistic: 0.807, 95% CI, 0.711-0.903 vs. 0.617, 95% CI, 0.494, 0.740; P = 1.68×10-4) and progression (C-statistic: 0.797, 95% CI, 0.712-0.882 vs. 0.665, 95% CI, 0.545-0.784; P = 0.003) in the external cohort. Improvements in NRIs, IDIs, and clinical utility were also evident in both cohorts (all P <0.05). In addition, lactate and citrate were associated to microvascular damage across macular and optic disc regions (all P <0.05). CONCLUSIONS: Metabolomic profiling has proven effective in identifying robust fingerprints for predicting future DR development and progression, providing novel insights into the early and advanced stages of DR pathophysiology.

Handgrip strength and risks of diabetic vascular complications: Evidence from Guangzhou Diabetic Eye Study and UK cohorts.

PURPOSE: The purpose is to investigate the association between handgrip strength (HGS) and the risk of future diabetic complications in multicountry cohorts. METHODS: The association between HGS and diabetic complications was evaluated using cox models among 84 453 patients with pre-diabetes and diabetes from the UK Biobank with a 12-year follow-up. The association between HGS and longitudinal microcirculatory damage rates was assessed among 819 patients with diabetes from the Guangzhou Diabetic Eye Study (GDES) with a 3-year follow-up. Participants were divided into three age groups (<56, 56-65 and ≥65 years), and each group was further subdivided into three HGS tertiles. RESULTS: A 5 kg reduction in HGS was associated with increased risk for all-cause mortality (women, HR=1.10, 95% CI: 1.05 to 1.14; p<0.001; men, HR=1.13, 95% CI: 1.11 to 1.15; p<0.001). Women and men in the lowest HGS group exhibited 1.6-times and 1.3-1.5-times higher risk of myocardial infarction and stroke compared with the highest HGS group. In men, there was a higher risk of developing end-stage renal disease (HR=1.83, 95% CI: 1.30 to 2.57; p=0.001), while this was not observed in women. Both sexes in the lowest HGS group had a 1.3-times higher risk of diabetic retinopathy compared with the highest HGS group. In the GDES group, individuals with the lowest HGS showed accelerated microcirculatory damage in retina (all p<0.05). CONCLUSIONS: Reduced HGS is significantly associated with a higher risk of diabetic complications and accelerated microvascular damage. HGS could serve as a practical indicator of vascular health in patients with pre-diabetes and diabetes.

Frailty and risk of microvascular disease in adults with prediabetes.

BACKGROUND AND AIMS: To assess the relationship between frailty phenotypes and the risk of MVD among prediabetics in two prospective cohorts. METHODS: The study included 66,068 and 226 participants with prediabetes from the UK Biobank (UKB) and Chinese Ocular Imaging Project (COIP) in Guangzhou, China, respectively. Frailty was evaluated using the Fried phenotype, which includes weight loss, fatigue, low grip strength, low physical activity, and slow walking pace. The outcome was incident microvascular diseases, including diabetic retinopathy, nephropathy, and neuropathy in UKB, and decline rate of retinal capillary density in COIP. Cox models were used to calculate hazard ratios (HRs) and 95 % confidential intervals (CIs), and mixed linear model was used to determine the ß and 95 % CIs. RESULTS: At baseline, 27,491 (41.6 %) and 3332 (5.0 %) prediabetics were classified as pre-frail and frail, respectively in UKB. During a median follow-up of 8.9 years, 3784 cases of incident microvascular diseases were identified. Pre-frailty and frailty were significantly associated with a higher risk of microvascular diseases (HR 1.21 [1.12, 1.30] for pre-frailty; HR 1.60 [1.42, 1.81] for frailty). Compared to no frailty, the adjusted HRs for frailty were 1.42 (0.73, 2.76) for retinopathy, 1.49 (1.31, 1.70) for nephropathy, and 2.37 (1.69, 3.33) for neuropathy. Fatigue and walking pace were the strongest mediators of frailty and microvascular diseases. In the COIP, the lowest handgrip strength group exhibited 62%-63 % faster annually decline in retinal capillary density compared with the highest group (all P<0.05). CONCLUSIONS: Each frailty point is important for prediabetics because both pre-frailty and frailty phenotypes are strongly associated with an increased risk of microvascular diseases and its subtypes. Lower handgrip strength presents with faster decline in retinal capillary density.

Association of preoperative retinal microcirculation and perioperative outcomes in patients undergoing congenital cardiac surgery.

BACKGROUND: Microcirculatory dysfunction is associated with increased morbidity and mortality in cardiac surgery patients. This study aimed to investigate the association between preoperative retinal microcirculation evaluated using optical coherence tomography angiography (OCTA) and perioperative outcomes in patients with congenital heart disease (CHD). METHODS: This prospective, observational study was performed from May 2017 to January 2021. OCTA was used to automatically quantify the vessel density (VD) of the superficial capillary plexus, deep capillary plexus (DCP), and radial peripapillary capillary (RPC) preoperatively. The primary outcome was excessive postoperative bleeding, defined as bleeding volume > 75th percentile for 24-hour postoperative chest tube output. The secondary outcome was composite adverse outcomes, including one or more operative mortalities, early postoperative complications, and prolonged length of stay. The association between retinal VD and outcomes was assessed using Poisson regression. RESULTS: In total, 173 CHD patients who underwent cardiac surgery were included (mean age, 26 years). Among them, 43 (24.9%) and 46 (26.6%) developed excessive postoperative bleeding and composite adverse outcomes, respectively. A lower VD of DCP (odds ratio [OR], 1.24; 95% confidence interval [CI], 1.08-1.43; P = 0.003) was independently associated with excessive postoperative bleeding, and a lower VD of RPC (OR, 1.97; 95% CI, 1.08-3.57; P = 0.027), and DCP (OR, 2.17; 95% CI, 1.08-4.37; P = 0.029) were independently associated with the postoperative composite adverse outcomes. CONCLUSION: Preoperative retinal hypoperfusion was independently associated with an increased risk of perioperative adverse outcomes in patients with CHD, suggesting that retinal microcirculation evaluation could provide valuable information about the outcomes of cardiac surgery, thereby aiding physicians in tailoring individualized treatment.

Serum cystatin C for risk stratification of prediabetes and diabetes populations.

BACKGROUND: The association between serum cystatin C level and vascular outcomes has not been fully elucidated in diabetes and is unclear in prediabetes. We aim to evaluate whether cystatin C level predicts future risk for mortality and vascular outcomes in prediabetes and diabetes. METHODS: A total of 85,371 participants with prediabetes and diabetes, and available baseline cystatin C in the UK biobank were included with a 14-year follow-up. Cox hazards models were used to calculate the associations between cystatin C level, mortality (all-cause, cause-specfic mortality) and vascular outcomes (myocardial infarction [MI], stroke, end-stage renal disease [ESRD] and diabetic retinopathy [DR]). The 1136 diabetes subjects in Guangzhou Diabetic Eye Study (GDES) were included for examing the impact of cystatin C on in vivo retinal degeneration and microvascular changes by using SS-OCT and OCTA. RESULTS: The highest cystatin C quartile had increased risks of all-cause (hazard ratio [HR], 2.02; 95% confidence interval [CI] 1.86-2.19), cardiovascular (HR, 2.29; 95% CI 1.97-2.67), cancer (HR, 1.86; 95% CI 1.65-2.10) and other-cause mortality (HR, 2.24; 95% CI 1.90-2.64), MI (HR, 1.40; 95% CI 1.26-1.55), stroke (HR, 1.88; 95% CI, 1.57-2.26), ESRD (HR, 7.33; 95% CI, 5.02-10.71), DR (HR, 1.17; 95% CI 1.03-1.32) than those in the lowest quartile. Adding cystatin C to the conventional model improved C-statistic for all-cause (0.699-0.724), cardiovascular (0.762-0.789), cancer (0.661-0.674) and other-cause mortality (0.675-0.715), MI (0.748-0.750), stroke (0.712-0.718), and ESRD (0.808-0.827). The GDES analysis identified a strong association between increased cystatin C levels and diminished retinal neural layers, as well as microvascular rarefaction in both macular and optic disc regions (all P < 0.05). CONCLUSIONS: Serum cystatin C refines the risk stratification for mortality and vascular outcomes among patients with prediabetes or diabetes.

Cardiovascular and microvascular outcomes according to vitamin D level and genetic variants among individuals with prediabetes: a prospective study.

BACKGROUND: Whether serum vitamin D mediate vascular diseases in prediabetic populations remains unclear. This study aimed to determine the associations between circulating 25-hydroxyvitamin D [25(OH)D] levels and vitamin D receptor (VDR) polymorphisms with the risk of macrovascular complications, including myocardial infarction and stroke, and microvascular complications such as diabetic nephropathy and retinopathy, among adults with prediabetes. METHODS: Participants with prediabetes in UK Biobank were included (N = 56,387). Multivariable dose-response and Cox proportion models were used to explore the relationship of serum 25(OH)D status and the risks of vascular complications. The interaction of VDR polymorphisms with serum 25(OH)D level on risks of vascular events was also assessed. RESULTS: During a median follow-up of 12 years, higher levels of 25(OH)D were significantly and nonlinearly associated with a lower risk of macrovascular diseases among prediabetic individuals. The adjusted hazard ratios (95% confidential interval) of serum 25(OH)D levels of ≥ 75.0 nmol/L versus < 25 nmol/L were 0.75 (0.63-0.88) for myocardial infarction, 0.74 (0.55-1.00) for stroke, 1.02 (0.60-1.74) for diabetic nephropathy, and 1.30 (0.92-1.84) for diabetic retinopathy, respectively. The rs2228570 (FokI) polymorphisms significantly interacted with 25(OH)D on incident myocardial infarction (P-interaction = 0.042) and stroke (P-interaction = 0.033). The individuals with serum 25(OH)D level of 50.0-74.9 nmol/L and rs2228570 (FokI) homozygotes had the lowest risks of vascular complications. CONCLUSIONS: Lower serum 25(OH)D levels are significantly and nonlinearly associated with an increased risk of cardiocerebrovascular diseases in prediabetic individuals, with VDR polymorphisms of rs2228570 (FokI) modify such associations. Monitoring a safe 25(OH)D concentration is suggested to prevent the vascular complications for prediabetes.

Normal-weight central obesity and risk of cardiovascular and microvascular events in adults with prediabetes or diabetes: Chinese and British cohorts.

OBJECTIVE: To investigate the relationship between body fat distribution and risk of cardiometabolic and microvascular events among individuals with prediabetes or diabetes with normal body mass index (BMI). METHODS: A total of 17,232 participants with prediabetes or diabetes from UK Biobank (UKB) with 12-year follow-up and 499 diabetic participants from China with 2-year follow-up with normal BMI were included. Anthropometric measurements of waist circumference (WC), waist-to-hip ratio (WHR) and waist-to-height ratio (WHtR), and body fat composition assessment of trunk-to-leg fat ratio (TLFR) were obtained. Outcomes included incident all-cause and cardiovascular mortality and macrovascular and microvascular diseases. RESULTS: In British cohort, participants with central obesity defined by WHR had 27%-54% higher risk of incident all-cause mortality (hazard ratio (HR) 1.42, 95% confidence interval (CI): 1.23-1.64), cardiovascular mortality (HR 1.54 [1.15-2.07]), myocardial infarction (HR = 1.43 [1.15, 1.78]), stroke (HR 1.26 [0.90, 1.75]), heart failure (HR = 1.27 [1.00, 1.61]), diabetic nephropathy (HR 1.33 [1.07, 1.65]), and diabetic retinopathy (DR) (HR = 1.48 [1.12, 1.96]) than those without obesity. Central obesity defined by WC and WHtR was associated with 40%-44% and 23%-98% higher risks of developing diabetic events, respectively. In the Chinese cohort, individuals with abdominal obesity, defined by WC (HR 1.44) or WHtR (HR 1.43) but not by WHR, carried more than 40% higher risk of developing DR than those without it. Higher TLFR carried 1.30-2.85 times higher risk of CVD and microvascular diseases among the dysglycemic population. CONCLUSIONS: Body fat distribution diseases among individuals with prediabetes or diabetes are associated with an increased risk of cardiometabolic and microvascular diseases independent of BMI.

Metabolomic phenotyping of obesity for profiling cardiovascular and ocular diseases.

BACKGROUND: We aimed to evaluate the impacts of metabolomic body mass index (metBMI) phenotypes on the risks of cardiovascular and ocular diseases outcomes. METHODS: This study included cohorts in UK and Guangzhou, China. By leveraging the serum metabolome and BMI data from UK Biobank, this study developed and validated a metBMI prediction model using a ridge regression model among 89,830 participants based on 249 metabolites. Five obesity phenotypes were obtained by metBMI and actual BMI (actBMI): normal weight (NW, metBMI of 18.5-24.9 kg/m2), overweight (OW, metBMI of 25-29.9 kg/m2), obesity (OB, metBMI ≥ 30 kg/m2), overestimated (OE, metBMI-actBMI > 5 kg/m2), and underestimated (UE, metBMI-actBMI < - 5 kg/m2). Additional participants from the Guangzhou Diabetes Eye Study (GDES) were included for validating the hypothesis. Outcomes included all-cause and cardiovascular (CVD)-cause mortality, as well as incident CVD (coronary heart disease, heart failure, myocardial infarction [MI], and stroke) and age-related eye diseases (age-related macular degeneration [AMD], cataracts, glaucoma, and diabetic retinopathy [DR]). RESULTS: In the UKB, although OE group had lower actBMI than NW group, the OE group had a significantly higher risk of all-cause mortality than those in NW prediction group (HR, 1.68; 95% CI 1.16-2.43). Similarly, the OE group had a 1.7-3.6-fold higher risk than their NW counterparts for cardiovascular mortality, heart failure, myocardial infarction, and coronary heart disease (all P < 0.05). In addition, risk of age-related macular denegation (HR, 1.96; 95% CI 1.02-3.77) was significantly higher in OE group. In the contrast, UE and OB groups showed similar risks of mortality and of cardiovascular and age-related eye diseases (all P > 0.05), though the UE group had significantly higher actBMI than OB group. In the GDES cohort, we further confirmed the potential of metabolic BMI (metBMI) fingerprints for risk stratification of cardiovascular diseases using a different metabolomic approach. CONCLUSIONS: Gaps of metBMI and actBMI identified novel metabolic subtypes, which exhibit distinctive cardiovascular and ocular risk profiles. The groups carrying obesity-related metabolites were at higher risk of mortality and morbidity than those with normal health metabolites. Metabolomics allowed for leveraging the future of diagnosis and management of 'healthily obese' and 'unhealthily lean' individuals.

Brain and Cognition Signature Fingerprinting Vascular Health in Diabetic Individuals: An International Multi-Cohort Study.

OBJECTIVE: To evaluate the correlation between cognitive signatures and the risk of diabetic vascular complications and mortality, based on a multicountry prospective study. METHODS: The participants comprised 27,773 diabetics from the UK Biobank (UKB) and 1307 diabetics from the Guangzhou Diabetic Eye Study (GDES) cohort. The exposures were brain volume and cognitive screening tests for UKB participants, whilst the global cognitive score (GCS) measuring orientation to time and attention, episodic memory, and visuospatial abilities were determined for GDES participants. The outcomes for the UKB group were mortality, as well as macrovascular (myocardial infarction [MI] and stroke), microvascular (end-stage renal disease [ESRD], and diabetic retinopathy [DR]) events. The outcomes for the GDES group were retinal and renal microvascular damage. RESULTS: In the UKB group, a 1-SD reduction in brain gray matter volume was associated with 34%-77% higher risks of incident MI, ESRD, and DR. The presence of impaired memory was associated with 18%-73% higher risk of mortality and ESRD; impaired reaction was associated with 1.2-1.7-fold higher risks of mortality, stroke, ESRD, and DR. In the GDES group, the lowest GCS tertile exhibited 1.4-2.2-fold higher risk of developing referable DR and a twofold faster decline in renal function and retinal capillary density compared with the highest tertile. Restricting data analysis to individuals aged less than 65 years produced consistent results. CONCLUSION: Cognitive decline significantly elevates the risk of diabetic vascular complications and is correlated with retinal and renal microcirculation damage. Cognitive screening tests are strongly recommended as routine tools for management of diabetes.

Influence of Serum Uric Acid on Macular Choroidal Thickness and Ganglion Cell Inner Plexiform Layer Thickness.

Purpose: The purpose of this study was to determine the influence of serum uric acid (UA) on macular choroidal and ganglion cell inner plexiform layer (GC-IPL) thickness. Methods: This cross-sectional study enrolled adult individuals in communities in Guangzhou, China. All participants underwent a comprehensive ophthalmologic examination. They were divided into four groups according to UA quartiles. The choroidal and GC-IPL thickness was measured by swept-source optical coherence tomography (SS-OCT). Results: A total of 719 subjects (1389 eyes) were included in the study. The average UA was 348.50 ± 86.16 mmol/L. The average choroidal and GC-IPL thickness decreased with UA quartiles (P < 0.001). Multivariate linear regression analyses showed that UA was negatively associated with average choroidal (ß = -0.073, 95% confidence interval [CI] = -0.117 to -0.028, P = 0.001) and GC-IPL thickness (ß = -0.006, 95% CI = -0.009 to -0.002, P = 0.001). After adjusting for confounding factors, the average choroidal thickness was decreased in quartile 4 as compared with quartile 1 by -14.737 µm (95% CI = -24.460 to -5.015, P = 0.003). The average GC-IPL thickness was decreased in quartile 4 versus quartile 1 by -1.028 (95% CI = -1.873 to -0.290, P = 0.007). Conclusions: Higher UA levels were independently associated with macular choroid and GC-IPL thinning. These contribute to a better understanding of ocular pathological mechanisms. Translational Relevance: The associated UA with choroidal and GC-IPL thickness helps to understand the ocular pathological and retinal neurodegenerative mechanism.

Impaired retinal microcirculation in patients with non-obstructive coronary artery disease.

PURPOSE: To quantitatively investigate alterations of retinal microcirculation in patients with non-obstructive coronary artery disease (NOCAD) using optical coherence tomography angiography (OCTA), and to identify the ability of retinal microcirculation parameters in differentiating coronary artery disease (CAD) subtypes. METHODS: All participants with angina pectoris underwent coronary computed tomography angiography. Patients with lumen diameter reduction of 20-50 % in all major coronary arteries were defined as NOCAD, while patients with at least one major coronary artery lumen diameter reduction ≥ 50 % were recruited as obstructive coronary artery disease (OCAD). Participants without a history of ophthalmic or systemic vascular disease were recruited as healthy controls. Retinal neural-vasculature was measured quantitatively by OCTA, including peripapillary retinal nerve fiber layer (RNFL) thickness and vessel density (VD) of the optic disc, superficial vessel plexus (SVP), deep vessel plexus (DVP), and foveal density (FD 300). p < 0.017 is considered significant in multiple comparisons. RESULTS: A total of 185 participants (65 NOCAD, 62 OCAD, and 58 controls) were enrolled. Except for the DVP fovea (p = 0.069), significantly reduced VD in all other regions of SVP and DVP was detected in both the NOCAD and OCAD groups compared to control group (all p < 0.017), while a more significant decrease was found in OCAD compared to NOCAD. Multivariate regression analysis showed that lower VD in superior hemi part of whole SVP (OR: 0.582, 95 % CI: 0.451-0.752) was an independent risk factor for NOCAD compared to controls, while lower VD in the whole SVP (OR: 0.550, 95 % CI: 0.421-0.719) was an independent risk factor for OCAD compared to NOCAD. Using the integration of retinal microvascular parameters, the area under the receiver operating characteristic curve (AUC) for NOCAD versus control and OCAD versus NOCAD were 0.840 and 0.830, respectively. CONCLUSION: Significant retinal microcirculation impairment, while milder than that in OCAD was observed in NOCAD patients, indicating retinal microvasculature assessment might provide a new systemic microcirculation observation window for NOCAD. Furthermore, retinal microvasculature may serve as a new indicator to assess the severity of CAD with good performance of retinal microvascular parameters in identifying different CAD subtypes.

Peripapillary Microvasculature Predicts the Incidence and Development of Diabetic Retinopathy: An SS-OCTA Study.

PURPOSE: To examine the associations of peripapillary microvascular metrics with diabetic retinopathy (DR) incidence and development using swept-source optical coherence tomography angiography (SS-OCTA). DESIGN: Prospective cohort study. METHODS: A total of 1033 eyes from 1033 patients with type 2 diabetes mellitus (T2DM) were included, with 2-year follow-up. The peripapillary microvascular metrics at the superficial capillary plexus (SCP) were measured by SS-OCTA at the baseline, including peripapillary vascular density (pVD) and peripapillary vascular length density (pVLD). The DR incidence and progression were evaluated with 7 standard fields of stereoscopic color fundus photographs. The associations were tested with logistic regression models after adjusting for established risk factors and confounding factors. The prediction value of OCTA metrics was examined with the elevation of area under the receiver operating characteristic curve (AUROC). RESULTS: The 2-year incidence of diabetic retinopathy (DR) was 25.1% (n = 222) in non-DR (NDR) eyes, 7.4% DR progression (n = 11) in DR eyes, and 4.17% RDR eyes (n = 43) in all eyes. After adjusting for established factors, lower whole-image pVD (wi-pVD) (relative risk [RR] = 0.81; 95% CI = 0.68-0.96; P = .015), circular pVD (circ-pVD) (RR = 0.79; 95% CI = 0.66-0.95; P = .013), whole-image pVLD (wi-pVLD) (RR = 0.79; 95% CI = 0.67-0.94; P = .008), and circular pVLD (circ-pVLD) (RR = 0.76; 95% CI = 0.63-0.91; P = .003) were significantly associated with increased risk of DR incidence; wi-pVD (RR = 0.48; 95% CI = 0.35-0.67; P < .001), circ-pVD (RR = 0.65; 95% CI = 0.45-0.94; P = .023), and wi-pVLD (RR = 0.46; 95% CI = 0.33-0.66; P < .001) were associated with incident risk of RDR. Both pVD and pVLD of SCP were not significantly associated with DR progression. The AUROC for the DR incidence risk prediction model increased from 0.631 to 0.658 (4.28%; P = .041) by circ-pVLD; the AUC of the RDR incidence risk prediction model increased from 0.631 to 0.752 by wi-pVD (19.18%; P = .009), to 0.752 by circ-pVD (19.18%; P=.009), and to 0.752 by wi-pVLD (19.18%; P = .009). CONCLUSION: Lower pVD and pVLD of SCP are associated with 2-year incident DR and RDR among the T2DM population. The peripapillary metrics imaged by SS-OCTA can provide additional value to the prediction of DR incidence and development.

Development and Validation of Retinal Vasculature Nomogram in Suspected Angina Due to Coronary Artery Disease.

AIMS: To develop and validate a nomogram using retinal vasculature features and clinical variables to predict coronary artery disease (CAD) in patients with suspected angina. METHODS: The prediction model consisting of 795 participants was developed in a training set of 508 participants with suspected angina due to CAD, and data were collected from January 2018 to June 2019. The held-out validation was conducted with 287 consecutive patients from July 2019 to November 2019. All patients with suspected CAD received optical coherence tomography angiography (OCTA) examination before undergoing coronary CT angiography. LASSO regression model was used for data reduction and feature selection. Multivariable logistic regression analysis was used to develop the retinal vasculature model for predicting the probability of the presence of CAD. RESULTS: Three potential OCTA parameters including vessel density of the nasal and temporal perifovea in the superficial capillary plexus and vessel density of the inferior parafovea in the deep capillary plexus were further selected as independent retinal vasculature predictors. Model clinical electrocardiogram (ECG) OCTA (clinical variables＋ECG＋OCTA) was presented as the individual prediction nomogram, with good discrimination (AUC of 0.942 [95% CI, 0.923-0.961] and 0.897 [95% CI, 0.861-0.933] in the training and held-out validation sets, respectively) and good calibration. Decision curve analysis indicated the clinical applicability of this retinal vasculature nomogram. CONCLUSIONS: The presented retinal vasculature nomogram based on individual probability can accurately identify the presence of CAD, which could improve patient selection and diagnostic yield of aggressive testing before determining a diagnosis.

Retinal microvasculature impairments in patients with coronary artery disease: An optical coherence tomography angiography study.

PURPOSE: To investigate the association between retinal microvasculature and the presence and severity of coronary artery disease (CAD) using optical coherence tomography angiography (OCTA). METHODS: The cross-sectional study was conducted in Guangdong Provincial People's Hospital, China. Retinal microvasculature parameters were measured by OCTA of the optic disc, including the vessel density (VD) and retinal nerve fibre thickness of the radial peripapillary capillary. In terms of the entire macula, VD of the superficial capillary plexus (SCP), deep capillary plexus (DCP) and foveal density (FD-300) were included. The Gensini score was used to evaluate the severity of coronary artery obstructive lesions in CAD patients. RESULTS: A total of 410 participants (270 CAD patients and 140 controls) were included. Overall, participants showed significantly greater odds of having CAD in the lower versus higher VD for mean SCP, OR = 2.33 (95% CI 1.49-3.65); in the parafoveal SCP, OR = 2.68 (95% CI 1.70-4.23); and in the perifoveal SCP, OR = 2.36 (95% CI 1.49-3.72). Additionally, participants showed significantly greater odds of having CAD in the lower versus higher VD for mean DCP, OR = 4.04 (95% CI 2.53-6.45); in the parafoveal DCP, OR = 4.08 (95% CI 2.54-6.55); and in the perifoveal DCP, OR = 3.88 (95% CI 2.43-6.19). Among CAD patients, lower VD of DCP was associated with significantly greater adjusted Gensini scores (p = 0.004 for mean DCP; p = 0.035 for parafoveal DCP; p = 0.006 for perifoveal DCP). CONCLUSIONS: SCP and DCP were found to be associated with the presence of CAD among the whole population, while DCP was found to be associated with Gensini scores in CAD patients. Retinal microvasculature was associated with the presence and severity of coronary artery stenosis in CAD patients.

Retinal Neurovascular Impairment in Non-diabetic and Non-dialytic Chronic Kidney Disease Patients.

Background: Widespread neural and microvascular injuries are common in chronic kidney disease (CKD), increasing risks of neurovascular complications and mortality. Early detection of such changes helps assess the risks of neurovascular complications for CKD patients. As an extension of central nervous system, the retina provides a characteristic window to observe neurovascular alterations in CKD. This study aimed to determine the presence of retinal neurovascular impairment in different stages of CKD. Methods: One hundred fifteen non-diabetic and non-dialytic CKD patients of all stages and a control group of 35 healthy subjects were included. Retinal neural and microvascular parameters were obtained by optical coherence tomography angiography (OCTA) examination. Results: CKD 1-2 group (versus control group) had greater odds of having decreased retinal ganglion cell-inner plexiform layer thickness (GC-IPLt) (odds ratio [OR]: 0.92; 95% confidence interval [CI]: 0.86-0.98), increased ganglion cell complex-focal loss volume (GCC-FLV) (OR: 3.51; 95% CI: 1.27-9.67), and GCC-global loss volume (GCC-GLV) (OR: 2.48; 95% CI: 1.27-4.82). The presence of advanced stages of CKD (CKD 3-5 group versus CKD 1-2 group) had greater odds of having decreased retinal vessel density in superficial vascular plexus (SVP)-WholeImage (OR: 0.77, 95% CI: 0.63-0.92), SVP-ParaFovea (OR: 0.83, 95% CI: 0.71-0.97), SVP-ParaFovea (OR: 0.76, 95% CI: 0.63-0.91), deep vascular plexus (DVP)-WholeImage (OR: 0.89, 95% CI: 0.81-0.98), DVP-ParaFovea (OR: 0.88, 95% CI: 0.78-0.99), and DVP-PeriFovea (OR: 0.90, 95% CI: 0.83-0.98). Besides, stepwise multivariate linear regression among CKD patients showed that ß2-microglobulin was negatively associated with GC-IPLt (ß: -0.294; 95% CI: -0.469 ∼ -0.118), and parathyroid hormone was positively associated with increased GCC-FLV (ß: 0.004; 95% CI: 0.002∼0.006) and GCC-GLV (ß: 0.007; 95% CI: 0.004∼0.01). Urine protein to creatinine ratio was positively associated with increased GCC-FLV (ß: 0.003; 95% CI: 0.001∼0.004) and GCC-GLV (ß: 0.003; 95% CI: 0.001∼0.006). Conclusion: Retinal neuronal impairment is present in early stages of CKD (stages 1-2), and it is associated with accumulation of uremic toxins and higher UACR, while retinal microvascular hypoperfusion, which is associated with worse eGFR, was only observed in relatively advanced stages of CKD (stages 3-5). The results highlight the importance of monitoring retinal neurovascular impairment in different stages of CKD.

Improved Retinal Microcirculation After Cardiac Surgery in Patients With Congenital Heart Disease.

Background: Microcirculatory changes in congenital heart disease (CHD) patients undergoing cardiac surgery are not fully understood. We aimed to investigate the changes of retinal microcirculation in CHD patients after cardiac surgery by optical coherence tomography angiography (OCTA) and explore the association between retinal microcirculation and surgical outcome. Methods: This prospective observational study consisted of 71 CHD patients aged ≥6 years undergoing cardiac surgery including 19 cyanotic CHD (CCHD) and 52 acyanotic CHD (ACHD). Optical coherence tomography angiography (OCTA) was used to measure vessel density (VD) and capillary density (CD) of radial peripapillary capillary (RPC) and peripapillary, VD of superficial capillary plexus (SCP) and deep capillary plexus (DCP), thickness of retinal nerve fiber layer (RNFL) and ganglion cell complex (GCC) preoperatively and 1 month postoperatively. Transthoracic echocardiography was conducted to measure macrocirculation. Results: In CCHD patients, VD and CD of RPC and peripapillary increased postoperatively (all P < 0.05). In ACHD patients, VD of peripapillary, CD of RPC and peripapillary, and RNFL thickness increased postoperatively (all P < 0.05). VD of SCP and DCP, and GCC thickness did not change significantly in CHD patients after surgery. Lower preoperative retinal microvascular density was associated with longer cardiopulmonary bypass (CPB) time and postoperative length of stay (PLOS). No correlation was found between microcirculatory and macrohemodynamic parameters (all P > 0.05). Conclusions: Improved retinal microcirculation was observed after congenital cardiac surgery and impaired preoperative retinal microvasculature was associated with prolonged CPB time and PLOS, which might provide potential information about the outcome of congenital cardiac surgery.

Reduced Retinal Microvascular Perfusion in Patients With Stroke Detected by Optical Coherence Tomography Angiography.

Currently there is a shortage of biomarkers for stroke, one of the leading causes of death and disability in aging populations. Retinal vessels offer a unique and accessible "window" to study the microvasculature in vivo. However, the relationship between the retinal microvasculature and stroke is not entirely clear. To investigate the retinal microvascular characteristics in stroke, we recruited patients with stroke and age-matched control subjects from a tertiary hospital in China. The macular vessel density (VD) in the superficial capillary plexus (SCP) and deep capillary plexus (DCP), foveal avascular zone (FAZ) metrics, and optical coherence tomography angiography (OCTA) measured optic disc VD were recorded for analysis. A total of 189 patients with stroke and 195 control subjects were included. After adjusting for sex, visual acuity, systolic and diastolic blood pressure, a history of smoking, levels of hemoglobulin (HbA1c), cholesterol, and high-density lipoprotein (HDL), the macular VD of SCP and DCP in all sectors was decreased in patients with stroke. In the stroke group, the VD around the FAZ and the VD of the optic disk were lower. Logistic regression found the parafovea-superior-hemi VD of DCP > 54.53% [odds ratio (OR): 0.169] as a protective factor of stroke. Using the integration of all OCTA parameters and traditional risk factors, the area under the receiver operating characteristic (AUC) curve of distinguishing patients with stroke was 0.962, with a sensitivity of 0.944 and a specificity of 0.871. Our study demonstrates that the retinal VD is decreased in patients with stroke independently of the traditional risk factors of stroke, which may shed light on the monitoring of stroke using the retinal microvascular parameters.

Herpes simplex virus type 1 related acute retinal necrosis following an encephalitis illness: a case report.

BACKGROUND: Virus encephalitis is found to be a risk factor for acute retinal necrosis (ARN). CASE PRESENTATION: We herein presented a case of a 20-year-old teenage boy who suffered from encephalitis of unknown etiology with early negative pathologic results, and was primarily treated with systemic administration of high-dose steroids without antiviral therapy. He later had sudden vision loss in his right eye. Intravitreal and intravenous antiviral treatments were immediately started due to suspected ARN. Herpes simplex virus (HSV)-1 was identified later in the vitreous humor of the patient. After the surgery of retinal detachment (RD), obvious improvements in vision were observed. However, the patient had recurrent RD and vision declination 5 weeks later. CONCLUSIONS: The case with suspected viral encephalitis should be treated with antiviral therapy regardless of early virologic results in order to avoid complications of a missed viral encephalitis diagnosis, especially if systemic steroid treatment is being considered.

Automatic prediction of treatment outcomes in patients with diabetic macular edema using ensemble machine learning.

BACKGROUND: This study aimed to predict the treatment outcomes in patients with diabetic macular edema (DME) after 3 monthly anti-vascular endothelial growth factor (VEGF) injections using machine learning (ML) based on pretreatment optical coherence tomography (OCT) images and clinical variables. METHODS: An ensemble ML system consisting of four deep learning (DL) models and five classical machine learning (CML) models was developed to predict the posttreatment central foveal thickness (CFT) and the best-corrected visual acuity (BCVA). A total of 363 OCT images and 7,587 clinical data records from 363 eyes were included in the training set (304 eyes) and external validation set (59 eyes). The DL models were trained using the OCT images, and the CML models were trained using the OCT images features and clinical variables. The predictive posttreatment CFT and BCVA values were compared with true outcomes obtained from the medical records. RESULTS: For CFT prediction, the mean absolute error (MAE), root mean square error (RMSE), and R2 of the best-performing model in the training set was 66.59, 93.73, and 0.71, respectively, with an area under receiver operating characteristic curve (AUC) of 0.90 for distinguishing the eyes with good anatomical response. The MAE, RMSE, and R2 was 68.08, 97.63, and 0.74, respectively, with an AUC of 0.94 in the external validation set. For BCVA prediction, the MAE, RMSE, and R2 of the best-performing model in the training set was 0.19, 0.29, and 0.60, respectively, with an AUC of 0.80 for distinguishing eyes with a good functional response. The external validation achieved a MAE, RMSE, and R2 of 0.13, 0.20, and 0.68, respectively, with an AUC of 0.81. CONCLUSIONS: Our ensemble ML system accurately predicted posttreatment CFT and BCVA after anti-VEGF injections in DME patients, and can be used to prospectively assess the efficacy of anti-VEGF therapy in DME patients.