An Exercise Immune Fitness Test to Unravel Disease Mechanisms-A Proof-of-Concept Heart Failure Study.

Background: Cardiorespiratory fitness positively correlates with longevity and immune health. Regular exercise may provide health benefits by reducing systemic inflammation. In chronic disease conditions, such as chronic heart failure and chronic fatigue syndrome, mechanistic links have been postulated between inflammation, muscle weakness, frailty, catabolic/anabolic imbalance, and aberrant chronic activation of immunity with monocyte upregulation. We hypothesize that (1) temporal changes in transcriptome profiles of peripheral blood mononuclear cells during strenuous acute bouts of exercise using cardiopulmonary exercise testing are present in adult subjects, (2) these temporal dynamic changes are different between healthy persons and heart failure patients and correlate with clinical exercise-parameters and (3) they portend prognostic information. Methods: In total, 16 Heart Failure (HF) patients and 4 healthy volunteers (HV) were included in our proof-of-concept study. All participants underwent upright bicycle cardiopulmonary exercise testing. Blood samples were collected at three time points (TP) (TP1: 30 min before, TP2: peak exercise, TP3: 1 h after peak exercise). We divided 20 participants into 3 clinically relevant groups of cardiorespiratory fitness, defined by peak VO2: HV (n = 4, VO2 ≥ 22 mL/kg/min), mild HF (HF1) (n = 7, 14 < VO2 < 22 mL/kg/min), and severe HF (HF2) (n = 9, VO2 ≤ 14 mL/kg/min). Results: Based on the statistical analysis with 20-100% restriction, FDR correction (p-value 0.05) and 2.0-fold change across the three time points (TP1, TP2, TP3) criteria, we obtained 11 differentially expressed genes (DEG). Out of these 11 genes, the median Gene Expression Profile value decreased from TP1 to TP2 in 10 genes. The only gene that did not follow this pattern was CCDC181. By performing 1-way ANOVA, we identified 8/11 genes in each of the two groups (HV versus HF) while 5 of the genes (TTC34, TMEM119, C19orf33, ID1, TKTL2) overlapped between the two groups. We found 265 genes which are differentially expressed between those who survived and those who died. Conclusions: From our proof-of-concept heart failure study, we conclude that gene expression correlates with VO2 peak in both healthy individuals and HF patients, potentially by regulating various physiological processes involved in oxygen uptake and utilization during exercise. Multi-omics profiling may help identify novel biomarkers for assessing exercise capacity and prognosis in HF patients, as well as potential targets for therapeutic intervention to improve VO2 peak and quality of life. We anticipate that our results will provide a novel metric for classifying immune health.

Intraocular Pressure Control Predicts Retinal Nerve Fiber Layer Thinning in Primary Angle Closure Disease: The CUPAL Study.

PURPOSE: To determine the relationship of intraocular pressure (IOP) control with subsequent retinal nerve fiber layer (RNFL) thinning in patients with primary angle closure disease (PACD). DESIGN: Prospective cohort study. METHODS: The study monitored 517 treated PACD eyes from 280 Chinese patients at least 24 months. IOP was measured every 3 months using Goldmann applanation tonometry, and RNFLs were measured by spectral-domain optical coherence tomography (Spectralis, Heidelberg Engineering) every 6 months. IOP mean and fluctuation were calculated as the average and the coefficient of variation of IOP measurements during the first 18 months of the study period. The relationship between IOP and subsequent RNFL changes over time were examined using multivariable linear mixed models. Intraclass correlations at the patient and eye levels were also controlled using nested random intercepts in the models. RESULTS: IOP mean (ß = -1.20 µm/y per 1 mm Hg, P < .001) and IOP fluctuation (ß = -3.10 µm/y per 10% unit change in the coefficient of variation, P < .001) were independently negatively associated with subsequent progressive global RNFL changes, after adjustment for age, sex, and baseline RNFL thickness. In the sectoral analysis, both higher mean IOP and IOP fluctuation predicted progressive RNFL thinning in the inferotemporal, superotemporal, superonasal, and temporal sectors in the order of strength of association. In the subgroup analysis by disease category, IOP fluctuation showed greater association with global RNFL thinning in eyes with primary angle closure glaucoma (P = .010) than in eyes without glaucomatous changes (P = .07). CONCLUSIONS: In treated PACD eyes, large IOP fluctuation is an independent predictor for subsequent progressive RNFL thinning in addition to high mean IOP during follow-up.

Combined Phacoemulsification-Endoscopic Cyclophotocoagulation versus Phacoemulsification Alone in Primary Angle-Closure Glaucoma: A Pilot Randomized Controlled Trial.

PURPOSE: To compare combined phacoemulsification plus endoscopic cyclophotocoagulation (ECP) versus phacoemulsification alone in primary angle-closure glaucoma (PACG) with coexisting cataract. DESIGN: Prospective randomized controlled clinical trial-a pilot study. PARTICIPANTS: Forty-eight PACG eyes of 48 patients with coexisting cataract. INTERVENTION: Recruited patients were randomized into undergoing phacoemulsification plus ECP or phacoemulsification alone. After surgery, patients were followed up every 3 months for 2 years. MAIN OUTCOME MEASURES: Intraocular pressure (IOP) and requirement for topical glaucoma drugs. RESULTS: Twenty-seven PACG eyes were randomized to receive combined phacoemulsification plus ECP, and 21 PACG eyes underwent phacoemulsification alone. There was no statistically significant difference in mean preoperative IOP between combined phacoemulsification plus ECP and phacoemulsification groups (20.0 mmHg vs. 20.7 mmHg; P = 0.71). Phacoemulsification plus ECP resulted in lower mean postoperative IOP than phacoemulsification alone at all follow-up visits, but the differences only reached statistical significance at 1 month (P = 0.01), 12 months (P = 0.01), and 24 months (P = 0.04) postoperatively. There was no statistically significant difference in mean preoperative number of topical glaucoma drugs between combined phacoemulsification plus ECP and phacoemulsification groups (3.3 vs 3.1, P = 0.71). Combined phacoemulsification plus ECP resulted in lower glaucoma drug requirement than phacoemulsification alone at all follow-up visits, but the differences did not reach statistical significance at any time points postoperatively (P ≥ 0.05). Both groups were comparable in visual improvement, complication rate, need for additional surgical intervention, and visual field changes. CONCLUSIONS: Combined phacoemulsification plus ECP is noninferior to phacoemulsification alone in controlling IOP in PACG eyes with cataract. Combined phacoemulsification plus ECP resulted in lower mean IOP and glaucoma drug requirement than phacoemulsification alone at all follow-up visits in this pilot study, but the differences did not reach statistical significance at the majority of time points. A large-scale randomized controlled trial is in progress to evaluate these differences.

Characterization of macular choroid in normal-tension glaucoma: a swept-source optical coherence tomography study.

PURPOSE: To investigate the features of the small-to-medium (choriocapillaris and Sattler's layer) and large (Haller's layer) sized vessel layers of the macular choroid in normal-tension glaucoma (NTG) patients using swept-source optical coherence tomography (SS-OCT). METHODS: We conducted an observational cross-sectional study in 234 NTG eyes from 134 patients, and 203 normal eyes from 109 non-glaucomatous control subjects. We used Image J to segment the choroidal layer and then a Python script to measure the average macular choroidal thickness (MCT) and choroidal vascular index (CVI) of two vessel layers at five different locations. Quantitative optical coherence tomography angiography (OCTA) metrics for the superficial capillary plexus (SCP) and deep capillary plexus (DCP) at macular region were also measured by a customized MATLAB program. Generalized estimating equations (GEE) models were performed to determine ocular and demographic factors associated with the choroidal metrics, adjusting for inter-eye correlation. RESULTS: Significant average MCT thinning was found in NTG eyes at all five locations of the two layers, in comparison with controls (all p ≤ 0.05). In addition, compared with control eyes, significant decrease in CVI was found in NTG eyes at all five sections of the large sized vessel layer: 500 µm nasal and temporal to macula (p = 0.002), 1500 µm nasal (p < 0.001), 2500 µm nasal (p = 0.001), 1500 µm temporal (p < 0.001) and 2500 µm temporal (p = 0.004). In contrast, no significant CVI difference was detected in the small-to-medium sized vessel layer. In the comparison of OCTA metrics of SCP and DCP at macular region between NTG and normal eyes, there were no significant difference of parafoveal vessel density (VD), foveal avascular zone (FAZ) area, FAZ circularity and fractal dimension (FD) in both layers. CONCLUSION: We found significant alterations in macular choroidal vascularity (reduced CVI and thinner layer) in NTG patients. Such alterations are more pronounced in the Haller's layer, rather than the choriocapillaris & Sattler's layer, in NTG. Choroidal layer may be more related to vasculature changes at macular region in NTG.

Efficacy and safety of selective laser trabeculoplasty and pattern scanning laser trabeculoplasty: a randomised clinical trial.

AIMS: To compare the intraocular pressure (IOP) lowering effect and safety profile between pattern scanning laser trabeculoplasty (PSLT) and selective laser trabeculoplasty (SLT) in patients with primary open-angle glaucoma (POAG) or ocular hypertension (OHT) over a 12-month follow-up. METHODS: 132 patients with POAG or OHT were consecutively enrolled and randomised (1:1) to receive PSLT (n=65) or SLT (n=67) in a single centre. IOP was measured before and then on 1 day, 1 week, 1, 3, 6, 9 and 12 months after PSLT/SLT. The primary outcome measure was the proportion of patients with ≥20% IOP reduction at 12 months without IOP-lowering medications (complete success). RESULTS: The mean baseline IOP was 21.2±4.1 mm Hg for eyes randomised to PSLT and 21.3±4.7 mm Hg for eyes randomised to SLT (p=0.898). At 12 months, the IOP was 18.3±3.1 and 17.8±3.4 mm Hg, respectively (p=0.402). IOP measurements were comparable between the groups over 12 months (overall mean difference 0.4 mm Hg, 95% CI: -0.5 to 1.3 mm Hg). 15.4% of PSLT-treated and 25.4% of SLT-treated patients achieved treatment success (difference: 10.0%, 95% CI: -3.6 to 23.6) (p=0.155), respectively. A higher baseline IOP and a greater percentage of IOP reduction at day 1 were associated with a greater percentage of IOP reduction at 12 months (p<0.001). There were no significant differences in visual field mean deviation, average retinal nerve fibre layer thickness, corneal endothelial cell count and visual acuity between the treatment groups at the baseline and 12-month follow-up (p≥0.062). CONCLUSIONS: PSLT was not superior to SLT in terms of safety and IOP-lowering efficacy in patients with POAG or OHT. TRIAL REGISTRATION NUMBER: The clinical trial was registered in the Centre for Research and Biostatistics Clinical Trials Registry, the Chinese University of Hong Kong (Identifier CUHK_CCT00407). The full trial protocol can be accessed from the authors on request.

Factors Associated With Long-term Intraocular Pressure Fluctuation in Primary Angle Closure Disease: The CUHK PACG Longitudinal (CUPAL) Study.

PURPOSE: To determine the demographic, ocular, and systemic factors associated with long-term intraocular pressure (IOP) fluctuation in primary angle closure disease (PACD). METHODS: This prospective cohort study included 422 PACD eyes from 269 Chinese patients, including 274 primary angle closure glaucoma (PACG) eyes and 152 primary angle closure/primary angle closure suspect (PAC/PACS) eyes. Long-term IOP fluctuation defined as the SD of all IOP measurements over 2 years (at least 5 measurements in total). Chinese patients with PACD were recruited and followed up 3 monthly. Eyes with IOP-lowering surgery or lens extraction performed within the 2-year study period were excluded. Patient demographics, received treatments, ocular biometry, retinal nerve fiber layer thickness, and systemic factors (eg, hypertension, smoking) were evaluated. Generalized estimating equations adjusting for inter-eye correlation were used to determine the associations. RESULTS: Eyes with PACG had significantly higher IOP fluctuation than PAC/PACS (2.4±1.2 versus 2.1±0.9 mm Hg; P=0.04). In the multivariate analysis with PACG eyes, higher baseline IOP (P<0.001), greater number of IOP-lowering medications (P<0.001), previous trabeculectomy (P=0.002), and current smoking (P=0.03) were significantly associated with larger IOP fluctuation, whereas diabetes mellitus was associated with lower IOP fluctuation (P=0.03). Among PAC/PACS eyes, younger age group (P<0.001), male sex (P=0.002), and higher baseline IOP (P<0.001) were significantly associated with larger IOP fluctuation. CONCLUSIONS: PACG eyes have greater IOP fluctuation than PAC/PACS eyes. Certain demographic, ocular, and systemic factors are associated with IOP fluctuation in PACD eyes.

Anterior chamber angle imaging with swept-source optical coherence tomography: measuring peripheral anterior synechia in glaucoma.

OBJECTIVE: To investigate the use of swept-source optical coherence tomography (OCT) for measuring the area and degree of peripheral anterior synechia (PAS) involvement in patients with angle-closure glaucoma. DESIGN: Cross-sectional study. PARTICIPANTS: Twenty-three eyes with PAS (detected by indentation gonioscopy) from 20 patients with angle-closure glaucoma (20 eyes had primary angle-closure glaucoma and 3 eyes had angle-closure glaucoma secondary to chronic anterior uveitis [n = 2] and Axenfeld-Rieger syndrome [n = 1]). METHODS: The anterior chamber angles were evaluated with indentation gonioscopy and imaged by swept-source OCT (Casia OCT, Tomey, Nagoya, Japan) in room light and in the dark using the "angle analysis" protocol, which was composed of 128 radial B-scans each with 512 A-scans (16-mm scan length). The area and degree of PAS involvement were measured in each eye after manual detection of the scleral spur and the anterior irido-angle adhesion by 2 masked observers. The interobserver variability of the PAS measurements was calculated. MAIN OUTCOME MEASURES: The agreement of PAS assessment by gonioscopy and OCT, the area and the degree of PAS involvement, and the intraclass correlation coefficient (ICC) of interobserver PAS measurements. RESULTS: The area of PAS (mean ± standard deviation) was 20.8 ± 16.9 mm(2) (range, 3.9-74.9 mm(2)), and the degree of PAS involvement was 186.5 ± 79.9 degrees (range, 42-314 degrees). There was no difference in the area of PAS (P = 0.90) and the degree of PAS involvement (P = 0.95) between images obtained in room light and in the dark. The interobserver ICCs were 0.99 (95% confidence interval [CI], 0.98-1.00) for the area of PAS and 0.99 (95% CI, 0.97-1.00) for the degree of PAS involvement. There was good agreement of PAS assessment between gonioscopy and OCT images (kappa = 0.79; 95% CI, 0.67-0.91). CONCLUSIONS: Swept-source OCT allows visualization and reproducible measurements of the area and degree of PAS involvement, providing a new paradigm for evaluation of PAS progression and risk assessment for development of angle-closure glaucoma. FINANCIAL DISCLOSURE(S): The author(s) have no proprietary or commercial interest in any materials discussed in this article.