興梠 貴英

AIMS: Hypoxia-inducible factor (HIF) signalling influences cardiomyocyte differentiation, maturation, and metabolic adaptation under pathological conditions. HIF-Prolyl hydroxylase domain (HIF-PH) inhibitors, which target this pathway, have been introduced for the treatment of renal anaemia. Their precise effect or safety on cardiac function remains unclear because their pharmacokinetics and distribution are not well-understood. This study aimed to examine HIF signalling activation in adult cardiomyocytes (CMs). METHODS AND RESULTS: We used tamoxifen (TAM)-inducible, CM-specific von Hippel-Lindau (VHL) knockout (VHL-MCM) mice to activate CM HIF signalling. Then we subjected the mice to normal ageing or high-fat diet (HFD) and L-NAME feeding, a murine model of heart failure with preserved ejection fraction (HFpEF). In normal ageing group, there was no difference in the echocardiographic parameters or tissue fibrosis between VHL-MCM and control mice. VHL-MCM mice exhibited significantly increased capillary density and higher expression levels of HIF-target genes (P = 0.0248, two-way ANOVA). Under HFD + L-NAME treatment, VHL-MCM mice showed transient but significantly preserved global longitudinal strain (GLS) at 12 weeks post-TAM injection compared to controls (P = 0.0284, two-way ANOVA). Sirius red staining indicated a trend towards reduced whole-heart and interstitial fibrosis with significant increase in capillary density in VHL-MCM mice. CONCLUSION: Sustained HIF signalling activation in adult CM does not impair the cardiac structure and function in normal ageing process and shows transient yet beneficial effect in murine HFpEF model.

Background Accurately predicting left ventricular ejection fraction (LVEF) recovery after percutaneous coronary intervention (PCI) in patients with chronic coronary syndrome (CCS) is crucial for clinical decision-making. Objective This study aimed to develop and compare multiple machine learning (ML) models to predict LVEF recovery and identify key contributing features. Methods We retrospectively analyzed 520 patients with CCS from the Clinical Deep Data Accumulation System database. Patients were categorized into 4 binary classification tasks based on baseline LVEF (≥50% or <50%) and degree of recovery: (1) good recovery, defined as an LVEF increase of >10% compared with ≤0%; and (2) normal recovery, defined as an LVEF increase of 0% to 10% compared with ≤0%. For each task, 3 feature selection strategies (all features, least absolute shrinkage and selection operator [LASSO] regression, and recursive feature elimination [RFE]) were combined with 4 ML algorithms (extreme gradient boosting [XGBoost], categorical boosting, light gradient boosting machine, and random forest), resulting in 48 models. Models were evaluated using 10-fold cross-validation and assessed by the area under the curve (AUC), decision curve analysis, and calibration plots. Results The highest AUCs were achieved by RFE combined with XGBoost (AUC=0.93) for preserved LVEF with good recovery, LASSO combined with XGBoost (AUC=0.79) for preserved LVEF with normal recovery, LASSO combined with XGBoost (AUC=0.88) for reduced LVEF with good recovery, and RFE combined with XGBoost (AUC=0.84) for reduced LVEF with normal recovery. Shapley Additive Explanation analysis identified uric acid, platelets, hematocrit, brain natriuretic peptide, glycated hemoglobin, glucose, creatinine, baseline LVEF, left ventricular end-diastolic internal diameter, heart rate, R wave amplitude in V5, and R wave amplitude in V6 as important predictive factors of LVEF recovery. Conclusions ML models incorporating feature selection strategies demonstrated strong predictive performance for LVEF recovery after PCI. These interpretable models may support clinical decision-making and can improve the management of patients with CCS after PCI.

OBJECTIVES: The association between blood pressure (BP) and the mortality risk may vary depending on the comorbidities. This study was conducted to investigate the subgroup-specific correlation between systolic BP (SBP) and mortality in patients with coronary artery disease undergoing percutaneous coronary intervention (PCI). METHODS: The Clinical Deep Data Accumulation System for PCI (CLIDAS-PCI), a nation-wide multicenter database with seven tertiary medical hospitals in Japan, retrospectively collected data on patients undergoing PCI for acute coronary syndrome or stable coronary artery disease. Cubic spline curves modeled the relationship between SBP and all-cause death in the entire cohort and subgroups stratified by age, sex, diabetes, left ventricular (LV) hypertrophy, renal function and LV systolic function. We assessed the SBP, which minimizes mortality risk. RESULTS: A total of 8384 patients [71 [IQR 64, 78] years, 6494 (77%) male] with SBP at hospital discharge were analyzed. During 2.7 years of median follow-up, 695 deaths occurred. In the overall population, spline analysis demonstrated a nadir range of mortality risk around an SBP of 110-130 mmHg. Subgroup analyses revealed that elderly (age ≥ 80 years), those with renal dysfunction, and those with preserved LV systolic function had higher SBP levels associated with lowest risk. Conversely, patients <80 years, those with better renal function, and those with LV systolic dysfunction exhibited lower SBP levels at lowest risk. CONCLUSION: This study demonstrated differential association between SBP and mortality risk in various subgroups, highlighting the need for personalized BP management in multimorbid patients with coronary artery disease.

BACKGROUND: There are few data verifying the utility of the CHADS-P2A2RC score in comparison with the CHADS2 score for estimating net adverse clinical events (NACE) in chronic coronary syndrome (CCS) patients without atrial fibrillation (AF) in real-world settings. METHODS: We performed analysis for a total of 3985 CCS patients without AF who underwent percutaneous coronary intervention (PCI) between April 2013 and March 2019 for whom information was obtained from the CLIDAS (Clinical Deep Data Accumulation System)-PCI database. The primary endpoint was NACE defined as the composite of 3-point major adverse cardiovascular events (3P-MACE) (cardiovascular death, non-fatal myocardial infarction, and non-fatal stroke) and GUSTO moderate/severe bleeding events. RESULTS: Kaplan-Meier analysis showed that both the CHADS-P2A2RC and CHADS2 scores stratified the risks. The incidences of NACE were stratified well by the very-high-risk category, which was uniquely defined as a CHADS-P2A2RC score of ≥6 (hazard ratio: 2.38, 95 % CI = 1.91-2.97, p-value <0.001). The area under the curve (AUC) in estimating NACE within 3 years was higher when the CHADS-P2A2RC score was used than when the CHADS2 score was used (0.67 vs. 0.62, p = 0.003). This was mainly due to the accuracy in estimating bleeding events (0.66 vs. 0.60, p = 0.006). CONCLUSIONS: The accuracy in estimating NACE after PCI for CCS patients without AF was higher when the CHADS-P2A2RC score was used than when the CHADS2 score was used, mainly due to the accuracy in predicting bleeding risk. Higher incidences of endpoints were well-stratified by a very-high-risk category defined as a CHADS-P2A2RC score of ≥6.

The prevalence of malignancies in patients undergoing percutaneous coronary intervention (PCI) is increasing with aging. Active malignancy is a significant contributor to high bleeding risk. For cancer patients requiring oral anticoagulant (OAC) therapy, the choice between direct oral anticoagulants (DOAC) and warfarin is critical. The aim of this study was to investigate long-term bleeding events in patients with malignancy undergoing PCI. The CLIDAS (Clinical Deep Data Accumulation System) multicenter database includes data from seven tertiary medical hospitals in Japan. This retrospective analysis included 6451 patients who underwent PCI between April 2013 and March 2019 and completed 3-year follow-up. The patients were divided into two groups; No malignancy (n = 5787) and Malignancy group (n = 664). Malignancy was defined by a history of cancer treatment. These groups were further subcategorized based on OAC therapy; (1) No malignancy without OAC (n = 5134), (2) No malignancy with DOAC (n = 261), (3) No malignancy with warfarin (n = 392), (4) Malignancy without OAC (n = 589), (5) Malignancy with DOAC (n = 38), and (6) Malignancy with warfarin (n = 37). The primary outcome was the incidence of bleeding events, defined according to the Global Use of Streptokinase and t-PA for Occluded Coronary Arteries classification of moderate and severe bleeding. The secondary outcomes were major adverse cardiac events (MACE) and net adverse clinical events (NACE). Multivariable Cox regression analysis showed that the malignancy with warfarin group had a significantly higher risk of bleeding events compared to the malignancy without OAC group (hazard ratio [HR], 3.64; 95% confidence interval [CI], 1.38-9.61, p value = 0.009). No significant differences were observed for MACE (HR, 1.39; 95% CI 0.59-3.25, p value = 0.454) or NACE (HR, 1.62; 95% CI, 0.80-3.29; p value = 0.184). Malignancy patients receiving warfarin were associated with a higher risk of bleeding events. DOACs may represent a preferable alternative to warfarin with regard to bleeding risk in patients with malignancy undergoing PCI.

BACKGROUND: Lipid-lowering therapy with high-intensity statins has not been widely implemented in Japan for patients with coronary artery disease who undergo percutaneous coronary intervention (PCI). We examined the efficacy and safety of high-intensity statin therapy in a real-world setting. METHODS AND RESULTS: We used the Clinical Deep Data Accumulation System (CLIDAS) to accumulate multimodal data from the electronic medical records of 7 cardiovascular centers. We analyzed 9,690 patients who underwent PCI between 2013 and 2019 and completed a median 2.5-year follow-up (CLIDAS-PCI database). The risk of developing major adverse cardiac and cerebrovascular events (MACCE) was significantly greater in patients with acute (ACS) than chronic (CCS) coronary syndrome. High-intensity statins were prescribed to 49% of ACS patients and 33% of CCS patients within the first 30 days after the index PCI. After propensity score matching, MACCE event rates were similar between the high- and moderate-intensity statin groups. Importantly, among ACS patients, Cox proportional hazard analysis revealed that the rate of myocardial infarction was lower (adjusted hazard ratio [aHR] 0.65; 95% confidence interval [CI] 0.44-0.97) and the rate of stroke was greater (aHR 1.71; 95% CI 1.12-2.62) in the high-intensity statin group, driven mostly by intracranial hemorrhage. CONCLUSIONS: The CLIDAS-PCI database provides real-world evidence for the efficacy and safety of high-intensity statins in Japanese ACS patients who have undergone PCI.

BACKGROUND: Dual antiplatelet drug administration is recommended after percutaneous coronary intervention (PCI) stent placement. Although prasugrel, a newer P2Y12 inhibitor, reportedly suppresses cardiovascular events more effectively than the traditional agent clopidogrel, its preventive effects on cerebrovascular disorders remain a topic of ongoing debate. This study aimed to examine the cerebrovascular efficacy and safety of post-PCI prasugrel and clopidogrel using extensive real-world data in Japan. METHODS: Using the CLIDAS (Clinical Deep Data Accumulation System) database, 7412 post-PCI patients who received dual antiplatelet therapy between April 2013 and March 2019 were identified. The primary end point was defined as the incidence of any stroke, while secondary end points included individual ischemic and hemorrhagic cerebrovascular events. The incidence of cerebrovascular events was compared between the prasugrel (2.5–3.75 mg daily; n=2219) and clopidogrel (75 mg daily; n=5193) groups using propensity-score inverse probability of treatment weighting and Fine and Gray models to account for competing risks. RESULTS: Within 1 year after PCI, the prasugrel group had a significantly lower incidence of cerebrovascular events (subdistribution hazard ratio, 0.46 [95% CI, 0.24–0.91]; P =0.027) than the clopidogrel group. The subgroup analyses did not show significant differences in the incidence of ischemic (subdistribution hazard ratio, 0.54 [95% CI, 0.25–1.14]; P =0.11) and hemorrhagic cerebrovascular events (subdistribution hazard ratio, 0.30 [95% CI, 0.084–1.10]; P =0.070) between the use of prasugrel and clopidogrel. One-year health care costs between patients treated with prasugrel and those treated with clopidogrel showed no significant differences. CONCLUSIONS: Our data suggest that post-PCI prasugrel use was associated with lower cerebrovascular events compared with the use of clopidogrel in combination with aspirin. Further research is necessary to substantiate the potential of prasugrel in lowering cerebrovascular risks after post-PCI while upholding a satisfactory safety profile.

The Japanese Society of Hypertension have established a blood pressure (BP) target of 130/80 mmHg for patients with coronary artery disease (CAD). We evaluated the data of 8793 CAD patients in the Clinical Deep Data Accumulation System database who underwent cardiac catheterization at six university hospitals and the National Cerebral and Cardiovascular Center (average age 70 ± 11 years, 78% male, 43% with acute coronary syndrome [ACS]). Patients were divided into two groups based on whether or not they achieved the guideline-recommended BP of <130/80 mmHg. We analyzed the relationship between BP classification and major adverse cardiac and cerebral event (MACCE) separately in two groups: those with ACS and those with chronic coronary syndrome (CCS). During an average follow-up period of 33 months, 710 MACCEs occurred. A BP below 130/80 mmHg was associated with fewer MACCEs in both the overall (hazard ratio [HR] 0.83, 95% confidence interval [CI] 0.70-1.00, p = 0.048) and the ACS group (HR 0.67, 95%CI 0.51-0.88, p = 0.003). In particular, stroke events were also lower among those with a BP below 130/80 mmHg in both the overall (HR 0.69, 95%CI 0.53-0.90, p = 0.006) and ACS groups (HR 0.44, 95%CI 0.30-0.67, p < 0.001). In conclusion, the achievement of BP guidelines was associated with improved outcomes in CAD patients, particularly in reducing stroke risk among those with ACS.

OBJECTIVE: This study aimed to investigate the association between heart failure (HF) severity measured based on brain natriuretic peptide (BNP) levels and future bleeding events after percutaneous coronary intervention (PCI). BACKGROUND: The Academic Research Consortium for High Bleeding Risk presents a bleeding risk assessment for antithrombotic therapy in patients after PCI. HF is a risk factor for bleeding in Japanese patients. METHODS: Using an electronic medical record-based database with seven tertiary hospitals in Japan, this retrospective study included 7160 patients who underwent PCI between April 2014 and March 2020 and who completed a 3-year follow-up and were divided into three groups: no HF, HF with high BNP level and HF with low BNP level. The primary outcome was bleeding events according to the Global Use of Streptokinase and t-PA for Occluded Coronary Arteries classification of moderate and severe bleeding. The secondary outcome was major adverse cardiovascular events (MACE). Furthermore, thrombogenicity was measured using the Total Thrombus-Formation Analysis System (T-TAS) in 536 consecutive patients undergoing PCI between August 2013 and March 2017 at Kumamoto University Hospital. RESULTS: Multivariate Cox regression showed that HF with high BNP level was significantly associated with bleeding events, MACE and all-cause death. In the T-TAS measurement, the thrombogenicity was lower in patients with HF with high BNP levels than in those without HF and with HF with low BNP levels. CONCLUSIONS: HF with high BNP level is associated with future bleeding events, suggesting that bleeding risk might differ depending on HF severity.

AIM: There is little information on the relationships of serum small dense low-density lipoprotein cholesterol (sdLDL-C) levels and serum triglyceride (TG) levels with cardiovascular events in patients with coronary artery disease (CAD) and type 2 diabetes mellitus (DM) who are receiving statins. The aim of this study was to evaluate the relationships of serum TG levels and sdLDL-C levels as residual risks for cardiovascular events in patients with CAD and type 2 DM who were being treated with statins. METHODS: The subjects were divided into four groups based on TG levels and sdLDL-C levels: sdLDL-C of ＜40.0 mg/dL and TG of ＜150 mg/dL, sdLDL-C of ≥ 40.0 mg/dL and TG of ＜150 mg/dL, sdLDL-C of ＜40.0 mg/dL and TG of ≥ 150 mg/dL, and sdLDL-C of ≥ 40.0 mg/dL and TG of ≥ 150 mg/dL. During a median follow-up period of 1419 days, cardiovascular events occurred in 34 patients. RESULTS: The incidences of cardiovascular events were significantly higher in patients with sdLDL-C of ≥ 40.0 mg/dL and TG of ＜150 mg/dL and in patients with sdLDL-C of ≥ 40.0 mg/dL and TG of ≥ 150 mg/dL, but not in patients with sdLDL-C of ＜40.0 mg/dL and TG of ≥ 150 mg/dL, than in patients with sdLDL-C of ＜40.0 mg/dL and TG of ＜150 mg/dL. CONCLUSIONS: Under the condition of treatment with statins, patients with CAD and type 2 DM who had sdLDL-C levels of ≥ 40.0 mg/dL had a high risk for cardiovascular events even though serum TG levels were controlled at ＜150 mg/dL.

Type 2 diabetes mellitus (T2DM) is a major cause of microvascular dysfunction. However, its effect on blood flow patterns during ischemic demand has not been adequately elucidated. In this study, we investigated the hypothesis that microvascular dysfunction in patients with T2DM manifests as brachial reactive hyperemia (BRH), defined as the ratio of peak blood flow velocities in a brachial artery before and after forearm cuff occlusion. The study enrolled 943 subjects (men, n = 152 [T2DM] and n = 371 [non-T2DM]; women, n = 107 [T2DM] and n = 313 [non-T2DM], respectively) with no history of cardiovascular disease. Semiautomatic measurements were obtained three times at 1.5-year intervals to confirm the reproducibility of factors involved in BRH for each sex. An age-adjusted mixed model demonstrated attenuated BRH in the presence of T2DM in both men (p = 0.022) and women (p = 0.031) throughout the study period. Post hoc analysis showed that the estimated BRH was significantly attenuated in patients with T2DM regardless of sex, except at baseline in women. In multivariate regression analysis, T2DM was a negative predictor of BRH at every measurement in men. For women, BRH was more strongly associated with alcohol consumption. Repeated measurements analysis revealed that T2DM was associated with attenuated postocclusion reactive hyperemia.

Chronic kidney disease is a progressive disease that may lead to end-stage renal disease. Interstitial fibrosis develops as the disease progresses. Therapies that focus on fibrosis to delay or reverse progressive renal failure are limited. We and others showed that sphingosine kinase 2-deficient mice (Sphk2^–/–) develop less fibrosis in mouse models of kidney fibrosis. Sphingosine kinase2 (SphK2), one of two sphingosine kinases that produce sphingosine 1-phosphate (S1P), is primarily located in the nucleus. S1P produced by SphK2 inhibits histone deacetylase (HDAC) and changes histone acetylation status, which can lead to altered target gene expression. We hypothesized that Sphk2 epigenetically regulates downstream genes to induce fibrosis, and we performed a comprehensive analysis using the combination of RNA-seq and ChIP-seq. Bst1/CD157 was identified as a gene that is regulated by SphK2 through a change in histone acetylation level, and Bst1^–/– mice were found to develop less renal fibrosis after unilateral ischemia-reperfusion injury, a mouse model of kidney fibrosis. Although Bst1 is a cell-surface molecule that has a wide variety of functions through its varied enzymatic activities and downstream intracellular signaling pathways, no studies on the role of Bst1 in kidney diseases have been reported previously. In the current study, we demonstrated that Bst1 is a gene that is regulated by SphK2 through epigenetic change and is critical in kidney fibrosis.

BACKGROUND: Elevated levels of triglyceride (TG) and non-high-density lipoprotein cholesterol (non-HDL-C) are regarded as a residual lipid risk in low-density lipoprotein cholesterol (LDL-C)-lowering therapy. This study investigated the association between lipid risk stratified by TG and non-HDL-C and the prognosis of patients with coronary artery disease (CAD), and the association between stratified lipid risk and flow-mediated dilatation (FMD) index.Methods and Results: The 624 CAD patients enrolled in flow-mediated dilation (FMD)-J study A were divided into 4 groups: low-risk group (n=413) with TG <150 mg/dL and non-HDL-C <170 mg/dL; hyper-TG group (n=180) with TG ≥150 mg/dL and non-HDL-C <170 mg/dL; hyper-non-HDL group (n=12) with TG <150 mg/dL and non-HDL-C ≥170 mg/dL; and high-risk group (n=19) with TG ≥150 mg/dL and non-HDL-C ≥170 mg/dL. Comparison of the groups showed the cumulative incidence of a 3-point major adverse cardiovascular event (MACE) was different and highest in the high-risk group in all the patients (P=0.009), and in patients with a FMD index ≥7.0% (P=0.021), but not in those with a FMD index <7.0%. Multivariable regression analysis showed that high lipid risk (P=0.019) and FMD <7.0% (P=0.040) were independently correlated with the incidence of a 3-point MACE. CONCLUSIONS: Novel stratification of lipid risk, simply using TG and non-HDL-C levels, combined with FMD measurement, is useful for predicting cardiovascular outcomes in patients with CAD.

BACKGROUND: The causal relationship between hyperuricemia and cardiovascular diseases is still unknown. We hypothesized that hyperuricemic patients after percutaneous coronary intervention (PCI) had a higher risk of major adverse cardiovascular events (MACE). METHODS: This was a large-scale multicenter cohort study. We enrolled patients with chronic coronary syndrome (CCS) after PCI between April 2013 and March 2019 using the database from the Clinical Deep Data Accumulation System (CLIDAS), and compared the incidence of MACE, defined as a composite of cardiovascular death, myocardial infarction, and hospitalization for heart failure, between hyperuricemia and non-hyperuricemia groups. RESULTS: In total, 9,936 patients underwent PCI during the study period. Of these, 5,138 patients with CCS after PCI were divided into two group (1,724 and 3,414 in the hyperuricemia and non-hyperuricemia groups, respectively). The hyperuricemia group had a higher prevalence of hypertension, atrial fibrillation, history of previous hospitalization for heart failure, and baseline creatinine, and a lower prevalence of diabetes than the non-hyperuricemia group, but the proportion of men and age were similar between the two groups. The incidence of MACE in the hyperuricemia group was significantly higher than that in the non-hyperuricemia group (13.1 vs. 6.4%, log-rank P < 0.001). Multivariable Cox regression analyses revealed that hyperuricemia was significantly associated with increased MACE [hazard ratio (HR), 1.52; 95% confidential interval (CI), 1.23-1.86] after multiple adjustments for age, sex, body mass index, estimated glomerular filtration rate, left main disease or three-vessel disease, hypertension, diabetes mellitus, dyslipidemia, history of myocardial infarction, and history of hospitalization for heart failure. Moreover, hyperuricemia was independently associated with increased hospitalization for heart failure (HR, 2.19; 95% CI, 1.69-2.83), but not cardiovascular death or myocardial infarction after multiple adjustments. Sensitive analyses by sex and diuretic use, B-type natriuretic peptide level, and left ventricular ejection fraction showed similar results. CONCLUSION: CLIDAS revealed that hyperuricemia was associated with increased MACE in patients with CCS after PCI. Further clinical trials are needed whether treating hyperuricemia could reduce cardiovascular events or not.

<sec><title>Background</title>The sympathetic nervous system regulates immune cell dynamics. However, the detailed role of sympathetic signaling in inflammatory diseases is still unclear because it varies according to the disease situation and responsible cell types. This study focused on identifying the functions of sympathetic signaling in macrophages in LPS-induced sepsis and renal ischemia-reperfusion injury (IRI). </sec><sec><title>Methods</title>We performed RNA sequencing of mouse macrophage cell lines to identify the critical gene that mediates the anti-inflammatory effect of <italic>β</italic>2-adrenergic receptor (Adrb2) signaling. We also examined the effects of salbutamol (a selective Adrb2 agonist) in LPS-induced systemic inflammation and renal IRI. Macrophage-specific <italic>Adrb2</italic> conditional knockout (cKO) mice and the adoptive transfer of salbutamol-treated macrophages were used to assess the involvement of macrophage Adrb2 signaling. </sec><sec><title>Results</title><italic>In vitro</italic>, activation of Adrb2 signaling in macrophages induced the expression of T cell Ig and mucin domain 3 (<italic>Tim3</italic>), which contributes to anti-inflammatory phenotypic alterations. <italic>In vivo</italic>, salbutamol administration blocked LPS-induced systemic inflammation and protected against renal IRI; this protection was mitigated in macrophage-specific <italic>Adrb2</italic> cKO mice. The adoptive transfer of salbutamol-treated macrophages also protected against renal IRI. Single-cell RNA sequencing revealed that this protection was associated with the accumulation of <italic>Tim3</italic>-expressing macrophages in the renal tissue. </sec><sec><title>Conclusions</title>The activation of Adrb2 signaling in macrophages induces anti-inflammatory phenotypic alterations partially via the induction of <italic>Tim3</italic> expression, which blocks LPS-induced systemic inflammation and protects against renal IRI. </sec>

Treatment of uveitis is complicated because of its multiple aetiologies and elevation of various inflammatory mediators. To determine the mediators that are elevated in the vitreous humor according to the aetiology of the uveitis, we examined the concentrations of 21 inflammatory cytokines, 7 chemokines, and 5 colony-stimulating/growth factors in vitreous samples from 57 eyes with uveitis associated with intraocular lymphoma (IOL, n = 13), sarcoidosis (n = 15), acute retinal necrosis (ARN, n = 13), or bacterial endophthalmitis (BE, n = 16). Samples from eyes with idiopathic epiretinal membrane (n = 15), which is not associated with uveitis, were examined as controls. Heat map analysis demonstrated that the patterns of inflammatory mediators in the vitreous humor in eyes with uveitis were disease-specific. Pairwise comparisons between the 5 diseases showed specific elevation of interferon-α2 in ARN and interleukin (IL)-6, IL-17A, and granulocyte-colony stimulating factor in BE. Pairwise comparisons between IOL, ARN, and BE revealed that levels of IL-10 in IOL, RANTES (regulated on activation, normal T cell expressed and secreted) in ARN, and IL-22 in BE were significantly higher than those in the other 2 types of uveitis. These mediators are likely to be involved in the immunopathology of specific types of uveitis and may be useful biomarkers.

Background Diagnostic criteria of flow-mediated vasodilation (FMD), an index of endothelial function, and nitroglycerin-induced vasodilation (NID), an index of vascular smooth muscle function, of the brachial artery have not been established. The purpose of this study was to propose diagnostic criteria of FMD and NID for normal endothelial function and normal vascular smooth muscle function. Methods and Results We investigated the cutoff values of FMD and NID in subjects with (risk group) and those without cardiovascular risk factors or cardiovascular diseases (no-risk group) in 7277 Japanese subjects (mean age 51.4±10.8 years) from the Flow-Mediated Dilation Japan study and the Flow-Mediated Dilatation Japan Registry study for analysis of the cutoff value of FMD and in 1764 Japanese subjects (62.2±16.1 years) from the registry of Hiroshima University Hospital for analysis of the cutoff value of NID. Receiver-operator characteristic curve analysis of FMD to discriminate subjects in the no-risk group from patients in the risk group showed that the optimal cutoff value of FMD to diagnose subjects in the no-risk group was 7.1%. Receiver-operator characteristic curve analysis of NID to discriminate subjects in the no-risk group from patients in the risk group showed that the optimal cutoff value of NID to diagnose subjects in the no-risk group was 15.6%. Conclusions We propose that the cutoff value for normal endothelial function assessed by FMD of the brachial artery is 7.1% and that the cutoff value for normal vascular smooth muscle function assessed by NID of the brachial artery is 15.6% in Japanese subjects. Clinical Trial Registration www.umin.ac.jp Unique identifiers: UMIN000012950, UMIN000012951, UMIN000012952, and UMIN000003409.