Background：The metabolic profile of arginine is a potential biomarker for coronary artery disease (CAD). The global arginine bioavailability ratio (GABR), the ratio of the serum arginine level to the sum of the serum levels of its metabolites [L-arginine/(L-citrulline + L-ornithine)], has been reported as a marker of arginine bioavailability. The association between GABR and CAD was examined in an outpatient setting. Methods and Results：Serum levels of arginine and its related metabolites were measured in 234 cardiovascular outpatients (185 male, 49 female; age, 66 ± 12 years). The patients were divided into two groups: 118 (50%) patients with CAD [CAD (+)] and 116 (50%) patients without CAD [CAD (−)]. There were significant differences in the serum concentrations for the CAD (+) vs. CAD (−) groups, respectively, as follows: L-arginine (86 ± 23 μmol/L vs. 78 ± 22 μmol/L; p=0.003), L-citrulline (138 ± 60 μmol/L vs. 115 ± 65 μmol/L; p=0.005), L-ornithine (64 ± 28 μmol/L vs. 50 ± 29 μmol/L; p<0.001), asymmetric dimethyl arginine (0.57 ± 0.18 μmol/L vs. 0.50 ± 0.18 μmol/L; p=0.004), the ratio of L-arginine (Arg) to L-citrulline (Cit) (0.70 ± 0.29 vs. 0.92 ± 0.61, p=0.001), and GABR (0.46 ± 0.15 vs. 0.55 ± 0.24, p=0.001). In multivariate logistic regression analysis adjusted for clinical variables, the ratio of Arg/Cit and GABR were significantly associated with CAD. Conclusions：Our results suggest that the metabolic profile of arginine, especially Arg/Cit and GABR, has independent predictive value for the presence of CAD over traditional risk factors in an outpatient setting.

Background：It is not clear whether pulse pressure (PP) is a predictor of incident cardiovascular events in treated hypertensives. We sought to examine whether brachial and central PP predict incident cardiovascular events in subjects in the Antihypertensives and Blood pressure of Central artery in Japan II study, which included 3,566 patients from 27 institutions. Methods：Brachial and central hemodynamics were evaluated with a semi-automatic tonometry device. The mean age was 66.0±10.9 years, and 50.6% of the subjects were men. The mean brachial and central PP were 60.0±14.5 and 50.4±15.2 mmHg, respectively. An incident cardiovascular event was defined as stroke, myocardial infarction, sudden cardiac death, or acute aortic dissection. We performed multivariable Cox regression analysis with incident cardiovascular events as a dependent variable, and brachial and central PP as independent variables. Results：The hazard ratio per 10-mmHg increase in brachial PP was 1.16 (95% confidence interval [CI] 0.97-1.39, p=0.11) and that per 10-mmHg increase in central PP was 1.17 (95% CI 0.99-1.39, p=0.07). The relationship remained insignificant even when PP was divided by quintiles. The spline curve between brachial or central PP and the relative incidence of cardiovascular events showed a sigmoid relationship. Linear relationships were seen only in the range of 50-70 mmHg in brachial PP and 40-60 mmHg in central PP. Conclusions：In treated hypertensive patients, brachial and central PP were not markers for incident cardiovascular events. These relationships were not linear, and PPs were associated with incident cardiovascular events only in a limited range.

Objectives: Earlier detection of vascular stiffness and endothelial dysfunction will be useful in preventing atherosclerotic catastrophic conditions. Individuals with high risks for future cardiovascular (CV) events should be recognized by physicians to strengthen preventive therapeutic procedures, such as antihypertensive therapy, antidiabetic therapy, and antidyslipidemic therapy. As such, various non-invasive devices have been developed and are currently applied in clinical settings. Among them, we previously reported arterial velocity pulse index (AVI) and arterial pressure volume index (API) measured using a cuff-oscillometric-based medical electronic blood pressure monitor. These are significantly correlated with arterial stiffness and cardiac overload; therefore, these indexes might be useful in predicting future CV events. Materials and methods: We performed survival and CV event analyses in a total of 180 subjects with various clinical implications who visited Yokohama City University Hospital between May 2013 and March 2015 and followed them up until March 2016. The mean age was 66±13 years, and 101 subjects (56.1%) were men. A total of 116 subjects (64.4%) had hypertension, 87 subjects (48.3%) had dyslipidemia, and 39 subjects (21.7%) had diabetes mellitus. The mean AVI and API were 23.3±7.7 and 31.8±8.4, respectively. Results: The mean follow-up duration was 769±275 days. A total of 13 major adverse cardiac events (MACEs) occurred during the observational period, which consisted of 1 cardiac death, 8 CV events, and 4 hospitalizations owing to heart failure. After we performed Kaplan-Meier analysis, univariate Cox proportional hazard regression analysis, and multivariate Cox proportional hazard regression analysis, we found that AVI is significantly correlated with the risk of MACE. Therefore, we successfully revealed the clinical implications of the new non-invasive indexes for CV mortality and morbidity. Conclusion: The new non-invasive vascular index, AVI, was significantly correlated with the CV outcomes in our Japanese cohort.

Background: Bilirubin and cholesterol are associated with cardiovascular disease, though the relationship between these metabolites has not been fully investigated. Methods: Healthy subjects were enrolled. Annual cross-sectional assessment (year; 2012, 2016) and retrospective longitudinal assessment (year; 2012 to 2016) were performed. The subjects with receiving statin treatment were analyzed separately. Bilirubin ratio was defined as direct (or conjugated) bilirubin divided by the total bilirubin level in serum. Then, differences among the measurement principles were examined (year; 2017). Results: Bilirubin ratio measured by the vanadate oxidation method (VA) was strongly correlated with the total cholesterol level in both the non-statin group (2012: r = −0.753, n = 740; 2016: r = −0.763, n = 792; all p < 0.001) and the statin group (2012: r = −0.825, n = 39; 2016: r = −0.855, n = 43; all p < 0.001). The percent change of the bilirubin ratio from 2012 to 2016 was negatively proportional to that of total cholesterol (r = −0.634, n = 538; p < 0.001). A comparison of the two different methods in 305 participants in 2017 showed that the correlation was stronger with the VA than with the bilirubin oxidase method (BOD), (VA: r = −0.759, p < 0.001; BOD: r = −0.160, p = 0.005). In a laboratory experiment, the addition of cholesterol to human serum reduced the bilirubin ratio in both methods. Conclusion: A strong association between cholesterol and the ratio of direct to total bilirubin was revealed.

Background：When macrophages are primed by lipopolysaccharides, mono sodium urate (MSU) crystals activate NLRP3 inflammasomes and promote IL-1β and IL-18 production after phagocytosis of MSU. It was previously reported that anti-IL-1β antibodies suppress symptoms of gout and the occurrence of cardiovascular disease. Thus, inhibition of NLRP3 inflammasomes, which produce IL-1β and IL-18, may be a novel therapeutic strategy against these diseases. Purpose：To reveal the effects of dotinurad, a selective urate reabsorption inhibitor, and other uric acid lowering agents on MSU crystal-induced activation of NLRP3 inflammasomes in macrophages. Methods：Activity of NLRP3 inflammasomes in J774 mouse macrophages was evaluated by quantifying secreted caspase-1 and IL-1β using a western blot and ELISA in both the absence and presence of dotinurad or other uric acid lowering agents. Results：MSU increased protein levels of caspase-1 and IL-1β. This effect was inhibited by a clinical concentration of dotinurad. Neither febuxostat nor allopurinol influenced the levels of caspase-1 and IL-1β, whereas benzbromarone decreased their levels. The inhibitory effects of dotinurad and other uric acid lowering agents on secretions of IL-1β from the macrophages were confirmed by ELISA. Conclusion：Dotinurad, a selective urate reabsorption inhibitor, suppresses MSU-induced activation of NLRP3 inflammasomes in macrophages.