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Background: Hypochloremia has been suggested as a strong marker of mortality in hospitalized patients with heart failure (HF). This study aimed to clarify whether incorporating hypochloremia into pre-existing prognostic models improved the performance of the models., Methods: We tested the prognostic value of hypochloremia (<97 mEq/L) measured at discharge in hospitalized patients with HF registered in the REALITY-AHF and NARA-HF studies. The primary outcome was 1-year mortality after discharge., Results: Among 2496 patients with HF, 316 (12.6 %) had hypochloremia at the time of discharge, and 387 (15.5 %) deaths were observed within 1 year of discharge. The presence of hypochloremia was strongly associated with higher 1-year mortality compared to those without hypochloremia (log-rank: p < 0.001), and this association remained even after adjustment for the Get With the Guideline-HF risk model (GWTG-HF), anemia, New York Heart Association (NYHA) classification, and log-brain natriuretic peptide (BNP) [hazard ratio (HR) 1.64; p < 0.001]. Furthermore, adding hypochloremia to the prediction model composed of GWTG-HF + anemia + NYHA class + log-BNP yielded a numerically larger area under the curve (0.740 vs 0.749; p = 0.059) and significant improvement in net reclassification (0.159, p = 0.010)., Conclusions: Incorporating the presence of hypochloremia at discharge into pre-existing risk prediction models provides incremental prognostic information for hospitalized patients with HF., Competing Interests: Declaration of competing interest Dr. Yuya Matsue is affiliated with a department endowed by Philips Respironics, ResMed, Teijin Home Healthcare, and Fukuda Denshi and received an honorarium from Otsuka Pharmaceutical Co and Novartis Japan. Dr. Keisuke Kida received honoraria from Daichi Sankyo Co., Ono Pharmaceutical Co., Ltd., AstraZeneca K.K., Otsuka Pharmaceutical Co., Ltd., and Novartis Pharmaceuticals Co., Ltd. Dr. Takahiro Okumura received research honoraria from Ono Yakuhin, Otsuka, Novartis, and Astrazeneca and research grants from Ono Yakuhin, Amgen Astellas, Pfizer, Alnylam, and Alexion (not in connection with the submitted work). Dr. Yoshihiko Saito received research funds from Otsuka Pharmaceutical Co., Ltd., Takeda Pharmaceutical Co., Ltd., Mitsubishi Tanabe Pharma Corporation, Actelion Pharmaceuticals Japan Ltd., Kyowa Kirin Co., Ltd., Dainippon Sumitomo Pharma Co., Ltd., Chugai Pharmaceutical Co., Ltd., Nihon Medi-Physics Co., Ltd., and Fuji Yakuhin Co., Ltd.; research expenses from Roche Diagnostics K.K., Otsuka Pharmaceutical Co., Ltd., Terumo Corporation, Kowa Company, Abbott Medical Japan LLC, Alnylam Japan K.K., and CMIC Holdings Co., Ltd.; speakers' bureau/honorarium from Alnylam Japan K.K., AstraZeneca K.K., Amicus Therapeutics, Inc., Amgen K.K. Edwards Lifesciences Corporation, Otsuka Pharmaceutical Co., Ltd., Ono Pharmaceutical Co., Ltd., Kyowa Kirin Co., Ltd., Kowa Pharmaceutical Co., Ltd., Daiichi Sankyo Co., Ltd., Mitsubishi Tanabe Pharma Corporation, Tsumura & Co., Toa Eiyo Ltd., Nippon Shinyaku Co., Ltd., Nippon Boehringer Ingelheim Co., Ltd., Novartis Pharma K.K., Bayer Yakuhin Ltd., Mochida Pharmaceutical Co., Ltd., and Janssen Pharmaceutical K.K.; consultation fees from AstraZeneca K.K., Novartis Pharma K.K., and Nippon Boehringer Ingelheim Co., Ltd.; and other remuneration (supervisor) from Towa Pharmaceutical Co., Ltd. The other authors have nothing to declare., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Background: Pulmonary hypertension (PH) has recently been described as a complex clinical syndrome affecting multiple organ systems, including the heart, lungs, and skeletal muscle, each of which plays an important role in exercise capacity. However, the relationship between exercise capacity and skeletal muscle abnormalities in patients with PH has not been fully elucidated., Methods: We retrospectively analysed the exercise capacity and measures of skeletal muscle of 107 patients with PH without left heart disease (mean age 63 ± 15 years, 32.7% males, n = 30/6/66/5 in the clinical classification Group 1/3/4/5)., Results: Sarcopenia, low appendicular skeletal muscle mass index, low grip strength, and slow gait speed, determined by international criteria, were found in 15 (14.0%), 16 (15.0%), 62 (57.9%), and 41 (38.3%) patients, respectively. The mean 6-min walk distance of all patients was 436 ± 134 m and was independently associated with sarcopenia (standardised β = -0.292, p < 0.001). All patients with sarcopenia showed reduced exercise capacity defined as 6-min walk distance < 440 m. Multivariable logistic regression analysis showed that each of the components of sarcopenia was associated with reduced exercise capacity (adjusted odds ratio and 95% confidence interval of appendicular skeletal muscle mass index: 0.39 [0.24-0.63] per 1 kg/m 2 , p = 0.006, grip strength: 0.83 [0.74-0.94] per 1 kg, p = 0.003, and gait speed: 0.31 [0.18-0.51] per 0.1 m/s, p < 0.001)., Conclusions: Sarcopenia and its components are associated with reduced exercise capacity in patients with PH. A multifaceted evaluation may be important in the management of reduced exercise capacity in patients with PH., Competing Interests: Declaration of Competing Interest All authors declare that they have no conflict of interest involved in this research., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background: Risk stratification is important in patients with acute heart failure (AHF), and a simple risk score that accurately predicts mortality is needed. The aim of this study is to develop a user-friendly risk-prediction model using a machine-learning method., Methods: A machine-learning-based risk model using least absolute shrinkage and selection operator (LASSO) regression was developed by identifying predictors of in-hospital mortality in the derivation cohort (REALITY-AHF), and its performance was externally validated in the validation cohort (NARA-HF) and compared with two pre-existing risk models: the Get With The Guidelines risk score incorporating brain natriuretic peptide and hypochloremia (GWTG-BNP-Cl-RS) and the acute decompensated heart failure national registry risk (ADHERE)., Results: In-hospital deaths in the derivation and validation cohorts were 76 (5.1 %) and 61 (4.9 %), respectively. The risk score comprised four variables (systolic blood pressure, blood urea nitrogen, serum chloride, and C-reactive protein) and was developed according to the results of the LASSO regression weighting the coefficient for selected variables using a logistic regression model (4 V-RS). Even though 4 V-RS comprised fewer variables, in the validation cohort, it showed a higher area under the receiver operating characteristic curve (AUC) than the ADHERE risk model (AUC, 0.783 vs. 0.740; p = 0.059) and a significant improvement in net reclassification (0.359; 95 % CI, 0.10-0.67; p = 0.006). 4 V-RS performed similarly to GWTG-BNP-Cl-RS in terms of discrimination (AUC, 0.783 vs. 0.759; p = 0.426) and net reclassification (0.176; 95 % CI, -0.08-0.43; p = 0.178)., Conclusions: The 4 V-RS model comprising only four readily available data points at the time of admission performed similarly to the more complex pre-existing risk model in patients with AHF., Competing Interests: Declaration of competing interest Dr. Yuya Matsue is affiliated to a department endowed by Philips Respironics, ResMed, Teijin Home Healthcare, and Fukuda Denshi and received an honorarium from Otsuka Pharmaceutical Co and Novartis Japan. Dr. Keisuke Kida received honorariums from Daichi Sankyo Co., Ono Pharmaceutical Co., Ltd., AstraZeneca K.K., Otsuka Pharmaceutical Co., Ltd., and Novartis Pharmaceuticals Co., Ltd. Dr. Takahiro Okumura received research honoraria from Ono Yakuhin, Otsuka, Novartis, and Astrazeneca and research grants from Ono Yakuhin, Amgen Astellas, Pfizer, Alnylam, and Alexion (not in connection with the submitted work). Dr. Yoshihiko Saito received research funds from Otsuka Pharmaceutical Co., Ltd., Takeda Pharmaceutical Co., Ltd., Mitsubishi Tanabe Pharma Corporation, Actelion Pharmaceuticals Japan Ltd., Kyowa Kirin Co., Ltd., Dainippon Sumitomo Pharma Co., Ltd., Chugai Pharmaceutical Co., Ltd., Nihon Medi-Physics Co., Ltd., Fuji Yakuhin Co., Ltd.; research expences from Roche Diagnostics K.K., Otsuka Pharmaceutical Co., Ltd., Terumo Corporation, Kowa Company, Abbott Medical Japan LLC, Alnylam Japan K.K. Cmic Holdings Co., Ltd.; Speakers' bureau/honorarium from Alnylam Japan K.K., AstraZeneca K.K., Amicus Therapeutics, Inc., Amgen K.K. Edwards Lifesciences Corporation, Otsuka Pharmaceutical Co., Ltd., Ono Pharmaceutical Co., Ltd., Kyowa Kirin Co., Ltd., Kowa Pharmaceutical Co., Ltd., Daiichi Sankyo Co., Ltd., Mitsubishi Tanabe Pharma Corporation, Tsumura & Co., Toa Eiyo Ltd., Nippon Shinyaku Co., Ltd., Nippon Boehringer Ingelheim Co., Ltd., Novartis Pharma K.K., Bayer Yakuhin Ltd., Mochida Pharmaceutical Co., Ltd., Janssen Pharmaceutical K.K.; Consultation fees from AstraZeneca K.K., Novartis Pharma K.K., Nippon Boehringer Ingelheim Co., Ltd.; Other remuneration (supervisor) from Towa Pharmaceutical Co., Ltd. The other authors have nothing to declare., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Backgrounds: Recently, there has been increasing awareness that bleeding may lead to adverse outcomes. Endothelial dysfunction is associated with increased risk of cardiovascular and bleeding events. This study aimed to investigate the association of endothelial dysfunction with major bleeding and specific causes of death in addition to major adverse cardiovascular events in patients with acute coronary syndrome., Methods: This single-centre retrospective observational study was conducted at a tertiary-care hospital; patients with acute coronary syndrome were included between June 2010 and November 2014 (median follow-up, 6.1 years). The reactive hyperaemia index was assessed before their discharge; reactive hyperaemia index <1.67 was defined as endothelial dysfunction. The main outcomes were the incidence of major bleeding, all-cause death, cardiovascular death, non-cardiovascular death, resuscitated cardiac arrest, non-fatal myocardial infarction, non-fatal stroke, and hospitalisation for heart failure., Results: Among the included 674 patients with acute coronary syndrome, 264 (39.2%) had endothelial dysfunction. Multivariable Cox-hazard analyses revealed an independent predictive value of endothelial dysfunction for major bleeding (hazard ratio 2.29, 95% confidence interval 1.17-4.48, P = 0.016) and major adverse cardiovascular events (hazard ratio 2.04, 95% confidence interval 1.43-2.89, P < 0.001). The endothelial dysfunction group patients had a 2.5-fold greater risk of cardiovascular death; however, no association was found with non-cardiovascular death., Conclusion: Endothelial dysfunction assessed using reactive hyperaemia index predicted future major cardiovascular event as well as major bleeding and cardiovascular death in patients with acute coronary syndrome., Competing Interests: Declaration of Competing Interest None declared., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background: Hypochloremia is a risk factor for poor outcomes in patients with acute heart failure (AHF). However, the changes in serum chloride levels during decongestion therapy and their impact on prognosis remain unknown., Methods: In total, 2798 patients with AHF were retrospectively studied and divided into four groups according to their admission and discharge serum chloride levels: (1) normochloremia (n=2,192, 78%); (2) treatment-associated hypochloremia, defined as admission normochloremia with a subsequent decrease (<98 mEq/L) during hospitalization (n=335, 12%); (3) resolved hypochloremia, defined as admission hypochloremia that disappeared at discharge (n=128, 5%); (4) persistent hypochloremia, defined as chloride <98 mEq/L at admission and discharge (n = 143, 5%). The primary outcome was all-cause death, and the secondary outcomes were cardiovascular death and a composite of cardiovascular death and rehospitalization for heart failure after discharge., Results: The mean age was 76 ± 12 years and 1584 (57%) patients were men. The mean left ventricular ejection fraction was 46 ± 16%. During a median follow-up period of 365 days, persistent hypochloremia was associated with an increased risk of all-cause death (adjusted hazard ratio [95% confidence interval]: 2.27 [1.53-3.37], p < 0.001), cardiovascular death (2.38 [1.46-3.87], p < 0.001), and a composite of cardiovascular death and heart failure rehospitalization (1.47 [1.06-2.06], p = 0.022). However, the outcomes were comparable between patients with resolved hypochloremia and normochloremia., Conclusions: Persistent hypochloremia was associated with worse clinical outcomes, while resolved hypochloremia and normochloremia showed a comparable prognosis. Changes in serum chloride levels can help identify patients with poor prognoses and can be used to determine subsequent treatment strategies., Competing Interests: Declaration of Competing Interest Dr. Kagiyama is affiliated with and receives a salary from a department funded by Philips Healthcare; Asahi KASEI Corporation; Inter Reha Co., Ltd.; and Toho Holdings Co., Ltd. based on collaborative research agreements. Dr. Kida received honorariums from Daichi Sankyo Co., Ono Pharmaceutical Co., Ltd., AstraZeneca K.K., Otsuka Pharmaceutical Co., Ltd., and Novartis Pharmaceuticals Co., Ltd. Dr. Matsue received an honorarium from Otsuka Pharmaceutical Co, Novartis Japan, Bayer Inc., and AstraZeneca, and collaborative research grant from Pfizer Japan Inc., Otsuka Pharmaceutical Co and EN Otsuka Pharmaceutical Co., Ltd., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Background Recent data suggest that the angiotensin receptor neprilysin inhibitor modulates plasma levels of natriuretic peptides and attenuates the risk of hyperkalemia in patients with heart failure (HF). However, the impact of natriuretic peptides on serum electrolyte abnormalities, especially abnormalities in sodium and potassium levels in patients with HF remains unclear. Methods We performed a post-hoc analysis of a multicenter prospective cohort study in 162 patients with acute HF (74.2 ± 13.3 years, 64.2% male, left ventricular ejection fraction 44 ± 15%) treated with intravenous carperitide, an exogenous atrial natriuretic peptide. Results The dose of carperitide was correlated with urine volume (σ = 0.205, p = 0.009), suggesting a significant diuretic effect. During the initial 48 h, serum sodium level remained unchanged both in 53 patients with carperitide alone (from 140 ± 4 to 140 ± 3 mEq/L, p = 0.653) and 109 patients treated with a combination of carperitide and furosemide (141 ± 4 to 141 ± 4 mEq/L, p = 0.644). On the contrary, serum potassium level was decreased both in patients with carperitide alone (from 4.32 ± 0.70 to 4.08 ± 0.47 mEq/L, p = 0.004) and patients treated with a combination of carperitide and furosemide (4.17 ± 0.55 to 3.98 ± 0.47, p < 0.001), with a significant association between urine volume and change in potassium level in patients treated with carperitide alone (σ = -0.313, p = 0.023). The incidence of hypokalemia at 24 h was higher in patients treated with 20 mg furosemide or more (12.5% vs. 2.8%, p = 0.039). Conclusions Serum potassium level decreased after HF treatment with exogenous atrial natriuretic peptide, with a significant correlation to urine volume. The risk of hypokalemia was low, unless treated with additional furosemide., (Copyright © 2021. Published by Elsevier Ltd.)

Background and Aims: Both low appendicular skeletal muscle index (ASMI) and specific abdominal fat composition [i.e., increased visceral to subcutaneous (V/S) fat ratio] have been associated with cardiovascular events. However, the combined impact of these 2 components on long-term outcomes remains unclear, especially in patients with ST-segment elevation myocardial infarction (STEMI)., Methods: In 303 patients with STEMI, ASMI and V/S fat ratio were assessed using dual-energy X-ray absorptiometry and abdominal computed tomography. Based on the criteria of the Asian Working Group for Sarcopenia and median of V/S fat ratio, sarcopenic obesity (SO) pattern was defined as low ASMI with high V/S fat ratio. The primary endpoint was composite outcomes of all-cause death, myocardial infarction, ischemic stroke, hospitalization for heart failure and unplanned revascularization., Results: During a median follow-up of 3.9 years, primary endpoint occurred in 67 patients. Patients with an SO pattern showed significantly lower event-free survival rate compared with those without (p=0.006 by log-rank). Notably, when stratified by median age (67 years), this trend was particularly prominent in the younger-age group (p <0.001), but not significant in the older-age group (p=0.38). In the younger-age group, the multivariate analysis revealed that patients with SO pattern had a 2.97 (1.10-7.53) fold higher risk for primary endpoints compared with those without., Conclusions: Low ASMI with high V/S fat ratio, or so-called sarcopenic obesity, was associated with poor prognosis after STEMI, particularly in younger-age patients. The combined assessment of skeletal muscle with abdominal fat distribution may help stratify the risk among patients with STEMI, rather than each component alone., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Background: This study aimed to simultaneously investigate diagnostic performance and limitation of quantitative flow reserve (QFR) for assessing functionally significant coronary stenosis, focusing on factors affecting diagnostic accuracy of QFR., Methods: This study evaluated 1) QFR diagnostic accuracy compared with fractional flow reserve (FFR) in patients with stable coronary artery disease (Cohort-A, n = 95) and 2) QFR reproducibility for non-culprit lesions (NCLs) assessment between acute and staged (14±5 days later) procedures in patients with ST-segment elevation myocardial infarction (STEMI) (Cohort-B, n = 65). All coronary angiography image acquisition was performed before the introduction of QFR system into our institution., Results: Cohort-A showed good correlation (r = 0.80, p<0.0001) between QFR and FFR; diagnostic accuracy of QFR for FFR ≤0.80 was 85.2% (sensitivity 80.4%, specificity 91.0%, positive predictive value 91.1%, negative predictive value 80.0%). There were 14 lesions showing discordance between QFR and FFR, which was primarily attributable to inadequate lesion visualization due to vessel overlap/tortuosity and/or insufficient intra-coronary contrast-media injection. In Cohort-B, there was also excellent correlation between acute and staged QFR; classification agreement of acute and staged QFR was 92.3%. Five lesions showed discordance between acute and staged QFR, 4 were due to limited image acquisition and/or high coronary flow velocity at acute phase of STEMI and 1 was borderline ischemia., Conclusions: QFR-derived physiological assessment of intermediate coronary stenosis is feasible, even in the acute setting of STEMI. Adjusting some technical factors may further improve the diagnostic performance of QFR., Competing Interests: Declaration of Competing Interest The authors have no conflicts of interest to disclose., (Copyright © 2020. Published by Elsevier Ltd.)

Background: The LHFRS is a simple score derived from three factors (history of hypertension, history of coronary artery disease/myocardial infarction, and red blood cell distribution width) deployed for the risk stratification of AHF in Greek population. This study aimed to validate the Larissa Heart Failure Risk Score (LHFRS) in patients with acute heart failure (AHF) in a Japanese population., Methods: We performed post-hoc analysis of 1670 consecutive patients enrolled in the REALITY-AHF. In all, 964 patients were finally enrolled. Exclusion criteria included patients with anemia, malignancies and sepsis. The primary outcome was defined as a composite of all-cause mortality and/or heart failure readmission, and the secondary outcome was defined as all-cause mortality., Results: The median admission LHFRS value was 1 (interquartile range [IQR]: 0-2). During a median follow-up of 365 (IQR: 161-365) days, the primary and secondary outcomes were observed in 321 and 157 patients, respectively. LHFRS was an independent predictor of both the primary (adjusted hazard ratio per 1-point increase, 95% confidence interval: 1.17 [1.04-1.32], p = 0.011), and the secondary outcomes (1.31 [1.12-1.55], p = 0.001). Patients with higher LHFRS scores (≥2) exhibited significantly worse outcomes than those with lower scores (<2) both for the primary outcome (1.40 [1.07-1.83], p = 0.014) and the secondary outcome (1.60 [1.09-2.34], p = 0.015). Additionally, LHFRS revealed an excellent goodness of fit (observed versus predicted outcomes) for predicting both the primary and the secondary outcomes (p > 0.99 and p = 0.99, respectively)., Conclusion: The simple LHFRS was proved as a reliable predictor of outcomes in patients with AHF., Competing Interests: Declaration of competing interest None., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Background: Worsening renal function, indicated by increased serum creatinine (SCr), is a common complication of percutaneous coronary procedures. Risk factors for increased SCr overlap with coronary risk factors involved in endothelial dysfunction. We hypothesized that endothelial dysfunction, measured using the reactive hyperemia peripheral arterial tonometry index (RHI), can predict periprocedure-increased SCr., Methods: RHI was assessed before elective coronary procedures in 316 consecutive stable patients with a preserved estimated glomerular filtration rate (eGFR, >60mL/min/1.73m 2 ). SCr was measured before and 2 days after procedures., Results: There was no significant correlation between natural logarithmic transformations of RHI (Ln-RHI) and basal Ln-eGFR. Periprocedure increase in SCr was observed in 148 (47%) patients. The increased SCr group had significantly lower Ln-RHI [0.48 (0.36, 0.62) vs. 0.59 (0.49, 0.76), p<0.001]. Multivariate linear regression analysis identified body mass index (BMI) (β=0.148, p=0.005) and Ln-RHI (β=-0.365, p<0.001) as significant determinants of percent changes in SCr. Multivariate logistic regression analysis identified Ln-RHI (per 0.1) [odds ratio (OR) 0.672, 95% confidence interval (95% CI) 0.586-0.722; p<0.001], Ln-B-type natriuretic peptide (OR: 1.484, 95% CI: 1.130-1.974; p=0.004), current smoking (OR: 2.563, 95% CI: 1.379-4.763, p=0.003), BMI (OR: 1.113, 95% CI: 1.031-1.203; p=0.007), coronary intervention (OR: 1.736, 95% CI: 1.036-2.909; p=0.036), and Ln-hemoglobin A1c (OR: 6.728, 95% CI: 1.093-41.392, p=0.040) as independent determinants of increased SCr. Receiver-operating characteristics curve analysis showed that Ln-RHI correlated significantly with increased SCr (area under the curve, 0.684, 95% CI: 0.626-0.742, p<0.001). The optimum cut-off point of Ln-RHI for the periprocedure increased SCr was 0.545., Conclusions: Pre-procedure measurement of endothelial function by RHI is an effective strategy to assess the patient's risk conditions for worsening renal function after percutaneous coronary procedures., (Copyright © 2017 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.)

Background: Epicardial adipose tissue (EAT), defined as the adipose tissue between the visceral pericardium and the outer margin of the myocardium, is associated with coronary artery disease in the general population. However, the clinical implications of EAT in patients with ST-segment elevation myocardial infarction (STEMI) remain unclear., Methods: A total of 142 patients with a first STEMI, who received reperfusion therapy within 12h from symptom onset, were enrolled. All patients underwent cardiac magnetic resonance imaging to evaluate infarct core (Core), area at risk (AAR), and EAT volume. Myocardial salvage index (MSI) was defined as AAR minus Core divided by AAR. Patients in the lower tertile of EAT volume were classified as the low EAT group (group L) and the other two-thirds as the high EAT group (group H)., Results: The mean MSI was lower in group L than in group H (0.43±0.13 vs 0.49±0.13, p=0.01), and the mean extent of Core was higher in group L than in group H (25±10% vs 19±10%, p<0.01). Multivariate linear regression analysis including coronary risk factors and previously reported predictors of infarct size demonstrated that EAT volume was an independent predictor of MSI (β coefficient=0.002 per 1mL, p=0.002)., Conclusions: A lower EAT volume is associated with less myocardial salvage and larger infarct size in patients with a first STEMI., (Copyright © 2015 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.)

Background: Polyvascular disease (PolyVD) refers to the coexistence of coronary artery disease (CAD), peripheral arterial disease (PAD), and/or cerebrovascular disease (CVD), and carries a high risk of cardiovascular mortality. Endothelial dysfunction plays a crucial role in cardiovascular pathophysiology. This study investigated the association between PolyVD and the presence of microvascular endothelial dysfunction., Methods: Consecutive stable patients (n=533) with diabetes mellitus and/or multiple cardiovascular risk factors were enrolled. Peripheral microvascular endothelial function in the finger microvasculature was assessed using the reactive hyperemia peripheral arterial tonometry index (RHI), and ankle-brachial index was measured for diagnosis of lower-extremity PAD prior to coronary angiography. Diagnosis of CVD was based on clinical symptoms, carotid ultrasound, and magnetic resonance imaging. PolyVD was defined as two or more coexisting vascular diseases from CAD, lower-extremity PAD, and CVD., Results: Natural logarithmic transformations of RHI (Ln-RHI) were significantly attenuated in 93 patients with PolyVD (0.44±0.20) compared with those in 440 patients without PolyVD (0.56±0.19; p<0.001) or in 299 patients with a single vascular disease (0.54±0.19; p<0.001). There was an independent correlation between Ln-RHI (per 0.1) and the presence of PolyVD in all high-risk patients [odds ratio (OR): 0.724; 95% confidence interval (CI): 0.610-0.859; p<0.001] and one or more vascular diseases (OR: 0.724; 95% CI: 0.605-0.867, p<0.001). Receiver-operating characteristics curve analysis showed that Ln-RHI correlated significantly with PolyVD (area under the curve, 0.682, 95% CI: 0.625-0.740, p<0.001). The optimum cut-off point of Ln-RHI for the existence of PolyVD was 0.479., Conclusions: Microvascular endothelial dysfunction is significantly associated with the presence of PolyVD. Severe impairment of endothelial function in peripheral microvasculature may be an important pathophysiological component of PolyVD., (Copyright © 2015 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.)

Background: Heart failure (HF) is associated with adverse metabolic influences and provokes fat loss as well as bone and muscle loss at the terminal stages. Pericardial fat is an ectopic fat depot that can potentially affect the myocardium, but the role of pericardial fat in HF is unclear. We sought to characterize pericardial fat in HF, particularly in association with bone tissue using cardiac computed tomography (CT)., Methods: In 61 consecutive hospitalized HF patients with left ventricular ejection fraction ≤50%, pericardial fat volume (PFV), CT density in the thoracic vertebrae, and ectopic calcification in the aortic valve were assessed simultaneously using electrocardiogram-gated non-contrast-enhanced CT., Results: The mean PFV was 93.5±50.6cm(3), which might reflect the total body fat measured with dual energy X-ray absorptiometry (Pearson's r=0.48, p=0.01). The PFV index, defined as the PFV/body surface area, was significantly higher among older patients (>65 years; 63.5±30.6cm(3)/m(2) vs. 42.7±17.1cm(3)/m(2), p<0.01) and among patients with atrial fibrillation (AF; 70.9±36.4cm(3)/m(2) vs. 48.8±21.2cm(3)/m(2), p<0.01) and hypertension (60.7±29.3cm(3)/m(2) vs. 41.5±18.2cm(3)/m(2), p<0.01) compared to patients without these conditions. The PFV indices were comparable between the patients with and without ischemic etiology, diabetes, and renal dysfunction. Patients with increased PFV indices (above the median) exhibited lower CT density in the thoracic vertebrae (134±41 Hounsfield units vs. 161±57 Hounsfield units, p=0.04), and were more likely to have aortic valve calcification (48% vs. 18%, p=0.02) and N-telopeptide (bone resorption marker; 20.7±5.2nmolBCE/mmolCr vs. 25.5±5.9nmolBCE/mmolCr, p=0.03) levels than those without increased PFV indices., Conclusions: We simultaneously assessed the pericardial fat and bone tissue of HF patients with CT and successfully characterized AF, hypertension, and advanced age as factors that are associated with increased PFV. PFV was correlated with bone tissues and alterations in bone turnover., (Copyright © 2015 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.)

Tetrabromobisphenol A (TeBBPA) is widely used type of brominated flame retardant. In this study, we newly synthesized materials for the debrominated congeners, 2,2',6-tribromobisphenol A (TriBBPA), 2,2'-dibromobisphenol A (2,2'-DiBBPA), 2,6-dibromobisphenol A (2,6-DiBBPA), and 2-monobromobisphenol A (MoBBPA) and evaluated the actual extent of contamination with bisphenol A (BPA), TeBBPA and debrominated congeners in Japanese breast milk samples. TriBBPA was detected at higher levels than that of TeBBPA, while DiBBPA and MoBBPA were detected at lower levels than that of TeBBPA. This observation suggested that humans are exposed to debrominated congeners, which might cause adverse effects. Contamination of the congeners in breast milk was concern about risk infant health, having vulnerable defense system. As pilot study by in vitro experiment, we assessed the toxic potency of debrominated congeners by studying their effect on adipocyte differentiation in 3T3-L1 cells. We observed 2,6-DiBBPA, TriBBPA and TeBBPA elevated the lipid accumulation and adipocyte-specific protein 2 expression in a manner dependent on the number of substituted bromines. Moreover, PPARγ transcriptional activities increased in a dose-dependent manner in the presence of 2,6-DiBBPA and TriBBPA as well as TeBBPA. Our study clarified that TeBBPA and its debrominated congeners accumulated in breast milk and the debrominated congeners promoted adipocyte differentiation, showing that a comprehensive evaluation of the influences of these compounds including the debrominated congeners of TeBBPA on health in infants is necessary., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Objective: Mitochondrial dysfunction plays an important role in cellular senescence and impaired function of vascular endothelium, resulted in cardiovascular diseases. Telmisartan is a unique angiotensin II type I receptor blocker that has been shown to prevent cardiovascular events in high risk patients. AMP-activated protein kinase (AMPK) plays a critical role in mitochondrial biogenesis and endothelial function. This study assessed whether telmisartan enhances mitochondrial function and alters cellular functions via AMPK in human coronary artery endothelial cells (HCAECs)., Methods and Results: In cultured HCAECs, telmisartan significantly enhanced mitochondrial activity assessed by mitochondrial reductase activity and intracellular ATP production and increased the expression of mitochondria related genes. Telmisartan prevented cellular senescence and exhibited the anti-apoptotic and pro-angiogenic properties. The expression of genes related anti-oxidant and pro-angiogenic properties were increased by telmisartan. Telmisartan increased endothelial NO synthase and AMPK phosphorylation. Peroxisome proliferator-activated receptor gamma signaling was not involved in telmisartan-induced improvement of mitochondrial function. All of these effects were abolished by inhibition of AMPK., Conclusions: Telmisartan enhanced mitochondrial activity and exhibited anti-senescence effects and improving endothelial function through AMPK in HCAECs. Telmisartan could provide beneficial effects on vascular diseases via enhancement of mitochondrial activity and modulating endothelial function through AMPK activation., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Coplanar polychlorinated/brominated biphenyls (Co-PXBs) are environmental pollutants previously identified in market fish samples. In this study, we observed that mother's milk in Japan is contaminated with Co-PXBs. Based on assumption that the toxicity of the same congener of PXDDs/DFs and Co-PXBs is nearly equal to that of the corresponding PCDDs/DFs and Co-PCBs, respectively, the toxic equivalent (TEQ) concentration was 10% of the total TEQ concentration (∑PCDDs/DFs, ∑PXDDs/DFs, ∑Co-PCBs and ∑Co-PXBs) in the milk. This observation suggested that humans, and especially infants, are exposed to high levels of Co-PXBs, which might cause adverse effects. However, the toxicity of Co-PXBs has to date not been reported. We assessed the toxic potency of Co-PXBs by studying their effect on the activity of cytochrome P450. Only the mRNA level and activity of CYP1A increased in a dose-dependent manner upon exposure to Co-PXBs. Substitution of bromine for chlorine into Co-PCBs provided higher CYP1A activity in in vitro and in vivo experiments. The expression level of aryl hydrocarbon receptor (AhR) mRNA was not altered, but luciferase activity, an indicator of AhR transcriptional activity, increased following treatment with Co-PXBs. The results suggest that CYP1A induction by Co-PXBs depended on AhR transcriptional activity and not on AhR expression. Although the TEFs of Co-PXBs are not set, if Co-PXBs are included in these calculations because of their higher toxicity compared to Co-PCBs, exposure to Co-PXBs cannot be neglected when assessing human health risks., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

To investigate how a human subject selects her neighbors (opponents) to play the Prisoner׳s Dilemma within a social network, we conducted a human-subject experiment. The results are as follows: (1) A subject is more likely to dismiss the links to her neighbors most frequently when the subject chooses C and when the neighbor chooses D; (2) a subject who has more neighbors is less likely to dismiss links than a subject who has fewer neighbors; and (3) a subject is more likely to create links to (=select) opponents who have more neighbors than to opponents who have fewer neighbors., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Background: As patients with chronic kidney disease (CKD) are at high risk of developing coronary artery disease (CAD), it is important to stratify their cardiovascular risk. We investigated whether peripheral endothelial dysfunction is associated with the presence of CAD in patients with CKD and is a predictor of cardiovascular events., Methods: We enrolled 383 CKD patients with at least one coronary risk factor. Peripheral endothelial function was assessed by reactive hyperemia peripheral arterial tonometry index (RHI). The presence of CAD was determined by coronary angiography. Cardiovascular events were assessed during follow-up., Results: Ln-RHI was significantly lower in risk factor-matched CKD patients (n=323) than risk factor-matched non-CKD patients (n=323) (0.527 ± 0.192 vs. 0.580 ± 0.218, p=0.001). In CKD patients (n=383), Ln-RHI was significantly lower in CAD (0.499 ± 0.183, n=262) than non-CAD (0.582 ± 0.206, n=121) (p<0.001) patients. Multivariate logistic regression analysis identified Ln-RHI as an independent factor associated with the presence of CAD (p=0.001). During a mean follow-up period of 30 months, 90 cardiovascular events were recorded in CKD patients. Multivariate Cox hazard analysis identified low-Ln-RHI as an independent predictor of cardiovascular events (hazard ratio=2.70, 95% confidence interval=1.62-4.51, p<0.001). The predictive value of combined Ln-RHI and Framingham risk score (FRS) was evaluated by net reclassification index (NRI) and C-statistics, which showed significant improvement (NRI=22%, p<0.001) (C-statistics: FRS=0.49, FRS+Ln-RHI=0.62, p=0.005)., Conclusions: Endothelial function was significantly impaired in CKD patients and correlated with the presence of CAD. Severe endothelial dysfunction was an independent and incremental predictor of cardiovascular events in CKD., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

Background: Left ventricular diastolic dysfunction (LVDD) plays an important role in heart failure with normal left ventricular ejection fraction (LVEF). Obesity is one of the major comorbid conditions of LVDD. Pericardial fat (PF) is an ectopic fat depot with possible paracrine or mechanical effects on the coronary circulation and myocardial function., Methods: We measured PF volume on 64 slice computed tomography and analyzed echocardiographic parameters to confirm LVDD in 229 consecutive patients suspected of coronary artery disease with LVEF of more than 50% and no symptomatic heart failure (59% men, 67±12 years). LVDD was defined as the ratio of transmitral Doppler early filling velocity to tissue Doppler early diastolic mitral annular velocity (E/e') >10., Results: PF volume correlated significantly with E/e' (r=0.21, p<0.01), left ventricular mass index (r=0.23, p<0.001), and left atrial diameter (r=0.32, p<0.001). The mean PF volume was significantly greater in patients with LVDD (184±61cm(3), n=141) than in those without LVDD (154±58, n=88, p<0.001). Multivariate logistic regression analysis indicated that PF volume correlated significantly with the presence of LVDD (odds ratio: 2.00 per 100cm(3) increase in PF volume, p=0.02) independent of age, gender, abdominal obesity, hypertension, and diabetes., Conclusions: PF volumes are significantly associated with LVDD, independent of other factors such as hypertension or diabetes. PF may be implicated in the pathogenesis of LVDD in patients with normal LVEF., (Copyright © 2012 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.)

Evolution of cooperation among genetically unrelated individuals has been of considerable concern in various fields such as biology, economics, and psychology. The evolution of cooperation is often explained by reciprocity. Under reciprocity, cooperation can prevail in a society because a donor of cooperation receives reciprocation from the recipient of the cooperation, called direct reciprocity, or from someone else in the community, called indirect reciprocity. Nowak and Sigmund [1993. Chaos and the evolution of cooperation. Proc. Natl. Acad. Sci. USA 90, 5091-5094] have demonstrated that directly reciprocal cooperation in two-person prisoner's dilemma games with mutation of strategies can be maintained dynamically as periodic or chaotic oscillation. Furthermore, Eriksson and Lindgren [2005. Cooperation driven by mutations in multi-person Prisoner's Dilemma. J. Theor. Biol. 232, 399-409] have reported that directly reciprocal cooperation in n-person prisoner's dilemma games (n>2) can be maintained as periodic oscillation. Is dynamic cooperation observed only in direct reciprocity? Results of this study show that indirectly reciprocal cooperation in n-person prisoner's dilemma games can be maintained dynamically as periodic or chaotic oscillation. This is, to our knowledge, the first demonstration of chaos in indirect reciprocity. Furthermore, the results show that oscillatory dynamics are observed in common in the evolution of reciprocal cooperation whether for direct or indirect.

Reputation building plays an important role in the evolution of reciprocal altruism when the same individuals do not interact repeatedly because, by referring to reputation, a reciprocator can know which partners are cooperative and can reciprocate with a cooperator. This reciprocity based on reputation is called indirect reciprocity. Previous studies of indirect reciprocity have focused only on two-person games in which only two individuals participate in a single interaction, and have claimed that indirectly reciprocal cooperation cannot be established under image scoring reputation criterion where the reputation of an individual who has cooperated (defected) becomes good (bad). In this study, we specifically examine three-person games, and reveal that indirectly reciprocal cooperation can be formed and maintained stably, even under image scoring, by a nucleus shield mechanism. In the nucleus shield, reciprocators are a shield that keeps out unconditional defectors, whereas unconditional cooperators are the backbone of cooperation that retains a good reputation among the population.

Recently many studies have investigated the evolution of indirect reciprocity through which cooperative action is returned by a third individual, e.g. individual A helped B and then receives help from C. Most studies on indirect reciprocity have presumed that only two individuals take part in a single interaction (group), e.g. A helps B and C helps A. In this paper, we investigate the evolution of indirect reciprocity when more than two individuals take part in a single group, and compare the result with direct reciprocity through which cooperative action is directly returned by the recipient. Our analyses show the following. In the population with discriminating cooperators and unconditional defectors, whether implementation error is included or not, (i) both strategies are evolutionarily stable and the evolution of indirect reciprocity becomes more difficult as group size increases, and (ii) the condition for the evolution of indirect reciprocity under standing reputation criterion where the third individuals distinguish between justified and unjustified defections is more relaxed than that under image scoring reputation criterion in which the third individuals do not distinguish with. Furthermore, in the population that also includes unconditional cooperators, (iii) in the presence of errors in implementation, the discriminating strategy is evolutionarily stable not only under standing but also under image scoring if group size is larger than two. Finally, (iv) in the absence of errors in implementation, the condition for the evolution of direct reciprocity is equivalent to that for the evolution of indirect reciprocity under standing, and, in the presence of errors, the condition for the evolution of direct reciprocity is very close to that for the evolution of indirect reciprocity under image scoring.