Norihiko Kotooka

The glucagon-like peptide 1 analog liraglutide reduces TNF-α-induced oxidative stress and inflammation in endothelial cells

OBJECTIVE Glucagon-like peptide 1 (GLP-1), one of the incretin hormones, has been reported to increase positive inotropic activity in cardiac myocytes and protect against myocardial injury. However, the effects upon endothelial cells and the mechanisms involved are not fully understood. We assessed the hypothesis that GLP-1 has protective effects against inflammation and oxidative stress on human endothelial cells. METHODS AND RESULTS The effects of the GLP-1 analog liraglutide upon TNF-α-induced injury of the human umbilical vein endothelial cells (HUVECs) were evaluated. First, ROS induced by TNF-α was measured by staining with CM-H(2)DCFDA. Intracellular ROS production of HUVECs was significantly decreased in a dose-dependent manner until 30 nM while liraglutide inhibited the induction of gp91(phox) and p22(phox), subunit of NADPH oxidase, by TNF-α. In addition, protein levels of SOD-2, catalase and GPx were significantly increased by liraglutide. Second, rapid translocation of PKC-α into the membrane following TNF-α was evident. Liraglutide significantly inhibited this very rapid TNF-α-induced translocation of PKC-α into membrane at 2.5 min. Third, liraglutide significantly inhibited NF-κB activation and upregulated I-κB family while phosphorylation of IKK-α/β, which is upstream of NF-κB signaling, was also downregulated after 15 min of TNF-α treatment. Finally, liraglutide inhibited apoptosis of HUVEC and expression of Pentraxin-3 induced by TNF-α. CONCLUSION Liraglutide exerts marked anti-oxidative and anti-inflammatory effects on endothelial cells with inhibition of PKC-α, NADPH oxidase, NF-κB signaling and upregulation of protective anti-oxidative enzymes.

Home telemonitoring study for Japanese patients with heart failure (HOMES-HF): protocol for a multicentre randomised controlled trial.

Introduction Despite the encouraging results from several randomised controlled trials (RCTs) and meta-analyses, the ability of home telemonitoring for heart failure (HF) to improve patient outcomes remains controversial as a consequence of the two recent large-scale RCTs. However, it has been suggested that there is a subgroup of patients with HF who may benefit from telemonitoring. The aim of the present study was to investigate whether an HF management programme using telemonitoring could improve outcomes in patients with HF under the Japanese healthcare system. Methods and analysis The Home Telemonitoring Study for Japanese Patients with Heart Failure (HOMES-HF) study is a prospective, multicentre RCT to investigate the effectiveness of home telemonitoring on the primary composite endpoint of all-cause death and rehospitalisation due to worsening HF in recently admitted HF patients (aged 20 and older, New York Heart Association classes II–III). The telemonitoring system is an automated physiological monitoring system including body weight, blood pressure and pulse rate by full-time nurses 7 days a week. Additionally, the system was designed to make it a high priority to support patients self-care instead of an early detection of HF decompensation. A total sample size of 420 patients is planned according to the Schoenfeld and Richter method. Eligible patients are randomly assigned via a website to either the telemonitoring group or the usual care group by using a minimisation method with biased-coin assignment balancing on age, left ventricular ejection fraction and a history of ischaemic heart disease. Participants will be enrolled until August 2013 and followed until August 2014. Time to events will be estimated using the Kaplan-Meier method, and HRs and 95% CIs will be calculated using the Cox proportional hazards models with stratification factors. Trial Registration: The study is registered at UMIN Clinical Trials Registry (UMIN000006839).

Pentraxin-3 regulates the inflammatory activity of macrophages

Background and aims Pentraxin-3 (PTX3) reportedly has protective roles in atherosclerosis and myocardial infarction, and is a useful biomarker of vascular inflammation. However, the detailed functions of PTX3 in inflammation are yet to be elucidated. This study aimed to investigate the function of PTX3 in macrophages. Methods PMA-treated THP-1 cell line (THP-1 macrophage) and monocyte-derived human primary macrophages were treated with recombinant PTX3. Cytokine and chemokine levels in the THP-1 culture medium were measured as well as monocyte chemoattractant protein (MCP-1) concentrations in the Raw 264.7 cell culture medium. PTX3-silenced apoptotic macrophages (THP-1 cell line) were generated to investigate the roles of PTX3 in phagocytosis. Results In the presence of PTX3, macrophage interleukin-1β (IL-1β), tumor necrosis factor-alpha (TNF-α) and MCP-1 levels were reduced significantly (−39%, P=0.007; −21%, P=0.008; and −67%, P=0.0003, respectively), whilst activated transforming growth factor-β (TGF−β) was detected in the THP-1 macrophages (P=0.0004). Additionally, PTX3 induced Akt phosphorylation and reduced nuclear factor-kappa B (NF-κB) activation by 35% (P=0.002), which was induced by TNF-α in THP-1 macrophages. Furthermore, silencing of PTX3 in apoptotic cells resulted in increased macrophage binding, elevated expression rate of HLA-DR (+30%, P=0.015) and CD86 (+204%, P=0.004) positive cells, and induction of IL-1β (+36%, P=0.024) production. Conversely, adding recombinant PTX3 to macrophages reduced CD86 and HLA-DR expression in a dose-dependent manner. Conclusions We identified PTX3 as a novel regulator of macrophage activity, and this function suggests that PTX3 acts to resolve inflammation.

Ebstein anomaly by cardiac magnetic resonance imaging.

![Figure][1] [![Graphic][3] ][3][![Graphic][4] ][4] We described a case of Ebstein anomaly in a 69-year-old woman with progressive dyspnea on exertion. Her electrocardiogram revealed type B Wolf-Parkinson-White syndrome. The patient underwent cardiac magnetic resonance imaging (

Design of a nationwide survey on palliative care for end-stage heart failure in Japan

BACKGROUND The term palliative care has historically been associated with support for individuals with advanced incurable cancer, so cardiologists and cardiac nurses may be unfamiliar with its principles and practice. However, palliative care is now a part of end-stage heart failure management. We conducted the first nationwide survey to investigate the status of palliative care for heart failure in Japan. METHODS AND RESULTS A self-reported questionnaire was mailed to all Japanese Circulation Society - authorized cardiology training hospitals (n=1004) in August 2016. The response deadline was December 2016. The survey focused on the following topics: basic information about the facility and multidisciplinary team, patient symptoms for palliative care, positive outcomes after providing palliative care, drug therapy as palliative care for patients with heart failure, advance care planning with patients and their families, and impediments to providing palliative care to patients with heart failure. The results of the survey will be reported in detail elsewhere. CONCLUSIONS Current guidelines on palliative care do not specifically address what team members should be involved, what drugs should be used, or when palliative care should be started. This survey collected information to improve the quality of palliative care and provide more specialized palliative care within the limits of resources.

N-terminal pro-brain natriuretic peptide and associated factors in the general working population: a baseline survey of the Uranosaki cohort study

Few data on clinical characteristics associated with N-terminal pro-brain natriuretic peptide (NT-proBNP) or the clinical value of measuring NT-proBNP in the working population are available. The aim of the present study was to investigate the levels of NT-proBNP and their association with clinical variables in the Japanese general working population by using baseline data from the Uranosaki cohort study. In the study, the plasma concentration of NT-proBNP and some biomarkers were measured in addition to the standard health checkups at the workplace. Questionnaires regarding health-related quality of life (HR-QOL) were also completed. A total of 2140 participants were enrolled in the study. Plasma levels of NT-proBNP were positively associated with age, female sex, systolic blood pressure, pulse pressure, prevalent hypertension, smoking habit, high-density lipoprotein cholesterol (HDL-C), and prevalent proteinuria, and negatively associated with body mass index, lipid profiles except HDL-C, uric acid, renal function, and hemoglobin. Both the plasma concentration of high-molecular weight adiponectin and that of high-sensitivity troponin T were positively and independently associated with NT-proBNP. In addition, the HR-QOL score regarding sleep disorder was independently associated with NT-proBNP. Thus, we have obtained evidence that the plasma NT-proBNP is affected by several clinical variables in the general working population.

Myeloid-related protein-8/14 in acute coronary syndrome

BACKGROUND The alarmin family member myeloid-related protein (MRP)-14 (S100A9), which has been identified by platelet transcriptional profiling as an acute myocardial infarction gene, regulates vascular inflammation and thrombosis. Elevated plasma levels of MRP-8/14 (S100A8/A9) heterodimer predict first and recurrent cardiovascular events. The aim of this study was to elucidate pathophysiological roles of MRP-8/14 in acute coronary syndrome (ACS). METHODS AND RESULTS In 38 consecutive ACS patients, the MRP-8/14 level in coronary artery blood obtained at thrombus aspiration was higher in 23 patients, in whom aspirated thrombus was confirmed, compared to the 15 patients, in whom it was absent [4.86 (1.95, 8.29) vs 2.94 (1.31, 4.44), P=0.017]. The MRP-8/14 level was correlated with myeloperoxidase (MPO) level (R2=0.52), but not with soluble P-selectin level (R2=0.0002) in the coronary artery blood. Immunohistochemistry of the aspirated thrombus exhibited that expression of MRP8/14 was co-localized with leukocytes positive for activated Mac-1. Finally, in cultured human umbilical vein endothelial cells, MRP-8/14 increased tissue factor expression. CONCLUSIONS Our findings indicate that MRP-8/14 concentration increases in coronary artery blood in association with thrombus formation in ACS, co-localizes with leukocytes, and is associated with leukocyte activation. MRP-8/14 is positioned as a unique biomarker at the interface of inflammation and thrombosis in ACS.

An Appropriate Indication for the Initiation of Beta-Blocker Therapy in Dilated Cardiomyopathy

Backgrounds: Although long-term treatment with beta-blockers has been shown to improve morbidity and mortality in dilated cardiomyopathy (DCM), patient re- sponses are heterogeneous. Methods: To establish the appropriate indication for the initiation of beta-blocker therapy, we retrospectively analyzed 38 DCM patients treated with beta-blockers (metoprolol or carvedilol) and examined differences in baseline profiles between patients who could continue the therapy (responders) and those who could not (non-responders). Results: In 13 non-responders, the duration from onset of symptoms to beta-blocker initiation was longer (p < 0.05), systolic blood pressure was lower (p < 0.001), serum sodium concentration was lower (p < 0.05), left ventricular posterior wall thickness was thinner (p < 0.05), left ventricular end-diastolic pressure was higher (p < 0.05) and left ventricular wall stress was lower (p < 0.05) than in 25 responders. In 19 patients receiving carvedilol, 5 non-responders showed higher levels of human atrial natriuretic peptide (p < 0.05) and brain natriuretic peptide (p < 0.01) than 13 responders. Discriminant analysis with a linear discriminant function showed the following equation predicted response to beta-blocker therapy: h = 0.004 × systolic blood pressure – 0.002 × brain natriuretic peptide + 0.667 (R2 = 0.67, p < 0.001). The probability of predicting the response was 94.1% with h ≧0.5. Conclusion: We conclude that h≧0.5 is the appropriate indication for the initiation of beta-blocker therapy in DCM.

Possible associations between palliative care conferences and positive outcomes when performing palliative care for patients with end-stage heart failure: a nationwide cross-sectional questionnaire survey

Palliative care for end-stage heart failure should be provided by a multidisciplinary team. However, the influence of each occupational category on patients receiving palliative care for end-stage heart failure remains unclear. Thus, this study investigated the relationships between palliative care conferences and positive outcomes of palliative care for end-stage heart failure patients. We sent questionnaires to all cardiology training hospitals authorized by the Japanese Circulation Society (n = 1004); of these, responses from the directors at 554 institutions were analyzed. We divided the responding institutions into two groups according to their implementation of palliative care conferences for patients with end-stage heart failure. The institutions that had held such conferences (n = 223) had a larger number of hospital beds, beds in the cardiovascular department, and patients admitted to the cardiovascular department, compared with institutions that had not held these conferences (n = 321). The usage rates of opioids, non-steroidal anti-inflammatory drugs, and sedatives were significantly higher in institutions that held these conferences. Multivariate analysis revealed that nutritionists and medical social workers had greater involvement in the improvement of mental symptoms and ensuring that patients could stay where they wished, respectively. The presence of palliative care physicians, physical therapists, or pharmacists was associated with multiple positive outcomes. This study indicated that there are possible associations between palliative care conferences and positive outcomes when performing palliative care for patients with end-stage heart failure.

Validity and Reliability of Three-chamber-View Three-directional Encoded Phase-contrast Magnetic Resonance Velocity-Vector Mapping for Transmitral Velocity Measurements: Comparison with Doppler Echocardiography and Intra- and Inter-observer Variability.

Purpose: Three-chamber view (3ch.) three-directional encoded phase-contrast magnetic resonance velocity vector mapping (PCMRVM) has been used for visualization and assessment of intra-cardiac flow. Although transmitral inflow velocity can be determined using this method by tracing mitral tips during the cardiac phase, its feasibility for clinical applications has not been established. Our aim was to investigate the validity and reproducibility of 3ch. PCMRVM for determining transmitral inflow velocity. Methods: We conducted 3ch. PCMRVM for 32 patients and eight healthy volunteers and analyzed the transmitral inflow pattern and early (E) and late (A) diastolic velocity. Nine patients also underwent Doppler echocardiography to evaluate correlations between the methods for E and A velocities and the E/A ratio. Intra- and inter-observer variability were calculated using intraclass correlation coefficients (ICC [1, 1] and ICC [2, 1]) for peak E and A velocities, Spearman’s rank correlation coefficient for the E/A ratio, and Cohen’s kappa coefficient for the inflow pattern. Results: Bland-Altman plots indicated that 3ch. PCMRVM showed systemically lower velocities than Doppler echocardiography for E (3 [25.8] 48.6) and A (−6.28 [21] 48.3); however, a strong correlation was observed (r = 0.81, p < 0.0001). The E/A ratio was not statistically different between the two modalities (p = 0.21). The intra- and inter-observer variabilities for peak E and A velocities and the E/A ratio demonstrated nearly perfect agreement or strong correlations, except for the peak E velocity (ICC [2, 1] = 0.751). Conclusion: Based on these results, 3ch. PCMRVM can be used for both visualization and assessment of intra-cardiac flow and evaluation of the transmitral inflow velocity.