Blood N-terminal Pro-brain Natriuretic Peptide and Interleukin-17 for Distinguishing Incomplete Kawasaki Disease from Infectious Diseases.

PubMed

Wu, Ling; Chen, Yuanling; Zhong, Shiling; Li, Yunyan; Dai, Xiahua; Di, Yazhen

2015-06-01

To explore the diagnostic value of blood N-terminal pro-brain natriuretic peptide (NT-proBNP) and interleukin-17(IL-17) for incomplete Kawasaki disease. Patients with Kawasaki disease, Incomplete Kawasaki disease and unclear infectious fever were included in this retrospective study. Their clinical features, and laboratory test results of blood NT-proBNP and IL-17 were collected and compared. 766 patients with complete clinical information were recruited, consisting of 291 cases of Kawasaki disease, 74 cases of incomplete Kawasaki disease, and 401 cases of unclear infectious diseases. When the consistency with indicator 2 and 3 in Kawasaki disease diagnosis criteria was assessed with blood IL-17 ?11.55 pg/mL and blood NT-proBNP ? 225.5 pg/dL as the criteria, the sensitivity and specificity for distinguishing incomplete Kawasaki disease and infectious diseases reached 86.5% and 94.8%, respectively. When we chose the consistency with indicator 1 and 2 in Kawasaki disease diagnosis criteria, the appearance of decrustation and/or the BCG erythema, blood IL-17 ?11.55 pg/mL and blood NT-Pro BNP ?225.5 pg/dL as the criteria, the sensitivity and specificity for distinguishing incomplete Kawasaki disease and infectious diseases was 43.2% and 100%, respectively. Blood NT-proBNP and IL-17 are useful laboratory indicators for distinguishing incomplete Kawasaki disease and infectious diseases at the early stage.

Prognostic value of N-terminal pro-brain natriuretic peptide in hospitalised patients with community-acquired pneumonia.

PubMed

Jeong, Ki Young; Kim, Kyuseok; Kim, Tae Yun; Lee, Christopher C; Jo, Si On; Rhee, Joong Eui; Jo, You Hwan; Suh, Gil Joon; Singer, Adam J

2011-02-01

The prognostic role of N-terminal pro-brain natriuretic peptide (NT-proBNP) in patients with community-acquired pneumonia (CAP) has not been evaluated. The aim of the present study was to investigate whether NT-proBNP level could predict mortality in hospitalised CAP patients. We performed a structured medical record review of all hospitalised CAP patients from May 2003 to October 2006, and classified patients into the 30-day survival and non-survival group. Data included demographic and clinical characteristics, and laboratory findings including NT-proBNP levels. The APACHE II scores, PSI (pneumonia severity index) and CURB65 (confusion, urea, respiratory rate, blood pressure and aged 65 or more) scores were calculated. Comparisons between survivors and non-survivors were made with χ(2), non-parametric tests and logistic regression and ROC analysis were used to compare the ability of NT-proBNP (adjusted for age, heart failure and creatinine), APACHE II, PSI and CURB65 to predict mortality. Of 502 patients, 61 (12.2%) died within 30 days. NT-proBNP levels were measured in 167 patients and were significantly higher in non-survivors compared to survivors (median 841.7 (IQR 267.1-3137.3) pg/ml vs 3658.0 (1863.0-7025.0) pg/ml, p=0.019). NT-proBNP was an independent predictor of mortality (adjusted OR 1.53; 95% CI 1.16 to 2.02, p=0.002). The AUC for NT-proBNP was 0.712 (95% CI, 0.613 to 0.812), which was comparable to those of PSI (0.749, p=0.531) and CURB65 (0.698, p=0.693), but inferior to that of APACHE II (0.831, p=0.037). Adding NT-proBNP to APACHE II, PSI and CURB65 did not significantly increase the AUCs, respectively. NT-proBNP level is an independent predictor of mortality in hospitalised CAP patients. The performance of NT-proBNP level is comparable to those of PSI and CURB65 in predicting mortality.

Diagnostic value of N-terminal pro-brain natriuretic peptide for pleural effusion due to heart failure: a meta-analysis.

PubMed

Zhou, Q; Ye, Z J; Su, Y; Zhang, J C; Shi, H Z

2010-08-01

N-terminal pro-brain natriuretic peptide (NT-proBNP) is a biomarker useful in diagnosis of pleural effusion due to heart failure. Thus far, its overall diagnostic accuracy has not been systematically reviewed. The aim of the present meta-analysis was to establish the overall diagnostic accuracy of the measurement of pleural NT-proBNP for identifying pleural effusion due to heart failure. After a systematic review of English-language studies, sensitivity, specificity, and other measures of accuracy of NT-proBNP concentrations in pleural fluid in the diagnosis of pleural effusion resulting from heart failure were pooled using fixed-effects models. Summary receiver operating characteristic curves were used to summarise overall test performance. Eight publications met the inclusion criteria. The summary estimates for pleural NT-proBNP in the diagnosis of pleural effusion attributable to heart failure were: sensitivity 0.95 (95% CI 0.92 to 0.97), specificity 0.94 (0.92 to 0.96), positive likelihood ratio 14.12 (10.23 to 19.51), negative likelihood ratio 0.06 (0.04 to 0.09) and diagnostic OR 213.87 (122.50 to 373.40). NT-proBNP levels in pleural fluid showed a high diagnostic accuracy and may help accurately differentiate cardiac from non-cardiac conditions in patients presenting with pleural effusion.

N-Terminal pro-brain natriuretic peptide levels in dichorionic diamniotic twins with selective intrauterine growth restriction.

PubMed

Fujioka, Kazumichi; Mizobuchi, Masami; Sakai, Hitomi; Iwatani, Sota; Wada, Keiko; Yoshimoto, Seiji; Nakao, Hideto

2014-03-04

Monochorionic diamniotic (MD) twins with selective intrauterine growth restriction (sIUGR) have known associations with cardiac complications. However, the cardiac load of dichorionic diamniotic (DD) twins with sIUGR (DD-sIUGR) remains unclear. N-terminal pro-brain natriuretic peptide (NT-pro BNP) is a convenient marker of cardiac dysfunction in neonates, and is elevated in MD twins with sIUGR (MD-sIUGR). However, there are no reports assessing serum NT-pro BNP levels in DD-sIUGR. Here, we aimed to clarify serum NT-pro BNP levels at birth in DD-sIUGR, and to compare them with those of MD-sIUGR. Forty-one DD twin pairs admitted to our center between October 2007 and January 2013 were enrolled in this study and separated into two groups: nine twins with sIUGR (DD-sIUGR group) and 32 twins without sIUGR (DD without sIUGR group). Sixteen MD twins with sIUGR (MD-sIUGR group) served as positive controls. Serum NT-pro BNP levels at birth in DD-sIUGR [median 2,115 pg/ml (range, 443-6,590 pg/ml)] were significantly higher than in DD without sIUGR [1,080 pg/ml (range, 313-3,470 pg/ml); p=0.001], and significantly lower than in MD twins with sIUGR [4,520 pg/ml (range, 529-62,400 pg/ml); p=0.04]. Serum NT-pro BNP levels between larger and smaller DD co-twins were significantly correlated (r = 0.582; p<0.0001). In conclusion, serum NT-pro BNP levels at birth in DD twins with sIUGR were higher than those without, and lower than in MD twins with sIUGR.

Diagnostic value of pleural fluid N-terminal pro-brain natriuretic peptide levels in patients with cardiovascular diseases.

PubMed

Liao, Huai; Na, Moon Jun; Dikensoy, Oner; Lane, Kirk B; Randal, Barnette; Light, Richard W

2008-01-01

The diagnosis of the cause of pleural effusions caused by cardiovascular diseases such as congestive heart failure (CHF) and acute pulmonary embolism is sometimes difficult. The purpose of the present study was to evaluate the utility of pleural fluid levels of N-terminal pro-brain natriuretic peptide (NT-proBNP) in differentiating pleural effusions due to CHF, pulmonary embolism and post-coronary artery bypass graft (CABG) surgery. The levels of pleural fluid NT-proBNP were measured by ELISA in a total of 40 patients: 10 with CHF, 10 with pulmonary embolism, 10 post-CABG and 10 with carcinoma. The median level of NT-proBNP in the pleural fluid of patients with CHF was 5390 pg/mL (25th to 75th percentiles, 4566 to 8158 pg/mL), which was significantly higher than that in patients with post-CABG effusions (424 pg/mL, 352 to 873), with pulmonary embolism (311 pg/mL, 212 to 1159), or with carcinoma (302 pg/mL, 208 to 626) (P < 0.001, CHF group vs all other groups). In receiver-operating curve analysis, an NT-proBNP level of >or=2220 pg/mL demonstrated a sensitivity of 100% and a specificity of 96.7% for the identification of CHF. Measurement of the NT-proBNP level in pleural fluid is accurate in diagnosing the etiology of the effusion as CHF. Pleural fluid levels above 2220 pg/mL are essentially diagnostic that the pleural effusion is due to CHF.

Impact of tocilizumab on N-terminal pro-brain natriuretic peptide levels in patients with active rheumatoid arthritis without cardiac symptoms.

PubMed

Yokoe, I; Kobayashi, H; Kobayashi, Y; Giles, J T; Yoneyama, K; Kitamura, N; Takei, M

2018-05-28

To prospectively investigate the effect of tocilizumab (TCZ) on the levels of N-terminal pro-brain natriuretic peptide (NT-proBNP), as a predictor of congestive heart failure (CHF) in patients with active rheumatoid arthritis (RA). Seventy patients with RA (median age 59 years, 86% female) free of cardiovascular disease were treated with TCZ and followed for 24 weeks. The NT-proBNP levels were measured at baseline and week 24. Thirty healthy controls were included for comparison of normal NT-proBNP levels with those of RA patients. The NT-proBNP level was significantly higher in patients with RA than in controls (median 42.5 pg/mL vs 109.0 pg/mL, p < 0.001). NT-proBNP levels decreased by 63% over the 24 weeks of TCZ treatment. Multiple linear regression analysis indicated that the percentage change in the NT-proBNP level was significantly associated with that of the Simplified Disease Activity Index (β = 0.356, p = 0.014), even after adjusting for the levels of rheumatoid factor, duration of RA, age, and anti-cyclic citrullinated peptide antibody. TCZ decreased the NT-proBNP level in patients with RA without preceding cardiovascular disease and CHF. TCZ may have a cardioprotective effect in those with active RA.

Early trends in N-terminal pro-brain natriuretic peptide values after left ventricular assist device implantation for chronic heart failure.

PubMed

Hasin, Tal; Kushwaha, Sudhir S; Lesnick, Timothy G; Kremers, Walter; Boilson, Barry A; Schirger, John A; Clavell, Alfredo L; Rodeheffer, Richard J; Frantz, Robert P; Edwards, Brooks S; Pereira, Naveen L; Stulak, John M; Joyce, Lyle; Daly, Richard; Park, Soon J; Jaffe, Allan S

2014-10-15

Left ventricular assist devices (LVADs) acutely decrease left ventricular wall stress. Thus, early postoperative levels of N-terminal pro-brain natriuretic peptide (NT-proBNP) should decrease. This study investigated postoperative changes in NT-proBNP levels, the parameters related to changes, and the possible association with complications by performing a retrospective analysis of changes in daily NT-proBNP (pg/ml) levels from admission to discharge both before and after LVAD implantation in a tertiary referral center. For 72 patients implanted with HeartMate II LVADs, baseline NT-proBNP levels were elevated at 3,943 ng/ml (interquartile range 1,956 to 12,964). Preoperative stabilization led to marked decreases in NT-proBNP. Levels peaked 3 days after surgery and subsequently decreased. Patients with complicated postoperative courses had higher early postoperative elevations. By discharge, NT-proBNP decreased markedly but was still 2.83 (1.60 to 5.76) times the age-based upper limit of normal. The 26% reduction in NT-proBNP between admission and discharge was due mostly to the preoperative reductions and not those induced by the LVAD itself. The decrease was not associated with decreases in LV volume. In conclusion, preoperative treatment reduces NT-proBNP values. The magnitude of early postoperative changes is related to the clinical course. Levels at discharge remain markedly elevated and similar to values after preoperative stabilization despite presumptive acute LV unloading. Copyright © 2014 Elsevier Inc. All rights reserved.

N-terminal pro-brain-type natriuretic peptide (NT-pro-BNP) and mortality risk in early inflammatory polyarthritis: results from the Norfolk Arthritis Registry (NOAR)

PubMed Central

Mirjafari, Hoda; Welsh, Paul; Verstappen, Suzanne M M; Wilson, Paddy; Marshall, Tarnya; Edlin, Helena; Bunn, Diane; Chipping, Jacqueline; Lunt, Mark; Symmons, Deborah P M; Sattar, Naveed; Bruce, Ian N

2014-01-01

Background We measured N-terminal pro-brain natriuretic peptide (NT-pro-BNP), a marker of cardiac dysfunction, in an inception cohort with early inflammatory polyarthritis (IP) and assessed its association with disease phenotype, cardiovascular disease (CVD), all-cause and CVD related mortality. Methods Subjects with early IP were recruited to the Norfolk Arthritis Register from January 2000 to December 2008 and followed up to death or until March 2010 including any data from the national death register. The associations of baseline NT-pro-BNP with IP related factors and CVD were assessed by linear regression. Cox proportional hazards models examined the independent association of baseline NT-pro-BNP with all-cause and CVD mortality. Results We studied 960 early IP subjects; 163 (17%) had prior CVD. 373 (39%) patients had a baseline NT-pro-BNP levels ≥100 pg/ml. NT-pro-BNP was associated with age, female gender, HAQ score, CRP, current smoking, history of hypertension, prior CVD and the presence of carotid plaque. 92 (10%) IP subjects died including 31 (3%) from CVD. In an age and gender adjusted analysis, having a raised NT-pro-BNP level (≥100 pg/ml) was associated with both all-cause and CVD mortality (adjusted HR (95% CI) 2.36 (1.42 to 3.94) and 3.40 (1.28 to 9.03), respectively). These findings were robust to adjustment for conventional CVD risk factors and prevalent CVD. Conclusions In early IP patients, elevated NT-pro-BNP is related to HAQ and CRP and predicts all-cause and CVD mortality independently of conventional CVD risk factors. Further study is required to identify whether NT-pro-BNP may be clinically useful in targeting intensive interventions to IP patients at greatest risk of CVD. PMID:23511225

Time course and prognostic value of plasma levels of N-terminal pro-brain natriuretic peptide in patients after ischemic stroke.

PubMed

Yip, Hon-Kan; Sun, Cheuk-Kwan; Chang, Li-Teh; Chen, Mien-Cheng; Liou, Chia-Wei

2006-04-01

The association between plasma levels of N-terminal pro-brain natriuretic peptide (NT-proBNP) and prognostic outcomes in patients after ischemic stroke remains unknown. The present study tested the hypothesis that NT-proBNP level is noticeably increased after ischemic stroke and that elevated NT-proBNP is associated with unfavorable clinical outcomes (UFCO). Blood samples for NT-proBNP levels were collected serially and examined with sandwich immunoassay after acute ischemic stroke in 86 consecutive patients. The NT-proBNP levels were also measured in 30 healthy control volunteers and 30 at-risk control subjects. The NT-proBNP levels were significantly higher at 4 intervals after ischemic stroke than in healthy and at-risk control subjects (all p<0.001). The NT-proBNP decreased to a significantly lower level on day 21 and to a substantially lower level on day 90. Additionally, the NT-proBNP level at any of the 4 intervals was significantly higher in patients with than in patients without UFCO (defined as combined congestive heart failure > or = class 3, acute myocardial infarction, recurrent stroke or any cause of death) (all p<0.01). Multivariate analysis demonstrated that age and NIH Stroke Scale were the 2 strongest independent predictors of increased NT-proBNP levels (all p<0.01). Furthermore, increased NT-proBNP (> or = 150 pg/ml) was the strongest independent predictor of long-term (mean follow-up: 24 months) UFCO (26 patients) (all p<0.05). The NT-proBNP level was markedly elevated after acute ischemic stroke and declined substantially thereafter. An increased NT-proBNP level was strongly and independently correlated with UFCO in patients after ischemic stroke.

Utility of N-terminal pro-brain natriuretic peptide for assessing hemodynamic significance of patent ductus arteriosus in dogs undergoing ductal repair.

PubMed

Hariu, Crystal D; Saunders, Ashley B; Gordon, Sonya G; Norby, Bo; Miller, Matthew W

2013-09-01

Determine if plasma N-terminal pro-brain natriuretic peptide (NT-proBNP) correlates with markers of hemodynamically significant patent ductus arteriosus (PDA) in dogs. Ten dogs with PDA and 30 healthy dogs of similar ages. Prospective case series with control population. Dogs with PDA were initially evaluated with thoracic radiographs, transthoracic echocardiography, pulmonary capillary wedge pressure (PCWP) and NT-proBNP. Following ductal occlusion, NT-proBNP and echocardiography were repeated within 24 h and at day 90. PCWP was repeated at day 90. Correlation between NT-proBNP and hemodynamic measurements was assessed, and accuracy of NT-proBNP for identifying PDA severity was estimated. NT-proBNP was significantly higher (median; absolute range) in dogs with PDA (895; 490-7118 pmol/L) than controls (663; 50-1318 pmol/L) (p = 0.025). NT-proBNP decreased significantly 90 days post-ductal closure (597; 154-1858 pmol/L) (p = 0.013). Left atrial and ventricular size decreased significantly within 24 h and at day 90 as did PCWP (day 90 only). NT-proBNP correlated with vertebral heart size (VHS) and indexed left ventricular systolic diameter (iLVIDs); concentrations ≥ 1224 pmol/L distinguished dogs with elevated VHS and iLVIDs. NT-proBNP is elevated in dogs with PDA, decreases following PDA closure and correlates with select radiographic and echocardiographic markers of cardiac remodeling. Copyright © 2013 Elsevier B.V. All rights reserved.

Plasma N-terminal pro-brain natriuretic peptide concentrations before and after pericardiocentesis in dogs with cardiac tamponade secondary to spontaneous pericardial effusion.

PubMed

Baumwart, R D; Hanzlicek, A S; Lyon, S D; Lee, P M

2017-10-01

To determine if concentrations of plasma N-terminal pro-brain natriuretic peptide (NT-proBNP) are increased in dogs with cardiac tamponade and if there is a significant increase in plasma NT-proBNP after pericardiocentesis. Ten client-owned dogs with spontaneous cardiac tamponade. Prospective clinical study. Cardiac tamponade was suspected from physical examination and confirmed with echocardiography. Blood was collected and plasma NT-proBNP concentrations were measured before and 30-60 min following pericardiocentesis and resolution of cardiac tamponade. Within-subject changes in plasma NT-proBNP were compared by the Wilcoxon signed-rank test. The plasma NT-proBNP concentrations measured within the reference interval in seven of 10 dogs before pericardiocentesis and in six of 10 dogs following pericardiocentesis. Following pericardiocentesis, there was a statistically significant increase in median NT-proBNP concentration (733 pmol/L, range 250-3,297) compared with the values measured before (643 pmol/L, range 250-3,210, P = 0.004). The NT-proBNP concentration increased in 90% of the dogs following pericardiocentesis. An upper reference limit of 900 pmol/L for plasma NT-proBNP is insensitive for the diagnosis of pericardial effusion and cardiac tamponade in dogs. Plasma NT-proBNP concentration commonly increases following pericardiocentesis, perhaps related to improved ventricular filling and stretch. Published by Elsevier B.V.

Relation between N-terminal pro-brain natriuretic peptide levels and response to enhanced external counterpulsation in chronic angina pectoris.

PubMed

Sahlén, Anders; Wu, Eline; Rück, Andreas; Hagerman, Inger; Förstedt, Gunilla; Sylvén, Christer; Berglund, Margareta; Jernberg, Tomas

2014-01-01

Although enhanced external counterpulsation (EECP) provides symptom reduction in many patients with severe angina pectoris, one-quarter of patients fail to respond. Earlier reports have not clearly established whether and how EECP responders may be identified pre-hoc. We hypothesized that clinical and biochemical data may be used to predict EECP response. We explored a database of n=53 patients who had undergone clinically indicated EECP during 35 1-h sessions in our unit (65±7 years; 49 male), and sought to clarify which factors are predictive of response. Efficiency of counterpulsation was measured as the diastolic augmentation (DA) ratio, and was recorded both at beginning and end of the EECP treatment course. An increase in 6-min walk (6MW) distance of 5% was indicative of clinical response. Response occurred in 28 patients (53%; nonresponse in n=25, 47%). Responders had shorter baseline 6MW distance (377±81 vs. 445±62 m; P<0.01), lower left ventricular ejection fraction (48±9 vs. 54±8%; P<0.05), frequently had an increase in DA ratio during the EECP treatment course (23/28 vs. 5/28 with unchanged or decreased DA ratio; P<0.05), and higher levels of N-terminal pro-brain natriuretic peptide [NT-proBNP; 256 (123-547) vs. 62 (26-444) ng/l, P<0.01]. In multivariate logistic regression, response was independently predicted by baseline 6MW distance and baseline NT-proBNP levels (P<0.05 for both; model sensitivity: 82%, specificity: 72%, accuracy: 79%). There is larger clinical benefit of EECP in patients with greater functional impairment and higher levels of NT-proBNP.

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

PubMed

Tanaka, Atsushi; Yoshida, Hisako; Kawaguchi, Atsushi; Oyama, Jun-Ichi; Kotooka, Norihiko; Toyoda, Shigeru; Inoue, Teruo; Natsuaki, Masafumi; Node, Koichi

2017-07-19

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.

Soluble ST2 and N-terminal pro-brain natriuretic peptide combination. Useful biomarker for predicting outcome of childhoodpulmonary arterial hypertension.

PubMed

Chida, Ayako; Sato, Hiroki; Shintani, Masaki; Nakayama, Tomotaka; Kawamura, Yoichi; Furutani, Yoshiyuki; Inai, Kei; Saji, Tsutomu; Matsuoka, Rumiko; Nonoyama, Shigeaki; Nakanishi, Toshio

2014-01-01

Some potential biomarkers have been reported recently in patients with pulmonary arterial hypertension (PAH), but the most clinically useful among these potential biomarkers, especially in childhood PAH, has not been identified. Therefore, this study investigated which biomarker is useful in assessing severity of and patient prognosis in childhood idiopathic PAH (IPAH)/heritable PAH (HPAH). Fifty-nine patients who were younger than 16 years at onset of IPAH/HPAH were selected. The following 10 biomarker candidates were quantified: high-sensitivity troponin T, human heart fatty acid-binding protein, N-terminal pro-brain natriuretic peptide (NT-proBNP), pentraxin-3, soluble ST2 (sST2), angiopoietin-2 (Ang-2), matrix metalloproteinase 2, tenascin C, endostatin (ES), and thymidine kinase. Functional characteristics and clinical outcomes were analyzed retrospectively. NT-proBNP, sST2, Ang-2, and ES correlated well with New York Heart Association class. On area under the receiver operating characteristic curve analysis, sST2 had a significantly good relationship with prognosis. On Kaplan-Meier curve and univariate Cox regression analyses, elevated sST2 and NT-proBNP level predicted poor outcome of the present patients with childhood IPAH/HPAH. Furthermore, patients with elevated sST2 had significantly worse prognosis among those with high NT-proBNP. The sST2 and NT-proBNP combination is a useful biomarker to predict clinical condition and outcome in patients with childhood IPAH/HPAH.  

Association of N-terminal pro-brain natriuretic peptide with the severity of coronary artery disease in patients with normal left ventricular ejection fraction.

PubMed

Wu, Naqiong; Ma, Fenglian; Guo, Yuanlin; Li, Xiaoling; Liu, Jun; Qing, Ping; Xu, Ruixia; Zhu, Chenggang; Jia, Yanjun; Liu, Geng; Dong, Qian; Jiang, Lixin; Li, Jianjun

2014-01-01

Backround N-terminal pro-brain natriuretic peptide (NT-proBNP) is a reliable predictor in acute coronary artery disease (CAD). Little is known about patients with stable CAD, especially Chinese patients with CAD. The aim of the present study was to investigate the association of NT-proBNP levels with the severity of CAD in patients with normal left ventricular ejection fraction. A total of 658 consecutive patients were divided into two groups based on angiograms: CAD group (n = 484) and angiographic normal control group (n = 174). The severity of CAD was evaluated by modified Gensini score, and its relationship with NT-proBNP was analyzed. The prevalence of risk factors such as age, male gender, diabetes mellitus (DM), dyslipidemia, smoking, and family history of CAD in the CAD group were higher than that in the control group. In multivariate regression model analysis, age, gender, and DM were determinants of the presence of CAD. NT-pro BNP was found to be an independent predictor for CAD (OR:1.66 (95% CI: 1.06-2.61), P < 0.05). In a receiver operating characteristic (ROC) curve analysis, an NT-proBNP value of 641.15 pmol/L was identified as a cut-off value in the diagnosis or exclusion of CAD (area under curve (AUC) = 0.56, 95% CI: 0.51-0.61). Furthermore, NT-proBNP was positively correlated with Gensini score (r = 0.14, P < 0.001) in patients with CAD. NT-proBNP was an independent predictor for Chinese patients with CAD, suggesting that the NT-proBNP level might be associated with the presence and the severity of CAD.

N-terminal Pro-brain Natriuretic Peptide, High-sensitivity Troponin and Pulmonary Artery Clot Score as Predictors of Right Ventricular Dysfunction in Echocardiography.

PubMed

Granér, Marit; Harjola, Veli-Pekka; Selander, Tuomas; Laiho, Mia K; Piilonen, Anneli; Raade, Merja; Mustonen, Pirjo

2016-06-01

We investigated the ability of cardiac biomarkers and total pulmonary artery (PA) clot score to predict right ventricular dysfunction (RVD) on admission and at seven-month follow-up in subjects with acute pulmonary embolism (APE). Sixty-three normotensive patients with APE were divided into two groups: patients with (n= 32, age 58±19 years) and without (n=31, age 55±16 years) echocardiographic RVD. Transthoracic echocardiography (TTE), N-terminal pro-brain natriuretic peptide (NT-proBNP), and high-sensitivity troponin T (hsTnT) were assessed upon arrival and repeated at seven months. Total PA clot score was determined on admission. The age- and sex dependent NT-proBNP on admission, on day 5, and at seven months exhibited the best sensitivity (admission 94%, day 5 100%, seven months 100%) and negative predictive value (NPV) (89%, 100%, 100%) for detecting RVD. Six patients (10%) had persistent RVD at seven months. Total PA clot score showed only low to moderate sensitivity (77%) and PPV (7%) for detection of RVD at seven months. Normal age- and sex dependent NT-proBNP on admission or measured five days later seems to be useful in exclusion of RVD at follow up. Total PA clot score shows only to be of modest benefit for predicting persistent RVD. Copyright © 2015 Australian and New Zealand Society of Cardiac and Thoracic Surgeons (ANZSCTS) and the Cardiac Society of Australia and New Zealand (CSANZ). Published by Elsevier B.V. All rights reserved.

Usefulness of N-terminal pro-brain natriuretic Peptide and brain natriuretic peptide to predict cardiovascular outcomes in patients with heart failure and preserved left ventricular ejection fraction.

PubMed

Grewal, Jasmine; McKelvie, Robert S; Persson, Hans; Tait, Peter; Carlsson, Jonas; Swedberg, Karl; Ostergren, Jan; Lonn, Eva

2008-09-15

More than 40% of patients hospitalized with heart failure have preserved left ventricular ejection fraction (HF-PLVEF) and are at high risk for cardiovascular (CV) events. The purpose of this study was to determine the value of N-terminal pro-brain natriuretic peptide (NT-proBNP) and brain natriuretic peptide (BNP) in predicting CV outcomes in patients with HF-PLVEF. Participants with an ejection fraction >40% in the prospective CHARM Echocardiographic Substudy were included in this analysis. Plasma NT-proBNP levels were measured, and 2 cut-offs were selected prospectively at 300 pg/ml and 600 pg/ml. BNP cut-off was set at 100 pg/ml. Clinical characteristics were recorded, and systolic and diastolic function were evaluated by echocardiography. The primary substudy outcome was the composite of CV mortality, hospitalization for heart failure, and myocardial infarction or stroke. A total of 181 patients were included, and there were 17 primary CV events (9.4%) during a median follow-up time of 524 days. In a model including clinical characteristics, echocardiographic measures, and BNP or NT-proBNP, the composite CV event outcome was best predicted by NT-proBNP >300 pg/ml (hazard ratio 5.8, 95% confidence intervals [CI] 1.3 to 26.4, p = 0.02) and moderate or severe diastolic dysfunction on echocardiography. When NT-proBNP >600 pg/ml was used in the model, it was the sole independent predictor of primary CV events (hazard ratio 8.0, 95% CI 2.6 to 24.8, p = 0.0003) as was BNP >100 pg/ml (hazard ratio 3.1, 95% CI 1.2 to 8.2, p = 0.02) in the BNP model. In conclusion, both elevated NT-proBNP and BNP are strong independent predictors of clinical events in patients with HF-PLVEF.

Autocatalytic activity and substrate specificity of the pestivirus N-terminal protease N{sup pro}

DOE Office of Scientific and Technical Information (OSTI.GOV)

Gottipati, Keerthi; Acholi, Sudheer; Ruggli, Nicolas

Pestivirus N{sup pro} is the first protein translated in the viral polypeptide, and cleaves itself off co-translationally generating the N-terminus of the core protein. Once released, N{sup pro} blocks the host's interferon response by inducing degradation of interferon regulatory factor-3. N{sup pro'}s intracellular autocatalytic activity and lack of trans-activity have hampered in vitro cleavage studies to establish its substrate specificity and the roles of individual residues. We constructed N{sup pro}-GFP fusion proteins that carry the authentic cleavage site and determined the autoproteolytic activities of N{sup pro} proteins containing substitutions at the predicted catalytic sites Glu22 and Cys69, at Arg100 thatmore » forms a salt bridge with Glu22, and at the cleavage site Cys168. Contrary to previous reports, we show that N{sup pro'}s catalytic activity does not involve Glu22, which may instead be involved in protein stability. Furthermore, N{sup pro} does not have specificity for Cys168 at the cleavage site even though this residue is conserved throughout the pestivirus genus. - Highlights: • N{sup pro'}s autoproteolysis is studied using N{sup pro}-GFP fusion proteins. • N-terminal 17 amino acids are dispensable without loss of protease activity. • The putative catalytic residue Glu22 is not involved in protease catalysis. • No specificity for Cys168 at the cleavage site despite evolutionary conservation. • N{sup pro} prefers small amino acids with non-branched beta carbons at the P1 position.« less

Effects of inspiratory muscle training on autonomic activity, endothelial vasodilator function, and N-terminal pro-brain natriuretic peptide levels in chronic heart failure.

PubMed

Laoutaris, Ioannis D; Dritsas, Athanasios; Brown, Margaret D; Manginas, Athanassios; Kallistratos, Manolis S; Chaidaroglou, Antigoni; Degiannis, Dimitrios; Alivizatos, Peter A; Cokkinos, Dennis V

2008-01-01

To assess the effects of inspiratory muscle training (IMT) on autonomic activity, endothelial function, and N-terminal pro-brain natriuretic peptide (NT-proBNP) levels in patients with chronic heart failure. Using age- and sex-matched controlled study, 23 patients (mean left ventricular ejection fraction 29 +/- 2%) were assigned to either a high-intensity training group (n = 14), New York Heart Association (NYHA) class II (n = 9)/III (n = 5), or a low-intensity training group (n = 9), NYHA class II (n = 6)/III (n = 3), exercising at 60% and 15% of sustained maximum inspiratory pressure (SPImax), respectively, 3 times per week for 10 weeks. Before and following IMT, patients underwent cardiopulmonary exercise testing and dyspnea evaluation on exertion. Sympathovagal balance was assessed by heart rate variability (HRV) from 24-hour electrocardiogram and endothelial function, using venous occlusion plethysmography. Serum levels of NT-proBNP were determined. High-intensity training group improved maximum inspiratory pressure (PImax, 105.4 +/- 5.3 vs 79.1 +/- 5 cm H2O, P = .001), SPImax (511 +/- 42 vs 308 +/- 28 cm H2O/sec/10, P = .001), peak oxygen consumption (19 +/- 1.2 vs 17.1 +/- 0.7 mL.kgmin, P = .01) and dyspnea (17.6 +/- 0.2 vs 18.1 +/- 0.1, P = .02). Endothelium-dependent vasodilation, HRV, and NT-proBNP levels were not altered. Low-intensity training group increased only the PImax (97.6 +/- 11.3 vs 84.2 +/- 8.7 cm H2O, P = .03). Improvement in dyspnea and exercise tolerance after IMT were not associated with changes in markers of HRV, endothelial function, and NT-proBNP in patients with mild to moderate chronic heart failure. Further studies on the effects of IMT in advanced heart failure would be worthwhile.

Growth-differentiation factor-15, endoglin and N-terminal pro-brain natriuretic peptide induction in athletes participating in an ultramarathon foot race.

PubMed

Tchou, Isabelle; Margeli, Alexandra; Tsironi, Maria; Skenderi, Katerina; Barnet, Marc; Kanaka-Gantenbein, Christina; Papassotiriou, Ioannis; Beris, Photis

2009-09-01

We investigated the actions of growth-differentiation factor (GDF)-15, endoglin and N-terminal pro-brain natriuretic peptide (NT-pro-BNP) in 15 male athletes who participated in the ultradistance foot race of the 246 km 'Sparthathlon'. Measurements were performed before (phase I), at the end of the race (phase II) and 48 h post-race (phase III). GDF-15 and endoglin serum concentrations were determined with enzyme-linked immunosorbent assay and NT-pro-BNP plasma levels by electrochemiluminescence. GDF-15 levels were increased from phase I (563.9 +/- 57.1 pg ml(-1)) to phase II (2311.1 +/- 462.3 pg ml(-1)) and decreased at phase III (862.0 +/- 158.0 pg ml(-1)) (p < 0.0002). NT-pro-BNP levels followed a similar pattern to that of GDF-15 from 38.1 +/- 4.8 pg ml(-1) at phase I to 1280.6 +/- 259.0 pg ml(-1) at phase II and 89.8 +/- 13.6 pg ml(-1) at phase III (p < 0.0001) and at the same time points, endoglin levels were 4.7 +/- 0.2 ng ml(-1) at phase I, 5.8 +/- 0.2 ng ml(-1) at phase II and 4.3 +/- 0.2 ng ml(-1) at phase III (p < 0.002). These findings indicate that circulating GDF-15, endoglin and NT-pro-BNP levels reflect a transient endothelial dysfunction in these athletes who participated in a foot race consisting of continuous, prolonged and brisk exercise.

Relationship between N-Terminal Pro-Brain Natriuretic Peptide, Obesity and the Risk of Heart Failure in Middle-Aged German Adults

PubMed Central

Wirth, Janine; Buijsse, Brian; di Giuseppe, Romina; Fritsche, Andreas; Hense, Hans W.; Westphal, Sabine; Isermann, Berend; Boeing, Heiner; Weikert, Cornelia

2014-01-01

Background Both high concentrations of N-terminal pro-brain natriuretic peptide (NT-proBNP) and obesity are related to higher heart failure risk. However, inverse relationships between NT-proBNP and obesity have been reported. Therefore, it was investigated whether the association between NT-proBNP and the risk of heart failure differed according to obesity status. Methods A case-cohort study was conducted within the European Prospective Investigation into Cancer and Nutrition (EPIC)-Potsdam, comprising a random sub-cohort (non-cases = 1,150, cases = 13, mean age: 50.5±9.0 years) and heart failure cases outside the sub-cohort (n = 197). Weighted Cox proportional hazards regression was used to examine the association between NT-proBNP and heart failure risk during a mean follow-up time of 8 years. Stratified analyses were performed according to obesity status as defined by body mass index (<30 kg/m2 versus ≥30 kg/m2). Results Overall, NT-proBNP was associated with higher risk of heart failure after multivariable adjustment (hazard ratio (HR) and 95% confidence interval (CI): 2.56 (1.49–4.41) for the top versus bottom tertile of NT-proBNP, ptrend:<0.01). In stratified analyses, the shape of association was linear in non-obese and U-shaped in obese participants: HRs (95%CI) from the first to the third tertile of NT-proBNP for non-obese: reference, 1.72 (0.85–3.49), 2.72 (1.42–5.22), and for obese: 3.29 (1.04–10.40), reference, 3.74 (1.52–9.21). Conclusions Although high circulating concentrations of NT-proBNP were positively associated with incident heart failure in the entire sample, the association differed according to obesity status. In obese, an increased risk of heart failure was also observed in those with low NT-proBNP concentrations. If confirmed, this observation warrants further investigation to understand underlying pathophysiological mechanisms. PMID:25423197

Relationship between N-terminal pro-brain natriuretic peptide, obesity and the risk of heart failure in middle-aged German adults.

PubMed

Wirth, Janine; Buijsse, Brian; di Giuseppe, Romina; Fritsche, Andreas; Hense, Hans W; Westphal, Sabine; Isermann, Berend; Boeing, Heiner; Weikert, Cornelia

2014-01-01

Both high concentrations of N-terminal pro-brain natriuretic peptide (NT-proBNP) and obesity are related to higher heart failure risk. However, inverse relationships between NT-proBNP and obesity have been reported. Therefore, it was investigated whether the association between NT-proBNP and the risk of heart failure differed according to obesity status. A case-cohort study was conducted within the European Prospective Investigation into Cancer and Nutrition (EPIC)-Potsdam, comprising a random sub-cohort (non-cases = 1,150, cases = 13, mean age: 50.5±9.0 years) and heart failure cases outside the sub-cohort (n = 197). Weighted Cox proportional hazards regression was used to examine the association between NT-proBNP and heart failure risk during a mean follow-up time of 8 years. Stratified analyses were performed according to obesity status as defined by body mass index (<30 kg/m2 versus ≥30 kg/m2). Overall, NT-proBNP was associated with higher risk of heart failure after multivariable adjustment (hazard ratio (HR) and 95% confidence interval (CI): 2.56 (1.49-4.41) for the top versus bottom tertile of NT-proBNP, ptrend:<0.01). In stratified analyses, the shape of association was linear in non-obese and U-shaped in obese participants: HRs (95%CI) from the first to the third tertile of NT-proBNP for non-obese: reference, 1.72 (0.85-3.49), 2.72 (1.42-5.22), and for obese: 3.29 (1.04-10.40), reference, 3.74 (1.52-9.21). Although high circulating concentrations of NT-proBNP were positively associated with incident heart failure in the entire sample, the association differed according to obesity status. In obese, an increased risk of heart failure was also observed in those with low NT-proBNP concentrations. If confirmed, this observation warrants further investigation to understand underlying pathophysiological mechanisms.

Favourable effects of exercise training on N-terminal pro-brain natriuretic peptide plasma levels in elderly patients after acute myocardial infarction.

PubMed

Giallauria, Francesco; Lucci, Rosa; De Lorenzo, Anna; D'Agostino, Mariantonietta; Del Forno, Domenico; Vigorito, Carlo

2006-11-01

regional or global impairment of left ventricular (LV) systolic or diastolic function leading to increased LV wall stress results in increased circulating levels of N-terminal pro-brain natriuretic peptide (NT-pro-BNP). this study aims at evaluating the effect of exercise training (ET) on NT-pro-BNP plasma levels in older patients recovering from acute myocardial infarction (AMI). prospective randomised study. Academic Medical Centre. forty older patients (33 males and 7 females) who experienced AMI. patients were randomised into two groups, each composed of 20 patients: Group A were enrolled in a 3-month exercise-based cardiac rehabilitation (CR) programme and Group B were discharged home with generic instructions to continue physical activity. NT-pro-BNP, cardiopulmonary and Doppler-echocardiographic parameters were measured at baseline and at 3-month follow-up. in Group A, ET reduced NT-pro-BNP levels (from 1446 +/- 475 to 435 +/- 251 pg/ml, P<0.001) and increased maximal exercise parameters; there was also an inverse correlation between changes in NT-pro-BNP levels and in VO(2peak) (r = -0.67, P<0.01), E-wave (r = -0.42, P<0.01) and E/A ratio (r = -0.60, P<0.01). In Group B, after 3 months, no changes were observed in NT-pro-BNP levels, exercise and echocardiographic parameters. LV volumes and left ventricular ejection fraction (LVEF) were unchanged after 3 months in both groups. three months ET in older patients after AMI was associated with a reduction in NT-pro-BNP levels and an overall improvement of exercise capacity, without negative LV remodelling and with improvement in early LV filling. Further investigation is required to evaluate whether in these patients the reduction of NT-pro-BNP levels at 3 months could be useful as a surrogate marker of favourable LV remodelling at a later follow-up.

N-terminal ProBNP distribution and correlations with biological characteristics in apparently healthy Greek population: ATTICA study.

PubMed

Fragopoulou, Elizabeth; Panagiotakos, Demosthenes B; Pitsavos, Christos; Chrysohoou, Christina; Nomikos, Tzortzis; Evangelopoulos, Angelos; Katsagoni, Christina; Skoumas, John; Antonopoulou, Smaragdi; Stefanadis, Christodoulos

2010-05-01

Brain natriuretic peptides are widely used as biomarkers of cardiovascular diseases and mainly heart failure. However, these markers are often found to be high even in apparently healthy participants, and little is known about which factors contribute to physiological change in plasma brain natriuretic peptide (BNP) and amino-terminal pro-B-type natriuretic peptide (NTproBNP) concentration in general populations. In this study, a random subsample of the ATTICA study was used (486 individuals) and serum NT-proBNP was measured. Approximately 20% of the participants had no detectable NT-proBNP values. Women had higher values of NT-proBNP than men (median [25th-75th percentiles]: 30.2 [15.8-54.3] vs 14.9 [4.0-28.1] pg/mL, P < .001]. Amino-terminal pro-B-type natriuretic peptide values were positively correlated with age (rho = .140, P = .006) and inversely with body mass index (BMI; rho = -.142, P = .005), creatinine (Cr) clearance (rho = -.349, P < .001), and hemoglobin (rho = -.249, P < .001) values. Linear regression analysis revealed that gender is the main contributor of NT-proBNP levels, followed by age, BMI, and Cr values.

N-terminal pro-brain natriuretic peptide and cardiac troponin I for the prognostic utility in elderly patients with severe sepsis or septic shock in intensive care unit: A retrospective study.

PubMed

Cheng, Hui; Fan, Wei-Ze; Wang, Sheng-Chi; Liu, Zhao-Hui; Zang, Hui-Ling; Wang, Li-Zhong; Liu, Hong-Juan; Shen, Xiao-Hui; Liang, Shao-Qing

2015-06-01

Using biomarkers to predict mortality in patient with severe sepsis or septic shock is of importance, as these patients frequently have high mortality and unsatisfied outcome. N-terminal pro-brain natriuretic peptide (NT-proBNP) and cardiac troponin I (cTnI) play extremely important roles in prognostic value in the mortality of severe sepsis and septic shock. The present study was retrospectively designed to evaluate the predicting mortality of NT-proBNP and cTnI in elderly patients with severe sepsis or septic shock administered in the intensive care unit (ICU) and also to evaluate whether the predicting ability of Acute Physiology and Chronic Health Evaluation II (APACHE-II) score or C-reactive protein (CRP) was increased in combination with the biomarkers. A cohort of 430 patients (aged ≥65 years) with severe sepsis or septic shock admitted to our ICU between October 2011 and December 2013 was included in the study. Patient data including clinical, laboratory, and survival and mortality were collected. All patients were examined with NT-proBNP, cTnI, CRP, and APACHE-II score and were categorized as the survived and deceased groups according to the outcome 30 days after ICU treatment. The levels of NT-proBNP and cTnI (P < .01) or CRP (P < .05) were significantly higher in the deceased group than those in the survived group. The predicting mortality of APACHE-II score alone was low but largely improved, when it was combined with both NT-proBNP and cTnI (P < .05). The alteration of NT-proBNP and cTnI levels strongly predicated the ICU prognosis in elderly patients with severe sepsis or septic shock. N-terminal pro-brain natriuretic peptide and cTnI were superior to CRP in predicting mortality. The predicting ability of APACHE-II score was improved only when combined with NT-proBNP and cTnI. Copyright © 2014 Elsevier Inc. All rights reserved.

N-terminal pro-brain natriuretic peptide is related with coronary flow velocity reserve and diastolic dysfunction in patients with asymmetric hypertrophic cardiomyopathy.

PubMed

Tesic, Milorad; Seferovic, Jelena; Trifunovic, Danijela; Djordjevic-Dikic, Ana; Giga, Vojislav; Jovanovic, Ivana; Petrovic, Olga; Marinkovic, Jelena; Stankovic, Sanja; Stepanovic, Jelena; Ristic, Arsen; Petrovic, Milan; Mujovic, Nebojsa; Vujisic-Tesic, Bosiljka; Beleslin, Branko; Vukcevic, Vladan; Stankovic, Goran; Seferovic, Petar

2017-10-01

The relations of elevated N-terminal pro-brain natriuretic peptide (NT-pro-BNP) and cardiac ischemia in hypertrophic cardiomyopathy (HCM) patients is uncertain. Therefore we designed the study with the following aims: (1) to analyze plasma concentrations of NT-pro-BNP in various subsets of HCM patients; (2) to reveal the correlations of NT-pro-BNP, myocardial ischemia, and diastolic dysfunction; (3) to assess predictors of the elevated plasma levels of NT-pro-BNP. In 61 patients (mean age 48.9±16.3 years; 26 male) with asymmetric HCM plasma levels of NT-pro-BNP were obtained. Standard transthoracic examination, tissue Doppler echocardiography with measurement of transthoracic coronary flow velocity reserve (CFVR) in left anterior descending artery (LAD) was done. Mean natural logarithm value of NT-pro-BNP was 7.11±0.95pg/ml [median value 1133 (interquartile range 561-2442)pg/ml]. NT-pro-BNP was significantly higher in patients with higher NYHA class, in obstructive HCM, more severe mitral regurgitation, increased left atrial volume index (LAVI), presence of calcified mitral annulus, elevated left ventricular (LV) filling pressure and in decreased CFVR. Levels of NT-pro-BNP significantly correlated with the ratio of E/e' (r=0.534, p<0.001), LV outflow tract gradient (r=0.503, p=0.024), LAVI (r=0.443, p<0.001), while inversely correlated with CFVR LAD (r=-0.569, p<0.001). When multivariate analysis was done only CFVR LAD and E/e' emerged as independent predictors of NT-pro-BNP. Plasma levels of NT-pro-BNP were significantly higher in HCM patients with more advanced disease. Elevated NT-pro-BNP not only reflects the diastolic impairment of the LV, but it might also be the result of cardiac ischemia in patients with HCM. Copyright © 2017 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.

Left ventricular remodelling in patients with moderate systolic dysfunction after myocardial infarction: favourable effects of exercise training and predictive role of N-terminal pro-brain natriuretic peptide.

PubMed

Giallauria, Francesco; Cirillo, Plinio; Lucci, Rosa; Pacileo, Mario; De Lorenzo, Anna; D'Agostino, Mariantonietta; Moschella, Sabino; Psaroudaki, Marianna; Del Forno, Domenico; Orio, Francesco; Vitale, Dino Franco; Chiariello, Massimo; Vigorito, Carlo

2008-02-01

To investigate the effects of exercise training (ET) on left ventricular (LV) volumes, cardiopulmonary functional capacity and N-terminal pro-brain natriuretic peptide (NT-proBNP) levels in postinfarction patients with moderate LV dysfunction. Sixty-one postinfarction patients were randomized into two groups: group T [n=30, LV ejection fraction (EF) 41.6+/-11.3%, mean+/-SD] entered a 6-month ET programme, whereas group C (n=31, EF 42.0+/-7.6%, P=NS) did not. NT-proBNP assay, Doppler-echocardiography and cardiopulmonary exercise test were performed upon enrolment and at sixth months. At sixth months, trained patients showed an improvement in workload (+26%, P<0.001), Vo2peak (+31%, P<0.001), LV end-diastolic volume index (LVEDVI; -9%, P<0.001), a reduction in NT-proBNP (-71%, P<0.001) and a significant correlation between changes in NT-proBNP and in LVEDVI (r=0.858, P<0.001). Baseline NT-proBNP correlated with changes in LVEDVI in both trained (r=0.673, P<0.001) and untrained (r=0.623, P<0.001) patients. Group C showed unfavourable LVEDVI dilation (+8%, P<0.001; T vs. C group, P<0.001) and a smaller reduction in NT-proBNP (-40%, P<0.001; T vs. C group, P<0.001). Six month ET induced a favourable LV remodelling and a marked fall in NT-proBNP that could predict LV remodelling in postinfarction patients with moderate LV dysfunction.

Right ventricular function and N-terminal pro-brain natriuretic peptide levels in adult patients with simple dextro-transposition of the great arteries.

PubMed

Martínez-Quintana, Efrén; Marrero-Negrín, Natalia; Gopar-Gopar, Silvia; Rodríguez-González, Fayna

2017-06-01

Dextro-transposition of the great arteries (d-TGA) patients is at high risk of developing right ventricular dysfunction and tricuspid regurgitation in adulthood. Determining the relation between echocardiographic parameters, N-terminal pro-brain natriuretic peptide (NT-pro-BNP) levels and the New York Heart Association (NYHA) functional class may help determining the best time to operate them. Patients with simple d-TGA operated in infancy with an atrial switch procedure (Mustard or Senning operation) were followed up in our Adult Congenital Heart Disease Unit. Analytical, echocardiographic, and clinical parameters were determined to evaluate the correlation between right echocardiographic ventricular function, NT-pro-BNP levels, and NYHA functional class. Twenty-four patients with d-TGA were operated in infancy of whom 17 alive patients had simple d-TGA. Nine patients had NT-pro-BNP levels lower than 200 pg/mL and eight patients were above 200 pg/mL. Patients with lower hemoglobin concentration, higher right ventricular diameter or under diuretic treatment showed significant higher NT-pro-BNP levels (above 200 pg/dL). The Spearman test showed a positive correlation between basal right ventricular diameter and tricuspid regurgitation with pro NT BNP levels (correlation coefficient of .624; P=.017 and .490; P=.046, respectively) and a negative correlation with the right ventricle fractional area change (-.508, P=.045). No correlation was seen between NT-pro-BNP levels and the rest of echocardiographic parameters or the NYHA functional class. NT-pro-BNP levels showed a positive correlation with basal right ventricular diameter and tricuspid regurgitation but not with NYHA association functional class in d-TGA patients. © 2017, Wiley Periodicals, Inc.

Propeptide big-endothelin, N-terminal-pro brain natriuretic peptide and mortality. The Ludwigshafen risk and cardiovascular health (LURIC) study.

PubMed

Gergei, Ingrid; Krämer, Bernhard K; Scharnagl, Hubert; Stojakovic, Tatjana; März, Winfried; Mondorf, Ulrich

The endothelin system (Big-ET-1) is a key regulator in cardiovascular (CV) disease and congestive heart failure (CHF). We have examined the incremental value of Big-ET-1 in predicting total and CV mortality next to the well-established CV risk marker N-Terminal Pro-B-Type Natriuretic Peptide (NT-proBNP). Big-ET-1 and NT-proBNP were determined in 2829 participants referred for coronary angiography (follow-up 9.9 years). Big-ET-1 is an independent predictor of total, CV mortality and death due to CHF. The conjunct use of Big-ET-1 and NT-proBNP improves the risk stratification of patients with intermediate to high risk of CV death and CHF. Big-ET-1improves risk stratification in patients referred for coronary angiography.

N-terminal pro-brain natriuretic peptide and high-sensitivity troponin T exhibit additive prognostic value for the outcome of critically ill patients.

PubMed

Lenz, Max; Krychtiuk, Konstantin A; Goliasch, Georg; Distelmaier, Klaus; Wojta, Johann; Heinz, Gottfried; Speidl, Walter S

2018-04-01

Patients treated at medical intensive care units suffer from various pathologies and often present with elevated troponin T (TnT) and N-terminal pro-brain natriuretic peptide (NT-proBNP) levels. Both markers may reflect different forms of cardiac involvement in critical illness. Therefore, the aim of our study was to examine the synergistic prognostic potential of NT-proBNP and high-sensitivity TnT (hs)TnT in unselected critically ill patients. We included all consecutive patients admitted to our intensive care unit within one year, excluding those suffering from acute myocardial infarction or undergoing cardiac surgery and measured NT-proBNP and TnT plasma levels on the day of admission and 72 hours thereafter. Of the included 148 patients, 52% were male, mean age was of 64.2 ± 16.8 years and 30-day mortality was 33.2%. Non-survivors showed significantly higher NT-proBNP and TnT plasma levels as compared with survivors ( p<0.01). An elevation of both markers exhibited an additive effect on mortality, as those with both NT-proBNP and TnT levels above the median had a 30-day mortality rate of 51.0%, while those with both markers below the median had a 16.7% mortality rate (hazard ratio 3.7). These findings were independent of demographic and clinical parameters ( p<0.05). Our findings regarding the individual predictive properties of NT-proBNP and TnT are in line with literature. However, we were able to highlight that they exhibit additive prognostic potential which exceeds their individual value. This might be attributed to a difference in underlying pathomechanisms and an assessment of synergistic risk factors.

N-Terminal Pro-Brain Natriuretic Peptide and Heart Failure Risk Among Individuals With and Without Obesity: The Atherosclerosis Risk in Communities (ARIC) Study.

PubMed

Ndumele, Chiadi E; Matsushita, Kunihiro; Sang, Yingying; Lazo, Mariana; Agarwal, Sunil K; Nambi, Vijay; Deswal, Anita; Blumenthal, Roger S; Ballantyne, Christie M; Coresh, Josef; Selvin, Elizabeth

2016-02-16

Obesity is a risk factor for heart failure (HF) but is associated with lower N-terminal pro-brain natriuretic peptide (NT-proBNP) levels. It is unclear whether the prognostic value and implications of NT-proBNP levels for HF risk differ across body mass index (BMI) categories. We followed up 12 230 ARIC participants free of prior HF at baseline (visit 2, 1990-1992) with BMI ≥18.5 kg/m(2). We quantified and compared the relative and absolute risk associations of NT-proBNP with incident HF across BMI categories. There were 1861 HF events during a median 20.6 years of follow-up. Despite increased HF risk in obesity, a weak inverse association was seen between baseline BMI and NT-proBNP levels (r=-0.10). Nevertheless, higher baseline NT-proBNP was associated with increased HF risk in all BMI categories. NT-proBNP improved HF risk prediction overall, even among those with severe obesity (BMI ≥35 kg/m(2); improvement in C statistic, 0.032; 95% confidence interval, 0.011-0.053). However, given the higher HF rates among those with obesity, at each NT-proBNP level, higher BMI was associated with greater absolute HF risk. Indeed, among those with NT-proBNP of 100 to <200 pg/mL, the average 10-year HF risk was <5% among normal-weight individuals but >10% among the severely obese. Despite its inverse relationship with BMI, NT-proBNP provides significant prognostic information on the risk of developing HF even among individuals with obesity. Given the higher baseline HF risk among persons with obesity, even slight elevations in NT-proBNP may have implications for increased absolute HF risk in this population. © 2016 American Heart Association, Inc.

Serial N-terminal pro-brain natriuretic peptide measurement as a predictor of significant patent ductus arteriosus in preterm infants beyond the first week of life.

PubMed

Letshwiti, Johannes Buca; Sirc, Jan; O'Kelly, Ruth; Miletin, Jan

2014-11-01

The aim of the study was to assess the role of plasma N-terminal pro-brain natriuretic peptide (NT-proBNP) concentration as a predictor of patent ductus arteriosus (PDA) in very low birth weight infants beyond the first week of life. This was a prospective observational study; newborns with a birth weight < 1500 g were eligible for enrolment. Enrolled infants were screened by echocardiography on day seven of life for the presence of a PDA. This was paired with a blood sample for NT-proBNP level. Echocardiography and NT-proBNP levels were repeated at weekly intervals. The primary outcome was correlation between PDA and NT-proBNP level and between measurements of PDA significance and NT-proBNP. Sixty-nine neonates were enrolled following parental consent. The mean birth weight was 1119 ± 257 g and mean gestational age was 28.6 ± 2.6 weeks. Median NT-proBNP level on day seven was 11469 ng/l in infants with a PDA vs. 898 ng/l in infants without a PDA (p < 0.0001). There was a statistically significant correlation between PDA diameter and NT-proBNP level on day seven, day 14 and day 21. NT-proBNP concentration is significantly increased in infants with a PDA and correlates well with PDA diameter in the first three weeks of life.

Differential processing of pro-neurotensin/neuromedin N and relationship to pro-hormone convertases.

PubMed

Kitabgi, Patrick

2006-10-01

Neurotensin (NT) is synthesized as part of a larger precursor that also contains neuromedin N (NN), a six amino acid neurotensin-like peptide. NT and NN are located in the C-terminal region of the precursor (pro-NT/NN) where they are flanked and separated by three Lys-Arg sequences. A fourth dibasic sequence is present in the middle of the precursor. Dibasics are the consensus sites recognized and cleaved by endoproteases that belong to the recently identified family of pro-protein convertases (PCs). In tissues that express pro-NT/NN, the three C-terminal Lys-Arg sites are differentially processed, whereas the middle dibasic is poorly cleaved. Pro-NT/NN processing gives rise mainly to NT and NN in the brain, to NT and a large peptide ending with the NN sequence at its C-terminus (large NN) in the gut and to NT, large NN and a large peptide ending with the NT sequence (large NT) in the adrenals. Recent evidence indicates that PC1, PC2 and PC5-A are the pro-hormone convertases responsible for the processing patterns observed in the gut, brain and adrenals, respectively. As NT, NN, large NT and large NN are all endowed with biological activity, the evidence reviewed here supports the idea that post-translational processing of pro-NT/NN in tissues may generate biological diversity.

Relationship of plasma N-terminal pro-brain natriuretic peptide concentrations to heart failure classification and cause of respiratory distress in dogs using a 2nd generation ELISA assay.

PubMed

Fox, P R; Oyama, M A; Hezzell, M J; Rush, J E; Nguyenba, T P; DeFrancesco, T C; Lehmkuhl, L B; Kellihan, H B; Bulmer, B; Gordon, S G; Cunningham, S M; MacGregor, J; Stepien, R L; Lefbom, B; Adin, D; Lamb, K

2015-01-01

Cardiac biomarkers provide objective data that augments clinical assessment of heart disease (HD). Determine the utility of plasma N-terminal pro-brain natriuretic peptide concentration [NT-proBNP] measured by a 2nd generation canine ELISA assay to discriminate cardiac from noncardiac respiratory distress and evaluate HD severity. Client-owned dogs (n = 291). Multicenter, cross-sectional, prospective investigation. Medical history, physical examination, echocardiography, and thoracic radiography classified 113 asymptomatic dogs (group 1, n = 39 without HD; group 2, n = 74 with HD), and 178 with respiratory distress (group 3, n = 104 respiratory disease, either with or without concurrent HD; group 4, n = 74 with congestive heart failure [CHF]). HD severity was graded using International Small Animal Cardiac Health Council (ISACHC) and ACVIM Consensus (ACVIM-HD) schemes without knowledge of [NT-proBNP] results. Receiver-operating characteristic curve analysis assessed the capacity of [NT-proBNP] to discriminate between dogs with cardiac and noncardiac respiratory distress. Multivariate general linear models containing key clinical variables tested associations between [NT-proBNP] and HD severity. Plasma [NT-proBNP] (median; IQR) was higher in CHF dogs (5,110; 2,769-8,466 pmol/L) compared to those with noncardiac respiratory distress (1,287; 672-2,704 pmol/L; P < .0001). A cut-off >2,447 pmol/L discriminated CHF from noncardiac respiratory distress (81.1% sensitivity; 73.1% specificity; area under curve, 0.84). A multivariate model comprising left atrial to aortic ratio, heart rate, left ventricular diameter, end-systole, and ACVIM-HD scheme most accurately associated average plasma [NT-proBNP] with HD severity. Plasma [NT-proBNP] was useful for discriminating CHF from noncardiac respiratory distress. Average plasma [NT-BNP] increased significantly as a function of HD severity using the ACVIM-HD classification scheme. Copyright © 2014 by the American College of

Estimated glomerular filtration rate is associated with both arterial stiffness and N-terminal pro-brain natriuretic peptide in newly diagnosed hypertensive patients.

PubMed

Gür, Mustafa; Uçar, Hakan; Kuloğlu, Osman; Kıvrak, Ali; Şeker, Taner; Türkoğlu, Caner; Özaltun, Betül; Kaypaklı, Onur; Şahin, Durmuş Yıldıray; Elbasan, Zafer; Tanboğa, Halil İbrahim; Çaylı, Murat

2014-01-01

Even a slight decrease in the glomerular filtration rate (GFR) is an independent risk factor for cardiovascular disease. Arterial stiffness, left ventricular hypertrophy and N-terminal pro-brain natriuretic peptide (NT-proBNP) are independent risk factors for cardiovascular disease, which are particularly common in end-stage renal disease. We aimed to evaluate the association between GFR with arterial stiffness, left ventricle mass (LVM) and NT-proBNP in hypertensive subjects with normal to mildly impaired renal function. The study population consisted of 285 newly diagnosed hypertensive patients (mean age; 49.9 ± 11.8 years). GFR was estimated (eGFR) by the Modification of Diet in Renal Disease formula. Pulse wave velocity (PWV) and augmentation index (AIx), which reflects arterial stiffness, were calculated using the single-point method via the Mobil-O-Graph® ARCsolver algorithm. LVM was obtained by echocardiography. Plasma NT-proBNP was measured by electrochemiluminescence. The patients were divided into two groups according to the median eGFR value (eGFRlow group <101 ml/min/1.73 m(2) and eGFRhigh group ≥ 101 ml/min/1.73 m(2)). LVM and NT-proBNP values were higher in eGFRlow group compared with eGFRhigh group (p<0.05). Pulse wave velocity and augmentation index values were higher in eGFRlow group compared with eGFRhigh group (p<0.05, for all). Multiple linear regression analysis showed that eGFR was independently associated with PWV (β=-0.422, p<0.001) and NT-proBNP (β=-0.404, p<0.001). Present study showed that eGFR was independently associated with PWV and NT-proBNP values. Importantly, these findings may explain, in part, the increase in cardiovascular risk in with slightly impaired renal function.

N-Terminal Pro-Brain Natriuretic Peptide Is Associated with a Future Diagnosis of Cancer in Patients with Coronary Artery Disease

PubMed Central

Tarín, Nieves; Cristóbal, Carmen; Lorenzo, Óscar; Blanco-Colio, Luis; Martín-Ventura, José Luis; Huelmos, Ana; Alonso, Joaquín; Aceña, Álvaro; Pello, Ana; Carda, Rocío; Asensio, Dolores; Mahíllo-Fernández, Ignacio; López Bescós, Lorenzo; Egido, Jesús; Farré, Jerónimo

2015-01-01

Objective Several papers have reported elevated plasma levels of natriuretic peptides in patients with a previous diagnosis of cancer. We have explored whether N-terminal pro-brain natriuretic peptide (NT-proBNP) plasma levels predict a future diagnosis of cancer in patients with coronary artery disease (CAD). Methods We studied 699 patients with CAD free of cancer. At baseline, NT-proBNP, galectin-3, monocyte chemoattractant protein-1, soluble tumor necrosis factor-like weak inducer of apoptosis, high-sensitivity C-reactive protein, and high-sensitivity cardiac troponin I plasma levels were assessed. The primary outcome was new cancer diagnosis. The secondary outcome was cancer diagnosis, heart failure requiring hospitalization, or death. Results After 2.15±0.98 years of follow-up, 24 patients developed cancer. They were older (68.5 [61.5, 75.8] vs 60.0 [52.0, 72.0] years; p=0.011), had higher NT-proBNP (302.0 [134.8, 919.8] vs 165.5 [87.4, 407.5] pg/ml; p=0.040) and high-sensitivity C-reactive protein (3.27 [1.33, 5.94] vs 1.92 [0.83, 4.00] mg/L; p=0.030), and lower triglyceride (92.5 [70.5, 132.8] vs 112.0 [82.0, 157.0] mg/dl; p=0.044) plasma levels than those without cancer. NT-proBNP (Hazard Ratio [HR]=1.030; 95% Confidence Interval [CI]=1.008-1.053; p=0.007) and triglyceride levels (HR=0.987; 95%CI=0.975-0.998; p=0.024) were independent predictors of a new cancer diagnosis (multivariate Cox regression analysis). When patients in whom the suspicion of cancer appeared in the first one-hundred days after blood extraction were excluded, NT-proBNP was the only predictor of cancer (HR=1.061; 95%CI=1.034-1.088; p<0.001). NT-proBNP was an independent predictor of cancer, heart failure, or death (HR=1.038; 95%CI=1.023-1.052; p<0.001) along with age, and use of insulin and acenocumarol. Conclusions NT-proBNP is an independent predictor of malignancies in patients with CAD. New studies in large populations are needed to confirm these findings. PMID:26046344

Elevation of serum N-terminal pro-brain natriuretic peptide after exercise is an index of myocardial damage or a cytoprotective reflection?

PubMed

Faviou, E; Zachari, A; Nounopoulos, C; Agrafiotis, E; Vourli, G; Dionyssiou-Asteriou, A

2008-03-01

Recent investigations have suggested the occurrence of transient cardiac dysfunction and reversible myocardial injury in healthy individuals after heavy exercise. Our purpose was to examine if the release of N-terminal pro-brain natriuretic peptide (NT-proBNP) after intense exercise in obviously healthy participants may have cytoprotective and growth-regulating effects or may result from myocardial dysfunction/damage with changes in cTnT as a marker for myocardial cell necrosis during exercise. In 43 highly-trained male athletes <35 years old, who were examined immediately after exercising as well as 2 days later, 21 age-matched male patients classified as stage-B according to ACC/AHA guidelines and 35 healthy age-matched males, we evaluated NT-proBNP and 3rd generation's cTnT by electrochemiluminescence immunoassay. All participants underwent a detailed cardiac protocol including echocardiography and electrocardiogram (ECG). In athletes, cTnT consistently remained <0.01 mg/L after exercising as well as after 2 days. NTproBNP immediately after exercising was 58.27+/-19.48 ng/L, without reaching pathological levels, decreasing 2 days later to 22.93+/-10.22 ng/L. Our patients maintained high levels of NTproBNP, as much as a six-fold increase with reference to the levels of our study's control group and with cTnT <0.01 mg/L. In the control group, cTnT and NTproBNP levels were statistically similar with those of the athletes 2 days after exercising. NT-proBNP as a biological marker can reliably discriminate pathological from physiological cardiac hypertrophy. A normal plasma concentration of NT-proBNP in consecutive routine check-up, before and after exercise, could minimize the possibility of cardiac dysfunction, whereas persistent elevated plasma concentrations warrant further cardiological evaluation.

Plasmatic levels of N-terminal pro-atrial natriuretic peptide in preeclamptic patients and healthy normotensive pregnant women.

PubMed

Reyna-Villasmil, Eduardo; Mejia-Montilla, Jorly; Reyna-Villasmil, Nadia; Mayner-Tresol, Gabriel; Herrera-Moya, Pedro; Fernández-Ramírez, Andreina; Rondón-Tapía, Marta

2018-05-11

To compare plasma N-terminal pro-atrial natriuretic peptide concentrations in preeclamptic patients and healthy normotensive pregnant women. A cases-controls study was done with 180 patients at Hospital Central Dr. Urquinaona, Maracaibo, Venezuela, that included 90 preeclamptic patients (group A; cases) and 90 healthy normotensive pregnant women selected with the same age and body mass index similar to group A (group B; controls). Blood samples were collected one hour after admission and prior to administration of any medication in group A to determine plasma N-terminal pro-atrial natriuretic peptide and other laboratory parameters. Plasma N-terminal pro-atrial natriuretic peptide concentrations in group A (mean 1.01 [0.26] pg/mL) showed a significant difference when compared with patients in group B (mean 0.55 [0.07] pg/mL; P<.001]. There was no significant correlation with systolic and diastolic blood pressure values in preeclamptic patients (P=ns). A cut-off value of 0.66ng/mL had an area under the curve of 0.93, sensitivity of 87.8%, specificity of 83.3%, a positive predictive value of 84.0% and a negative predictive value of 87.2%, with a diagnostic accuracy of 85.6%. Preeclamptic patients have significantly higher concentrations of plasma N-terminal pro-atrial natriuretic peptide compared with healthy normotensive pregnant women, with high predictive values for diagnosis. Copyright © 2017 Elsevier España, S.L.U. All rights reserved.

Association of N-Terminal Pro-Brain Natriuretic Peptide with Cognitive Function and Depression in Elderly People with Type 2 Diabetes

PubMed Central

Feinkohl, Insa; Sattar, Naveed; Welsh, Paul; Reynolds, Rebecca M.; Deary, Ian J.; Strachan, Mark W. J.; Price, Jackie F.

2012-01-01

Background Type 2 diabetes mellitus is associated with risk of congestive heart failure (CHF), cognitive dysfunction and depression. CHF itself is linked both to poor cognition and depression. The ventricular N-terminal pro-brain natriuretic peptide (NT-proBNP) is a marker of CHF, suggesting potential as a marker for cognitive impairment and/or depression. This was tested in the Edinburgh Type 2 Diabetes Study (ET2DS). Methodology and Principal Findings Cross-sectional analysis of 1066 men and women aged 60–75 with type 2 diabetes. Results from seven neuropsychological tests were combined in a standardised general cognitive ability factor, ‘g’. A vocabulary-based test estimated pre-morbid cognitive ability. The Hospital Anxiety and Depression Scale (HADS) assessed possible depression. After adjustment for age and sex, raised plasma NT-proBNP was weakly associated with lower ‘g’ and higher depression scores (ß −0.09, 95% CI −0.13 to −0.03, p = 0.004 and ß 0.08, 95% CI 0.04 to 0.12, p<0.001, respectively). Comparing extreme quintiles of NT-proBNP, subjects in the highest quintile were more likely to have reduced cognitive ability (within the lowest tertile of ‘g’) and ‘possible’ depression (HADS depression ≥8) (OR 1.80; 95% CI: 1.20, 2.70; p = 0.005 and OR 2.18; 95% CI: 1.28, 3.71; p = 0.004, respectively). Associations persisted when pre-morbid ability was adjusted for, but as expected were no longer statistically significant following the adjustment for diabetes-related and vascular co-variates (β −0.02, 95% CI −0.07 to 0.03, p>0.05 for ‘g’; β 0.03, 95% CI −0.02 to 0.07, p>0.05 for depression scores). Conclusion Raised plasma NT-proBNP was weakly but statistically significantly associated with poorer cognitive function and depression. The prospective phases of the ET2DS will help determine whether or not NT-proBNP can be considered a risk marker for subsequent cognitive impairment and incident depression and

Altered expression of BDNF, BDNF pro-peptide and their precursor proBDNF in brain and liver tissues from psychiatric disorders: rethinking the brain-liver axis.

PubMed

Yang, B; Ren, Q; Zhang, J-C; Chen, Q-X; Hashimoto, K

2017-05-16

Brain-derived neurotrophic factor (BDNF) has a role in the pathophysiology of psychiatric disorders. The precursor proBDNF is converted to mature BDNF and BDNF pro-peptide, the N-terminal fragment of proBDNF; however, the precise function of these proteins in psychiatric disorders is unknown. We sought to determine whether expression of these proteins is altered in the brain and peripheral tissues from patients with psychiatric disorders. We measured protein expression of proBDNF, mature BDNF and BDNF pro-peptide in the parietal cortex, cerebellum, liver and spleen from control, major depressive disorder (MDD), schizophrenia (SZ) and bipolar disorder (BD) groups. The levels of mature BDNF in the parietal cortex from MDD, SZ and BD groups were significantly lower than the control group, whereas the levels of BDNF pro-peptide in this area were significantly higher than controls. In contrast, the levels of proBDNF and BDNF pro-peptide in the cerebellum of MDD, SZ and BD groups were significantly lower than controls. Moreover, the levels of mature BDNF from the livers of MDD, SZ and BD groups were significantly higher than the control group. The levels of mature BDNF in the spleen did not differ among the four groups. Interestingly, there was a negative correlation between mature BDNF in the parietal cortex and mature BDNF in the liver in all the subjects. These findings suggest that abnormalities in the production of mature BDNF and BDNF pro-peptide in the brain and liver might have a role in the pathophysiology of psychiatric disorders, indicating a brain-liver axis in psychiatric disorders.

N-terminal pro-brain natriuretic peptide as a useful predictor of early surgery in neonates with congenital heart diseases: a prospective observational study.

PubMed

Makimura, Mika; Koga, Hiroshi

2014-01-01

Pediatric studies have found a correlation between the clinical heart failure score and N-terminal pro-brain natriuretic peptide (NT-proBNP) levels. However, the clinical usefulness of this marker remains unclear in neonates. At hospitals without pediatric cardiologists, neonatologists or general pediatricians must judge whether surgery is indicated and transfer patients to a specialized hospital in a timely fashion as required. Thus, we tested the hypothesis that increased NT-proBNP levels predict short-term outcomes in neonates with congenital heart diseases (CHDs) and are thus a useful tool for evaluating clinical status and guiding treatment. Subjects were term or near-term newborns (≥36 weeks' gestation) with CHDs confined to left-to-right shunt lesions. Clinical parameters and NT-proBNP levels were measured on the first 7, 14, 21, and 28 days of life (DOL). We divided patients into a surgical (n = 7) and a conservative-treatment group (n = 21), and then compared clinical variables and outcomes between the groups. In the surgical group, NT-proBNP levels had a tendency to increase during the first 14 postnatal days and were significantly greater than in the conservative-treatment group on 7 DOL [median (range), 13,983 pg/mL (4,732-26,524) vs. 1,954 pg/mL (671-10,881); p = 0.0028] and on 14 DOL [29,274 pg/mL (14,006-33,740) vs. 2,050 pg/mL (1,304-9,250); p = 0.0055]. In contrast, NT-proBNP levels tended to decrease sequentially in the conservative-treatment group. The values of additional markers, such as mean NT-proBNP level on 7 and 14 DOLs (M7-14) and NT-proBNP level on 14 DOL minus that on 7 DOL (Δ7-14), were both significantly greater in the surgical group than in the conservative-treatment group. To examine the usability of M7-14 and Δ7-14 when the difference and mean cut-off levels were set at 10,000 and 3,000 pg/mL, respectively, the sensitivity and specificity were both 100 %. In neonates who had CHDs with left

Computerized tomography measured liver fat is associated with low levels of N-terminal pro-brain natriuretic protein (NT-proBNP). Multi-Ethnic Study of Atherosclerosis

PubMed Central

Sanchez, Otto A.; Mariana, Lazo-Elizondo; Irfan, Zeb; Tracy, Russell P; Bradley, Ryan; Duprez, Daniel A.; Bahrami, Hossein; Peralta, Carmen A.; Daniels, Lori B.; Lima, João A.; Maisel, Alan; Jacobs, David R.; MJ, Budoff

2016-01-01

Background and aims N-terminal pro B-type natriuretic peptide (NT-proBNP) is inversely associated with diabetes mellitus, obesity and metabolic syndrome. We aim to characterize the association between NT-proBNP and nonalcoholic fatty liver disease (NAFLD), a condition strongly associated with metabolic syndrome. Methods 4529 participants from the Multi-Ethnic Study of Atherosclerosis (MESA) free of cardiovascular disease, without self-reported liver disease and not diabetic at their baseline visit in 2000- 2002 were included in this analysis. NAFLD was defined by a liver attenuation <40 HU. Relative prevalence (RP) for NAFLD was assessed adjusted for age, race, and sex, percent of dietary calories derived from fat, total intentional exercise, alcoholic drinks per week, and interleukin-6 by quintiles of NT-proBNP. Adjusted linear spline model was used to characterize a non-linear association between NT-proBNP and liver fat. The inflection point (IP) was the NT-proBNP concentration where there was a change in slope in the association between liver attenuation and NT-proBNP. Results RP for NAFLD decreased by 30% from the lowest to the highest quintile of NT-proBNP, p = 0.01. We observed an inverse linear association between NT-proBNP and liver fat, which plateaued (IP) at an NT-proBNP concentration of 45 pg/mL. Linear regression coefficient (SE) per unit of NT-proBNP < and ≥ IP was of 0.05 (0.02), p = 0.001 and 0.0006 (0.0008), p = 0.5, respectively, differences between slopes p < 0.0001. Conclusions In this cross-sectional study of a community based multiethnic sample of non-diabetic adults, low levels of NT-proBNP are associated with greater prevalence of NAFLD. PMID:27085779

Relation between N-terminal pro-brain natriuretic peptide and cardiac remodeling and function assessed by cardiovascular magnetic resonance imaging in patients with arrhythmogenic right ventricular cardiomyopathy.

PubMed

Cheng, Huaibing; Lu, Minjie; Hou, Cuihong; Chen, Xuhua; Wang, Jing; Yin, Gang; Chu, Jianmin; Zhang, Shu; Prasad, Sanjay K; Pu, Jielin; Zhao, Shihua

2015-02-01

Although N-terminal pro-brain natriuretic peptide (NT-proBNP) is a useful screening test of impaired right ventricular (RV) function in conditions affecting the right-sided cardiac muscle, the role of NT-proBNP remains unclear in patients with arrhythmogenic right ventricular cardiomyopathy (ARVC). This study was designed to clarify the relation between the plasma NT-proBNP level and the RV function evaluated by cardiovascular magnetic resonance (CMR) imaging. We selected 56 patients with confirmed ARVC only when their blood specimens for NT-proBNP measurements were collected within 48 hours of a CMR scan. The NT-proBNP level was significantly higher in patients with RV dysfunction than in patients without RV dysfunction (median of 655.3 [interquartile range 556.4 to 870.0] vs 347.0 [interquartile range 308.0 to 456.2] pmol/L, p <0.001). The NT-proBNP levels were positively correlated with RV end-diastolic and end-systolic volume indices (r = 0.49 and 0.70, respectively) and negatively correlated with RV ejection fraction (r = -0.76, all p <0.001), which remained significant after adjustment for age, gender, and body mass index. The area under the receiver-operating characteristic curve for NT-proBNP was 0.91 (95% confidence interval 0.80 to 0.97, p <0.001). The cut-off value of NT-proBNP (458 pmol/L) was associated with sensitivity, specificity, and positive and negative predictive values of 91%, 89%, 67%, and 98%, respectively. In conclusion, NT-proBNP is a useful marker for the detection of RV dysfunction and associated with extent of RV dilatation and dysfunction determined by CMR in patients with ARVC. Copyright © 2015 Elsevier Inc. All rights reserved.

HBpF-proBDNF: A New Tool for the Analysis of Pro-Brain Derived Neurotrophic Factor Receptor Signaling and Cell Biology.

PubMed

Gaub, Perrine; de Léon, Andrès; Gibon, Julien; Soubannier, Vincent; Dorval, Geneviève; Séguéla, Philippe; Barker, Philip A

2016-01-01

Neurotrophins activate intracellular signaling pathways necessary for neuronal survival, growth and apoptosis. The most abundant neurotrophin in the adult brain, brain-derived neurotrophic factor (BDNF), is first synthesized as a proBDNF precursor and recent studies have demonstrated that proBDNF can be secreted and that it functions as a ligand for a receptor complex containing p75NTR and sortilin. Activation of proBDNF receptors mediates growth cone collapse, reduces synaptic activity, and facilitates developmental apoptosis of motoneurons but the precise signaling cascades have been difficult to discern. To address this, we have engineered, expressed and purified HBpF-proBDNF, an expression construct containing a 6X-HIS tag, a biotin acceptor peptide (BAP) sequence, a PreScission™ Protease cleavage site and a FLAG-tag attached to the N-terminal part of murine proBDNF. Intact HBpF-proBDNF has activities indistinguishable from its wild-type counterpart and can be used to purify proBDNF signaling complexes or to monitor proBDNF endocytosis and retrograde transport. HBpF-proBDNF will be useful for characterizing proBDNF signaling complexes and for deciphering the role of proBDNF in neuronal development, synapse function and neurodegenerative disease.

Reduction of N terminal-pro-brain (B-type) natriuretic peptide levels with exercise-based cardiac rehabilitation in patients with left ventricular dysfunction after myocardial infarction.

PubMed

Giallauria, Francesco; De Lorenzo, Anna; Pilerci, Francesco; Manakos, Athanasio; Lucci, Rosa; Psaroudaki, Marianna; D'Agostino, Mariantonietta; Del Forno, Domenico; Vigorito, Carlo

2006-08-01

N-terminal-pro-brain (B-type) natriuretic peptide (NT-pro-BNP) is a peptide hormone released from ventricles in response to myocyte stretch. The aim of the study was to investigate the influence of exercise training on plasma NT-pro-BNP to verify if this parameter could be used as a biological marker of left ventricular remodelling in myocardial infarction patients undergoing an exercise training programme. Forty-four patients after myocardial infarction were enrolled into a cardiac rehabilitation programme, and were randomized in two groups of 22 patients each. Group A patients followed a 3-month exercise training programme, while group B patients received only routine recommendations. All patients underwent NT-pro-BNP assay, and cardiopulmonary exercise test before hospital discharge and after 3 months. In Group A, exercise training reduced NT-pro-BNP levels (from 1498+/-438 to 470+/-375 pg/ml, P=0.0026), increased maximal (VO2peak+4.3+/-2.9 ml/kg per min, P<0.001; Powermax+38+/-7, P<0.001) exercise parameters and work efficiency (Powermax/VO2peak+1.3+/-0.4 Power/ml per kg per min, P<0.001); there was also an inverse correlation between changes in NT-pro-BNP levels and in VO2peak (r=-0.72, P<0.001), E-wave (r=-0.51, P<0.001) and E/A ratio (r=0.59, P<0.001). In group B, at 3 months, no changes were observed in NT-pro-BNP levels, exercise and echocardiographic parameters. Three months exercise training in patients with moderate left ventricular systolic dysfunction after myocardial infarction induced a reduction in NT-pro-BNP levels, an improvement of exercise capacity and early left ventricular diastolic filling, without negative left ventricular remodelling. Whether the reduction of NT-pro-BNP levels could be useful as a surrogate marker of favourable left ventricular remodelling at a later follow-up remains to be further explored.

Electrochemiluminescence quenching of luminol by CuS in situ grown on reduced graphene oxide for detection of N-terminal pro-brain natriuretic peptide.

PubMed

Li, Xiaojian; Lu, Peng; Wu, Bin; Wang, Yaoguang; Wang, Huan; Du, Bin; Pang, Xuehui; Wei, Qin

2018-07-30

A novel electrochemiluminescence (ECL) signal-off strategy based on CuS in situ grown on reduced graphene oxide (CuS-rGO) quenching luminol/H 2 O 2 system was firstly proposed. Luminol was grafted on the surface of Au@Fe 3 O 4 -Cu 3 (PO 4 ) 2 nanoflowers (Luminol-Au@Fe 3 O 4 -Cu 3 (PO 4 ) 2 ) which exhibited excellent catalytic effect towards the reduction of H 2 O 2 to enhance the ECL intensity of luminol. Cu 3 (PO 4 ) 2 nanoflowers showed large surface area which can immobilize more Fe 3 O 4 and Au nanoparticles. The quenching mechanism of CuS-rGO was due to ECL resonance energy transfer (RET). The spectral overlap between fluorescence spectrum of Luminol-Au@Fe 3 O 4 -Cu 3 (PO 4 ) 2 and UV-vis absorption spectrum of CuS-rGO revealed that resonance energy transfer was possible. Au nanoparticles were immobilized on the surface of CuS-rGO to capture secondary antibodies. After a sandwich-type immunoreaction, a remarkable decrease of ECL signal was observed. Under the optimal conditions, the immunosensor showed excellent performance for N-terminal pro-brain natriuretic peptide (NT-proBNP) detection with a wide detection range from 0.5 pg mL -1 to 20 ng mL -1 and a low detection limit of 0.12 pg mL -1 (S/N = 3). The prepared NT-proBNP immunosensor displayed high sensitivity, excellent stability and good specificity. Copyright © 2018 Elsevier B.V. All rights reserved.

Clinical characteristics and serum N-terminal pro-brain natriuretic peptide as a diagnostic marker of Kawasaki disease in infants younger than 3 months of age.

PubMed

Bae, Hyun Kyung; Lee, Do Kyung; Kwon, Jung Hyun; Kim, Hae Soon; Sohn, Sejung; Hong, Young Mi

2014-08-01

The incidence of Kawasaki disease (KD) is rare in young infants (less than 3 months of age), who present with only a few symptoms that fulfill the clinical diagnostic criteria. The diagnosis for KD can therefore be delayed, leading to a high risk of cardiac complications. We examined the clinical characteristics and measured the serum levels of N-terminal pro-brain natriuretic peptide (NT-proBNP) levels of these patients for assessing its value in the early detection of KD. We retrospectively reviewed the data of young infants diagnosed with KD from 2004 to 2012. The control group included 20 hospitalized febrile patients. Laboratory data, including NT-proBNP were obtained for each patient in both groups. Incomplete KD was observed in 21/24 patients (87.5%). The mean fever duration on admission was 1.36±1.0 days in the KD group. Common symptoms included erythema at the site of Bacille Calmette-Guerin inoculation (70.8%), skin rash (50.0%), changes of oropharyngeal mucosa (29.1%), and cervical lymphadenopathy (20.8%). The mean number of major diagnostic criteria fulfilled was 2.8±1.4. Five KD patients (20.8%) had only one symptom matching these criteria. The incidence of coronary artery complications was 12.5%. The mean serum NT-proBNP level in the acute phase, in the KD and control groups, were 4,159±3,714 pg/mL and 957±902 pg/mL, respectively, which decreased significantly in the convalescent phase. Incomplete KD was observed in 87.5% patients. Serum NT-proBNP might be a valuable biomarker for the early detection of KD in febrile infants aged <3 months.

N-terminal pro-B-type natriuretic peptide and the prediction of primary cardiovascular events: results from 15-year follow-up of WOSCOPS

PubMed Central

Welsh, Paul; Doolin, Orla; Willeit, Peter; Packard, Chris; Macfarlane, Peter; Cobbe, Stuart; Gudnason, Vilmundur; Di Angelantonio, Emanuele; Ford, Ian; Sattar, Naveed

2013-01-01

Aims To test whether N-terminal pro-B-type natriuretic peptide (NT-proBNP) was independently associated with, and improved the prediction of, cardiovascular disease (CVD) in a primary prevention cohort. Methods and results In the West of Scotland Coronary Prevention Study (WOSCOPS), a cohort of middle-aged men with hypercholesterolaemia at a moderate risk of CVD, we related the baseline NT-proBNP (geometric mean 28 pg/mL) in 4801 men to the risk of CVD over 15 years during which 1690 experienced CVD events. Taking into account the competing risk of non-CVD death, NT-proBNP was associated with an increased risk of all CVD [HR: 1.17 (95% CI: 1.11–1.23) per standard deviation increase in log NT-proBNP] after adjustment for classical and clinical cardiovascular risk factors plus C-reactive protein. N-terminal pro-B-type natriuretic peptide was more strongly related to the risk of fatal [HR: 1.34 (95% CI: 1.19–1.52)] than non-fatal CVD [HR: 1.17 (95% CI: 1.10–1.24)] (P= 0.022). The addition of NT-proBNP to traditional risk factors improved the C-index (+0.013; P < 0.001). The continuous net reclassification index improved with the addition of NT-proBNP by 19.8% (95% CI: 13.6–25.9%) compared with 9.8% (95% CI: 4.2–15.6%) with the addition of C-reactive protein. N-terminal pro-B-type natriuretic peptide correctly reclassified 14.7% of events, whereas C-reactive protein correctly reclassified 3.4% of events. Results were similar in the 4128 men without evidence of angina, nitrate prescription, minor ECG abnormalities, or prior cerebrovascular disease. Conclusion N-terminal pro-B-type natriuretic peptide predicts CVD events in men without clinical evidence of CHD, angina, or history of stroke, and appears related more strongly to the risk for fatal events. N-terminal pro-B-type natriuretic peptide also provides moderate risk discrimination, in excess of that provided by the measurement of C-reactive protein. Clinical trial registration WOSCOPS was carried out and

Epicardial fat thickness in stable coronary artery disease: its relationship with high-sensitive cardiac troponin T and N-terminal pro-brain natriuretic peptide.

PubMed

Börekçi, Abdurrezzak; Gür, Mustafa; Özaltun, Betül; Baykan, Ahmet Oytun; Harbalioğlu, Hazar; Seker, Taner; Sen, Ömer; Acele, Armağan; Gözükara, Mehmet Yavuz; Kuloğlu, Osman; Koç, Mevlüt; Çayli, Murat

2014-12-01

Epicardial adipose tissue is related to coronary atherosclerosis, left ventricle hypertrophy, myocardial dysfunction, cardiomyopathy, and inflammation, which produces a variety of cytokines that influence key pathogenic mechanisms of atherogenesis. The main goal of this study is to examine the relationship between epicardial fat thickness (EFT) and cardiovascular risk markers as well as the complexity of coronary artery disease (CAD) in patients with stable CAD. We prospectively included 439 stable CAD patients undergoing coronary angiography in the present study (mean age: 62.2±10.7 years). Patients were divided into two groups (EFTlow and EFThigh groups) according to their median EFT values. EFT was evaluated by two-dimensional echocardiography before angiography. The SYNTAX score was calculated in all patients. N-terminal pro-brain natriuretic peptide (NT-proBNP), high-sensitive C-reactive protein (hs-CRP), high-sensitive cardiac troponin T (hs-cTnT), uric acid, and other biochemical markers were also measured. Age, SYNTAX score, frequencies of diabetes, hyperlipidemia, and hypertension, NT-proBNP, hs-CRP, hs-cTnT, and uric acid levels were higher in EFThigh group compared with the EFTlow group (P<0.05 for all). EFT was associated independently with age (β=-0.102, P=0.001), diabetes (β=-0.083, P=0.011), SYNTAX score (β=0.352, P<0.001), hs-CRP level (β=0.217, P<0.001), hs-cTnT level (β=0.197, P<0.001), and NT-proBNP level (β=0.300, P<0.001) in multivariate analysis. EFT obtained by echocardiograpy may not only be an easy tool but also an important tool for early detection of increased cardiac risk as well as the extent and complexity of CAD in patients with stable CAD.

Sequential N-Terminal Pro-B-Type Natriuretic Peptide and High-Sensitivity Cardiac Troponin Measurements During Albumin Replacement in Patients With Severe Sepsis or Septic Shock.

PubMed

Masson, Serge; Caironi, Pietro; Fanizza, Caterina; Carrer, Sara; Caricato, Anselmo; Fassini, Paola; Vago, Tarcisio; Romero, Marilena; Tognoni, Gianni; Gattinoni, Luciano; Latini, Roberto

2016-04-01

Myocardial dysfunction is a frequent complication in patients with severe sepsis and can worsen the prognosis. We investigated whether circulating biomarkers related to myocardial function and injury predicted outcome and were associated with albumin replacement. A multicenter, randomized clinical trial about albumin replacement in severe sepsis or septic shock (the Albumin Italian Outcome Sepsis trial). Forty ICUs in Italy. Nine hundred and ninety-five patients with severe sepsis or septic shock. Randomization to albumin and crystalloid solutions or crystalloid solutions alone. Plasma concentrations of N- terminal pro-B-type natriuretic peptide and high-sensitivity cardiac troponin T were measured 1, 2, and 7 days after enrollment. We tested the relationship of single marker measurements or changes over time with clinical events, organ dysfunctions, albumin replacement, and ICU or 90-day mortality in the overall population and after stratification by shock. N-terminal pro-B-type natriuretic peptide levels were abnormal in 97.4% of the patients and high-sensitivity cardiac troponin T in 84.5%, with higher concentrations in those with shock. After extensive adjustments, N-terminal pro-B-type natriuretic peptide concentrations predicted ICU or 90-day mortality, better than high-sensitivity cardiac troponin T. Early changes in N-terminal pro-B-type natriuretic peptide or high-sensitivity cardiac troponin T concentrations were independently associated with subsequent mortality in patients with shock. Patients given albumin had significantly higher N-terminal pro-B-type natriuretic peptide levels; in addition, early rise in N-terminal pro-B-type natriuretic peptide was associated with a better outcome in this subgroup. Circulating N-terminal pro-B-type natriuretic peptide and high-sensitivity cardiac troponin T are frequently elevated in severe sepsis or septic shock and have relevant prognostic value, which may be important in monitoring the clinical efficacy of

Usefulness of Age-Stratified N-Terminal Prohormone of Brain Natriuretic Peptide for Diagnosing Kawasaki Disease

PubMed Central

Lee, Sang Hoon; Yoon, Somy; Hong, Seunghee; Yang, Eun Mi; Eom, Gwang Hyeon

2017-01-01

N-terminal prohormone of brain natriuretic peptide (NT-proBNP) was recently reported as a biomarker for diagnosing Kawasaki disease (KD). The basal NT-proBNP level, however, gradually decreases with age. We investigated the usefulness of an age-stratified cutoff value of NT-proBNP for diagnosing KD. All the patients enrolled in this study visited Chonnam National University Hospital between December 2007 and March 2016. The KD groups consisted of 214 patients with complete KD and 129 patients with incomplete KD. The control group included 62 children with simple febrile illness but without heart disease. Laboratory data including NT-proBNP level were evaluated. Each group was divided into subgroups according to patient age (<6 months, 6–12 months, 12–24 months, and >24 months), and different cutoff values of NT-proBNP were calculated. The cutoff values of NT-proBNP used to diagnose total KD and incomplete KD were 762 and 762 pg/mL (<6 months), 310 and 310 pg/mL (6–12 months), 326 and 326 pg/mL (12–24 months), and 208 and 137 pg/mL (>24 months), respectively. In conclusion, age-stratified NT-proBNP is a useful biomarker for the differential diagnosis of KD in patients with a simple febrile illness. PMID:29358841

Biologic variability of N-terminal pro-brain natriuretic peptide in healthy dogs and dogs with myxomatous mitral valve disease.

PubMed

Winter, Randolph L; Saunders, Ashley B; Gordon, Sonya G; Buch, Jesse S; Miller, Matthew W

2017-04-01

To determine the biologic variability of N-terminal pro-brain natriuretic peptide (NTproBNP) in healthy dogs and dogs with various stages of myxomatous mitral valve disease (MMVD). Thirty-eight privately owned dogs: 28 with MMVD and 10 healthy controls. Prospective clinical study with comprehensive evaluation used to group dogs as healthy or into three stages of MMVD based on current guidelines. NTproBNP was measured hourly, daily, and weekly. For each group, analytical (CV A ), within-subject (CV I ), and between-subject (CV G ) coefficients of variability were calculated in addition to percent critical change value (CCV) and index of individuality (IoI). For healthy dogs, calculated NTproBNP values were: CV A  = 4.2%; CV I  = 25.2%; CV G  = 49.3%; IoI = 0.52, and CCV = 70.8%. For dogs with MMVD, calculated NTproBNP values were: CV A  = 6.2%; CV I  = 20.0%; CV G  = 61.3%; IoI = 0.34, and CCV = 58.2%. Biologic variability affects NTproBNP concentrations in healthy dogs and dogs with MMVD. Monitoring serial individual changes in NTproBNP may be clinically relevant in addition to using population-based reference ranges to determine changes in disease status. Copyright © 2016 Elsevier B.V. All rights reserved.

Diagnostic potential of serum N-terminal pro-B-type brain natriuretic peptide level in detection of cardiac wall stress in women with polycystic ovary syndrome: a cross-sectional comparison study.

PubMed

Celik, Onder; Sahin, Ibrahim; Celik, Nilufer; Hascalik, Seyma; Keskin, Lezzan; Ozcan, Hamdi; Uckan, Ahmet; Kosar, Feridun

2007-11-01

In addition to the negative effect on fertility, polycystic ovary syndrome (PCOS) has been associated with cardiac pathology. Brain natriuretic peptide (BNP) is a possible marker for cardiac risk, therefore we investigated whether N-terminal pro-B-type BNP (NT-proBNP) increases in women with PCOS compared with healthy women of comparable age and body mass index. Thirty women with PCOS and 30 healthy women not suffering from overt cardiac disease were involved in the study. Fasting insulin and serum NT-proBNP levels were measured, and M-Mode echocardiography was performed. Insulin resistance was calculated using the homeostasis model assessment insulin resistance index (HOMA-IR). PCOS subjects had higher NT-proBNP levels than the control subjects (P < 0.001). Abnormal echocardiography indices were detected in 14 of the PCOS subjects (but none of the controls), including valvular heart disease in nine, diastolic dysfunction in two, right ventricular enlargement in one, right atrial enlargement in one and pulmonary hypertension in one. PCOS subjects (n = 30) showed an increased left ventricular mass (LVM) (P < 0.001) and left ventricular posterior wall thickness (LVPWT) (P = 0.006). In addition, NT-proBNP concentration was positively correlated with LVM (r = 0.587, P = 0.001) and negatively correlated with sex-hormone-binding globulin (r = -0.528, P = 0.003). There was a positive correlation between LVM and HOMA-IR (r = 0.295, P = 0.03) while LVPWT was positively correlated with fasting insulin and HOMA-IR (r = 0.335, P = 0.031 and r = 0.346, P = 0.045, respectively) in PCOS subjects (n = 30). The present study demonstrated that the level of NT-proBNP was increased in PCOS subjects with asymptomatic heart disease.

Plasma N-Terminal Pro B-Type Natriuretic Peptide Concentrations in Dogs with Pulmonic Stenosis

PubMed Central

KOBAYASHI, Keiya; HORI, Yasutomo; CHIMURA, Syuuichi

2014-01-01

ABSTRACT The detailed information between plasma N-terminal pro B-type natriuretic peptide (NT-proBNP) concentrations and dogs with pulmonic stenosis (PS) is still unknown. The aim of the present study was to investigate the clinical utility of measuring plasma NT-proBNP concentrations in dogs with PS and to determine whether plasma NT-proBNP concentration could be used to assess disease severity. This retrospective study enrolled 30 client-owned, untreated dogs with PS (asymptomatic [n=23] and symptomatic [n=7]) and 11 healthy laboratory beagles. Results of physical examination, thoracic radiography and echocardiography were recorded. Plasma NT-proBNP concentrations were measured using commercial laboratories. Compared to the healthy control dogs, cardiothoracic ratio was significantly increased in dogs with both asymptomatic and symptomatic PS. Similarly, the ratio of the main pulmonary artery to aorta was significantly decreased in dogs with both asymptomatic and symptomatic PS. The pulmonic pressure gradient in the symptomatic PS dogs was significantly higher than that in the asymptomatic PS dogs. Plasma NT-proBNP concentration was significantly elevated in the symptomatic PS dogs compared to the healthy control dogs and the asymptomatic PS dogs. Furthermore, the Doppler-derived pulmonic pressure gradient was significantly correlated with the plasma NT-proBNP concentration (r=0.78, r2=0.61, P<0.0001). Plasma NT-proBNP concentration >764 pmol/l to identify severe PS had a sensitivity of 76.2% and specificity of 81.8%. The plasma NT-proBNP concentration increased by spontaneous PS, i.e. right-sided pressure overload and can be used as an additional method to assess the severity of PS in dogs. PMID:24561377

Plasma N-terminal pro B-type natriuretic peptide concentrations in dogs with pulmonic stenosis.

PubMed

Kobayashi, Keiya; Hori, Yasutomo; Chimura, Syuuichi

2014-06-01

The detailed information between plasma N-terminal pro B-type natriuretic peptide (NT-proBNP) concentrations and dogs with pulmonic stenosis (PS) is still unknown. The aim of the present study was to investigate the clinical utility of measuring plasma NT-proBNP concentrations in dogs with PS and to determine whether plasma NT-proBNP concentration could be used to assess disease severity. This retrospective study enrolled 30 client-owned, untreated dogs with PS (asymptomatic [n=23] and symptomatic [n=7]) and 11 healthy laboratory beagles. Results of physical examination, thoracic radiography and echocardiography were recorded. Plasma NT-proBNP concentrations were measured using commercial laboratories. Compared to the healthy control dogs, cardiothoracic ratio was significantly increased in dogs with both asymptomatic and symptomatic PS. Similarly, the ratio of the main pulmonary artery to aorta was significantly decreased in dogs with both asymptomatic and symptomatic PS. The pulmonic pressure gradient in the symptomatic PS dogs was significantly higher than that in the asymptomatic PS dogs. Plasma NT-proBNP concentration was significantly elevated in the symptomatic PS dogs compared to the healthy control dogs and the asymptomatic PS dogs. Furthermore, the Doppler-derived pulmonic pressure gradient was significantly correlated with the plasma NT-proBNP concentration (r=0.78, r(2)=0.61, P<0.0001). Plasma NT-proBNP concentration >764 pmol/l to identify severe PS had a sensitivity of 76.2% and specificity of 81.8%. The plasma NT-proBNP concentration increased by spontaneous PS, i.e. right-sided pressure overload and can be used as an additional method to assess the severity of PS in dogs.

Use of N-terminal prohormone brain natriuretic peptide assay for etiologic diagnosis of acute dyspnea in elderly patients.

PubMed

Berdagué, Philippe; Caffin, Pierre-Yves; Barazer, Isabelle; Vergnes, Christine; Sedighian, Shahin; Letrillard, Sébastien; Pilossof, Romain; Goutorbe, Frédéric; Piot, Christophe; Reny, Jean-Luc

2006-03-01

B-type peptide assay (brain natriuretic peptide [BNP] and N-terminal prohormone brain natriuretic peptide [NT-proBNP]) is useful for the diagnosis of heart failure (HF), but few data are available on the use of these markers in elderly subjects. The aim of this study was to evaluate NT-proBNP assay for the diagnosis of acute left HF in patients older than 70 years hospitalized for acute dyspnea. We prospectively enrolled 256 elderly patients with acute dyspnea. They were categorized by 2 cardiologists unaware of NT-proBNP values into a cardiac dyspnea subgroup (left HF) and a noncardiac dyspnea subgroup (all other causes). Mean age was 81 +/- 7 years, and 52% of the patients were women. The diagnoses made in the emergency setting were incorrect or uncertain in 45% of cases. The median NT-proBNP value was higher (P < .0001) in patients with cardiac dyspnea (n = 142; 7906 pg/mL) than in patients with noncardiac dyspnea (n = 112; 1066 pg/mL). The area under the receiver operating characteristic curve was 0.86 (95% CI 0.81-0.91). At a cutoff of 2000 pg/mL, NT-proBNP had a sensitivity of 86%, a specificity of 71%, and an overall accuracy of 80% for cardiac dyspnea. The use of 2 cutoffs (< 1200 and > 4500 pg/mL) resulted in an 8% error rate and a gray area englobing 32% of values. NT-proBNP appears to be a sensitive and specific means of distinguishing pulmonary from cardiac causes of dyspnea in elderly patients. An optimal diagnostic strategy requires the use of 2 cutoffs and further investigations of patients with values in the gray area.

The inclusion of N-terminal pro-brain natriuretic peptide in a sensitive screening strategy for systemic sclerosis-related pulmonary arterial hypertension: a cohort study

PubMed Central

2013-01-01

Introduction Pulmonary arterial hypertension (PAH) is a major cause of mortality in systemic sclerosis (SSc). Screening guidelines for PAH recommend multiple investigations, including annual echocardiography, which together have low specificity and may not be cost-effective. We sought to evaluate the predictive accuracy of serum N-terminal pro-brain natriuretic peptide (NT-proBNP) in combination with pulmonary function tests (PFT) (‘proposed’ algorithm) in a screening algorithm for SSc-PAH. Methods We evaluated our proposed algorithm (PFT with NT-proBNP) on 49 consecutive SSc patients with suspected pulmonary hypertension undergoing right heart catherisation (RHC). The predictive accuracy of the proposed algorithm was compared with existing screening recommendations, and is presented as sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV). Results Overall, 27 patients were found to have pulmonary hypertension (PH) at RHC, while 22 had no PH. The sensitivity, specificity, PPV and NPV of the proposed algorithm for PAH was 94.1%, 54.5%, 61.5% and 92.3%, respectively; current European Society of Cardiology (ESC)/European Respiratory Society (ERS) guidelines achieved a sensitivity, specificity, PPV and NPV of 94.1%, 31.8%, 51.6% and 87.5%, respectively. In an alternate case scenario analysis, estimating a PAH prevalence of 10%, the proposed algorithm achieved a sensitivity, specificity, PPV and NPV for PAH of 94.1%, 54.5%, 18.7% and 98.8%, respectively. Conclusions The combination of NT-proBNP with PFT is a sensitive, yet simple and non-invasive, screening strategy for SSc-PAH. Patients with a positive screening result can be referred for echocardiography, and further confirmatory testing for PAH. In this way, it may be possible to shift the burden of routine screening away from echocardiography. The findings of this study should be confirmed in larger studies. PMID:24246100

Amino-terminal pro-brain natriuretic peptide as a predictor of outcome in patients admitted to intensive care. A prospective observational study.

PubMed

De Geer, Lina; Fredrikson, Mats; Oscarsson, Anna

2012-06-01

Amino-terminal pro-brain-type natriuretic peptide is known to predict outcome in patients with heart failure, but its role in an intensive care setting is not yet fully established. To assess the incidence of elevated amino-terminal pro-brain natriuretic peptide (NT-pro-BNP) on admission to intensive care and its relation to death in the ICU and within 30 days. Prospective, observational cohort study. A mixed non-cardiothoracic tertiary ICU in Sweden. NT-pro-BNP was collected from 481 consecutive patients on admission to intensive care, in addition to data on patient characteristics and outcome. A receiver-operating characteristic curve was used to identify a discriminatory level of significance, a stepwise logistic regression analysis to correct for other clinical factors and a Kaplan-Meier analysis to assess survival. The correlation between Simplified Acute Physiology Score (SAPS) 3, Sequential Organ Failure Assessment score (SOFA) and NT-pro-BNP was analysed using Spearman's correlation test. Quartiles of NT-pro-BNP elevation were compared for baseline data and outcome using a logistic regression model. An NT-pro-BNP more than 1380 ng -l on admission was an independent predictor of death in the ICU and within 30 days [odds ratio (OR) 2.6; 95% confidence interval (CI), 1.5 to 4.4] and was present in 44% of patients. Thirty-three percent of patients with NT-pro-BNP more than 1380 ng -1, and 14.6% of patients below that threshold died within 30 days (log rank P=0.005). NT-pro-BNP correlated moderately with SAPS 3 and with SOFA on admission (Spearman's ρ 0.5552 and 0.5129, respectively). In quartiles of NT-pro-BNP elevation on admission, severity of illness and mortality increased significantly (30-day mortality 36.1%; OR 3.9; 95% CI, 2.0 to 7.3 in the quartile with the highest values, vs. 12.8% in the lowest quartile). We conclude that NT-pro-BNP is commonly elevated on admission to intensive care, that it increases with severity of illness and that it is an

Urine albumin/creatinine ratio, high sensitivity C-reactive protein and N-terminal pro brain natriuretic peptide--three new cardiovascular risk markers--do they improve risk prediction and influence treatment?

PubMed

Olsen, Michael H; Sehestedt, Thomas; Lyngbaek, Stig; Hansen, Tine W; Rasmussen, Susanne; Wachtell, Kristian; Torp-Pedersen, Christian; Hildebrandt, Per R; Ibsen, Hans

2010-01-01

In order to prioritize limited health resources in a time of increasing demands optimal cardiovascular risk stratification is essential. We tested the additive prognostic value of 3 relatively new, but established cardiovascular risk markers: N-terminal pro brain natriuretic peptide (Nt-proBNP), related to hemodynamic cardiovascular risk factors, high sensitivity C-reactive protein (hsCRP), related to metabolic cardiovascular risk factors and urine albumin/creatinine ratio (UACR), related to hemodynamic as well as metabolic risk factors. In healthy subjects with a 10-year risk of cardiovascular death lower than 5% based on HeartScore and therefore not eligible for primary prevention, the actual 10-year risk of cardiovascular death exceeded 5% in a small subgroup of subjects with UACR higher than the 95-percentile of approximately 1.6 mg/mmol. Combined use of high UACR or high hsCRP identified a larger subgroup of 16% with high cardiovascular risk in which primary prevention may be advised despite low-moderate cardiovascular risk based on HeartScore. Furthermore, combined use of high UACR or high Nt-proBNP in subjects with known cardiovascular disease or diabetes identified a large subgroup of 48% with extremely high cardiovascular risk who should be referred for specialist care to optimize treatment.

Pro-life role for c-Jun N-terminal kinase and p38 mitogen-activated protein kinase at rostral ventrolateral medulla in experimental brain stem death

PubMed Central

2012-01-01

Background Based on an experimental brain stem death model, we demonstrated previously that activation of the mitogen-activated protein kinase kinase 1/2 (MEK1/2)/extracellular signal-regulated kinase 1/2 (ERK1/2)/ mitogen-activated protein kinase signal-interacting kinase 1/2 (MNK1/2) cascade plays a pro-life role in the rostral ventrolateral medulla (RVLM), the origin of a life-and-death signal detected from systemic arterial pressure, which sequentially increases (pro-life) and decreases (pro-death) to reflect progressive dysfunction of central cardiovascular regulation during the advancement towards brain stem death in critically ill patients. The present study assessed the hypothesis that, in addition to ERK1/2, c-Jun NH2-terminal kinase (JNK) and p38 mitogen-activated protein kinase (p38MAPK), the other two mammalian members of MAPKs that are originally identified as stress-activated protein kinases, are activated specifically by MAPK kinase 4 (MAP2K4) or MAP2K6 and play a pro-life role in RVLM during experimental brain stem death. We further delineated the participation of phosphorylating activating transcriptional factor-2 (ATF-2) and c-Jun, the classical transcription factor activated by JNK or p38MAPK, in this process. Results An experimental model of brain stem death that employed microinjection of the organophosphate insecticide mevinphos (Mev; 10 nmol) bilaterally into RVLM of Sprague–Dawley rats was used, alongside cardiovascular, pharmacological and biochemical evaluations. Results from ELISA showed that whereas the total JNK, p38MAPK, MAP2K4 and MAP2K6 were not affected, augmented phosphorylation of JNK at Thr183 and Tyr185 and p38MAPK at Thr180 and Tyr182, accompanied by phosphorylation of their upstream activators MAP2K4 at Ser257 and Thr261 and MAP2K6 at Ser207 and Thr211 in RVLM occurred preferentially during the pro-life phase of experimental brain stem death. Moreover, the activity of transcription factors ATF-2 at Thr71 and c-Jun at Ser73

Pro-life role for c-Jun N-terminal kinase and p38 mitogen-activated protein kinase at rostral ventrolateral medulla in experimental brain stem death.

PubMed

Chang, Alice Y W

2012-11-17

Based on an experimental brain stem death model, we demonstrated previously that activation of the mitogen-activated protein kinase kinase 1/2 (MEK1/2)/extracellular signal-regulated kinase 1/2 (ERK1/2)/ mitogen-activated protein kinase signal-interacting kinase 1/2 (MNK1/2) cascade plays a pro-life role in the rostral ventrolateral medulla (RVLM), the origin of a life-and-death signal detected from systemic arterial pressure, which sequentially increases (pro-life) and decreases (pro-death) to reflect progressive dysfunction of central cardiovascular regulation during the advancement towards brain stem death in critically ill patients. The present study assessed the hypothesis that, in addition to ERK1/2, c-Jun NH2-terminal kinase (JNK) and p38 mitogen-activated protein kinase (p38MAPK), the other two mammalian members of MAPKs that are originally identified as stress-activated protein kinases, are activated specifically by MAPK kinase 4 (MAP2K4) or MAP2K6 and play a pro-life role in RVLM during experimental brain stem death. We further delineated the participation of phosphorylating activating transcriptional factor-2 (ATF-2) and c-Jun, the classical transcription factor activated by JNK or p38MAPK, in this process. An experimental model of brain stem death that employed microinjection of the organophosphate insecticide mevinphos (Mev; 10 nmol) bilaterally into RVLM of Sprague-Dawley rats was used, alongside cardiovascular, pharmacological and biochemical evaluations. Results from ELISA showed that whereas the total JNK, p38MAPK, MAP2K4 and MAP2K6 were not affected, augmented phosphorylation of JNK at Thr183 and Tyr185 and p38MAPK at Thr180 and Tyr182, accompanied by phosphorylation of their upstream activators MAP2K4 at Ser257 and Thr261 and MAP2K6 at Ser207 and Thr211 in RVLM occurred preferentially during the pro-life phase of experimental brain stem death. Moreover, the activity of transcription factors ATF-2 at Thr71 and c-Jun at Ser73, rather than Elk-1 at

Prohormone convertases differentially process pro-neurotensin/neuromedin N in tissues and cell lines.

PubMed

Kitabgi, Patrick

2006-08-01

Neurotensin (NT) is synthesized as part of a larger precursor that also contains neuromedin N (NN), a six-amino acid neurotensin-like peptide. NT and NN are located in the C-terminal region of the precursor (pro-NT/NN) where they are flanked and separated by three Lys-Arg sequences. A fourth dibasic sequence is present in the middle of the precursor. Dibasics are the consensus sites recognized and cleaved by specialized endoproteases that belong to the family of proprotein convertases (PCs). In tissues that express pro-NT/NN, the three C-terminal Lys-Arg sites are differentially processed, whereas the middle dibasic is poorly cleaved. Processing gives rise mainly to NT and NN in the brain, to NT and a large peptide with a C-terminal NN moiety (large NN) in the gut, and to NT, large NN, and a large peptide with a C-terminal NT moiety (large NT) in the adrenals. Recent evidence indicates that PC1, PC2, and PC5-A are the prohormone convertases responsible for the processing patterns observed in the gut, brain, and adrenals, respectively. As NT, NN, large NT, and large NN are all endowed with biological activity, the evidence reviewed in this paper supports the idea that posttranslational processing of pro-NT/NN in tissues may generate biological diversity of pathophysiological relevance.

Incremental value of a combination of cardiac troponin T, N-terminal pro-brain natriuretic peptide and C-reactive protein for prediction of mortality in end-stage renal disease.

PubMed

Hallén, Jonas; Madsen, Lene; Ladefoged, Søren; Fagerland, Morten W; Serebruany, Victor L; Agewall, Stefan; Atar, Dan

2011-03-01

To determine the relative prognostic merits of C-reactive protein (CRP), cardiac troponin T (cTnT) and N-terminal pro-brain natriuretic peptide (NT-pro-BNP) for prediction of all-cause death in patients with end-stage renal disease (ESRD) receiving haemodialysis. This prospective, controlled cohort study included 109 patients. Biomarkers were sampled at inclusion and considered as categorical and continuous variables in Cox proportional hazard models. Mean follow-up ± SD was 926 ± 385 days, during which 52 patients (48%) died. All three markers were predictive of death in univariate analysis. In multivariable analysis, elevated cTnT (> 0.01 μg/l) and CRP (> 1.0 mg/dl) remained significantly associated with mortality [hazard ratio (95% confidence interval), 3.2 (1.2-8.5), p = 0.017 for cTnT; 2.0 (1.0-3.8), p = 0.032 for CRP], while NT-pro-BNP lost independent prognostic power. Addition of cTnT and CRP to established risk factors significantly improved the global fit of the model (p < 0.001), increased the c statistic from 0.726 to 0.758 and significantly increased the integrated discrimination improvement (p < 0.001). The results suggest that cTnT and CRP can be used in combination for risk stratification in patients with ESRD and highlight the additive effect they confer in this regard.

Exercise capacity and N-terminal pro-brain natriuretic peptide levels with biventricular vs. right ventricular pacing for atrioventricular block: results from the PREVENT-HF German Substudy.

PubMed

Stockburger, Martin; de Teresa, Eduardo; Lamas, Gervasio; Desaga, Martin; Koenig, Carsten; Habedank, Dirk; Cobo, Erik; Navarro, Xavier; Wiegand, Uwe

2014-01-01

Previous studies showed unfavourable effects of right ventricular (RV) pacing. Ventricular pacing (VP), however, is required in many patients with atrioventricular (AV) block. The PREVENT-HF study explored left ventricular (LV) remodelling during RV vs. biventricular (BIV) pacing in AV block without advanced heart failure. The pre-specified PREVENT-HF German Substudy examined exercise capacity and N-terminal pro-brain natriuretic peptide (NT-proBNP). Patients with expected VP ≥80% were randomized to RV or BIV pacing. Endpoints were peak oxygen uptake (pVO2), oxygen uptake at the anaerobic threshold (VO2AT), ventilatory efficiency (VE/VCO2), and logNT-proBNP. Considering crossover, intention to treat (ITT), and on-treatment (OT) analyses of covariance (ANCOVA) were performed. For exercise testing 44 (RV: 25, BIV: 19), and for NT-proBNP 53 patients (RV: 29, BIV: 24) were included. The ITT analysis revealed significant differences in pVO2 [ANCOVA effect 2.83 mL/kg/min, confidence interval (CI) 0.83-4.91, P = 0.007], VO2AT (ANCOVA effect 2.14 mL/min/k, CI 0.14-4.15, P = 0.03), and VE/VCO2 (ANCOVA effect -5.46, CI -10.79 to -0.13, P = 0.04) favouring BIV randomization. The significant advantage in pVO2 persisted in OT analysis, while VO2AT and VE/VCO2 showed trends favouring BIV pacing. LogNT-proBNP did not differ between groups. (ITT: ANCOVA effect 0.008, CI -0.40 to +0.41, P = 0.97; OT: ANCOVA effect -0.03, CI -0.44 to 0.30, P = 0.90). Our study suggests that BIV pacing produces better exercise capacity over 1 year compared with RV pacing in patients without advanced heart failure and AV block. In contrast, we observed no significant changes of NT-proBNP. Larger trials will allow appraising the clinical usefulness of BIV pacing in AV block. ClinicalTrials.gov Identifier: NCT00170326.

Correlation between plasma N-terminal pro-brain natriuretic peptide levels and changes in New York Heart Association functional class, left atrial size, left ventricular size and function after mitral and/or aortic valve replacement.

PubMed

Elasfar, Abdelfatah

2012-01-01

Elevated plasma brain natriuretic peptide (BNP) levels have been demonstrated in patients with chronic valvular disease. We designed the present study to assess whether changes in N-terminal pro-brain natriuretic peptide (NT-proBNP) levels after mitral, aortic and double mitral and aortic valve replacement reflect changes in heart failure (HF) symptoms including New York Heart Association (NYHA) class and changes in left atrium (LA) size, left ventricle (LV) size and LV function. A prospective observational nonrandomized study among consecutive patients undergoing mitral and/or aortic valve replacement in our center. The study population consisted of 24 patients (mean [SD] age of 55.3 [16.2] years, 58% were males) who underwent surgical mitral valve replacement (12 patients), aortic valve replacement (8 patients) and combined mitral and aortic valve replacement (4 patients). NT-proBNP measurements, transthoracic echocardiography and NYHA class assessments were performed before and 6 months after surgery. The decrease in NT-proBNP was associated with decrease in left atrial dimension (r = 0.73, P < .002), LV end-diastolic dimension (r=0.65, P=.001), LV end-systolic dimension (r=0.53, P=.036), and increase in ejection fraction (r=-0.65, P=.001) after 6 months postoperatively. Furthermore, a decreasing NT-proBNP was associated with improvement in NYHA class. NT-proBNP levels after mitral, aortic and double valve replacement correlates with changes in HF manifestations as well as changes in LA size and LV dimension and function. Thus, we hypothesize that interval measurement of the NT-proBNP level at clinic visits can allow early detection of any clinical deterioration as well as the possibility of assessment of the long-term outcome of those patients.

Relation of N-terminal pro-brain natriuretic peptide levels and their prognostic power in chronic stable heart failure to obesity status.

PubMed

Frankenstein, Lutz; Remppis, Andrew; Nelles, Manfred; Schaelling, Bernd; Schellberg, Dieter; Katus, Hugo; Zugck, Christian

2008-11-01

To investigate the relationship between body mass index (BMI) and N-terminal pro-brain natriuretic peptide (NTproBNP) level and resultant prognostic capacity in chronic heart failure (CHF) controlled for known confounders. We formed 206 triplets of patients (n = 618) with stable systolic CHF matched with respect to age, sex, renal function (MDRD, modification of diet in renal disease formula), and NYHA class, each with a BMI >30 kg/m(2) (group 3), 20-24.9 kg/m(2) (group 1), and 25-29.9 kg/m(2) (group 2). BMI conveys a 4% drop in NTproBNP per unit increase. This influence remained significant after correction for age, sex, MDRD, NYHA, heart rate, rhythm, and ejection fraction. NTproBNP remained an independent predictor of adverse outcome after correction for age, sex, BMI, NYHA, MDRD, and ejection fraction. Despite numerical differences, prognostic power was comparable between BMI groups (log-transformed NTproBNP; group 1: hazard ratio (HR) 1.435, 95% CI 1.046-1.967, chi(2) 5.02, P = 0.03; group 2: HR 1.604, 95% CI 1.203-2.138, chi(2) 10.36, P = 0.001; group 3: HR 1.735, 95% CI 1.302-2.313, chi(2) 14.12, P = 0.0002) (P = NS, all). An NTproBNP correction factor was calculated. Even matched for NYHA, age, sex, and renal function, BMI exerts a significant and independent inverse influence on NTproBNP in patients with stable CHF. NTproBNP retained equal statistical power in all three BMI groups.

N-terminal pro-B-type natriuretic peptide variability in stable dialysis patients.

PubMed

Fahim, Magid A; Hayen, Andrew; Horvath, Andrea R; Dimeski, Goce; Coburn, Amanda; Johnson, David W; Hawley, Carmel M; Campbell, Scott B; Craig, Jonathan C

2015-04-07

Monitoring N-terminal pro-B-type natriuretic peptide (NT-proBNP) may be useful for assessing cardiovascular risk in dialysis patients. However, its biologic variation is unknown, hindering the accurate interpretation of serial concentrations. The aims of this prospective cohort study were to estimate the within- and between-person coefficients of variation of NT-proBNP in stable dialysis patients, and derive the critical difference between measurements needed to exclude biologic and analytic variation. Fifty-five prevalent hemodialysis and peritoneal dialysis patients attending two hospitals were assessed weekly for 5 weeks and then monthly for 4 months between October 2010 and April 2012. Assessments were conducted at the same time in the dialysis cycle and entailed NT-proBNP testing, clinical review, electrocardiography, and bioimpedance spectroscopy. Patients were excluded if they became unstable. This study analyzed 136 weekly and 113 monthly NT-proBNP measurements from 40 and 41 stable patients, respectively. Results showed that 22% had ischemic heart disease; 9% and 87% had left ventricular systolic and diastolic dysfunction, respectively. Respective between- and within-person coefficients of variation were 153% and 27% for weekly measurements, and 148% and 35% for monthly measurements. Within-person variation was unaffected by dialysis modality, hydration status, inflammation, or cardiac comorbidity. NT-proBNP concentrations measured at weekly intervals needed to increase by at least 46% or decrease by 84% to exclude change due to biologic and analytic variation alone with 90% certainty, whereas monthly measurements needed to increase by at least 119% or decrease by 54%. The between-person variation of NT-proBNP was large and markedly greater than within-person variation, indicating that NT-proBNP testing might better be applied in the dialysis population using a relative-change strategy. Serial NT-proBNP concentrations need to double or halve to confidently

N-Terminal Pro-B-Type Natriuretic Peptide Is Related to Retinal Microvascular Damage: The Rotterdam Study.

PubMed

Mutlu, Unal; Ikram, M Arfan; Hofman, Albert; de Jong, Paulus T V M; Klaver, Caroline C W; Ikram, M Kamran

2016-08-01

N-terminal pro-B-type natriuretic peptide (NT-proBNP) is a marker of cardiac dysfunction and has been linked to various indices of large vessel disease. However, it remains unclear whether NT-proBNP also relates to microvascular damage. In a community-dwelling population, we studied the association between NT-proBNP and retinal microvascular damage. From the population-based Rotterdam Study, we included 8437 participants (mean age 64.1 years and 59% women) without a history of cardiovascular disease, with NT-proBNP data and gradable retinal images. NT-proBNP serum levels were measured using an immunoassay. Retinopathy signs, that is, exudates, microaneurysms, cotton wool spots, and dot/blot hemorrhages, present on fundus photographs were graded in the total study population; retinal vascular calibers, that is, arteriolar and venular calibers, were semiautomatically measured in a subsample (n=2763) of the study population. We conducted cross-sectional analyses on the association between NT-proBNP and retinal microvascular damage using logistic and linear regression models, adjusting for age, sex, and cardiovascular risk factors. We found that NT-proBNP was associated with the presence of retinopathy (adjusted odds ratio [95% confidence interval] per SD increase in natural log-transformed NT-proBNP: 1.14 [1.03-1.27]). We also found that higher NT-proBNP was associated with narrower arteriolar calibers (adjusted mean difference in arteriolar caliber per SD increase in natural log-transformed NT-proBNP: -0.89 µm [-1.54 to -0.24]). This association remained unchanged after excluding participants with retinopathy signs. In participants free of clinical cardiovascular disease, higher levels of NT-proBNP are associated with retinal microvascular damage, suggesting a potential role for NT-proBNP as marker for small vessel disease. © 2016 American Heart Association, Inc.

Prognostic impact of plasma N-terminal pro-brain natriuretic peptide in severe chronic congestive heart failure: a substudy of the Carvedilol Prospective Randomized Cumulative Survival (COPERNICUS) trial.

PubMed

Hartmann, Franz; Packer, Milton; Coats, Andrew J S; Fowler, Michael B; Krum, Henry; Mohacsi, Paul; Rouleau, Jean L; Tendera, Michal; Castaigne, Alain; Anker, Stefan D; Amann-Zalan, Ildiko; Hoersch, Silke; Katus, Hugo A

2004-09-28

The utility of N-terminal proBNP (NT-proBNP) to predict the occurrence of death and hospitalization was prospectively evaluated in the COPERNICUS study, which enrolled patients with an ejection fraction <25% and symptoms of chronic congestive heart failure at rest or on minimal exertion. Baseline plasma concentrations of NT-proBNP were measured in a subgroup of 814 men and 197 women with symptoms at rest or on minimal exertion who were enrolled in the COPERNICUS study and were randomized to placebo (n=506) or carvedilol (n=505). Values of NT-proBNP were markedly increased despite the requirement that patients be euvolemic before the start of treatment (mean+/-SD, 3235+/-4392 pg/mL; median, 1767 pg/mL). By univariate Cox regression analysis, NT-proBNP was found to be a powerful predictor of subsequent all-cause mortality (relative risk [RR], 2.7; 95% CI, 1.7 to 4.3; P=0.0001 for above versus below median) and all-cause mortality or hospitalization for heart failure (RR, 2.4; 95% CI, 1.8 to 3.4; P=0.0001 for above versus below median). The predictive value of NT-proBNP was similar when both placebo and carvedilol patients were analyzed separately. No significant interaction was found between NT-proBNP and treatment group (P=0.93 for above- versus below-median NT-proBNP). NT-proBNP was consistently associated with increased risk for all-cause mortality and for all-cause mortality or hospitalization for heart failure in patients with severe congestive heart failure, even in those who were clinically euvolemic. This marker therefore may be a useful tool in risk stratification of patients with severe congestive heart failure.

Diagnostic and prognostic value of N-terminal pro B-type natriuretic peptide (NT-proBNP) in patients with chronic aortic regurgitation.

PubMed

Weber, Michael; Hausen, Michael; Arnold, Roman; Moellmann, Helge; Nef, Holger; Elsaesser, Albrecht; Mitrovic, Vesselin; Hamm, Christian

2008-07-21

BNP and its N-terminal fragment NT-proBNP have proven to be of diagnostic and prognostic value in patients with valvular aortic stenosis. Data regarding those biomarkers in patients with chronic aortic regurgitation (AR) are sparse. Thus it was the aim of the present study to evaluate the diagnostic and the long term prognostic value of NT-proBNP in patients presenting with AR. This study included 60 patients with isolated AR of varying severity (AR I mild, AR II moderate and AR III severe) and preserved left ventricular function. Patients were followed over a median period of 824 (770-921) days. NT-proBNP at baseline was related to disease severity and to functional status (161 (70-456) pg/ml in AR I, 226 (100-666) pg/ml in AR II and 1268 (522-5446) pg/ml in AR III (p=0.003)). Patients (n=6) experiencing an adverse event had higher NT-proBNP values at baseline as event free survivors (1271 (613-2992) pg/ml vs. 215 (92-534) pg/ml; p=0.034). The AUC of the ROC curve for NT-proBNP as a predictor for an adverse event was 0.76 (p<0.036) with an optimised cut-off value of 602 pg/ml. Consequently, in Kaplan-Meier analysis NT-proBNP values dichotomised at this cut-off were able to discriminate patients with an adverse outcome in the entire study group (Log rank 9.98, p=0.0016) and even better in the conservative group (Log rank 26.92, p<0.001). NT-proBNP is linked to disease severity in patients with chronic aortic regurgitation reflecting hemodynamic stress due to volume overload. It provides prognostic information for the clinical outcome and thus might be a useful biomarker for risk stratification.

Elevated admission N-terminal pro-brain natriuretic peptide level predicts the development of atrial fibrillation in general surgical intensive care unit patients.

PubMed

Chokengarmwong, Nalin; Yeh, Daniel Dante; Chang, Yuchiao; Ortiz, Luis Alfonso; Kaafarani, Haytham M A; Fagenholz, Peter; King, David R; DeMoya, Marc; Butler, Kathryn; Lee, Jarone; Velmahos, George; Januzzi, James Louis; Lee-Lewandrowski, Elizabeth; Lewandrowski, Kent

2017-09-01

New onset atrial fibrillation (AF) in critically ill surgical patients is associated with significant morbidity and increased mortality. N-terminal pro-B type natriuretic peptide (NT-proBNP) is released by cardiomyocytes in response to stress and may predict AF development after surgery. We hypothesized that elevated NT-proBNP level at surgical intensive care unit (ICU) admission predicts AF development in a general surgical and trauma population. From July to October 2015, NT-proBNP concentrations were measured at ICU admission. Abnormal NT-proBNP concentrations were defined by age-adjusted cut-offs. We examined the relationship between the development of AF and demographics, clinical variables, and NT-proBNP level using univariate analysis and a multivariable logistic regression model. Three hundred eighty-seven subjects were included in the cohort, none of whom were in AF at ICU admission. The median age was 63 years (52-73 years), and 40.3% were women. The risk of developing AF was higher for abnormal versus normal NT-proBNP (22% vs. 4%; p < 0.0001). Using optimal derived cutoffs (regardless of age), the risk of developing AF was 2% for NT-proBNP less than 600 ng/L, 15% for NT-proBNP of 600 ng/L to 1,999 ng/L, and 27% for NT-proBNP of 2,000 ng/L or greater. Multiple logistic regression analysis identified three independent predictors for new-onset AF: age, older than 70 years (odds ratio [OR], 3.7, 95% confidence interval [CI], 1.5-9.3), history of AF (OR, 25.3; 95% CI, 9.6-67.0), and NT-proBNP of 600 or greater (OR, 4.3; 95% CI, 1.3-14.2). When none or only one predictor was present, AF incidence was less than 1%. When all three predictors were present, AF incidence was 66%. For subjects 70 years or older but no history of AF, AF incidence was 12.8% when NT-proBNP was 600 or greater compared with 0% when NT-proBNP was less than 600. For subjects younger than 70 years with a history of AF, AF incidence was 44.4% when NT-proBNP was 600 or higher compared to 0

N-terminal pro B-type natriuretic peptide predicts mortality in patients with left ventricular hypertrophy.

PubMed

Garcia, Santiago; Akbar, Muhammad S; Ali, Syed S; Kamdar, Forum; Tsai, Michael Y; Duprez, Daniel A

2010-09-03

Left ventricular hypertrophy adversely affects outcomes in patients with hypertension. Whether N-terminal pro B-type natriuretic peptide (NT-proBNP) adds incremental prognostic information in patients with hypertension and left ventricular hypertrophy (LVH) is not well established. We aimed to study the prognostic value of NT-proBNP in hypertensive patients with LVH. Echocardiography was performed in 232 patients (mean age 61±15, 102 males, 130 females) for the diagnosis of left ventricular hypertrophy. Left ventricular mass was measured according to The American Society of Echocardiography guidelines. A blood sample was taken for NT-proBNP determination. NT-proBNP levels were analyzed in quartiles after log transformation. Long term survival was established by review of electronic medical records. Arterial hypertension was present in 130 patients (56%) and left ventricular hypertrophy was present in 105 patients (45%). In patients with left ventricular hypertrophy, NT-proBNP levels predicted long term survival (Chi-square=10, p=0.01). After adjusting by age, presence of coronary artery disease, ejection fraction, diabetes status, and hypertension; patients in highest NT pro-BNP quartile were twice as likely to die when compared to patients in the lowest NT-ptoBNP quartile (OR=2.2, 95% CI=1.0-4.6, p=0.03). NT-proBNP is an independent predictor of survival in patients with hypertension and increased left ventricular mass. Copyright © 2009 Elsevier B.V. All rights reserved.

N-terminal pro-B-type natriuretic peptide levels for dynamic risk stratification of patients with acute coronary syndromes.

PubMed

Heeschen, Christopher; Hamm, Christian W; Mitrovic, Veselin; Lantelme, Nicte-Ha; White, Harvey D

2004-11-16

Elevated baseline levels of B-type natriuretic peptide (BNP) and the N-terminal fragments of its prohormone, N-terminal-pro-BNP (NT-proBNP), have been associated with adverse long-term outcome in patients with acute coronary syndromes, whereas the prognostic implications of serial NT-proBNP measurements have not been investigated to date. NT-proBNP, troponin T, and C-reactive protein were measured at baseline and at 48 and 72 hours in 1791 patients with non-ST-elevation acute coronary syndromes. Death and myocardial infarction were recorded during 30 days of follow-up. After adjustment for independent predictors of cardiac risk, baseline NT-proBNP levels >250 ng/L were associated with higher event rates (adjusted OR, 3.7; 95% CI, 2.3 to 5.7; P<0.001). In troponin T-negative patients, NT-proBNP identified a subgroup of high-risk patients (OR, 5.9; 95% CI, 2.6 to 13.3; P<0.001). The risk in those patients (7.2%) did not significantly differ from that in troponin T-positive patients (9.8%; P=0.25). Importantly, clinical stabilization without refractory ischemia was associated with a rapid (as soon as 48 hours after onset of symptoms) and significant (48 hours; -24%; 72 hours, -49%; both P<0.001) decline in NT-proBNP levels. In patients with high NT-proBNP baseline levels, lack of a rapid decline in NT-proBNP levels (< or =250 ng/L) was linked to an adverse short-term prognosis (OR, 33.7; 95% CI, 8.2 to 138.8; P<0.001). In patients with low NT-proBNP baseline levels, a rise in NT-proBNP levels over 72 hours to >250 ng/L was also linked to an adverse 30-day prognosis (OR, 24.0; 95% CI, 8.4 to 68.5; P<0.001). Neurohumoral activation as evidenced by NT-proBNP appears as a unifying feature that is independent of other biochemical markers (myocardial necrosis, inflammation) and is a powerful and independent determinant of the short-term cardiac risk in patients with acute coronary syndromes. Whether serial measurements of NT-proBNP in patients with ACS may be used to more

Long-term outcome of patients with triphasic mitral flow with a mid-diastolic L wave: prognostic role of left atrial volume and N-terminal pro-brain natriuretic peptide.

PubMed

Kim, Sung-Ai; Son, Jungwoo; Shim, Chi-Young; Choi, Eui-Young; Ha, Jong-Won

2017-09-01

A mid-diastolic L wave has been recognized as a marker of advanced left ventricular (LV) diastolic dysfunction. However, its prognostic implication is unclear. This study assessed long-term prognosis and independent predictors of adverse outcomes in patients with a mid-diastolic L wave. A total of 144 consecutive patients (mean age 63 ± 12 years, 88 female) with a mid-diastolic L wave of ≥0.2 m/s and in sinus rhythm were identified. Patients with significant valvular heart disease, low LV ejection fraction and arrhythmias were excluded. Subjects were followed up for cardiovascular (CV) mortality and hospitalization for heart failure (HF). During follow-up for a median of 44 months (1-76), CV deaths and hospitalization for HF occurred in 41 (28%) patients. In multivariate Cox analysis, age (hazard ratio [HR], 1.07; 95% confidence interval [CI], 1.02-1.11; p = 0.001), log N-terminal pro-brain natriuretic peptide (NT-proBNP)(HR 3.81; 95% CI 1.78-8.15; p = 0.001), and left atrial volume index (HR 1.02; 95% CI 1.01-1.04; p = 0.019) were independent predictors of adverse outcomes in patients with a mid-diastolic L wave. In a stepwise model, NT-proBNP showed an incremental prognostic value for prediction of adverse outcomes when added to the clinical and echocardiographic parameters (Chi square from 30.1 to 41.1, p < 0.001). Patients with a mid-diastolic L wave and clinical, biochemical, and echocardiographic evidence of advanced diastolic dysfunction showed poor long-term clinical outcome.

24 CFR 203.462 - Pro rata payment of premium before termination.

Code of Federal Regulations, 2010 CFR

2010-04-01

... Pro rata payment of premium before termination. No contract of insurance shall be terminated until the lender has paid to the Commissioner the pro rata portion of the current annual insurance premium. ... 24 Housing and Urban Development 2 2010-04-01 2010-04-01 false Pro rata payment of premium before...

24 CFR 203.462 - Pro rata payment of premium before termination.

Code of Federal Regulations, 2011 CFR

2011-04-01

... Pro rata payment of premium before termination. No contract of insurance shall be terminated until the lender has paid to the Commissioner the pro rata portion of the current annual insurance premium. ... 24 Housing and Urban Development 2 2011-04-01 2011-04-01 false Pro rata payment of premium before...

Clinical implications of B-type natriuretic peptide and N-terminal pro--B-type natriuretic peptide in the care of the vascular surgery patient.

PubMed

Wayne Causey, Marlin; Singh, Niten

2014-12-01

B-type natriuretic peptide (also known as brain natriuretic peptide or BNP) is a physiologic marker that is often used to assess a patient's global cardiovascular health. BNP is secreted from the ventricular cardiac myocytes in response to stretch that occurs due to increased intravascular volume. PreproBNP is cleaved into BNP and N-terminal proBNP (NT proBNP) to cause diuresis, natriuresis, and vasodilation, and can be measured with a blood laboratory assay test or point-of-care testing. BNP/NT proBNP has been most extensively studied in the diagnosis and management of heart failure, but within the past 5 years, interest has carried over to vascular surgery patients. Studies have demonstrated that elevated levels of BNP/NT-proBNP (typically >100 pg/mL/>300 pg/mL) are associated with major adverse cardiac events at 30 and 180 days. Additional analysis of BNP/NT-proBNP has demonstrated that patients can be classified as very low risk (<19 pg/mL), low risk (<100 pg/mL), intermediate risk (100 to 400 pg/mL), or high risk (>400 pg/mL). BNP/NT-proBNP in the low- and very-low-risk groups suggests patients are unlikely to have a major adverse cardiac event. An elevated BNP/NT-proBNP, excluding those with reasons for abnormal values, suggests the need for additional risk stratification and medical risk factor optimization. A preoperative measure of BNP or NT-proBNP affords an easy and rapid opportunity to individually and objectively quantify perioperative cardiovascular risk. Recent studies have also identified other biomarkers, none superior to BNP or NT-proBNP, but that, when used concomitantly, aid in further stratifying perioperative risk and will likely be the focus of future investigations. Published by Elsevier Inc.

N-terminal pro-B-type Natriuretic Peptide in three different mechanisms of dysnatremia onset after a child's craniopharyngioma surgery.

PubMed

Spatenkova, Vera; Hradil, Jan; Suchomel, Petr

2017-10-01

Craniopharyngioma, due to its sellar location, can be perioperatively complicated by different types of dysnatremia. We present a rare postoperative onset of a combination of three different mechanisms of dysnatremia with N-terminal pro-B-type Natriuretic Peptide (NT-proBNP) and renal function parameters in a boy with a good outcome after craniopharyngioma surgery: 1/ Central diabetes insipidus (CDI) onset immediately after the operation, hypernatremia with peak serum sodium (SNa) 158 mmol/l) caused by free water polyuria (electrolyte-free water clearance, EWC 0.104 ml/s), NT-proBNP 350 pg/ml; 2/ cerebral salt wasting (CSW) onset on day 7, hyponatremia (SNa 128 mmol/l) with hypoosmolality (measured serum osmolality, SOsm 265 mmol/kg) caused by natriuresis (sodium - daily output 605 mmol/day, fractional excretion 0.035), NT-proBNP 191 pg/ml; 3/ Polydypsia onset on day 11 caused hyponatremia (SNa 132 mmol/l), EWC 0.015, NT-proBNP 68 pg/ml.

The effect of glycosylation on plasma N-terminal proBNP-76 levels in patients with heart or renal failure.

PubMed

Nishikimi, Toshio; Ikeda, Masashi; Takeda, Yosuke; Ishimitsu, Toshihiko; Shibasaki, Ikuko; Fukuda, Hirotsugu; Kinoshita, Hideyuki; Nakagawa, Yasuaki; Kuwahara, Koichiro; Nakao, Kazuwa

2012-01-01

Pro-brain natriuretic peptide (proBNP)-108 and N-terminal proBNP-76 (NT-BNP) contain seven sites for O-linked oligosaccharide attachment. Currently, levels of glycosylated NT-BNP are probably underestimated because it is not recognised by one antibody in the sandwich assay system. The pathophysiological significance of cardiac and plasma levels of non-glycosylated (nonglyNT-BNP) and glycosylated NT-BNP (glyNT-BNP) in heart failure (HF) and chronic renal failure (CRF) was investigated. Plasma samples from 186 patients with HF and 76 patients with CRF on haemodialysis were studied, together with 11 atrial tissue samples. To measure nonglyNT-BNP and glyNT-BNP, samples were incubated with or without deglycosylating enzymes and NT-BNP was measured using Roche Elecsys proBNP I. The percentage glyNT-BNP was calculated as glyNT-BNP/(glyNT-BNP + nonglyNT-BNP). In HF, plasma BNP, nonglyNT-BNP and glyNT-BNP levels all increased with increasing disease severity (New York Heart Association class; p<0.0001), though the molar ratio remained constant (molar ratio, BNP:nonglyNT-BNP:glyNT-BNP = 1:2.4:9.6). Before haemodialysis for CRF, plasma BNP and nonglyNT-BNP were somewhat elevated, and glyNT-BNP was markedly increased (molar ratio, BNP:nonglyNT-BNP:glyNT-BNP = 1:8.5:82). After haemodialysis, plasma BNP, nonglyNT-BNP, atrial natriuretic protein and cGMP all declined (p<0.0001), but glyNT-BNP was unchanged. Notably, the percentage of glyNT-BNP was elevated before haemodialysis, and was further increased after haemodialysis (p<0.0001). Atrial tissue levels of BNP, nonglyNT-BNP and glyNT-BNP were similar. THE findings suggest that most endogenous plasma NT-BNP is glycosylated and therefore undetectable with the current assay system, and that the relative glycosylation level is increased by haemodialysis.

C-reactive protein and N-terminal prohormone brain natriuretic peptide as biomarkers in acute exacerbations of COPD leading to hospitalizations.

PubMed

Chen, Yu-Wei Roy; Chen, Virginia; Hollander, Zsuzsanna; Leipsic, Jonathon A; Hague, Cameron J; DeMarco, Mari L; FitzGerald, J Mark; McManus, Bruce M; Ng, Raymond T; Sin, Don D

2017-01-01

There are currently no accepted and validated blood tests available for diagnosing acute exacerbations of chronic obstructive pulmonary disease (AECOPD). In this study, we sought to determine the discriminatory power of blood C-reactive protein (CRP) and N-terminal prohormone brain natriuretic peptide (NT-proBNP) in the diagnosis of AECOPD requiring hospitalizations. The study cohort consisted of 468 patients recruited in the COPD Rapid Transition Program who were hospitalized with a primary diagnosis of AECOPD, and 110 stable COPD patients who served as controls. Logistic regression was used to build a classification model to separate AECOPD from convalescent or stable COPD patients. Performance was assessed using an independent validation set of patients who were not included in the discovery set. Serum CRP and whole blood NT-proBNP concentrations were highest at the time of hospitalization and progressively decreased over time. Of the 3 classification models, the one with both CRP and NT-proBNP had the highest AUC in discriminating AECOPD (cross-validated AUC of 0.80). These data were replicated in a validation cohort with an AUC of 0.88. A combination of CRP and NT-proBNP can reasonably discriminate AECOPD requiring hospitalization versus clinical stability and can be used to rapidly diagnose patients requiring hospitalization for AECOPD.

N-terminal pro B-type natriuretic peptide in the early evaluation of suspected acute myocardial infarction.

PubMed

Haaf, Philip; Balmelli, Cathrin; Reichlin, Tobias; Twerenbold, Raphael; Reiter, Miriam; Meissner, Julia; Schaub, Nora; Stelzig, Claudia; Freese, Michael; Paniz, Patricia; Meune, Christophe; Drexler, Beatrice; Freidank, Heike; Winkler, Katrin; Hochholzer, Willibald; Mueller, Christian

2011-08-01

Myocardial ischemia is a strong trigger of N-terminal pro-B-type natriuretic peptide (NT-proBNP) release. As ischemia precedes necrosis in acute myocardial infarction, we hypothesized that NT-proBNP might be useful in the early diagnosis and risk stratification of patients with suspected acute myocardial infarction. In a prospective multicenter study, NT-proBNP was measured at presentation in 658 consecutive patients with acute chest pain. The final diagnosis was adjudicated by 2 independent cardiologists. Patients were followed long term regarding mortality. Acute myocardial infarction was the adjudicated final diagnosis in 117 patients (18%). NT-proBNP levels at presentation were significantly higher in acute myocardial infarction as compared with patients with other final diagnoses (median 886 pg/mL vs 135 pg/mL, P <.001). The diagnostic accuracy of NT-proBNP for acute myocardial infarction as quantified by the area under the receiver operating characteristic curve (AUC) was 0.79 (95% confidence interval [CI], 0.75-0.83). When added to cardiac troponin T, NT-proBNP significantly increased the AUC from 0.89 (95% CI, 0.84-0.93) to 0.91 (95% CI, 0.88-0.94; P=.033). Cumulative 24-month mortality rates were 0% in the first, 1.3% in the second, 8.3% in the third, and 23.3% in the fourth quartile of NT-proBNP (P <.001). NT-proBNP (AUC 0.85, 95% CI, 0.81-0.89) predicted all-cause mortality independently of and more accurately than both cardiac troponin T (AUC 0.66, 95% CI, 0.58-0.74; P <.001) and the Thrombolysis in Myocardial Infarction risk score (AUC 0.79, 95% CI, 0.74-0.84; P <.001). Net reclassification improvement (Thrombolysis in Myocardial Infarction vs additionally NT-proBNP) was 0.188 (P <.009), and integrated discrimination improvement was 0.100 (P <.001). Use of NT-proBNP improves the early diagnosis and risk stratification of patients with suspected acute myocardial infarction. Copyright © 2011 Elsevier Inc. All rights reserved.

Relation of adiponectin and high-sensitivity C-reactive protein to pulse-wave velocity and N-terminal pro-B-type natriuretic peptide in the general population.

PubMed

Sung, Shih-Hsien; Chuang, Shao-Yuan; Sheu, Wayne Huey-Herng; Lee, Wen-Jane; Chou, Pesus; Chen, Chen-Huan

2009-05-15

The roles of metabolic syndrome and chronic subclinical inflammation in arterial stiffening and the development of heart failure remain to be elucidated. Whether adiponectin and high-sensitivity C-reactive protein (hs-CRP) were independently related to brachial-ankle pulse-wave velocity (ba-PWV) and N-terminal pro-brain natriuretic peptide (NT-pro-BNP) in the general population were investigated. Eligible study subjects were 445 Chinese residents aged > or =40 years who participated in a community-based survey, underwent examination of ba-PWV, and had complete data of serum adiponectin, hs-CRP (<10 mg/L), and NT-pro-BNP. Adiponectin, but not hs-CRP, was independently related to ba-PWV (standardized regression parameter -0.107, p <0.05) when age, gender, body mass index, and number of metabolic syndrome components were accounted for. On the other hand, ba-PWV, adiponectin, and hs-CRP were independently related to NT-pro-BNP (standardized regression parameters 0.116, 0.188, and 0.094, respectively; all p <0.05) when age, gender, body mass index, number of metabolic syndrome components, and renal function were accounted for. In conclusion, adiponectin, but not hs-CRP, is independently associated with both ba-PWV and NT-pro-BNP in the general population. Because adiponectin, hs-CRP, ba-PWV, and NT-pro-BNP may represent markers for metabolic syndrome, chronic subclinical inflammation, arterial stiffness, and ventricular dysfunction, respectively, our results suggest that adiponectin may directly modulate both arterial stiffening and ventricular dysfunction. In contrast, hs-CRP may independently contribute to ventricular dysfunction, but not arterial stiffening.

Prospective Validation of a Screening Biomarker Approach Combining Amino-Terminal Pro-Brain Natriuretic Peptide With Galectin-3 Predicts Death and Cardiovascular Events in Asymptomatic Hemodialysis Patients.

PubMed

Voroneanu, Luminita; Siriopol, Dimitrie; Apetrii, Mugurel; Hogas, Simona; Onofriescu, Mihai; Nistor, Ionut; Kanbay, Mehmet; Dumea, Raluca; Cusai, Silvia; Cianga, Petru; Constantinescu, Daniela; Covic, Adrian

2018-05-01

Cardiovascular (CV) disease is a major cause of death in hemodialysis patients. Biomarkers used to identify high-risk asymptomatic patients would allow early evaluation of cardiac dysfunction and appropriate therapeutic intervention. Amino-terminal pro-brain natriuretic peptide (NT-proBNP) and galectin-3 (Gal-3) may serve this purpose. Plasma levels of NT-proBNP and Gal-3 were measured in 173 patients. Patients were prospectively followed for occurrences of major CV events or death. The association of NT-proBNP and Gal-3 with outcome was analyzed. The prognostic abilities for the combined outcome of Gal-3 and/or NT-proBNP were evaluated. During a median follow-up of 36 months, there were 47 incident outcomes (death and CV events). In the univariable Cox analysis, age, hypertension, albumin, phosphorus levels, and combined elevation of NT-proBNP with Gal-3 above the median (hazard ratio [HR] = 3.65, 95% confidence interval [CI] = 1.45-9.21) were associated with outcomes. In multivariable Cox analysis, both NT-proBNP and Gal-3 values above the median remained associated with outcomes (HR = 3.34, 95% CI = 1.30-8.56). In clinically asymptomatic dialysis patients, combined use of NT-proBNP and Gal-3 may improve risk stratification for death and CV events.

N-terminal pro-B-type natriuretic peptide is an independent predictor of outcome in an unselected cohort of critically ill patients.

PubMed

Meyer, Brigitte; Huelsmann, Martin; Wexberg, Paul; Delle Karth, Georg; Berger, Rudolf; Moertl, Deddo; Szekeres, Thomas; Pacher, Richard; Heinz, Gottfried

2007-10-01

Natriuretic peptides emerged during recent years as potent prognostic markers in patients with heart failure and acute myocardial infarction. In addition, natriuretic peptides show strong predictive value in patients with pulmonary embolism, sepsis, renal failure, and shock. The present study tests the prognostic information of N-terminal pro-B-type natriuretic peptide (NT-pro-BNP) in an unselected cohort of critically ill patients. Prospective, observational study. A tertiary intensive care unit in a university hospital. A total of 289 consecutive patients admitted to the intensive care unit during a 16-month period with the following data: age 64 +/- 14 yrs, male n = 191, Simplified Acute Physiology Score II of 52 +/- 24, mechanical ventilation n = 180 (62%), vasopressors n = 179 (62%), renal failure n = 24 (8%). None. Plasma NT-pro-BNP samples (Roche Diagnostics) were obtained on intensive care unit admission. Data are given as median [range]. Intensive care unit survivors had significantly lower NT-pro-BNP values compared with intensive care unit nonsurvivors (3394 [24-35,000] vs. 6776 [303-35,000] pg/mL, survivors vs. nonsurvivors, respectively, p = .001). Hospital survivors were characterized by significantly lower NT-pro-BNP values (2656 [24-35,000] vs. 8390 [303-35,000] pg/mL, survivors vs. nonsurvivors, respectively, p = .001). NT-pro-BNP levels were not significantly different in patients with primary cardiac diagnosis compared with those with a noncardiac admission diagnosis (4794 [26-35,000], n = 202 vs. 3349 [24-35,000], n = 87, cardiac vs. noncardiac, respectively, p = .28). In a logistic regression model, Simplified Acute Physiology Score II and NT-pro-BNP were independently associated with hospital survival (chi = 35.6, p = .0001 and chi = 11.3, p = .0008, Simplified Acute Physiology Score II and NT-pro-BNP, respectively). Areas under the receiver operating characteristic curves of NT-pro-BNP and Simplified Acute Physiology Score II were not

Plasma atrial natriuretic peptide and N-terminal pro B-type natriuretic peptide concentrations in dogs with right-sided congestive heart failure

PubMed Central

KANNO, Nobuyuki; HORI, Yasutomo; HIDAKA, Yuichi; CHIKAZAWA, Seishiro; KANAI, Kazutaka; HOSHI, Fumio; ITOH, Naoyuki

2015-01-01

The clinical utility of plasma natriuretic peptide concentrations in dogs with right-sided congestive heart failure (CHF) remains unclear. We investigated whether plasma levels of atrial natriuretic peptide (ANP) and N-terminal pro B-type natriuretic peptide (NT-proBNP) are useful for assessing the congestive signs of right-sided heart failure in dogs. This retrospective study enrolled 16 healthy dogs and 51 untreated dogs with presence (n=28) or absence (n=23) of right-sided CHF. Medical records of physical examinations, thoracic radiography and echocardiography were reviewed. The plasma concentration of canine ANP was measured with a chemiluminescent enzyme immunoassay. Plasma NT-proBNP concentrations were determined using an enzyme immunoassay. Plasma ANP and NT-proBNP concentrations in dogs with right-sided CHF were significantly higher than in healthy controls and those without right-sided CHF. The plasma NT-proBNP concentration >3,003 pmol/l used to identify right-sided CHF had a sensitivity of 88.5% and specificity of 90.3%. An area under the ROC curve (AUC) was 0.93. The AUC for NT-proBNP was significantly higher than the AUCs for the cardiothoracic ratio, vertebral heart score, ratio of right ventricular end-diastolic internal diameter to body surface area, tricuspid late diastolic flow and ratio of the velocities of tricuspid early to late diastolic flow. These results suggest that plasma ANP and NT-proBNP concentrations increase markedly in dogs with right-sided CHF. Particularly, NT-proBNP is simple and helpful biomarkers to assess the right-sided CHF. PMID:26607133

Elevated N-terminal pro-brain natriuretic peptide levels predict an enhanced anti-hypertensive and anti-proteinuric benefit of dietary sodium restriction and diuretics, but not angiotensin receptor blockade, in proteinuric renal patients.

PubMed

Slagman, Maartje C J; Waanders, Femke; Vogt, Liffert; Damman, Kevin; Hemmelder, Marc; Navis, Gerjan; Laverman, Gozewijn D

2012-03-01

Renin-angiotensin aldosterone system (RAAS) blockade only partly reduces blood pressure, proteinuria and renal and cardiovascular risk in chronic kidney disease (CKD) but often requires sodium targeting [i.e. low sodium diet (LS) and/or diuretics] for optimal efficacy. However, both under- and overtitration of sodium targeting can easily occur. We evaluated whether N-terminal pro-brain natriuretic peptide (NT-proBNP), a biomarker of volume expansion, predicts the benefits of sodium targeting in CKD patients. In a cross-over randomized controlled trial, 33 non-diabetic CKD patients (proteinuria 3.8 ± 0.4 g/24 h, blood pressure 143/86 ± 3/2 mmHg, creatinine clearance 89 ± 5 mL/min) were treated during 6-week periods with placebo, angiotensin receptor blockade (ARB; losartan 100 mg/day) and ARB plus diuretics (losartan 100 mg/day plus hydrochlorothiazide 25 mg/day), combined with LS (93 ± 52 mmol Na(+)/24 h) and regular sodium diet (RS; 193 ± 62 mmol Na(+)/24 h, P < 0.001 versus LS), in random order. As controls, 27 healthy volunteers were studied. NT-proBNP was elevated in patients during placebo + RS [90 (60-137) versus 35 (27-45) pg/mL in healthy controls, P = 0.001]. NT-proBNP was lowered by LS, ARB and diuretics and was normalized by ARB + diuretic + LS [39 (26-59) pg/mL, P = 0.65 versus controls]. NT-proBNP levels above the upper limit of normal (>125 pg/mL) predicted a larger reduction of blood pressure and proteinuria by LS and diuretics but not by ARB, during all steps of the titration regimen. Elevated NT-proBNP levels predict an enhanced anti-hypertensive and anti-proteinuric benefit of sodium targeting, but not RAAS blockade, in proteinuric CKD patients. Importantly, this applies to the untreated condition, as well as to the subsequent treatment steps, consisting of RAAS blockade and even RAAS blockade combined with diuretics. NT-proBNP can be a useful tool to identify CKD patients in whom sodium targeting can improve blood pressure and proteinuria.

Changes in N-terminal pro-B-type natriuretic peptide and incidence of diabetes: The Multi-Ethnic Study of Atherosclerosis (MESA)

PubMed Central

Sanchez, O.A.; Duprez, D.A.; Bahrami, H.; Peralta, C.A.; Daniels, L.B.; Lima, J.A.; Maisel, A.; Folsom, A.R.; Jacobs, D.R.

2016-01-01

Aims This study looked at whether the inverse association of circulating N-terminal pro-B-type natriuretic peptide (NT-proBNP) with incident diabetes is modified by changes in NT-proBNP (ΔNT-proBNP) levels. Methods lasma NT-proBNP was assayed at baseline and 3.2 years later (visit 3) in the Multi-Ethnic Study of Atherosclerosis (MESA).ΔNT-proBNP was calculated as NT-proBNPvisit3 − NT-proBNPbaseline. A Poisson distribution was fitted to determine the incidence density of diabetes, adjusted for age, race, gender, educational attainment, antihypertensive medication, total intentional exercise and plasma IL-6 levels. In the primary analysis (n = 3236 without diabetes up to visit 3, followed for a mean of 6.3 years), incidence density was regressed for the following categories of baseline NT-proBNP: (1) <54.4 pg/mL; (2) 54.4–85.9 pg/mL; and (3) 86–54.2 pg/mL. This was crossed with categories of ΔNT-proBNP as medians (ranges): (1) −6.2 (−131–11.7) pg/mL; (2) 19.8 (11.8–30.1) pg/mL; (3) 44.0 (30.2–67.9) pg/mL; and (4) 111.2 (68.0–3749.9) pg/mL. Results The incidence density of diabetes followed a U-shaped association across categories of ΔNT-proBNP within categories of baseline NT-proBNP after adjusting for other covariates (P = 0.02). At each level of baseline NT-proBNP, the incidence density of diabetes was lowest for small-to-moderate increases in NT-proBNP. Conclusion This analysis suggests that NT-proBNP has a biphasic association with diabetes in which the risk of incident diabetes decreases within a ‘physiological range’ of ΔNT-proBNP, and plateaus or increases as NT-proBNP concentrations increase, probably in response to pathophysiological conditions leading to high levels of NT-proBNP. PMID:26047677

Physical Activity in Older Men: Longitudinal Associations with Inflammatory and Hemostatic Biomarkers, N-Terminal Pro-Brain Natriuretic Peptide, and Onset of Coronary Heart Disease and Mortality

PubMed Central

Jefferis, Barbara J; Whincup, Peter H; Lennon, Lucy T; Papacosta, Olia; Goya Wannamethee, S

2014-01-01

Objectives To examine associations between habitual physical activity (PA) and changes in PA and onset of coronary heart disease (CHD) and the pathways linking PA to CHD. Design British Regional Heart Study population-based cohort; men completed questionnaires in 1996 and 1998 to 2000, attended rescreen in 1998 to 2000, and were followed up to June 2010. Setting Community. Participants Of 4,252 men recruited from primary care centers (77% of those invited and eligible) who were rescreened in 1998 to 2000, 3,320 were ambulatory and free from CHD, stroke, and heart failure and participated in the current study. Measurements Usual PA (regular walking and cycling, recreational activity and sport). Outcome was first fatal or nonfatal myocardial infarction. Results In 3,320 ambulatory men, 303 first and 184 fatal CHD events occurred during a median of 11 years of follow-up; 9% reported no usual PA, 23% occasional PA, and 68% light or more-intense PA. PA was inversely associated with novel risk markers C-reactive protein, D-dimer, von Willebrand Factor and N-terminal pro-brain natriuretic peptide (NT-proBNP). Compared with no usual PA, hazard ratios (HRs) for CHD events, adjusted for age and region, were 0.52 (95% confidence interval (CI) = 0.34–0.79) for occasional PA, 0.47 (95% CI = 0.30–0.74) for light PA, 0.51 (95% CI = 0.32–0.82) for moderate PA, and 0.44 (95% CI = 0.29–0.65) for moderately vigorous or vigorous PA (P for linear trend = .004). Adjustment for established and novel risk markers somewhat attenuated HRs and abolished linear trends. Compared with men who remained inactive, men who maintained at least light PA had an HR for CHD events of 0.73 (95% CI = 0.53–1.02) and men whose PA level increased had an HR of 0.86 (95% CI = 0.55–1.35). Conclusion Even light PA was associated with significantly lower risk of CHD events in healthy older men, partly through inflammatory and hemostatic mechanisms and cardiac function (NT-proBNP). PMID

Release kinetics of N-terminal pro-B-type natriuretic peptide in a clinical model of acute myocardial infarction.

PubMed

Liebetrau, Christoph; Gaede, Luise; Dörr, Oliver; Troidl, Christian; Voss, Sandra; Hoffmann, Jedrzej; Paszko, Agata; Weber, Michael; Rolf, Andreas; Hamm, Christian; Nef, Holger; Möllmann, Helge

2014-02-15

N-terminal segment of B-type natriuretic peptide prohormone (NT-proBNP) is elevated in patients with acute myocardial infarction (AMI) thus providing both diagnostic information and prognostic information. The aim of the present study was to determine the time course of NT-proBNP release in patients undergoing transcoronary ablation of septal hypertrophy (TASH) a procedure mimicking AMI. We analyzed the release kinetics of NT-proBNP in 18 consecutive patients with hypertrophic obstructive cardiomyopathy undergoing TASH. Serum samples were collected prior to and at 15, 30, 45, 60, 75, 90, and 105 min, and 2, 4, 8, and 24h after TASH. NT-proBNP concentrations showed a continuous increase during the first 75 min with a significant percent change compared to baseline value already 15 min after TASH (105.6% [IQR 102.2-112.7]; P<0.001). All patients had a significant increase of NT-proBNP at 45 min (range of percent increase [min-max]: 103.5-137.2%; range of absolute increase [min-max]: 23.5-304.0 ng/L). NT-proBNP concentrations decreased below the baseline value until the 8th h after initiation of myocardial infarction. NT-proBNP concentration increases immediately after induction of myocardial infarction proving early evidence of myocardial injury despite the decrease of the left ventricular wall stress due to the TASH related reduction of the left ventricular outflow gradient. Copyright © 2013 Elsevier B.V. All rights reserved.

Relation of N-Terminal Pro-B-Type Natriuretic Peptide and Left Ventricular Diastolic Function to Exercise Tolerance in Patients With Significant Valvular Heart Disease and Normal Left Ventricular Systolic Function.

PubMed

Hwang, Ji-Won; Park, Sung-Ji; Cho, Eun Jeong; Kim, Eun Kyoung; Lee, Ga Yeon; Chang, Sung-A; Choi, Jin-Oh; Lee, Sang-Chol; Park, Seung Woo

2017-06-01

An association between N-terminal prohormone brain natriuretic peptide (NT-proBNP) and exercise tolerance in patients with valvular heart disease (VHD) has been suggested; however, there are few data available regarding this relation. The aim of this study is to evaluate the correlation between exercise tolerance and NT-proBNP in patients with asymptomatic or mildly symptomatic significant VHD and normal left ventricular ejection fraction (LV EF). A total of 96 patients with asymptomatic or mildly symptomatic VHD and normal LV EF (≥50%) underwent cardiopulmonary exercise echocardiography. NT-proBNP levels were determined at baseline and after exercise in 3 hours. Patients were divided in 2 groups based on lower (<26 ml/kg/min, n = 47) or higher (≥26 ml/kg/min, n = 49) peak oxygen consumption (VO 2 ) as a representation of exercise tolerance. In the 2 groups, after adjusting for age and gender, the NT-proBNP level after exercise in 3 hours, left atrial volume index before exercise, right ventricular systolic pressure before exercise, E velocity after exercise, and E/e' ratio after exercise varied significantly. In addition, peak VO 2 was inversely related to NT-proBNP before (r = -0.352, p <0.001) and after exercise (r = -0.351, p <0.001). The NT-proBNP level before exercise was directly related to the left atrial volume index, E/e' ratio, and right ventricular systolic pressure before and after exercise. NT-proBNP after exercise was also directly related to the same parameters. NT-proBNP levels both before and after exercise were higher in the group with lower exercise tolerance. In conclusion, through the correlation among exercise tolerance, NT-proBNP, and parameters of diastolic dysfunction, we demonstrated that diastolic dysfunction and NT-proBNP could predict exercise tolerance in patients with significant VHD and normal LV EF. Copyright © 2017 Elsevier Inc. All rights reserved.

N-terminal pro-B-type natriuretic peptide diagnostic algorithm versus American Heart Association algorithm for Kawasaki disease.

PubMed

Dionne, Audrey; Meloche-Dumas, Léamarie; Desjardins, Laurent; Turgeon, Jean; Saint-Cyr, Claire; Autmizguine, Julie; Spigelblatt, Linda; Fournier, Anne; Dahdah, Nagib

2017-03-01

Diagnosis of Kawasaki disease (KD) can be challenging in the absence of a confirmatory test or pathognomonic finding, especially when clinical criteria are incomplete. We recently proposed serum N-terminal pro-B-type natriuretic peptide (NT-proBNP) as an adjunctive diagnostic test. We retrospectively tested a new algorithm to help KD diagnosis based on NT-proBNP, coronary artery dilation (CAD) at onset, and abnormal serum albumin or C-reactive protein (CRP). The goal was to assess the performance of the algorithm and compare its performance with that of the 2004 American Heart Association (AHA)/American Academy of Pediatrics (AAP) algorithm. The algorithm was tested on 124 KD patients with NT-proBNP measured on admission at the present institutions between 2007 and 2013. Age at diagnosis was 3.4 ± 3.0 years, with a median of five diagnostic criteria; and 55 of the 124 patients (44%) had incomplete KD. CA complications occurred in 64 (52%), with aneurysm in 14 (11%). Using this algorithm, 120/124 (97%) were to be treated, based on high NT-proBNP alone for 79 (64%); on onset CAD for 14 (11%); and on high CRP or low albumin for 27 (22%). Using the AHA/AAP algorithm, 22/47 (47%) of the eligible patients with incomplete KD would not have been referred for treatment, compared with 3/55 (5%) with the NT-proBNP algorithm (P < 0.001). This NT-proBNP-based algorithm is efficient to identify and treat patients with KD, including those with incomplete KD. This study paves the way for a prospective validation trial of the algorithm. © 2016 Japan Pediatric Society.

N-Terminal Pro-B Type Natriuretic Peptide is Associated with Mild Cognitive Impairment in the General Population.

PubMed

Kara, Kaffer; Mahabadi, Amir Abbas; Weimar, Christian; Winkler, Angela; Neumann, Till; Kälsch, Hagen; Dragano, Nico; Moebus, Susanne; Erbel, Raimund; Jöckel, Karl-Heinz; Jokisch, Martha

2017-01-01

N-terminal pro-B type natriuretic peptide (NT-proBNP) is a marker of cardiac stress and is linked with silent cardiac diseases. While associations of cognitive impairment with manifest cardiovascular diseases are established, data on whether subclinical elevation of NT-proBNP levels below clinically established threshold of heart failure is related with cognitive functioning, especially mild cognitive impairment (MCI), is rare. Aim of the present study was to investigate the cross-sectional association of NT-proBNP levels and MCI in a population-based study sample without heart failure. We used data from the second examination of the population based Heinz-Nixdorf-Recall-Study. Subjects with overt coronary heart disease and subjects with NT-proBNP levels indicating potential heart failure (NT-proBNP≥300 pg/ml) were excluded from this analysis. Participants performed a validated brief cognitive assessment and were classified either as MCI [subtypes: amnestic-MCI (aMCI), non-amnestic-MCI (naMCI)], or cognitively-normal. We included 419 participants with MCI (63.1±7.4 y; 47% men; aMCI n = 209; naMCI n = 210) and 1,206 cognitively normal participants (62.42±7.1 y; 48% men). NT-proBNP-levels≥125 pg/ml compared to <125 pg/ml were associated with MCI in fully adjusted models (OR 1.65 (1.23;2.23) in the total sample, 1.73 (1.09;2.74) in men and 1.63(1.10;2.41) in women). For aMCI, the fully adjusted OR was 1.53 (1.04;2.25) and for naMCI, the fully adjusted OR was 1.34 (1.09; 166) in the total sample. Within normal ranges and without manifest heart failure, higher NT-proBNPlevels are associated with MCI and both MCI subtypes independent of traditional cardiovascular risk factors and sociodemographic parameters.

Direct comparison of mid-regional pro-atrial natriuretic peptide with N-terminal pro B-type natriuretic peptide in the diagnosis of patients with atrial fibrillation and dyspnoea.

PubMed

Eckstein, Jens; Potocki, Mihael; Murray, Karsten; Breidthardt, Tobias; Ziller, Ronny; Mosimann, Tamina; Klima, Theresia; Hoeller, Rebeca; Moehring, Berit; Sou, Seoung Mann; Rubini Gimenez, Maria; Morgenthaler, Nils G; Mueller, Christian

2012-10-01

Due to different release mechanisms, mid-regional pro-atrial natriuretic peptide (MR proANP) may be superior to N-terminal pro-B-type natriuretic peptide (NT proBNP) in the diagnosis of acute heart failure (AHF) in patients with atrial fibrillation (AF). We compared MR proANP and NT proBNP for their diagnostic value in patients with AF and sinus rhythm (SR). Prospective cohort study. University hospital, emergency department. 632 consecutive patients presenting with acute dyspnoea. MR proANP and NT proBNP plasma levels were determined. The diagnosis of AHF was adjudicated by two independent cardiologists using all available data. Patients received long-term follow-up. AF was present in 151 patients (24%). MR proANP and NT proBNP levels were significantly higher in the AF group compared with the SR group (385 (258-598) versus 201 (89-375) pmol/l for MR proANP, p<0.001 and 4916 (2169-10285) versus 1177 (258-5166) pg/ml, p<0.001 for NT proBNP). Diagnostic accuracy in AF patients was similar for MR proANP (0.90, 95% CI 0.84 to 0.95) and NT proBNP (0.89, 95% CI 0.81 to 0.96). Optimal cut-off levels in AF patients were significantly higher compared with the optimal cut-off levels for patients in SR (MR proANP 240 vs 200 pmol/l; NT proBNP 2670 vs 1500 pg/ml respectively). After adjustment in multivariable Cox proportional hazard analysis, MR proANP strongly predicted one-year all-cause mortality (HR=1.13 (1.09-1.17), per 100 pmol/l increase, p<0.001). In AF patients, NT proBNP and MR proANP have similar diagnostic value for the diagnosis of AHF. The rhythm at presentation has to be taken into account because plasma levels of both peptides are significantly higher in patients with AF compared with SR.

Increased serum N-terminal pro-B-type natriuretic peptide levels in patients with medial arterial calcification and poorly compressible leg arteries.

PubMed

Jouni, Hayan; Rodeheffer, Richard J; Kullo, Iftikhar J

2011-01-01

To determine whether serum levels of N-terminal (NT) pro-B-type natriuretic peptide (pro-BNP) are higher in patients with poorly compressible arteries (PCA) than in patients with peripheral artery disease (PAD) and control subjects without PCA or PAD. Medial arterial calcification in the lower extremities results in PCA and may be associated with increased arterial stiffness and hemodynamic/myocardial stress. PCA was defined as having an ankle-brachial index >1.4 or an ankle blood pressure >255 mm Hg, whereas PAD was defined as having an ankle-brachial index ≤0.9. Study participants with PCA (n=100; aged 71±10 years; 70% men) and age- and sex-matched patients with PAD (n=300) were recruited from the noninvasive vascular laboratory. Age- and sex-matched controls (n=300) were identified from a community-based cohort and had no history of PAD. NT pro-BNP levels were approximately 2.5-fold higher in patients with PCA than in patients with PAD and approximately 4-fold higher than in age- and sex-matched controls. In multivariable regression analyses that adjusted for age, sex, smoking, hypertension, history of coronary heart disease/stroke, systolic blood pressure, and serum creatinine, NT pro-BNP levels remained significantly higher in patients with PCA than in patients with PAD and controls (P<0.001). Patients with medial arterial calcification and PCA have higher serum levels of NT pro-BNP than patients with PAD and controls, which is suggestive of an adverse hemodynamic milieu and increased risk for adverse cardiovascular outcomes.

N-Terminal Pro-B-type Natriuretic Peptide Is Useful to Predict Cardiac Complications Following Lung Resection Surgery

PubMed Central

Lee, Chang Young; Bae, Mi Kyung; Lee, Jin Gu; Kim, Kwan-Wook; Park, In Kyu

2011-01-01

Background Cardiovascular complications are major causes of morbidity and mortality following non-cardiac thoracic operations. Recent studies have demonstrated that elevation of N-Terminal Pro-B-type natriuretic peptide (NT-proBNP) levels can predict cardiac complications following non-cardiac major surgery as well as cardiac surgery. However, there is little information on the correlation between lung resection surgery and NT-proBNP levels. We evaluated the role of NT-proBNP as a potential marker for the risk stratification of cardiac complications following lung resection surgery. Material and Methods Prospectively collected data of 98 patients, who underwent elective lung resection from August 2007 to February 2008, were analyzed. Postoperative adverse cardiac events were categorized as myocardial injury, ECG evidence of ischemia or arrhythmia, heart failure, or cardiac death. Results Postoperative cardiac complications were documented in 9 patients (9/98, 9.2%): Atrial fibrillation in 3, ECG-evidenced ischemia in 2 and heart failure in 4. Preoperative median NT-proBNP levels was significantly higher in patients who developed postoperative cardiac complications than in the rest (200.2 ng/L versus 45.0 ng/L, p=0.009). NT-proBNP levels predicted adverse cardiac events with an area under the receiver operating characteristic curve of 0.76 [95% confidence interval (CI) 0.545~0.988, p=0.01]. A preoperative NT-proBNP value of 160 ng/L was found to be the best cut-off value for detecting postoperative cardiac complication with a positive predictive value of 0.857 and a negative predictive value of 0.978. Other factors related to cardiac complications by univariate analysis were a higher American Society of Anesthesiologists grade, a higher NYHA functional class and a history of hypertension. In multivariate analysis, however, high preoperative NT-proBNP level (>160 ng/L) only remained significant. Conclusion An elevated preoperative NT-proBNP level is identified as an

Prognostic value of N-terminal pro-B-type natriuretic peptide in patients with acute coronary syndromes undergoing left main percutaneous coronary intervention.

PubMed

Jaberg, Laurenz; Toggweiler, Stefan; Puck, Marietta; Frank, Michelle; Rufibach, Kaspar; Lüscher, Thomas F; Corti, Roberto

2011-01-01

Patients undergoing acute left main (LM) coronary artery revascularization have a high mortality and natriuretic peptides such as N-terminal pro-B-type (NT-proBNP) have been shown to have prognostic value in patients with acute coronary syndromes. The present study looked at the prognostic value of NT-proBNP in these patients. We studied all consecutive patients undergoing acute LM coronary artery percutaneous coronary intervention between January 2005 and December 2008 in whom NT-proBNP was measured (n=71). We analyzed the clinical characteristics and the short- and long-term outcomes in relation to NT-proBNP level at admission. Median NT-proBNP was 1,364 ng/L, ranging from 46 to 70,000 ng/L. NT-proBNP was elevated in 63 (89%) patients and was ≥1,000ng/L in 42 (59%). Log NT-proBNP (hazard ratio [HR] 3.51, 95% confidence interval [CI] 1.55-7.97, P=0.003) and left ventricular ejection fraction (HR 0.95, 95%CI 0.91-0.99, P=0.007) were predictors for all-cause mortality. Log NT-proBNP was the only independent significant predictor of cardiovascular mortality. In-hospital mortality was 0% for patients with NT-proBNP <1,000, but 17% for those with NT-proBNP ≥1,000 (P=0.036). NT-proBNP is a strong predictor of outcome in patients undergoing acute LM coronary artery stenting. Mortality in such patients is high, but those with NT-proBNP < 1,000ng/L may have a favorable short- and long-term prognosis. Further research, including a larger patient population, is needed to determine the optimal cut-off value for NT-proBNP in patients undergoing acute LM coronary artery intervention.

No effect of group-based aerobic interval training on N-terminal pro- B-type natriuretic peptide levels in patients with chronic heart failure.

PubMed

Nilsson, Birgitta Blakstad; Westheim, Arne; Risberg, May Arna; Arnesen, Harald; Seljeflot, Ingebjørg

2010-08-01

Exercise training might improve cardiac function as well as functional capacity in patients with chronic heart failure (CHF). N-terminal pro-B-type natriuretic peptide (NT pro-BNP), is associated with the severity of the disease, and has been reported to be an independent predictor of outcome in CHF. We evaluated the effect of a four months group-based aerobic interval training program on circulating levels of NT pro-BNP in patients with CHF. We have previously reported improved functional capacity in 80 patients after exercise in this exercise program. Seventy-eight patients with stable CHF (21% women; 70+/-8 years; left ventricular ejection fraction 30+/-8.6%) on optimal medical treatment were randomized either to interval training (n=39), or to a control group (n=39). Circulating levels of NT pro-BNP, a six minute walk test (6MWT) and cycle ergometer test were evaluated at baseline, post exercise, and further after 12 months. There were no significant differences in NT pro-BNP levels from baseline to either post exercise or long-term follow-up between or within the groups. Inverse correlations were observed between NT pro-BNP and 6MWT (r=-0.24, p=0.035) and cycle exercise time (r=-0.48, p<0.001) at baseline. But no significant correlations were observed between change in NT pro-BNP and change in functional capacity (6MWT; r=0.12, p=0.33, cycle exercise time; r=0.04, p=0.72). No significant changes in NT pro-BNP levels were observed after interval training, despite significant improvement of functional capacity.

Cocoa flavanols reduce N-terminal pro-B-type natriuretic peptide in patients with chronic heart failure.

PubMed

De Palma, Rodney; Sotto, Imelda; Wood, Elizabeth G; Khan, Noorafza Q; Butler, Jane; Johnston, Atholl; Rothman, Martin T; Corder, Roger

2016-06-01

Poor prognosis in chronic heart failure (HF) is linked to endothelial dysfunction for which there is no specific treatment currently available. Previous studies have shown reproducible improvements in endothelial function with cocoa flavanols, but the clinical benefit of this effect in chronic HF has yet to be determined. Therefore, the aim of this study was to assess the potential therapeutic value of a high dose of cocoa flavanols in patients with chronic HF, by using reductions in N-terminal pro-B-type natriuretic peptide (NT-proBNP) as an index of improved cardiac function. Thirty-two patients with chronic HF, stable on guideline-directed medical therapy, were randomized to consume 50 g/day of high-flavanol dark chocolate (HFDC; 1064 mg of flavanols/day) or low-flavanol dark chocolate (LFDC; 88 mg of flavanols/day) for 4 weeks and then crossed over to consume the alternative dark chocolate for a further 4 weeks. Twenty-four patients completed the study. After 4 weeks of HFDC, NT-proBNP (mean decrease % ± standard deviation) was significantly reduced compared with baseline (-44 ± 69%), LFDC (-33 ± 72%), and follow-up (-41 ± 77%) values. HFDC also reduced diastolic blood pressure compared with values after LFDC (-6.7 ± 10.1 mmHg). Reductions in blood pressure and NT-proBNP after HFDC indicate decreased vascular resistance resulting in reduced left ventricular afterload. These effects warrant further investigation in patients with chronic HF.

N-terminal pro-B-type Natriuretic Peptides' Prognostic Utility Is Overestimated in Meta-analyses Using Study-specific Optimal Diagnostic Thresholds.

PubMed

Potgieter, Danielle; Simmers, Dale; Ryan, Lisa; Biccard, Bruce M; Lurati-Buse, Giovanna A; Cardinale, Daniela M; Chong, Carol P W; Cnotliwy, Miloslaw; Farzi, Sylvia I; Jankovic, Radmilo J; Lim, Wen Kwang; Mahla, Elisabeth; Manikandan, Ramaswamy; Oscarsson, Anna; Phy, Michael P; Rajagopalan, Sriram; Van Gaal, William J; Waliszek, Marek; Rodseth, Reitze N

2015-08-01

N-terminal fragment B-type natriuretic peptide (NT-proBNP) prognostic utility is commonly determined post hoc by identifying a single optimal discrimination threshold tailored to the individual study population. The authors aimed to determine how using these study-specific post hoc thresholds impacts meta-analysis results. The authors conducted a systematic review of studies reporting the ability of preoperative NT-proBNP measurements to predict the composite outcome of all-cause mortality and nonfatal myocardial infarction at 30 days after noncardiac surgery. Individual patient-level data NT-proBNP thresholds were determined using two different methodologies. First, a single combined NT-proBNP threshold was determined for the entire cohort of patients, and a meta-analysis conducted using this single threshold. Second, study-specific thresholds were determined for each individual study, with meta-analysis being conducted using these study-specific thresholds. The authors obtained individual patient data from 14 studies (n = 2,196). Using a single NT-proBNP cohort threshold, the odds ratio (OR) associated with an increased NT-proBNP measurement was 3.43 (95% CI, 2.08 to 5.64). Using individual study-specific thresholds, the OR associated with an increased NT-proBNP measurement was 6.45 (95% CI, 3.98 to 10.46). In smaller studies (<100 patients) a single cohort threshold was associated with an OR of 5.4 (95% CI, 2.27 to 12.84) as compared with an OR of 14.38 (95% CI, 6.08 to 34.01) for study-specific thresholds. Post hoc identification of study-specific prognostic biomarker thresholds artificially maximizes biomarker predictive power, resulting in an amplification or overestimation during meta-analysis of these results. This effect is accentuated in small studies.

Assessment of a bedside test for N-terminal pro B-type natriuretic peptide (NT-proBNP) to differentiate cardiac from non-cardiac causes of pleural effusion in cats.

PubMed

Wurtinger, Gabriel; Henrich, Estelle; Hildebrandt, Nicolai; Wiedemann, Nicola; Schneider, Matthias; Hassdenteufel, Esther

2017-12-20

Cats with pleural effusion represent common emergencies in small animal practice. The aim of this prospective study was to investigate the diagnostic ability of a point-of-care ELISA (POC-ELISA) for the measurement of N-terminal pro B-type natriuretic peptide (NT-proBNP) to differentiate cardiac from non-cardiac disease in cats with pleural effusion. The sample material for use of this rapid test was either plasma or diluted pleural effusion. Twenty cats with moderate to severe pleural effusion were prospectively recruited. The cats were grouped into two groups, with or without congestive heart failure (CHF; N-CHF), after complete work-up. Blood and effusion were collected in EDTA tubes. Plasma and pleural effusion supernatants were transferred into stabilizer tubes and frozen. POC-ELISA for NT-proBNP was performed with plasma and diluted effusion (1:1). Quantitative NT-proBNP measurement was performed in plasma and diluted and undiluted effusions. Six cats were assigned to the CHF group. Of the 14 cats in the N-CHF group, 6 had concurrent cardiac abnormalities that were not responsible for the effusion. For the detection of CHF, the test displayed respective sensitivities and specificities of 100% and 79% in plasma and 100% and 86% in diluted pleural fluid. Receiver operating characteristic (ROC) analysis for quantitative NT-proBNP measurement of plasma and diluted and undiluted pleural effusions displayed areas under the curve of 0.98, sensitivities of 100% and specificities of 86%. The optimum cut-off was calculated at 399 pmol/l in plasma and 229 pmol/l in the diluted effusion and 467 pmol/l in the undiluted effusion. POC-ELISA for NT-proBNP in both plasma and diluted pleural effusion was suitable to differentiate cardiac from non-cardiac causes of feline pleural effusion. According to our results, use of pleural effusion is feasible, but dilution of the effusion before measurement seems to improve specificity.

Comparison of usefulness of N-terminal pro-brain natriuretic peptide as an independent predictor of cardiac function among admission cardiac serum biomarkers in patients with anterior wall versus nonanterior wall ST-segment elevation myocardial infarction undergoing primary percutaneous coronary intervention.

PubMed

Haeck, Joost D E; Verouden, Niels J W; Kuijt, Wichert J; Koch, Karel T; Van Straalen, Jan P; Fischer, Johan; Groenink, Maarten; Bilodeau, Luc; Tijssen, Jan G P; Krucoff, Mitchell W; De Winter, Robbert J

2010-04-15

The purpose of the present study was to determine the prognostic value of N-terminal pro-brain natriuretic peptide (NT-pro-BNP), among other serum biomarkers, on cardiac magnetic resonance (CMR) imaging parameters of cardiac function and infarct size in patients with ST-segment elevation myocardial infarction undergoing primary percutaneous coronary intervention. We measured NT-pro-BNP, cardiac troponin T, creatinine kinase-MB fraction, high-sensitivity C-reactive protein, and creatinine on the patients' arrival at the catheterization laboratory in 206 patients with ST-segment elevation myocardial infarction. The NT-pro-BNP levels were divided into quartiles and correlated with left ventricular function and infarct size measured by CMR imaging at 4 to 6 months. Compared to the lower quartiles, patients with nonanterior wall myocardial infarction in the highest quartile of NT-pro-BNP (> or = 260 pg/ml) more often had a greater left ventricular end-systolic volume (68 vs 39 ml/m(2), p <0.001), a lower left ventricular ejection fraction (42% vs 54%, p <0.001), a larger infarct size (9 vs 4 g/m(2), p = 0.002), and a larger number of transmural segments (11% of segments vs 3% of segments, p <0.001). Multivariate analysis revealed that a NT-pro-BNP level of > or = 260 pg/ml was the strongest independent predictor of left ventricular ejection fraction in patients with nonanterior wall myocardial infarction compared to the other serum biomarkers (beta = -5.8; p = 0.019). In conclusion, in patients with nonanterior wall myocardial infarction undergoing primary percutaneous coronary intervention, an admission NT-pro-BNP level of > or = 260 pg/ml was a strong, independent predictor of left ventricular function assessed by CMR imaging at follow-up. Our findings suggest that NT-pro-BNP, a widely available biomarker, might be helpful in the early risk stratification of patients with nonanterior wall myocardial infarction. Copyright 2010 Elsevier Inc. All rights reserved.

N-terminal fragment of cardiac myosin binding protein-C triggers pro-inflammatory responses in vitro

PubMed Central

Lipps, Christoph; Nguyen, Jenine H.; Pyttel, Lukas; Lynch, Thomas L.; Liebetrau, Christoph; Aleshcheva, Ganna; Voss, Sandra; Dörr, Oliver; Nef, Holger M.; Möllmann, Helge; Hamm, Christian W.; Sadayappan, Sakthivel; Troidl, Christian

2016-01-01

Myocardial infarction (MI) leads to loss and degradation of contractile cardiac tissue followed by sterile inflammation of the myocardium through activation and recruitment of innate and adaptive cells of the immune system. Recently, it was shown that cardiac myosin binding protein-C (cMyBP-C), a protein of the cardiac sarcomere, is degraded following MI, releasing a predominant N-terminal 40-kDa fragment (C0C1f) into myocardial tissue and the systemic circulation. We hypothesized that early release of C0C1f contributes to the initiation of inflammation and plays a key role in recruitment and activation of immune cells. Therefore, we investigated the role of C0C1f on macrophage / monocyte activation using both mouse bone marrow-derived macrophages and human monocytes. Here we demonstrate that C0C1f leads to macrophage / monocyte activation in vitro. Furthermore, C0C1f induces strong upregulation of pro-inflammatory cytokines (interleukin-6 (IL-6), tumor necrosis factor α (TNFα), and interleukin-1β (IL-1β)) in cultured murine macrophages and human monocytes, resulting in a pro-inflammatory phenotype. We identified the toll-like receptor 4 (TLR4), toll-like receptor 2 (TLR2), and Advanced Glycosylation End Product-Specific Receptor (RAGE) as potential receptors for C0C1f whose activation leads to mobilization of the NFκB signaling pathway, a central mediator of the pro-inflammatory signaling cascade. Thus, C0C1f appears to be a key player in the initiation of inflammatory processes and might also play an important role upon MI. PMID:27616755

Impact of Body Mass Index on Plasma N-Terminal ProB-Type Natriuretic Peptides in Chinese Atrial Fibrillation Patients without Heart Failure

PubMed Central

Zheng, Li-hui; Wu, Ling-min; Yao, Yan; Chen, Wen-sheng; Bao, Jing-ru; Huang, Wen; Shi, Rui; Zhang, Kui-jun; Zhang, Shu

2014-01-01

Background An inverse relationship between body mass index (BMI) and circulating levels of N-terminal proB-type natriuretic peptide (NT-proBNP) has been demonstrated in subjects with and without heart failure. Obesity also has been linked with increased incidence of atrial fibrillation (AF), but its influence on NT-proBNP concentrations in AF patients remains unclear. This study aimed to investigate the effect of BMI on NT-proBNP levels in AF patients without heart failure. Methods A total of 239 consecutive patients with AF undergoing catheter ablation were evaluated. Levels of NT-proBNP and clinical characteristics were compared in overweight or obese (BMI≥25 kg/m2) and normal weight (BMI<25 kg/m2) patients. Results Of 239 patients, 129 (54%) were overweight or obese. Overweight or obese patients were younger, more likely to have a history of nonparoxysmal AF, hypertension, and diabetes mellitus. Levels of NT-proBNP were significantly lower in overweight or obese than in normal weight subjects (P<0.05). The relationship of obesity and decreased NT-proBNP levels persisted in subgroup of hypertension, both gender and both age levels (≥65 yrs and <65 yrs).Multivariate linear regression identified BMI as an independent negative correlate of LogNT-proBNP level. Conclusions An inverse relationship between BMI and plasma NT-proBNP concentrations have been demonstrated in AF patients without heart failure. Overweight or obese patients with AF appear to have lower NT-proBNP levels than normal weight patients. PMID:25144363

N-terminal pro-brain natriuretic peptide measurements in hemodynamically significant patent ductus arteriosus in preterm infants.

PubMed

Alenazi, Shehab Ahmed

2016-01-01

Evaluate the role of NT-proBNP levels in Preterm neonates suffering from PDA and used as a screening tool for predicting HsPDA and guiding physicians to consider early echocardiographic evaluation. This is a monocentric prospective blind study which was conducted at Arar Central Hospital, Ar'ar, Saudi Arabia, during the period between Jan 2014 to June 2014. Thirty-three (33) preterm infants born at less than 31 weeks of gestation or weighing less than 1200 g at birth infants were initially enrolled during a 6-month period. Blood samples were collected along with routine blood tests on days 1, 2, 3, and 7 of life for NT-proBNP analysis. Two echocardiographies were systematically performed on day two of life to ascertain about the status of Ductus Arteriosus. The Plasma NT-proBNP levels were high on day one of life and decline from day three to day seven of life except in those infants with significant hsPDA. Plasma NT-proNBP levels on day 2 of infants in the HsPDA group were significantly higher (<0.001) than those in non-HsPDA group. Echocardiogram parameters indicates the significant difference (p<0.002) in Left Atrial and Aortic ratio (LA/AO), Interventricular septum thickness (P<0.03), Left ventricular posterior wall thickness (p<0.05), diastole PDA gradient (p<0.005) between HsPDA and non-HsPDA. Plasma NT-proBNP level peaked during the first few days after birth and declined rapidly within a week. Therefore, its level may have a role as a screening tool to predict HsPDA and provide more information regarding its spontaneous closure or otherwise.

Comparable increase of B-type natriuretic peptide and amino-terminal pro-B-type natriuretic peptide levels in patients with severe sepsis, septic shock, and acute heart failure.

PubMed

Rudiger, Alain; Gasser, Stefan; Fischler, Manuel; Hornemann, Thorsten; von Eckardstein, Arnold; Maggiorini, Marco

2006-08-01

B-type natriuretic peptide (BNP) and N-terminal pro-BNP measurements are used for the diagnosis of congestive heart failure (HF). However, the diagnostic value of these tests is unknown under septic conditions. We compared patients with severe sepsis or septic shock and patients with acute HF to unravel the influence of the underlying diagnosis on BNP and N-terminal pro-BNP levels. Prospective, clinical study. Academic medical intensive care unit (ICU). A total of 249 consecutive patients were screened for the diagnosis of sepsis or HF. Sepsis was defined according to published guidelines. HF was diagnosed in the presence of an underlying heart disease and congestive HF, pulmonary edema, or cardiogenic shock. BNP and N-terminal pro-BNP were measured from blood samples that were drawn daily for routine analysis. We identified 24 patients with severe sepsis or septic shock and 51 patients with acute HF. At admission, the median (range) BNP and N-terminal pro-BNP levels were 572 (13-1,300) and 6,526 (198-70,000) ng/L in patients with sepsis and 581 (6-1,300) and 4,300 (126-70,000) ng/L in patients with HF. The natriuretic peptide levels increased during the ICU stay, but the differences between the groups were not significant. Nine patients with sepsis and eight patients with HF were monitored with a pulmonary artery catheter. Mean (sd) pulmonary artery occlusion pressure were 16 (4.2) and 22 (5.3) mm Hg (p = .02), and cardiac indexes were 4.6 (2.8) and 2.2 (0.6) L/min/m (p = .03) in patients with sepsis and HF, respectively. Despite these clear hemodynamic differences BNP and N-terminal pro-BNP levels were not statistically different between the two groups. In patients with severe sepsis or septic shock, BNP and N-terminal pro-BNP values are highly elevated and, despite significant hemodynamic differences, comparable with those found in acute HF patients. It remains to be determined how elevations of natriuretic peptide levels are linked to inflammation and sepsis

Coincidence of moderately elevated N-terminal pro-B-type natriuretic peptide, endothelial progenitor cells deficiency and propensity to exercise-induced myocardial ischemia in stable angina.

PubMed

Surdacki, Andrzej; Marewicz, Ewa; Rakowski, Tomasz; Szumańska, Monika; Szastak, Grzegorz; Pryjma, Juliusz; Dubiel, Jacek S

2010-01-01

To assess endothelial progenitor cells (EPC) counts, a novel prognostic marker, in relation to classical adverse outcome predictors - N-terminal pro-B-type natriuretic peptide (NT-proBNP), impaired left ventricular (LV) relaxation and exercise-induced ischemia - in stable coronary artery disease (CAD) with preserved LV systolic function. We studied 30 non-diabetic men with one-vessel CAD, LV ejection fraction 60% and normal LV diastolic function (n=16) or impaired LV relaxation (by ultrasound including tissue Doppler) (n=14), and 14 non-CAD controls matched for risk profile and medication. CD34+/kinase-insert domain receptor (KDR)+ cells (CD34+/KDR+ cells), a leukocytes subpopulation enriched for EPC, were enumerated by flow cytometry. CAD patients with abnormal LV relaxation exhibited significantly elevated NT-proBNP and decreased CD34+/KDR+ cells vs. CAD with regular diastolic function and non-CAD controls. An inverse NT-proBNP-CD34+/KDR+ cells relationship was precipitated by the clustering of high resting NT-proBNP and low CD34+/KDR+ cells in the subjects with a lower Duke treadmill score. Propensity to symptomatic exertional ischemia may underlie the coincidence of moderately elevated NT-proBNP and EPC deficiency in stable angina. Additionally, chronic subclinical ischemia can also be involved in these associations. These might result from BNP overexpression in the ischemic myocardium and a hypothetical exhaustion of the bone marrow capacity to mobilize EPC at multiple ischemic episodes, thus contributing to NT-proBNP prognostic effect irrespective of hemodynamic factors.

High N-Terminal Pro-B-Type Natriuretic Peptide Levels Are Associated with Reduced Heart Rate Variability in Acute Myocardial Infarction

PubMed Central

Lorgis, Luc; Moreau, Daniel; Mock, Laurent; Daumas, Bernadette; Potard, Daniel; Touzery, Claude; Cottin, Yves; Zeller, Marianne

2012-01-01

Aim We investigated the relationships between the autonomic nervous system, as assessed by heart rate variability (HRV) and levels of N-terminal Pro-B-type Natriuretic Peptide (Nt-proBNP) in patients with acute myocardial infarction (MI). Methods and Results The mean of standard deviation of RR intervals (SDNN), the percentage of RR intervals with >50 ms variation (pNN50), square root of mean squared differences of successive RR intervals (rMSSD), and frequency domain parameters (total power (TP), high frequency and low frequency power ratio (LF/HF)) were assessed by 24 h Holter ECG monitoring. 1018 consecutive patients admitted <24 h for an acute MI were included. Plasma Nt-proBNP (Elecsys, Roche) was measured from blood samples taken on admission. The median (IQR) Nt-proBNP level was 681(159–2432) pmol/L. Patients with the highest quartile of Nt-proBNP were older, with higher rate of risk factors and lower ejection fraction. The highest Nt-proBNP quartile group had the lowest SDNN, LF/HF and total power but similar pNN50 and rMSSD levels. Nt-proBNP levels correlated negatively with SDNN (r = −0.19, p<0.001), LF/HF (r = −0.37, p<0.001), and LF (r = −0.29, p<0.001) but not HF (r = −0.043, p = 0.172). Multiple regression analysis showed that plasma propeptide levels remained predictive of LF/HF (B(SE) = −0.065(0.015), p<0.001)), even after adjustment for confounders. Conclusions In conclusion, our population-based study highlights the importance of Nt-proBNP levels to predict decreased HRV after acute MI. PMID:23071500

Structure and Function of the Sterol Carrier Protein-2 N-Terminal Presequence†

PubMed Central

Martin, Gregory G.; Hostetler, Heather A.; McIntosh, Avery L.; Tichy, Shane E.; Williams, Brad J.; Russell, David H.; Berg, Jeremy M.; Spencer, Thomas A.; Ball, Judith; Kier, Ann B.; Schroeder, Friedhelm

2008-01-01

Although sterol carrier protein-2 (SCP-2) is encoded as a precursor protein (proSCP-2), little is known regarding the structure and function of the 20-amino acid N-terminal presequence. As shown herein, the presequence contains significant secondary structure and alters SCP-2: (i) secondary structure (CD), (ii) tertiary structure (aqueous exposure of Trp shown by UV absorbance, fluorescence, fluorescence quenching), (iii) ligand binding site [Trp response to ligands, peptide cross-linked by photoactivatable free cholesterol (FCBP)], (iv) selectivity for interaction with anionic phospholipid-rich membranes, (v) interaction with a peroxisomal import protein [FRET studies of Pex5p(C) binding], the N-terminal presequence increased SCP-2’s affinity for Pex5p(C) by 10-fold, and (vi) intracellular targeting in living and fixed cells (confocal microscopy). Nearly 5-fold more SCP-2 than proSCP-2 colocalized with plasma membrane lipid rafts/caveolae (AF488-CTB), 2.8-fold more SCP-2 than proSCP-2 colocalized with a mitochondrial marker (Mitotracker), but nearly 2-fold less SCP-2 than proSCP-2 colocalized with peroxisomes (AF488-antibody to PMP70). These data indicate the importance of the N-terminal presequence in regulating SCP-2 structure, cholesterol localization within the ligand binding site, membrane association, and, potentially, intracellular targeting. PMID:18465878

Association of N-Terminal Pro B-Type Natriuretic Peptide With Blood Pressure and Pulse Pressure in Elderly People　- A Cross-Sectional Population Study.

PubMed

Sasaki, Nobuo; Yamamoto, Hideya; Ozono, Ryoji; Fujiwara, Saeko; Kihara, Yasuki

2018-05-23

N-Terminal pro B-type natriuretic peptide (NT-proBNP) is widely used as a marker of ventricular dysfunction. However, data regarding the association of NT-proBNP with blood pressure (BP) and pulse pressure (PP) in the elderly population are limited.Methods and Results:The present cross-sectional study involved 6,529 participants, aged ≥70 years, without cardiovascular disease (CVD), who underwent general health examinations. Serum NT-proBNP concentrations were determined, with high NT-proBNP concentrations defined as those ≥125 pg/mL. Subjects were divided into five groups based on PP (<50, ≥50 to <60, ≥60 to <70, ≥70 to <80, and ≥80 mmHg). NT-proBNP was positively associated with systolic BP, whereas a U-shaped association was found between diastolic BP and NT-proBNP. The odds ratios for high NT-proBNP concentrations in the PP ≥80 and ≥70 to <80 mmHg groups (OR 1.83 [P<0.001] and 1.40 [P<0.005], respectively) were significantly higher than in the PP <50 mmHg group. All data were adjusted for age, sex, body mass index, hemoglobin concentration, serum creatinine, pulse rate, smoking, alcohol intake, and antihypertensive medication intake, and the presence of diabetes and dyslipidemia. The results suggest that NT-proBNP concentrations may be a marker of not only ventricular dysfunction, but also arterial stiffness in the elderly population without CVD.

Dynamic detection of N-terminal pro-B-type natriuretic peptide helps to predict the outcome of patients with major trauma.

PubMed

Qian, A; Zhang, M; Zhao, G

2015-02-01

NT-proBNP and BNP have been demonstrated to be prognostic markers in cardiac disease and sepsis. However, the prognostic value and the dynamic changes of BNP or NT-proBNP in trauma patients remain unclear. The present study was conducted to investigate the dynamic changes of NT-proBNP in patients with major trauma (injury severity score ≥16), determine whether NT-proBNP could be used as a simple index to predict mortality in major trauma patients. This prospective observational study included 60 patients with major trauma. Serum NT-proBNP levels were measured on the 1st, 3rd and 7th day after injury The NT-proBNP levels in survivors were compared with those in non-survivors. The efficacy of NT-proBNP to predict survival was analyzed using receiver operating characteristic curves. An analysis of correlations between NT-proBNP and various factors, including injury severity score, Glasgow coma score, acute physiology and chronic health evaluation II, central venous pressure, creatine kinase-MB, cardiac troponin I and procalcitonin (PCT) was performed. NT-proBNP levels in patients with traumatic brain injury were compared with those in patients without traumatic brain injury. A comparison of NT-proBNP levels between patients with and without sepsis was also performed at each time point. NT-proBNP levels in non-survivors were significantly higher than those in survivors at all the indicated time points. In the group of non-survivors, NT-proBNP levels on the 7th day were markedly higher than those on the 1st day. In contrast, NT-proBNP levels in survivors showed a reduction over time. The efficacy of NT-proBNP to predict survival was analyzed using ROC curves, and there was no difference in the area under the ROC between NT-proBNP and APACHE II/ISS at the three time points. A significant correlation was found between NT-proBNP and ISS on the 1st day, NT-proBNP and CK-MB, Tn-I and APACHE II on the 3rd day, NT-proBNP and PCT on the 7th day. There were no significant

Brain-Targeted (Pro)Renin Receptor Knockdown attenuates Angiotensin II-Dependent Hypertension

PubMed Central

Li, Wencheng; Peng, Hua; Cao, Theresa; Sato, Ryosuke; McDaniels, Sarah. J.; Kobori, Hiroyuki; Navar, L. Gabriel; Feng, Yumei

2012-01-01

The (pro)renin receptor is a newly discovered member of the brain renin-angiotensin system. To investigate the role of brain (pro)renin receptor in hypertension, adeno-associated virus-mediated (pro)renin receptor shRNA was used to knockdown (pro)renin receptor expression in the brain of non-transgenic normotensive and human renin-angiotensinogen double transgenic hypertensive mice. Blood pressure was monitored using implanted telemetric probes in conscious animals. Real-time PCR and immunostaining were performed to determine (pro)renin receptor, angiotensin II type 1 receptor and vasopressin mRNA levels. Plasma vasopressin levels were determined by Enzyme-Linked Immuno Sorbent Assay. Double transgenic mice exhibited higher blood pressure, elevated cardiac and vascular sympathetic tone, and impaired spontaneous baroreflex sensitivity. Intracerebroventricular delivery of (pro)renin receptor shRNA significantly reduced blood pressure, cardiac and vasomotor sympathetic tone, and improved baroreflex sensitivity compared to the control virus treatment in double transgenic mice. (Pro)renin receptor knockdown significantly reduced angiotensin II type 1 receptor and vasopressin levels in double transgenic mice. These data indicate that (pro)renin receptor knockdown in the brain attenuates angiotensin II-dependent hypertension and is associated with a decrease insympathetic tone and an improvement of the baroreflex sensitivity. In addition, brain-targeted (pro)renin receptor knockdown is associated with down-regulation of angiotensin II type 1 receptor and vasopressin levels. We conclude that central (pro)renin receptor contributes to the pathogenesis of hypertension in human renin-angiotensinogen transgenic mice. PMID:22526255

SES, Heart Failure, and N-terminal Pro-b-type Natriuretic Peptide: The Atherosclerosis Risk in Communities Study.

PubMed

Vart, Priya; Matsushita, Kunihiro; Rawlings, Andreea M; Selvin, Elizabeth; Crews, Deidra C; Ndumele, Chiadi E; Ballantyne, Christie M; Heiss, Gerardo; Kucharska-Newton, Anna; Szklo, Moyses; Coresh, Josef

2018-02-01

Compared with coronary heart disease and stroke, the association between SES and the risk of heart failure is less well understood. In 12,646 participants of the Atherosclerosis Risk in Communities Study cohort free of heart failure history at baseline (1987-1989), the association of income, educational attainment, and area deprivation index with subsequent heart failure-related hospitalization or death was examined while accounting for cardiovascular disease risk factors and healthcare access. Because SES may affect threshold of identifying heart failure and admitting for heart failure management, secondarily the association between SES and N-terminal pro-b-type natriuretic peptide (NT-proBNP) levels, a marker reflecting cardiac overload, was investigated. Analysis was conducted in 2016. During a median follow-up of 24.3 years, a total of 2,249 participants developed heart failure. In a demographically adjusted model, the lowest-SES group had 2.2- to 2.5-fold higher risk of heart failure compared with the highest SES group for income, education, and area deprivation. With further adjustment for time-varying cardiovascular disease risk factors and healthcare access, these associations were attenuated but remained statistically significant (e.g., hazard ratio=1.92, 95% CI=1.69, 2.19 for the lowest versus highest income), with no racial interaction (p>0.05 for all SES measures). Similarly, compared with high SES, low SES was associated with both higher baseline level of NT-proBNP in a multivariable adjusted model (15% higher, p<0.001) and increase over time (~1% greater per year, p=0.023). SES was associated with clinical heart failure as well as NT-proBNP levels inversely and independently of traditional cardiovascular disease factors and healthcare access. Copyright © 2018 American Journal of Preventive Medicine. Published by Elsevier Inc. All rights reserved.

Regional differences in the expression of brain-derived neurotrophic factor (BDNF) pro-peptide, proBDNF and preproBDNF in the brain confer stress resilience.

PubMed

Yang, Bangkun; Yang, Chun; Ren, Qian; Zhang, Ji-Chun; Chen, Qian-Xue; Shirayama, Yukihiko; Hashimoto, Kenji

2016-12-01

Using learned helplessness (LH) model of depression, we measured protein expression of brain-derived neurotrophic factor (BDNF) pro-peptide, BDNF precursors (proBDNF and preproBDNF) in the brain regions of LH (susceptible) and non-LH rats (resilience). Expression of preproBDNF, proBDNF and BDNF pro-peptide in the medial prefrontal cortex of LH rats, but not non-LH rats, was significantly higher than control rats, although expression of these proteins in the nucleus accumbens of LH rats was significantly lower than control rats. This study suggests that regional differences in conversion of BDNF precursors into BDNF and BDNF pro-peptide by proteolytic cleavage may contribute to stress resilience.

Association of cardiac and renal function with extreme N-terminal fragment pro-B-type natriuretic peptide levels in elderly patients.

PubMed

Cui, Hua; Huo, Guoliang; Liu, Lin; Fan, Li; Ye, Ping; Cao, Jian; Bai, Yongyi; Wang, Fan; Hu, Yixin

2012-07-26

The data are inconsistent regarding whether extreme N-terminal fragment pro-B-type natriuretic peptide (NT pro-BNP) levels are associated with impaired renal function. Furthermore, the relationship between extreme NT pro-BNP levels and cardiac and renal function in elderly patients has not been reported. The aim of the present study was to examine a hypothesis that extreme NT pro-BNP levels may be associated with impaired cardiac and renal function in elderly patients. We retrospectively analyzed the data of demographic, clinical, and echocardiographic features on 152 consecutive elderly patients aged more than 80 years old (average age, 83.65 ± 3.58 years) with NT pro-BNP levels ≥ 3000 pg/ml. The participants were divided into two categories according to their NT pro-BNP levels: (1) 3000-10000 pg/mL and (2) >10000 pg /mL. The number of patients with impaired renal function (P = 0.019) and the mortality (P < 0.001) in the period of inpatient was higher in the group with NT pro-BNP > 10000 pg /mL. The levels of serum creatinine and creatine kinase MB (CK-MB) in the group of NT pro-BNP > 10000 pg / mL were higher than those in the group of NT pro-BNP = 3000-10000 pg/mL (P = 0.001 and P = 0.023, respectively). Furthermore, no significant difference in the distribution by NYHA class in different NT pro-BNP levels was observed. Multiple linear regression analyses demonstrated that with NT pro-BNP levels as the dependent variable, NT pro-BNP levels were positively correlated with CK-MB (β = 0.182, P = 0.024) and creatinine levels (β = 0.281, P = 0.001). The area under the receiver-operating characteristic (ROC) curve of NT pro-BNP levels and clinical diagnosis of impaired renal function was 0.596 and reached significant difference (95%CI:0.503-0.688, P = 0.044). These data suggest that the extreme elevation of NT pro-BNP levels (≥3000 pg/ml) is mainly determined by impaired renal function in

[Expression of proBNP and NT-proBNP in Sudden Death of Coronary Heart Disease].

PubMed

Zeng, Q; Sun, R F; Li, Z; Zhai, L Q; Liu, M Z; Guo, X J; Gao, C R

2017-10-01

To study the expression change of pro-brain natriuretic peptide （proBNP） and N-terminal pro-brain natriuretic peptide （NT-proBNP） in sudden death of coronary atherosclerotic heart disease, and to explore its application in forensic diagnosis. Myocardial and blood samples were collected from normal control group, sudden death of coronary atherosclerotic heart disease group and single coronary stenosis group （20 cases in each group）. The expression of proBNP in myocardial samples were detected by immunohistochemical staining and Western blotting, and that of BNP mRNA were detected by reverse transcription PCR （RT-PCR）. The content of NT-proBNP in plasma were detected by ELISA. Immunohistochemical staining showed positive expression of proBNP in both sudden death of coronary atherosclerotic heart disease group and single coronary stenosis group. There was no positive expression in normal control group. For sudden death of coronary atherosclerotic heart disease group and single coronary stenosis group, the relative expression of proBNP protein and BNP mRNA in myocardial tissue and the NT-proBNP content in plasma were higher than that of normal control group （ P <0.05）. The NT-proBNP content in plasma of sudden death of coronary atherosclerotic heart disease group was higher than that of single coronary stenosis group （ P <0.05）. In myocardial ischemia condition, the higher expression of proBNP in cardiac muscle cell shows that the detection of NT-proBNP in plasma can be useful to differentially diagnose the degree of coronary atherosclerotic heart disease and determine whether the sudden death due to coronary atherosclerotic heart disease. Copyright© by the Editorial Department of Journal of Forensic Medicine

Association between N-terminal proB-type Natriuretic Peptide and Depressive Symptoms in Patients with Acute Myocardial Infarction

PubMed Central

Ren, Yan; Jia, Jiao; Sa, Jian; Qiu, Li-Xia; Cui, Yue-Hua; Zhang, Yue-An; Yang, Hong; Liu, Gui-Fen

2017-01-01

Background: While depression and certain cardiac biomarkers are associated with acute myocardial infarction (AMI), the relationship between them remains largely unexplored. We examined the association between depressive symptoms and biomarkers in patients with AMI. Methods: We performed a cross-sectional study using data from 103 patients with AMI between March 2013 and September 2014. The levels of depression, N-terminal proB-type natriuretic peptide (NT-proBNP), and troponin I (TnI) were measured at baseline. The patients were divided into two groups: those with depressive symptoms and those without depressive symptoms according to Zung Self-rating Depression Scale (SDS) score. Baseline comparisons between two groups were made using Student's t-test for continuous variables, Chi-square or Fisher's exact test for categorical variables, and Wilcoxon test for variables in skewed distribution. Binomial logistic regression and multivariate linear regression were performed to assess the association between depressive symptoms and biomarkers while adjusting for demographic and clinical variables. Results: Patients with depressive symptoms had significantly higher NT-proBNP levels as compared to patients without depressive symptoms (1135.0 [131.5, 2474.0] vs. 384.0 [133.0, 990.0], Z = −2.470, P = 0.013). Depressive symptoms were associated with higher NT-proBNP levels (odds ratio [OR] = 2.348, 95% CI: 1.344 to 4.103, P = 0.003) and higher body mass index (OR = 1.169, 95% confidence interval [CI]: 1.016 to 1.345, P = 0.029). The total SDS score was associated with the NT-proBNP level (β = 0.327, 95% CI: 1.674 to 6.119, P = 0.001) after multivariable adjustment. In particular, NT-proBNP was associated with three of the depressive dimensions, including core depression (β = 0.299, 95% CI: 0.551 to 2.428, P = 0.002), cognitive depression (β = 0.320, 95% CI: 0.476 to 1.811, P = 0.001), and somatic depression (β = 0.333, 95% CI: 0.240 to 0.847, P = 0.001). Neither the

Long-term effects of peroxisome proliferator-activated receptor ligand bezafibrate on N-terminal pro-B type natriuretic peptide in patients with advanced functional capacity impairment

PubMed Central

Node, Koichi; Inoue, Teruo; Boyko, Valentin; Goldberg, Ilan; Fisman, Enrique Z; Adler, Yehuda; Schwammenthal, Ehud; Matas, Zipora; Behar, Solomon; Tenenbaum, Alexander

2009-01-01

Background The effects of pan-peroxisome proliferator-activated receptor (PPAR) ligand bezafibrate on N-terminal pro-B type natriuretic peptide (ProBNP) level in patients with coronary artery disease (CAD) is unknown. The current study aimed to investigate the long-term effects of bezafibrate on ProBNP level in patients with pre-existing CAD and advanced functional capacity impairment. Methods Metabolic and inflammatory parameters were analyzed from stored frozen serum samples obtained from 108 patients enrolled in the Bezafibrate Infarction Prevention (BIP) Study. They presented with New York Heart Association (NYHA) functional class III, comprising 58 patients in the bezafibrate group and 50 in the placebo groups, and completed a 2-year prospective, double-blind, placebo-controlled follow-up. Results During follow-up ProBNP level did not change significantly in the placebo group, whereas it increased slightly in the bezafibrate group, which was older and with lower baseline ProBNP values. No significant differences between the groups were found for ProBNP levels after 2 year of follow-up. Analysis-of-covariance (ANCOVA) -taking into account age and baseline ProBNP level- showed that bezafibrate was not associated with longitudinal ProBNP changes during the follow-up period (p = 0.3). Conclusion Long-term treatment by bezafibrate was not associated with longitudinal ProBNP changes in patients with pre-existing CAD and advanced functional capacity impairment. PMID:19173749

Cautious Application of Pleural N-Terminal Pro-B-Type Natriuretic Peptide in Diagnosis of Congestive Heart Failure Pleural Effusions among Critically Ill Patients

PubMed Central

Yeh, Jiann-Horng; Huang, Chun-Ta; Liu, Chia-Hsiung; Ruan, Sheng-Yuan; Tsai, Yi-Ju; Chien, Ying-Chun; Yang, Ching-Yao; Huang, Chun-Kai; Hsu, Chia-Lin; Kuo, Lu-Cheng; Lee, Pei-Lin; Ku, Shih-Chi; Kuo, Ping-Hung; Yu, Chong-Jen

2014-01-01

Background and Objective Several studies on diagnostic accuracy of pleural N-terminal pro-B-type natriuretic peptide (NT-pro-BNP) for effusions from congestive heart failure (CHF) conclude that pleural NT-pro-BNP is a useful biomarker with high diagnostic accuracy for distinguishing CHF effusions. However, its applicability in critical care settings remains uncertain and requires further investigations. Methods NT-proBNP was measured in pleural fluid samples of a prospective cohort of intensive care unit patients with pleural effusions. Receiver operating characteristic curve analysis was performed to determine diagnostic accuracy of pleural NT-proBNP for prediction of CHF effusions. Results One hundred forty-seven critically ill patients were evaluated, 38 (26%) with CHF effusions and 109 (74%) with non-CHF effusions of various causes. Pleural NT-proBNP levels were significantly elevated in patients with CHF effusions. Pleural NT-pro-BNP demonstrated the area under the curve of 0.87 for diagnosing effusions due to CHF. With a cutoff of 2200 pg/mL, pleural NT-proBNP displayed high sensitivity (89%) but moderate specificity (73%). Notably, 29 (27%) of 109 patients with non-CHF effusions had pleural NT-proBNP levels >2200 pg/mL and these patients were more likely to experience septic shock (18/29 vs. 10/80, P<0.001) or acute kidney injury (19/29 vs. 9/80, P<0.001). Conclusions Among critically ill patients, pleural NT-proBNP measurements remain a useful diagnostic aid in evaluation of pleural effusions. However, patients with non-CHF effusions may exhibit high pleural NT-proBNP concentrations if they suffer from septic shock or acute kidney injury. Accordingly, it is suggested that clinical context should be taken into account when interpreting pleural NT-proBNP values in critical care settings. PMID:25502236

N-Terminal Pro-B Type Natriuretic Peptide as a Marker of Bronchopulmonary Dysplasia or Death in Very Preterm Neonates: A Cohort Study

PubMed Central

Sellmer, Anna; Hjortdal, Vibeke Elisabeth; Bjerre, Jesper Vandborg; Schmidt, Michael Rahbek; McNamara, Patrick J.; Bech, Bodil Hammer; Henriksen, Tine Brink

2015-01-01

Background Bronchopulmonary dysplasia (BPD) is a serious complication of preterm birth. Plasma N-terminal pro-B type natriuretic peptide (NT-proBNP) has been suggested as a marker that may predict BPD within a few days after birth. Objectives To investigate the association between NT-proBNP day three and bronchopulmonary dysplasia (BPD) or death and further to assess the impact of patent ductus arteriosus (PDA) on this association in neonates born before 32 gestational weeks. Methods A cohort study of 183 neonates born before 32 gestational weeks consecutively admitted to the Neonatal Intensive Care Unit, Aarhus University Hospital, Denmark. On day three plasma samples were collected and echocardiography carried out. NT-proBNP was measured by routine immunoassays. The combined outcome BPD or death was assessed at 36 weeks of postmenstrual age. Receiver operator characteristic (ROC) analysis was performed to determine the discrimination ability of NT-proBNP by the natural log continuous measure to recognize BPD or death. The association of BPD or death was assessed in relation to natural log NT-proBNP levels day three. Results The risk of BPD or death increased 1.7-fold with one unit increase of natural log NT-proBNP day three when adjusted for gestational age at birth (OR = 1.7, 95% CI 1.3; 2.3). The association was found both in neonates with and without a PDA. Adjusting for GA, PDA diameter, LA:Ao-ratio, or early onset sepsis did not change the estimate. Conclusion We found NT-proBNP to be associated with BPD or death in very preterm neonates. This association was not only explained by the PDA. We speculate that NT-proBNP may help the identification of neonates at risk of BPD as early as postnatal day three. PMID:26452045

Usefulness of repeated N-terminal pro-B-type natriuretic peptide measurements as incremental predictor for long-term cardiovascular outcome after vascular surgery.

PubMed

Goei, Dustin; van Kuijk, Jan-Peter; Flu, Willem-Jan; Hoeks, Sanne E; Chonchol, Michel; Verhagen, Hence J M; Bax, Jeroen J; Poldermans, Don

2011-02-15

Plasma N-terminal pro-B-type natriuretic peptide (NT-pro-BNP) levels improve preoperative cardiac risk stratification in vascular surgery patients. However, single preoperative measurements of NT-pro-BNP cannot take into account the hemodynamic stress caused by anesthesia and surgery. Therefore, the aim of the present study was to assess the incremental predictive value of changes in NT-pro-BNP during the perioperative period for long-term cardiac mortality. Detailed cardiac histories, rest left ventricular echocardiography, and NT-pro-BNP levels were obtained in 144 patients before vascular surgery and before discharge. The study end point was the occurrence of cardiovascular death during a median follow-up period of 13 months (interquartile range 5 to 20). Preoperatively, the median NT-pro-BNP level in the study population was 314 pg/ml (interquartile range 136 to 1,351), which increased to a median level of 1,505 pg/ml (interquartile range 404 to 6,453) before discharge. During the follow-up period, 29 patients (20%) died, 27 (93%) from cardiovascular causes. The median difference in NT-pro-BNP in the survivors was 665 pg/ml, compared to 5,336 pg/ml in the patients who died (p = 0.01). Multivariate Cox regression analyses, adjusted for cardiac history and cardiovascular risk factors (age, angina pectoris, myocardial infarction, stroke, diabetes mellitus, renal dysfunction, body mass index, type of surgery and the left ventricular ejection fraction), demonstrated that the difference in NT-pro-BNP level between pre- and postoperative measurement was the strongest independent predictor of cardiac outcome (hazard ratio 3.06, 95% confidence interval 1.36 to 6.91). In conclusion, the change in NT-pro-BNP, indicated by repeated measurements before surgery and before discharge is the strongest predictor of cardiac outcomes in patients who undergo vascular surgery. Copyright © 2011 Elsevier Inc. All rights reserved.

Value of amino-terminal pro B-natriuretic peptide in diagnosing Kawasaki disease.

PubMed

McNeal-Davidson, Ariane; Fournier, Anne; Spigelblatt, Linda; Saint-Cyr, Claire; Mir, Thomas S; Nir, Amiram; Dallaire, Frédéric; Cousineau, Jocelyne; Delvin, Edgard; Dahdah, Nagib

2012-10-01

The aim of the present study was to investigate the diagnostic value of the N-terminal B-type natriuretic peptide (NT-proBNP) in acute Kawasaki disease (KD) given that the clinical criteria and the current basic laboratory tests lack the necessary specificity for accurate diagnosis. Basic biological tests and serum NT-proBNP levels obtained from acute KD patients were compared to that of febrile controls. NT-proBNP was considered abnormal based on the following definitions: above a cut-off determined on receiver operator characteristic (ROC) analysis, above the upper limit for age, or above 2 SD calculated from healthy children. Analyses were also performed for KD cases with complete or incomplete criteria combined and separately. There were 81 patients and 49 controls aged 3.60 ± 2.77 versus 4.25 ± 3.88 years (P= 0.69). ROC analysis yielded significant area under the curve for NT-proBNP. The sensitivity, specificity, positive and negative predictive values were 70.4-88.9%, 69.4-91.8%, 82.8-93.4%, and 65.2-79.1%. The odds ratios based on NT-proBNP definitions varied between 18.13 (95% confidence interval [CI]: 7.21-45.57), 20.82 (95%CI: 8.18-53.0), and 26.71 (95%CI: 8.64-82.57; P < 0.001). Results were reproducible for cases with complete or incomplete criteria separately. NT-proBNP is a reliable marker for the diagnosis of KD. Prospective clinical studies with emphasis on NT-proBNP in a diagnostic algorithm are needed. © 2012 The Authors. Pediatrics International © 2012 Japan Pediatric Society.

Outcome of hospitalised heart failure in Japan and the United Kingdom stratified by plasma N-terminal pro-B-type natriuretic peptide.

PubMed

Shiraishi, Yasuyuki; Nagai, Toshiyuki; Kohsaka, Shun; Goda, Ayumi; Nagatomo, Yuji; Mizuno, Atsushi; Kohno, Takashi; Rigby, Alan; Fukuda, Keiichi; Yoshikawa, Tsutomu; Clark, Andrew L; Cleland, John G F

2018-05-21

Mortality subsequent to a hospitalisation for heart failure is reported to be much lower in Japan than in the United Kingdom (UK). This could reflect differences in disease severity or in management. Accordingly, we directly compared patient backgrounds and outcomes between Japan and UK. Consecutive patients admitted to academic hospitals in the UK and Japan with heart failure had a common set of variables, including plasma concentrations of N-terminal pro-B-type natriuretic peptide (NT-proBNP), collected during admission. Mortality during hospitalisations, at 90 and 180 days was recorded and stratified by quintile of NT-proBNP. Overall, 935 patients were enrolled; 197 from UK and 738 from Japan. Median (interquartile range) age [UK: 78 (71-88) vs. Japan: 78 (70-84) years; p = 0.947], glomerular filtration rate [UK: 49 (34-68) vs. Japan: 49 (33-65) ml/min/1.73 m 2 ; p = 0.209] and plasma NT-proBNP [UK: 4957 (2278-10,977) vs. Japan: 4155 (1972-9623) ng/l; p = 0.186] were similar, but systolic blood pressure was lower in the UK [118 (105-131) vs. 137 (118-159) mmHg; p < 0.001]. Patients with a higher plasma NT-proBNP had a worse prognosis in both countries; in-hospital and post-discharge mortality rates were higher in the UK even after adjusting for prognostic variables including NT-proBNP. This analysis suggests that either unobserved differences in patient characteristics or differences in care (formal or informal) rather than greater heart failure severity may account for the worse outcome of heart failure in the UK compared to Japan.

N-terminal fraction of pro-B-type natriuretic peptide versus clinical risk scores for prognostic stratification in chronic systolic heart failure.

PubMed

Arzilli, Chiara; Aimo, Alberto; Vergaro, Giuseppe; Ripoli, Andrea; Senni, Michele; Emdin, Michele; Passino, Claudio

2018-05-01

Background The Seattle heart failure model or the cardiac and comorbid conditions (3C-HF) scores may help define patient risk in heart failure. Direct comparisons between them or versus N-terminal fraction of pro-B-type natriuretic peptide (NT-proBNP) have never been performed. Methods Data from consecutive patients with stable systolic heart failure and 3C-HF data were examined. A subgroup of patients had the Seattle heart failure model data available. The endpoints were one year all-cause or cardiovascular death. Results The population included 2023 patients, aged 68 ± 12 years, 75% were men. At the one year time-point, 198 deaths were recorded (10%), 124 of them (63%) from cardiovascular causes. While areas under the curve were not significantly different, NT-proBNP displayed better reclassification capability than the 3C-HF score for the prediction of one year all-cause and cardiovascular death. Adding NT-proBNP to the 3C-HF score resulted in a significant improvement in risk prediction. Among patients with Seattle heart failure model data available ( n = 798), the area under the curve values for all-cause and cardiovascular death were similar for the Seattle heart failure model score (0.790 and 0.820), NT-proBNP (0.783 and 0.803), and the 3C-HF score (0.770 and 0.800). The combination of the 3C-HF score and NT-proBNP displayed a similar prognostic performance to the Seattle heart failure model score for both endpoints. Adding NT-proBNP to the Seattle heart failure model score performed better than the Seattle heart failure model alone in terms of reclassification, but not discrimination. Conclusions Among systolic heart failure patients, NT-proBNP levels had better reclassification capability for all-cause and cardiovascular death than the 3C-HF score. The inclusion of NT-proBNP to the 3C-HF and Seattle heart failure model score resulted in significantly better risk stratification.

Unraveling the Molecular Complexity of O-Glycosylated Endogenous (N-Terminal) pro-B-Type Natriuretic Peptide Forms in Blood Plasma of Patients with Severe Heart Failure.

PubMed

Halfinger, Bernhard; Hammerer-Lercher, Angelika; Amplatz, Benno; Sarg, Bettina; Kremser, Leopold; Lindner, Herbert H

2017-01-01

Currently, N-terminal pro-B-type natriuretic peptide (NT-proBNP) and its physiologically active counterpart, BNP, are most frequently used as biomarkers for diagnosis, prognosis, and disease monitoring of heart failure (HF). Commercial NT-proBNP and BNP immunoassays cross-react to varying degrees with unprocessed proBNP, which is also found in the circulation. ProBNP processing and immunoassay response are related to O-linked glycosylation of NT-proBNP and proBNP. There is a clear and urgent need to identify the glycosylation sites in the endogenously circulating peptides requested by the community to gain further insights into the different naturally occurring forms. The glycosylation sites of (NT-) proBNP (NT-proBNP and/or proBNP) were characterized in leftovers of heparinized plasma samples of severe HF patients (NT-proBNP: >10000 ng/L) by using tandem immunoaffinity purification, sequential exoglycosidase treatment for glycan trimming, β-elimination and Michael addition chemistry, as well as high-resolution nano-flow liquid chromatography electrospray multistage mass spectrometry. We describe 9 distinct glycosylation sites on circulating (NT-) proBNP in HF patients. Differentially glycosylated variants were detected based on highly accurate mass determination and multistage mass spectrometry. Remarkably, for each of the identified proteolytic glycopeptides, a nonglycosylated form also was detectable. Our results directly demonstrate for the first time a rather complex distribution of the endogenously circulating glycoforms by mass spectrometric analysis in HF patients, and show 9 glycosites in human (NT-) proBNP. This information may also have an impact on commercial immunoassays applying antibodies specific for the central region of (NT-) proBNP, which detect mostly nonglycosylated forms. © 2016 American Association for Clinical Chemistry.

Association of N-Terminal Pro-B-Type Natriuretic Peptide with Left Ventricular Structure and Function in Chronic Kidney Disease (From the Chronic Renal Insufficiency Cohort [CRIC])

PubMed Central

Mishra, Rakesh K.; Li, Yongmei; Ricardo, Ana C.; Yang, Wei; Keane, Martin; Cuevas, Magdalena; Christenson, Robert; DeFilippi, Christopher; Chen, Jing; He, Jiang; Kallem, Radhakrishna R.; Raj, Dominic S.; Schelling, Jeffrey R.; Wright, Jackson; Go, Alan S.; Shlipak, Michael G.

2017-01-01

We evaluated the cross-sectional associations of N-terminal pro-B-type natriuretic peptide (NT-proBNP) with cardiac structural and functional abnormalities in a cohort of chronic kidney disease (CKD) patients without clinical heart failure (HF), the Chronic Renal Insufficiency Cohort (n=3,232). Associations of NT-proBNP with echocardiographically determined left ventricular (LV) mass and LV systolic and diastolic function were evaluated by multivariable logistic and linear regression models. Reclassification of participants’ predicted risk of LV hypertrophy (LVH), systolic and diastolic dysfunction was performed using a category-free net reclassification improvement (NRI) index that compared a clinical model with and without NT-proBNP. The median (interquartile range) NT-proBNP was 126.6 pg/ml (55.5–303.7). The highest quartile of NT-proBNP was associated with nearly three-fold odds of LVH (odds ratio (OR) 2.7, 95% confidence interval (CI) 1.8–4.0) and LV systolic dysfunction (2.7, 1.7–4.5) and two-fold odds of diastolic dysfunction (2.0, 1.3–2.9) in the fully adjusted models. When evaluated alone as a screening test, NT-proBNP functioned modestly for the detection of LVH (area under the curve, AUC 0.66) and LV systolic dysfunction (AUC 0.62), and poorly for the detection of diastolic dysfunction (AUC 0.51). However, when added to the clinical model, NT-proBNP significantly reclassified participants’ likelihood of having LVH (NRI 0.14, 95% CI 0.13–0.15; p<0.001) and LV systolic dysfunction (0.28, 0.27–0.30; p<0.001), but not diastolic dysfunction (0.10, 0.10–0.11; p=0.07). In conclusion, in this large CKD cohort without HF, NT-proBNP had strong associations with prevalent LVH and LV systolic dysfunction. PMID:23178053

A combination of increased Rho kinase activity and N-terminal pro-B-type natriuretic peptide predicts worse cardiovascular outcome in patients with acute coronary syndrome

PubMed Central

Dong, Ming; Liao, James K.; Yan, Bryan; Li, Ruijie; Zhang, Mang; Yu, Cheuk-Man

2013-01-01

Background Recent experimental evidence suggests that the Rho/Rho-kinase (ROCK) system may play an important role in the pathogenesis of acute coronary syndrome (ACS) but there are little clinical data. This study examined if ROCK activity is increased in patients with acute coronary syndrome and if ROCK activity predicts long-term cardiovascular event. Method Blood samples were collected from 188 patients within 12 h after admission for ACS (53% men; aged 70±13) and from 61 control subject. The main outcome measures were all cause mortality, readmission with ACS or congestive heart failure (CHF) from presentation within around 2 years (mean:14.4±7.2 months; range: 0.5 to 26 months). Results ROCK activity increased in ST elevation myocardial infarction (STEMI, n=90) (3.33±0.93), non-STEMI (NSTEMI, n=68) (3.37±1.04) and unstable angina (UA, n=30) (2.53±0.59) groups when compared with disease controls (n=31) (2.06±0.38, all p<0.001) and healthy controls (n=30) (1.54±0.43, all p<0.001). There were 24 deaths, 34 readmissions with ACS and 15 admissions with CHF within 2 years. Patients with a high N-terminal pro-B-type natriuretic peptide (NT-proBNP) and high ROCK activity on admission had a five-fold risk of a cardiovascular event (RR: 5.156; 95% CI: 2.180–12.191) when compared to those with low NT-proBNP and low ROCK activity. Conclusion ROCK activity was increased in patients with ACS, particularly in those with myocardial infarction. The combined usage of both ROCK activity and NT-proBNP might identify a subset of ACS patients at particularly high risk. PMID:22921817

N-terminal acetylation modulates Bax targeting to mitochondria.

PubMed

Alves, Sara; Neiri, Leire; Chaves, Susana Rodrigues; Vieira, Selma; Trindade, Dário; Manon, Stephen; Dominguez, Veronica; Pintado, Belen; Jonckheere, Veronique; Van Damme, Petra; Silva, Rui Duarte; Aldabe, Rafael; Côrte-Real, Manuela

2018-02-01

The pro-apoptotic Bax protein is the main effector of mitochondrial permeabilization during apoptosis. Bax is controlled at several levels, including post-translational modifications such as phosphorylation and S-palmitoylation. However, little is known about the contribution of other protein modifications to Bax activity. Here, we used heterologous expression of human Bax in yeast to study the involvement of N-terminal acetylation by yNaa20p (yNatB) on Bax function. We found that human Bax is N-terminal (Nt-)acetylated by yNaa20p and that Nt-acetylation of Bax is essential to maintain Bax in an inactive conformation in the cytosol of yeast and Mouse Embryonic Fibroblast (MEF) cells. Bax accumulates in the mitochondria of yeast naa20Δ and Naa25 -/- MEF cells, but does not promote cytochrome c release, suggesting that an additional step is required for full activation of Bax. Altogether, our results show that Bax N-terminal acetylation by NatB is involved in its mitochondrial targeting. Copyright © 2017 Elsevier Ltd. All rights reserved.

NT-pro Brain Natriuretic Peptide Levels and the Risk of Death in the Cooperative Study of Sickle Cell Disease

PubMed Central

Machado, Roberto F.; Hildesheim, Mariana; Mendelsohn, Laurel; Remaley, Alan T.; Kato, Gregory J.; Gladwin, Mark T.

2011-01-01

Epidemiological studies support a hypothesis that pulmonary hypertension (PH) is a common complication of sickle cell disease (SCD) that is associated with a high risk of death and evolves as a complication of haemolytic anaemia. This fundamental hypothesis has been recently challenged and remains controversial. In order to further test this hypothesis in a large and independent cohort of SCD patients we obtained plasma samples from the Cooperative Study of Sickle Cell Disease (CSSCD) for analysis of a biomarker, N-terminal-pro brain natriuretic peptide (NT-proBNP), which is elevated in the setting of pulmonary arterial and venous hypertension. A NT-pro-BNP value previously identified to predict PH in adults with SCD was used to determine the association between the risk of mortality in 758 CSSCD participants (428 children and 330 adults). An abnormally high NT-proBNP level ≥160 ng/l was present in 27.6 % of adult SCD patients. High levels were associated with markers of haemolytic anaemia, such as low haemoglobin level (P<0.001), high lactate dehydrogenase (P<0.001), and high total bilirubin levels (P<0.007). A NT-proBNP level ≥160 ng/l was an independent predictor of mortality (RR 6.24, 95% CI 2.9–13.3, P<0.0001). These findings provide further support for an association between haemolytic anaemia and cardiovascular complications in this patient population. PMID:21689089

NT-pro brain natriuretic peptide levels and the risk of death in the cooperative study of sickle cell disease.

PubMed

Machado, Roberto F; Hildesheim, Mariana; Mendelsohn, Laurel; Remaley, Alan T; Kato, Gregory J; Gladwin, Mark T

2011-08-01

Epidemiological studies support a hypothesis that pulmonary hypertension (PH) is a common complication of sickle cell disease (SCD) that is associated with a high risk of death and evolves as a complication of haemolytic anaemia. This fundamental hypothesis has been recently challenged and remains controversial. In order to further test this hypothesis in a large and independent cohort of SCD patients we obtained plasma samples from the Cooperative Study of Sickle Cell Disease (CSSCD) for analysis of a biomarker, N-terminal-pro brain natriuretic peptide (NT-proBNP), which is elevated in the setting of pulmonary arterial and venous hypertension. A NT-pro-BNP value previously identified to predict PH in adults with SCD was used to determine the association between the risk of mortality in 758 CSSCD participants (428 children and 330 adults). An abnormally high NT-proBNP level ≥160ng/l was present in 27·6% of adult SCD patients. High levels were associated with markers of haemolytic anaemia, such as low haemoglobin level (P<0·001), high lactate dehydrogenase (P<0·001), and high total bilirubin levels (P<0·007). A NT-proBNP level ≥160ng/l was an independent predictor of mortality (RR 6·24, 95% CI 2·9-13·3, P<0·0001). These findings provide further support for an association between haemolytic anaemia and cardiovascular complications in this patient population. © 2011 Blackwell Publishing Ltd.

Associations between N-terminal pro-B-type natriuretic peptide and cardiac function in adults with corrected tetralogy of Fallot.

PubMed

Eindhoven, Jannet A; Menting, Myrthe E; van den Bosch, Annemien E; Cuypers, Judith A A E; Ruys, Titia P E; Witsenburg, Maarten; McGhie, Jackie S; Boersma, Eric; Roos-Hesselink, Jolien W

2014-07-01

Amino-terminal B-type natriuretic peptide (NT-proBNP) may detect early cardiac dysfunction in adults with tetralogy of Fallot (ToF) late after corrective surgery. We aimed to determine the value of NT-proBNP in adults with ToF and establish its relationship with echocardiography and exercise capacity. NT-proBNP measurement, electrocardiography and detailed 2D-echocardiography were performed on the same day in 177 consecutive adults with ToF (mean age 34.6 ± 11.8 years, 58% male, 89% NYHA I, 29.3 ± 8.5 years after surgical correction). Thirty-eight percent of the patients also underwent a cardiopulmonary-exercise test. Median NT-proBNP was 16 [IQR 6.7-33.6] pmol/L, and was elevated in 55%. NT-proBNP correlated with right ventricular (RV) dilatation (r = 0.271, p < 0.001) and RV systolic dysfunction (r = -0.195, p = 0.022), but more strongly with LV systolic dysfunction (r=-0.367, p<0.001), which was present in 69 patients (39%). Moderate or severe pulmonary regurgitation was not associated with higher NT-proBNP. Tricuspid and pulmonary regurgitation peak velocities correlated with NT-proBNP (r = 0.305, p < 0.001 and r = 0.186, p = 0.045, respectively). LV twist was measured with speckle-tracking echocardiography in 71 patients. An abnormal LV twist (20 patients, 28%) was associated with elevated NT-proBNP (p = 0.030). No relationship between NT-proBNP and exercise capacity was found. NT-proBNP levels are elevated in more than 50% of adults with corrected ToF, while they are in stable clinical condition. Higher NT-proBNP is most strongly associated with elevated pulmonary pressures, and with LV dysfunction rather than RV dysfunction. NT-proBNP has the potential to become routine examination in patients with ToF to monitor ventricular function and may be used for timely detection of clinical deterioration. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

The influence of metabolic syndrome and diabetes mellitus on the N-terminal pro-B-type natriuretic peptide level and its prognostic performance in patients with coronary artery disease.

PubMed

Huang, Fang-Yang; Peng, Yong; Deng, Xue-Xue; Huang, Bao-Tao; Xia, Tian-Li; Gui, Yi-Yue; Liu, Rui-Shuang; Yang, Yong; Pu, Xiao-Bo; Chen, Shi-Jian; Chen, Fei; Zhu, Ye; Chen, Mao

2017-03-01

Our aim was to investigate whether the presence of metabolic syndrome (MetS) and diabetes mellitus (DM) influenced the N-terminal pro-B-type natriuretic peptide (NT-proBNP) level and its prognostic performance in coronary artery disease (CAD). The present study enrolled a total of 1638 CAD patients. Multivariate regression analyses were carried out to relate NT-proBNP to metabolic components, nondiabetic MetS, DM, and MetS score. Furthermore, we examined the prognostic performance of NT-proBNP in patients with non-MetS, nondiabetic MetS, and DM. NT-proBNP levels correlated inversely with BMI (β=-0.11, P=0.003) and correlated positively with fasting glucose (β=0.12, P=0.001). There were no significant relationships of NT-proBNP with other metabolic parameters. Compared with non-MetS, the presence of DM significantly increased NT-proBNP levels (P=0.004), whereas nondiabetic MetS did not influence NT-proBNP levels (P=0.954). During the median follow-up of 21 months, 109 all-cause deaths occurred. NT-proBNP levels independently predicted all-cause deaths irrespective of the presence of nondiabetic MetS and DM (Pinteraction=0.43). DM, but not nondiabetic MetS, is associated with higher NT-proBNP levels. NT-proBNP can still predict death in patients with CAD, even with the confounding effect of MetS and diabetes.

Association between serum N-terminal pro-B-type natriuretic peptide levels and characteristics of coronary atherosclerotic plaque detected by coronary computed tomography angiography.

PubMed

Gan, Lu; Feng, Cong; Liu, Chunlei; Tian, Shuping; Song, Xiang; Yang, Li

2016-08-01

The aim of the present study was to explore the association between the levels of serum N-terminal pro-B-type natriuretic peptide (NT-pro BNP) and the characteristics of coronary atherosclerotic plaque detected by coronary computed tomography angiography (CCTA), in patients with unstable angina (UA). A total of 202 patients (age range, 47-82 years) were divided into the following three groups: Non-cardiac disease group (57 patients); stable angina pectoris (SAP) group (62 patients); and UA group (83 patients). There were significant differences between the serum NT-pro BNP levels among the three groups (P=0.007). However, in multivariant diagnoses, NT-pro BNP level was not an independent risk factor for UA. The levels of serum NT-pro BNP were observed to be positively correlated with the number of vessels involved (r=0.462; P<0.001), SIS (r=0.475; P<0.001), segment-stenosis score (r=0.453; P<0.001), coronary calcification score (r=0.412; P=0.001), number of obstructive diseases (r=0.346; P<0.001), and the number of segments with non-calcified plaque (r=0.235; P=0.017), mixed plaque (r=0.234; P=0.017) and calcified plaque (r=0.431; P<0.001). The levels of serum NT-pro BNP were significantly higher in patients with UA and left main-left anterior descending (LM-LAD) disease, compared with UA patients without LM-LAD disease (P<0.001). In addition, serum NT-pro BNP was significantly higher in patients with obstructive disease and UA than in those without obstructive disease (P<0.001). The area under the curve of log(NT-pro BNP) was 0.656 (P=0.006; optimal cut-off value, 1.74; sensitivity, 77.6%; specificity, 51.9%). In conclusion, the levels of serum NT-pro BNP are associated with the burden and severity of coronary artery atherosclerotic disease in patients with UA, and may be helpful in risk stratification of patients with UA.

Association between serum N-terminal pro-B-type natriuretic peptide levels and characteristics of coronary atherosclerotic plaque detected by coronary computed tomography angiography

PubMed Central

Gan, Lu; Feng, Cong; Liu, Chunlei; Tian, Shuping; Song, Xiang; Yang, Li

2016-01-01

The aim of the present study was to explore the association between the levels of serum N-terminal pro-B-type natriuretic peptide (NT-pro BNP) and the characteristics of coronary atherosclerotic plaque detected by coronary computed tomography angiography (CCTA), in patients with unstable angina (UA). A total of 202 patients (age range, 47–82 years) were divided into the following three groups: Non-cardiac disease group (57 patients); stable angina pectoris (SAP) group (62 patients); and UA group (83 patients). There were significant differences between the serum NT-pro BNP levels among the three groups (P=0.007). However, in multivariant diagnoses, NT-pro BNP level was not an independent risk factor for UA. The levels of serum NT-pro BNP were observed to be positively correlated with the number of vessels involved (r=0.462; P<0.001), SIS (r=0.475; P<0.001), segment-stenosis score (r=0.453; P<0.001), coronary calcification score (r=0.412; P=0.001), number of obstructive diseases (r=0.346; P<0.001), and the number of segments with non-calcified plaque (r=0.235; P=0.017), mixed plaque (r=0.234; P=0.017) and calcified plaque (r=0.431; P<0.001). The levels of serum NT-pro BNP were significantly higher in patients with UA and left main-left anterior descending (LM-LAD) disease, compared with UA patients without LM-LAD disease (P<0.001). In addition, serum NT-pro BNP was significantly higher in patients with obstructive disease and UA than in those without obstructive disease (P<0.001). The area under the curve of log(NT-pro BNP) was 0.656 (P=0.006; optimal cut-off value, 1.74; sensitivity, 77.6%; specificity, 51.9%). In conclusion, the levels of serum NT-pro BNP are associated with the burden and severity of coronary artery atherosclerotic disease in patients with UA, and may be helpful in risk stratification of patients with UA. PMID:27446259

Investigation of an N-Terminal Prohormone of Brain Natriuretic Peptide Point-of-Care ELISA in Clinically Normal Cats and Cats With Cardiac Disease.

PubMed

Harris, A N; Beatty, S S; Estrada, A H; Winter, B; Bohannon, M; Sosa, I; Hanscom, J; Mainville, C A; Gallagher, A E

2017-07-01

N-terminal prohormone of brain natriuretic peptide (NT-proBNP) concentrations may be increased in cats with various cardiac disorders. The point-of-care (POC) ELISA assay uses the same biologic reagents as the quantitative NT-proBNP ELISA. Previous studies have evaluated the sensitivity and specificity of the POC ELISA in cats with cardiac disease. To prospectively evaluate the diagnostic utility of the POC ELISA in a select population of cats. Thirty-eight client-owned cats presented to the University of Florida Cardiology Service for cardiac evaluation. Fifteen apparently healthy cats recruited as part of another study. Physical examination and echocardiography were performed in all cats. The POC ELISA was assessed visually as either positive or negative by a reader blinded to the echocardiographic findings, and results were analyzed relative to quantitative assay results. Twenty-six cats were diagnosed with underlying cardiac disease, and 27 cats were considered free of cardiac disease. Cats with cardiac disease included: 21 with hypertrophic cardiomyopathy, 2 with unclassified cardiomyopathy, 2 with restrictive cardiomyopathy, and 1 with 3rd degree atrioventricular (AV) block. The POC ELISA differentiated cats with cardiac disease with a sensitivity of 65.4% and specificity of 100%. The POC NT-proBNP ELISA performed moderately well in a selected population of cats. A negative test result cannot exclude the presence of underlying cardiac disease, and a positive test result indicates that cardiac disease likely is present, but further diagnostic investigation would be indicated for a definitive diagnosis. Copyright © 2017 The Authors. Journal of Veterinary Internal Medicine published by Wiley Periodicals, Inc. on behalf of the American College of Veterinary Internal Medicine.

Limitations of N-Terminal Pro-B-Type Natriuretic Peptide in the Diagnosis of Heart Disease among Cancer Patients Who Present with Cardiac or Pulmonary Symptoms.

PubMed

Wieshammer, Siegfried; Dreyhaupt, Jens; Müller, Dirk; Momm, Felix; Jakob, Andreas

2016-01-01

Recognizing heart disease is relevant to oncologists because cancer patients are at an increased risk of cardiac mortality due to shared risk factors and the adverse effects of cancer therapy. This study assessed the extent to which the measurement of N-terminal pro-B-type natriuretic peptide (NT-proBNP) aids in the diagnosis of heart disease in addition to a history of coronary artery disease and the presence of atrial fibrillation (composite test). The NT- proBNP cutoff value was 100 pg/ml. A series of 583 consecutive cancer patients (68.4 ± 11.0 years) who were referred because of cardiac or pulmonary symptoms prospectively underwent a diagnostic work-up. Heart disease was diagnosed if at least one of the following conditions was present: (a) history of coronary artery disease, (b) atrial fibrillation, (c) impaired left ventricular systolic function, (d) significant valvular disease, (e) pulmonary hypertension, or (f) left ventricular hypertrophy. Except for (a), all 6 conditions were associated with NT-proBNP >100 pg/ml. The sensitivity/specificity values of the composite test were 0.92/0.50 for any heart disease. Several extracardiac covariates were associated with NT-proBNP >100 pg/ml, which contributed to the low test specificity. The low specificity of NT-proBNP limits its value for the diagnosis of heart disease in cancer patients. © 2016 The Author(s) Published by S. Karger AG, Basel.

Prognostic value of plasma midregional pro-adrenomedullin and C-terminal-pro-endothelin-1 in chronic heart failure outpatients.

PubMed

Adlbrecht, Christopher; Hülsmann, Martin; Strunk, Guido; Berger, Rudolf; Mörtl, Deddo; Struck, Joachim; Morgenthaler, Nils G; Bergmann, Andreas; Jakowitsch, Johannes; Maurer, Gerald; Lang, Irene M; Pacher, Richard

2009-04-01

The identification of chronic heart failure (CHF) patients at high risk of adverse outcome remains a challenge. New peptides are emerging that may give additional information. In CHF patients, endothelin (ET) levels predict mortality risk. Adrenomedullin has been shown to predict mortality in ischaemic heart failure, but not in unselected or non-ischaemic CHF patients. Moreover, ADM and ET have never been assessed in one model. The aim of the present study was to assess the prognostic value of midregional-pro-adrenomedullin (MR-proADM) and C-terminal-pro-endothelin-1 (CT-proET-1) in outpatients with CHF. We measured plasma MR-proADM and CT-proET-1 levels in 786 consecutive CHF outpatients and compared them with B-type natriuretic peptide (BNP) levels. At 24-month follow-up, 233 patients had died. A stepwise forward Cox regression model with age, sex, estimated glomerular filtration rate, NYHA > II, left ventricular ejection fraction (LVEF), MR-proADM, CT-proET-1, and BNP as possible predictors revealed that MR-proADM levels [hazard ratio (HR) = 1.77, P < 0.001] in addition to age (HR = 1.02, P = 0.004), ejection fraction (HR = 0.98, P = 0.004), and NYHA > II (HR = 1.86, P < 0.001) were predictors of death at 24 months. When the analysis was repeated dependent on NYHA-stage, MR-proADM (HR = 2.12, P < 0.001) and LVEF (HR = 0.96, P = 0.006) were significant markers, but only in patients with mild/moderate CHF. Our data suggest that MR-proADM may be an important prognostic humoral marker, especially in mild/moderately symptomatic and non-ischaemic CHF patients.

The interrelationship between preoperative anemia and N-terminal pro-B-type natriuretic peptide: the effect on predicting postoperative cardiac outcome in vascular surgery patients.

PubMed

Goei, Dustin; Flu, Willem-Jan; Hoeks, Sanne E; Galal, Wael; Dunkelgrun, Martin; Boersma, Eric; Kuijper, Ruud; van Kuijk, Jan-Peter; Winkel, Tamara A; Schouten, Olaf; Bax, Jeroen J; Poldermans, Don

2009-11-01

N-terminal pro-B-type natriuretic peptide (NT-proBNP) predicts adverse cardiac outcome in patients undergoing vascular surgery. However, several conditions might influence this prognostic value, including anemia. In this study, we evaluated whether anemia confounds the prognostic value of NT-proBNP for predicting cardiac events in patients undergoing vascular surgery. A detailed cardiac history, resting echocardiography, and hemoglobin and NT-proBNP levels were obtained in 666 patients before vascular surgery. Anemia was defined as serum hemoglobin <13 g/dL for men and <12 g/dL for women. Troponin T measurements and 12-lead electrocardiograms were performed on postoperative days 1, 3, 7, and 30 and whenever clinically indicated. The primary end point of the study was the composite of 30-day postoperative cardiovascular death, nonfatal myocardial infarction, and troponin T release. Receiver operating characteristic curve analysis was used to assess the optimal cutoff value of NT-proBNP for the prediction of the composite end point. Multivariable regression analysis was used to assess the additional value of NT-proBNP for the prediction of postoperative cardiac events in nonanemic and anemic patients. Anemia was present in 206 patients (31%) before surgery. Hemoglobin level was inversely related with the NT-proBNP levels (beta coefficient = -2.242; P = 0.025). The optimal predictive cutoff value of NT-proBNP for predicting the composite cardiovascular outcome was 350 pg/mL. After adjustment for clinical cardiac risk factors, both anemia (odds ratio [OR] 1.53; 95% confidence interval [CI]: 1.07-2.99) and increased levels of NT-proBNP (OR 4.09; 95% CI: 2.19-7.64) remained independent predictors for postoperative cardiac events. However, increased levels of NT-proBNP were not predictive for the risk of adverse cardiac events in the subgroup of anemic patients (OR 2.16; 95% CI: 0.90-5.21). Both anemia and NT-proBNP are independently associated with an increased risk for

Association of plasma N-terminal pro-B-type natriuretic peptide concentration with mitral regurgitation severity and outcome in dogs with asymptomatic degenerative mitral valve disease.

PubMed

Chetboul, V; Serres, F; Tissier, R; Lefebvre, H P; Sampedrano, C Carlos; Gouni, V; Poujol, L; Hawa, G; Pouchelon, J -L

2009-01-01

The clinical outcome of dogs affected by degenerative mitral valve disease (MVD) without overt clinical signs is still poorly defined, and criteria for identification of animals that are at a higher risk of early decompensation have not yet been determined. N-terminal pro-B-type natriuretic peptide plasma concentration (NT-proBNP) is correlated with mitral regurgitation (MR) severity and can predict disease progression in dogs with asymptomatic MVD. Seventy-two dogs with asymptomatic MVD, with or without heart enlargement (International Small Animal Cardiac Health Council: ISACHC classes 1a and 1b), and a control group of 22 dogs were prospectively recruited. Severity of MR was quantitatively assessed from the regurgitation fraction (RF) by the proximal isovelocity surface area method. Consequences of MR were evaluated from measurements of the left atrium/aorta ratio (LA/Ao), fractional shortening (FS), end-diastolic and end-systolic left ventricular volumes indexed to body surface area (EDVI and ESVI). The relevance of these echo-Doppler indices and NT-proBNP for prediction of outcome at 12 months was studied. A significant correlation was found between NT-proBNP and RF, LA/Ao, FS, and EDVI (P < .05). NT-proBNP was higher in dogs with MVD (ISACHC classes 1a and 1b) compared with the control group (P= .025 and < .001, respectively). The difference was not significant when only dogs from ISACHC class 1a with RF < 30% were considered. Lastly, NT-proBNP was higher in dogs that underwent MVD decompensation at 12 months (P < .05). NT-proBNP is correlated with MVD severity and prognosis in dogs with asymptomatic MVD.

Immunohistochemical evidence for the involvement of protein convertases 5A and 2 in the processing of pro-neurotensin in rat brain.

PubMed

Villeneuve, P; Lafortune, L; Seidah, N G; Kitabgi, P; Beaudet, A

2000-08-28

The neuropeptides/neurotransmitters neurotensin (NT) and neuromedin (NN) are synthesized by endoproteolytic cleavage of a common inactive precursor, pro-NT/NN. In vitro studies have suggested that the prohormone convertases PC5A and PC2 might both be involved in this process. In the present study, we used dual immunohistochemical techniques to determine whether either one or both of these two convertases were co-localized with pro-NT/NN maturation products and could therefore be involved in the physiological processing of this propeptide in rat brain. PC2-immunoreactive neurons were present in all regions immunopositive for NT. All but three regions expressing NT were also immunopositive for PC5A. Dual localization of NT with either convertase revealed that NT was extensively co-localized with both PC5A and PC2, albeit with regional differences. These results strongly suggest that PC5A and PC2 may play a key role in the maturation of pro-NT/NN in mammalian brain. The regional variability in NT/PC co-localization patterns may account for the region-specific maturation profiles previously reported for pro-NT/NN. The high degree of overlap between PC5A and PC2 in most NT-rich areas further suggests that these two convertases may act jointly to process pro-NT/NN. At the subcellular level, PC5A was largely co-localized with the mid-cisternae Golgi marker MG-160. By contrast, PC2 was almost completely excluded from MG-160-immunoreactive compartments. These results suggest that PC5A, which is particularly efficient at cleaving the two C-terminal-most dibasics of pro-NT/NN, may be acting as early as in the Golgi apparatus to release NT, whereas PC2, which is considerably more active than PC5A in cleaving the third C-terminal doublet, may be predominantly involved further distally along the secretory pathway to release NN. Copyright 2000 Wiley-Liss, Inc.

Prognostic Value of N-Terminal Pro-B-Type Natriuretic Peptide Levels in Heart Failure Patients With and Without Atrial Fibrillation.

PubMed

Kristensen, Søren Lund; Jhund, Pardeep S; Mogensen, Ulrik M; Rørth, Rasmus; Abraham, William T; Desai, Akshay; Dickstein, Kenneth; Rouleau, Jean L; Zile, Michael R; Swedberg, Karl; Packer, Milton; Solomon, Scott D; Køber, Lars; McMurray, John J V

2017-10-01

Patients with heart failure (HF) and atrial fibrillation (AF) have higher circulating levels of NT-proBNP (N-terminal pro-B-type natriuretic peptide) than HF patients without AF. There is uncertainty about the prognostic importance of a given concentration of NT-proBNP in HF patients with and without AF. We investigated this question in a large cohort of patients with HF and reduced ejection fraction. We studied 14 737 patients with HF and reduced ejection fraction and a measurement of NT-proBNP at time of screening, enrolled in either the PARADIGM-HF trial (Prospective Comparison of ARNI With ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure) or the ATMOSPHERE trial (Aliskiren Trial to Minimize Outcomes in Patients With Heart Failure), of whom 3575 (24%) had AF on their baseline ECG. Median (Q1, Q3) levels of NT-proBNP were 1817 pg/mL (1095-3266 pg/mL) in those with AF and 1271 pg/mL (703-2569 pg/mL) in those without ( P <0.0001). Patients with AF were older (67 versus 62 years), had worse New York Heart Association class (III/IV; 36% versus 24%), and experienced fewer previous HF hospitalizations (52% versus 61%) or myocardial infarction (30% versus 46%); all P <0.001. We categorized patients with and without AF into 5 NT-proBNP bands: <400, 400 to 999 (reference), 1000 to 1999, 2000 to 2999, and ≥3000 pg/mL. For the primary composite outcome of cardiovascular death or HF hospitalization, event rates differed for patients with and without AF in the lowest band (<400 pg/mL; 8.2 versus 5.0 per 100 patient-years), but not for the higher bands (400-999 pg/mL, 7.4 versus 7.7 per 100 patient-years; 1000-1999 pg/mL, 9.8 versus 11.4 per 100 patient-year; 2000-2999 pg/mL, 13.5 versus 13.4 per 100 patient-years; ≥3000 pg/mL, 22.7 versus 23.0 per 100 patient-years). These findings were consistent whether NT-proBNP was examined as a categorical or continuous variable and before and after adjustment for other prognostic variables. We found

Effects of pre- and pro-sequence of thaumatin on the secretion by Pichia pastoris.

PubMed

Ide, Nobuyuki; Masuda, Tetsuya; Kitabatake, Naofumi

2007-11-23

Thaumatin is a 22-kDa sweet-tasting protein containing eight disulfide bonds. When thaumatin is expressed in Pichia pastoris using the thaumatin cDNA fused with both the alpha-factor signal sequence and the Kex2 protease cleavage site from Saccharomyces cerevisiae, the N-terminal sequence of the secreted thaumatin molecule is not processed correctly. To examine the role of the thaumatin cDNA-encoded N-terminal pre-sequence and C-terminal pro-sequence on the processing of thaumatin and efficiency of thaumatin production in P. pastoris, four expression plasmids with different pre-sequence and pro-sequence were constructed and transformed into P. pastoris. The transformants containing pre-thaumatin gene that has the native plant signal, secreted thaumatin molecules in the medium. The N-terminal amino acid sequence of the secreted thaumatin molecule was processed correctly. The production yield of thaumatin was not affected by the C-terminal pro-sequence, and the pro-sequence was not processed in P. pastoris, indicating that pro-sequence is not necessary for thaumatin synthesis.

Relative Importance of History of Heart Failure Hospitalization and N-Terminal Pro-B-Type Natriuretic Peptide Level as Predictors of Outcomes in Patients With Heart Failure and Preserved Ejection Fraction.

PubMed

Kristensen, Søren L; Jhund, Pardeep S; Køber, Lars; McKelvie, Robert S; Zile, Michael R; Anand, Inder S; Komajda, Michel; Cleland, John G F; Carson, Peter E; McMurray, John J V

2015-06-01

The aim of this study was to investigate N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels and recent heart failure (HF) hospitalization as predictors of future events in heart failure - preserved ejection fraction (HF-PEF). Recently, doubt has been expressed about the value of a history of HF hospitalization as a predictor of adverse cardiovascular outcomes in patients with HF and HF-PEF. We estimated rates and adjusted hazard ratios (HRs) for the composite endpoint of cardiovascular death or HF hospitalization, according to history of recent HF hospitalization and baseline NT-proBNP level in the I-PRESERVE (Irbesartan in Heart Failure with Preserved systolic function) trial. Rates of composite endpoints in patients with (n = 804) and without (n = 1,963) a recent HF hospitalization were 12.78 (95% confidence interval [CI]: 11.47 to 14.24) and 4.49 (95% CI: 4.04 to 4.99) per 100 person-years, respectively (HR: 2.71; 95% CI: 2.33 to 3.16). For patients with NT-proBNP concentrations >360 pg/ml (n = 1,299), the event rate was 11.51 (95% CI: 10.54 to 12.58) compared to 3.04 (95% CI: 2.63 to 3.52) per 100 person-years in those with a lower level of NT-proBNP (n = 1468) (HR: 3.19; 95% CI: 2.68 to 3.80). In patients with no recent HF hospitalization and NT-proBNP ≤360 pg/ml (n = 1,187), the event rate was 2.43 (95% CI: 2.03 to 2.90) compared with 17.79 (95% CI: 15.77 to 20.07) per 100 person-years when both risk predictors were present (n = 523; HR: 6.18; 95% CI: 4.96 to 7.69). Recent hospitalization for HF or an elevated level of NT-proBNP identified patients at higher risk for cardiovascular events, and this risk was increased further when both factors were present. Copyright © 2015 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

BDNF and its pro-peptide are stored in presynaptic dense core vesicles in brain neurons

PubMed Central

Dieni, Sandra; Matsumoto, Tomoya; Dekkers, Martijn; Rauskolb, Stefanie; Ionescu, Mihai S.; Deogracias, Ruben; Gundelfinger, Eckart D.; Kojima, Masami; Nestel, Sigrun; Frotscher, Michael

2012-01-01

Although brain-derived neurotrophic factor (BDNF) regulates numerous and complex biological processes including memory retention, its extremely low levels in the mature central nervous system have greatly complicated attempts to reliably localize it. Using rigorous specificity controls, we found that antibodies reacting either with BDNF or its pro-peptide both stained large dense core vesicles in excitatory presynaptic terminals of the adult mouse hippocampus. Both moieties were ∼10-fold more abundant than pro-BDNF. The lack of postsynaptic localization was confirmed in Bassoon mutants, a seizure-prone mouse line exhibiting markedly elevated levels of BDNF. These findings challenge previous conclusions based on work with cultured neurons, which suggested activity-dependent dendritic synthesis and release of BDNF. They instead provide an ultrastructural basis for an anterograde mode of action of BDNF, contrasting with the long-established retrograde model derived from experiments with nerve growth factor in the peripheral nervous system. PMID:22412021

Predictive abilities of baseline measurements of fluid overload, assessed by bioimpedance spectroscopy and serum N-terminal pro-B-type natriuretic peptide, for mortality in hemodialysis patients

PubMed Central

Siriopol, Ianis; Voroneanu, Luminita; Covic, Adrian

2017-01-01

Introduction Fluid overload is one of the most important, yet modifiable, risk factors associated with worse outcomes in hemodialysis (HD) patients. However, its precise assessment in clinical practice is still under investigation. Material and methods This is an observational prospective study which included 285 stable patients with end-stage renal disease on standard thrice-weekly HD therapy. Overhydration was assessed by the combination of relative fluid overload (RFO), using bioimpedance spectroscopy, and N-terminal pro-B-type natriuretic peptide (NT-proBNP). The outcome of interest was all-cause mortality. Results The median values for NT-proBNP and RFO were 4595 pg/ml and 6.9%, respectively. We divided the study population into four groups according to these median levels: group 1 – low NT-proBNP and low RFO; group 2 – high NT-proBNP and low RFO; group 3 – low NT-proBNP and high RFO; group 4 – high NT-proBNP and high RFO. During the follow-up (mean: 41.1, median: 48.7 months), 89 (31.2%) patients died. In the univariable Cox survival analysis only patients in group 4, and not those from group 2 or 3, had significantly higher HRs as compared to those in group 1 (HR = 1.5, 95% CI: 0.8–2.8, HR = 1.6, 95% CI: 0.8–2.9 and HR = 2.4, 95% CI: 1.3–4.2, for group 2, 3 and 4, respectively). Furthermore, these results were maintained in the multivariable Cox analysis. Conclusions Including both bioimpedance and NT-proBNP monitoring in a more comprehensive fluid status assessment could improve the diagnosis of fluid overload with a final improvement in patients’ outcome. PMID:28883854

Association between N-terminal pro B-type natriuretic peptide and day-to-day blood pressure and heart rate variability in a general population: the Ohasama study.

PubMed

Satoh, Michihiro; Hosaka, Miki; Asayama, Kei; Kikuya, Masahiro; Inoue, Ryusuke; Metoki, Hirohito; Tsubota-Utsugi, Megumi; Hara, Azusa; Hirose, Takuo; Obara, Taku; Totsune, Kazuhito; Hoshi, Haruhisa; Mano, Nariyasu; Node, Koichi; Imai, Yutaka; Ohkubo, Takayoshi

2015-08-01

In addition to day-to-day variability in blood pressure (BP) or heart rate (HR), N-terminal pro B-type natriuretic peptide (NT-proBNP) has been reported to be a predictor of cardiovascular disease. Here, we tested the hypothesis that day-to-day BP or HR variability calculated as the intraindividual standard deviation (SD) of home BP or HR is associated with elevated NT-proBNP in a cross-sectional study. Among 664 participants (mean age, 61.9 years; female, 70.5%) from a general Japanese population without a history of heart disease, 86 (13.0%) had NT-proBNP at least 125 pg/ml. Each 1 SD increase in the SD of home systolic BP (SBP) [odds ratio (OR), 1.82; P < .0001) and in the SD of home HR (OR, 1.44; P = 0.008) were significantly associated with the prevalence of NT-proBNP at least 125 pg/ml after adjustment for possible confounding factors including home SBP and HR. Among the four groups defined by the median SD of home SBP and of home HR, the group with higher SDs in home SBP (≥8.0 mmHg) and HR (≥5.0 bpm) had the greatest OR for the prevalence of NT-proBNP at least 125 pg/ml (OR, 4.80; P = 0007 vs. a reference group with lower SDs of home SBP and HR). These results suggest that day-to-day variability in BP and HR may be associated with target-organ damage or complications, which can lead to an elevated NT-proBNP level. An elevated NT-proBNP level may be involved in the prognostic significance of day-to-day variability in BP or HR.

Multimarker Strategy for Heart Failure Prognostication. Value of Neurohormonal Biomarkers: Neprilysin vs NT-proBNP.

PubMed

Bayes-Genis, Antoni; Barallat, Jaume; Galán, Amparo; de Antonio, Marta; Domingo, Mar; Zamora, Elisabet; Gastelurrutia, Paloma; Vila, Joan; Peñafiel, Judith; Gálvez-Montón, Carolina; Lupón, Josep

2015-12-01

Neprilysin breaks down numerous vasoactive peptides. The soluble form of neprilysin, which was recently identified in heart failure, is associated with cardiovascular outcomes. Within a multibiomarker strategy, we directly compared soluble neprilysin and N-terminal pro-B-type natriuretic peptide as risk stratifiers in a real-life cohort of heart failure patients. Soluble neprilysin, N-terminal pro-B-type natriuretic peptide, ST2, and high-sensitivity troponin T levels were measured in 797 consecutive ambulatory heart failure patients followed up for 4.7 years. Comprehensive multivariable analyses and soluble neprilysin vs N-terminal pro-B-type natriuretic peptide head-to-head assessments of performance were performed. A primary composite endpoint included cardiovascular death or heart failure hospitalization. A secondary endpoint explored cardiovascular death alone. Median soluble neprilysin and N-terminal pro-B-type natriuretic peptide concentrations were 0.64ng/mL and 1187 ng/L, respectively. Both biomarkers significantly correlated with age (P<.001) and ST2 (P<.001), but only N-terminal pro-B-type natriuretic peptide significantly correlated with estimated glomerular filtration rate (P<.001), body mass index (P<.001), left ventricular ejection fraction (P=.02) and high-sensitivity troponin T (P<.001). In multivariable Cox regression analyses, soluble neprilysin remained independently associated with the composite endpoint (hazard ratio=1.14; 95% confidence interval, 1.02-1.27; P=.03) and cardiovascular death (hazard ratio=1.15; 95% confidence interval, 1.01-1.31; P=.04), but N-terminal pro-B-type natriuretic peptide did not. The head-to-head soluble neprilysin vs N-terminal pro-B-type natriuretic peptide comparison showed good calibration and similar discrimination and reclassification for both neurohormonal biomarkers, but only soluble neprilysin improved overall goodness-of-fit. When added to a multimarker strategy, soluble neprilysin remained an independent

P43/pro-EMAPII: A Potential Biomarker for Discriminating Traumatic Versus Ischemic Brain Injury

PubMed Central

Yao, Changping; Williams, Anthony J.; Ottens, Andrew K.; Lu, X.-C. May; Liu, Ming Cheng; Hayes, Ronald L.; Wang, Kevin K.; Tortella, Frank C.

2009-01-01

Abstract To gain additional insights into the pathogenic cellular and molecular mechanisms underlying different types of brain injury (e.g., trauma versus ischemia), recently attention has focused on the discovery and study of protein biomarkers. In previous studies, using a high-throughput immunoblotting (HTPI) technique, we reported changes in 29 out of 998 proteins following acute injuries to the rat brain (penetrating traumatic versus focal ischemic). Importantly, we discovered that one protein, endothelial monocyte-activating polypeptide II precursor (p43/pro-EMAPII), was differentially expressed between these two types of brain injury. Among other functions, p43/pro-EMAPII is a known pro-inflammatory cytokine involved in the progression of apoptotic cell death. Our current objective was to verify the changes in p43/pro-EMAPII expression, and to evaluate the potentially important implications that the differential regulation of this protein has on injury development. At multiple time points following either a penetrating ballistic-like brain injury (PBBI), or a transient middle cerebral artery occlusion (MCAo) brain injury, tissue samples (6–72 h), CSF samples (24 h), and blood samples (24 h) were collected from rats for analysis. Changes in protein expression were assessed by Western blot analysis and immunohistochemistry. Our results indicated that p43/pro-EMAPII was significantly increased in brain tissues, CSF, and plasma following PBBI, but decreased after MCAo injury compared to their respective sham control samples. This differential expression of p43/pro-EMAPII may be a useful injury-specific biomarker associated with the underlying pathologies of traumatic versus ischemic brain injury, and provide valuable information for directing injury-specific therapeutics. PMID:19317603

Caveolins: targeting pro-survival signaling in the heart and brain

PubMed Central

Stary, Creed M.; Tsutsumi, Yasuo M.; Patel, Piyush M.; Head, Brian P.; Patel, Hemal H.; Roth, David M.

2012-01-01

The present review discusses intracellular signaling moieties specific to membrane lipid rafts (MLRs) and the scaffolding proteins caveolin and introduces current data promoting their potential role in the treatment of pathologies of the heart and brain. MLRs are discreet microdomains of the plasma membrane enriched in gylcosphingolipids and cholesterol that concentrate and localize signaling molecules. Caveolin proteins are necessary for the formation of MLRs, and are responsible for coordinating signaling events by scaffolding and enriching numerous signaling moieties in close proximity. Specifically in the heart and brain, caveolins are necessary for the cytoprotective phenomenon termed ischemic and anesthetic preconditioning. Targeted overexpression of caveolin in the heart and brain leads to induction of multiple pro-survival and pro-growth signaling pathways; thus, caveolins represent a potential novel therapeutic target for cardiac and neurological pathologies. PMID:23060817

Amino terminal pro brain natriuretic peptide predicts all-cause mortality in patients with chronic obstructive pulmonary disease: Systematic review and meta-analysis.

PubMed

Pavasini, Rita; Tavazzi, Guido; Biscaglia, Simone; Guerra, Federico; Pecoraro, Alessandro; Zaraket, Fatima; Gallo, Francesco; Spitaleri, Giosafat; Contoli, Marco; Ferrari, Roberto; Campo, Gianluca

2017-05-01

Natriuretic peptides (NPs) are a family of prognostic biomarkers in patients with heart failure (HF). HF is one of the most frequent comorbidities in patients with chronic obstructive pulmonary disease (COPD). However, the prognostic role of NP in COPD patients remains unclear. The aim of this meta-analysis was to evaluate the relation between NP and all-cause mortality in COPD patients. We performed a systematic review and meta-analysis of observational studies assessing prognostic implications of elevated NP levels on all-cause mortality in COPD patients. Nine studies were considered for qualitative analysis for a total of 2788 patients. Only two studies focused on Mid Regional-pro Atrial Natriuretic Peptide (MR-proANP) and brain natriuretic peptide (BNP), respectively, but seven studies focused on pro-BNP (NT-proBNP) and were included in the quantitative analysis. Elevated NT-proBNP values were related to increased risk of all-cause mortality in COPD patients both with and without exacerbation (hazard ratio (HR): 2.87, p < 0.0001 and HR: 3.34, p = 0.04, respectively). The results were confirmed also after meta-regression analysis for confounding factors (previous cardiovascular history, hypertension, HF, forced expiratory volume at 1 second and mean age). NT-proBNP may be considered a reliable predictive biomarker of poor prognosis in patients with COPD.

Impacts of the N-terminal fragment analog of human parathyroid hormone on structure, composition and biomechanics of bone.

PubMed

Chunxiao, Wang; Yu, Zhang; Wentao, Liu; Jingjing, Liu; Jiahui, Ye; Qingmei, Chen

2012-12-18

Osteoporosis is a skeletal disease characterized by low bone mass and microarchitectural deterioration of bone tissue, and it is a serious threat to human lives. We previously showed that the N-terminal peptide analog of human parathyroid hormone (Pro-Pro-PTH(1-34)) enhanced plasma calcium concentration. In this paper, we study the impact of PTH N-terminal fragment analog on the structure, component, and mechanical properties of the rat bones. Daily subcutaneous injections of Pro-Pro-hPTH (1-34) induces 26.5-32.8% increase in femur bone mineral density (BMD), 23.0-34.2% decrease the marrow cavity or increase in trabecular bone area. The peptide also increases 16.0-59.5%, 28.8-48.2% and 14.0-17.8% of bone components of calcium, phosphorus and collagen, respectively. In terms of mechanic properties, administration of the peptide elevates the bone rigidity by 45.4-76.6%, decreases the flexibility by 23.0-31.6%, and improves modulus of elasticity by 32.8-63.4%. The results suggest that Pro-Pro-hPTH (1-34) has a positive effect on bone growth and strength, and possesses anti-fracture capability, thus a potential candidate for the application for the treatment of osteoporosis. Copyright © 2012 Elsevier B.V. All rights reserved.

Irradiation induces regionally specific alterations in pro-inflammatory environments in rat brain

PubMed Central

Lee, Won Hee; Sonntag, William E.; Mitschelen, Matthew; Yan, Han; Lee, Yong Woo

2010-01-01

Purpose Pro-inflammatory environments in the brain have been implicated in the onset and progression of neurological disorders. In the present study, we investigate the hypothesis that brain irradiation induces regionally specific alterations in cytokine gene and protein expression. Materials and methods Four month old F344 × BN rats received either whole brain irradiation with a single dose of 10 Gy γ-rays or sham-irradiation, and were maintained for 4, 8, and 24 h following irradiation. The mRNA and protein expression levels of pro-inflammatory mediators were analysed by real-time reverse transcriptase-polymerase chain reaction (RT-PCR), enzyme-linked immunosorbent assay (ELISA), and immunofluorescence staining. To elucidate the molecular mechanisms of irradiation-induced brain inflammation, effects of irradiation on the DNA-binding activity of pro-inflammatory transcription factors were also examined. Results A significant and marked up-regulation of mRNA and protein expression of pro-inflammatory mediators, including tumour necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and monocyte chemoattractant protein-1 (MCP-1), was observed in hippocampal and cortical regions isolated from irradiated brain. Cytokine expression was regionally specific since TNF-α levels were significantly elevated in cortex compared to hippocampus (57% greater) and IL-1β levels were elevated in hippocampus compared to cortical samples (126% greater). Increases in cytokine levels also were observed after irradiation of mouse BV-2 microglial cells. A series of electrophoretic mobility shift assays (EMSA) demonstrated that irradiation significantly increased activation of activator protein-1 (AP-1), nuclear factor-κB (NF-κB), and cAMP response element-binding protein (CREB). Conclusion The present study demonstrated that whole brain irradiation induces regionally specific pro-inflammatory environments through activation of AP-1, NF-κB, and CREB and overexpression of TNF-α, IL

N-terminal pro-B-type natriuretic peptide testing improves the management of patients with suspected acute heart failure: primary results of the Canadian prospective randomized multicenter IMPROVE-CHF study.

PubMed

Moe, Gordon W; Howlett, Jonathan; Januzzi, James L; Zowall, Hanna

2007-06-19

The diagnostic utility of N-terminal pro-B-type natriuretic peptide (NT-proBNP) in heart failure has been documented. However, most of the data were derived from countries with high healthcare resource use, and randomized evidence for utility of NT-proBNP was lacking. We tested the hypothesis that NT-proBNP testing improves the management of patients presenting with dyspnea to emergency departments in Canada by prospectively comparing the clinical and economic impact of a randomized management strategy either guided by NT-proBNP results or without knowledge of NT-proBNP concentrations. Five hundred patients presenting with dyspnea to 7 emergency departments were studied. The median NT-proBNP level among the 230 subjects with a final diagnosis of heart failure was 3697 compared with 212 pg/mL in those without heart failure (P<0.00001). Knowledge of NT-proBNP results reduced the duration of ED visit by 21% (6.3 to 5.6 hours; P=0.031), the number of patients rehospitalized over 60 days by 35% (51 to 33; P=0.046), and direct medical costs of all ED visits, hospitalizations, and subsequent outpatient services (US $6129 to US $5180 per patient; P=0.023) over 60 days from enrollment. Adding NT-proBNP to clinical judgment enhanced the accuracy of a diagnosis; the area under the receiver-operating characteristic curve increased from 0.83 to 0.90 (P<0.00001). In a universal health coverage system mandating judicious use of healthcare resources, inclusion of NT-proBNP testing improves the management of patients presenting to emergency departments with dyspnea through improved diagnosis, cost savings, and improvement in selected outcomes.

Predicting short-term mortality in advanced decompensated heart failure - role of the updated acute decompensated heart failure/N-terminal pro-B-type natriuretic Peptide risk score.

PubMed

Scrutinio, Domenico; Ammirati, Enrico; Passantino, Andrea; Guida, Pietro; D'Angelo, Luciana; Oliva, Fabrizio; Ciccone, Marco Matteo; Iacoviello, Massimo; Dentamaro, Ilaria; Santoro, Daniela; Lagioia, Rocco; Sarzi Braga, Simona; Guzzetti, Daniela; Frigerio, Maria

2015-01-01

The first few months after admission are the most vulnerable period in patients with acute decompensated heart failure (ADHF). We assessed the association of the updated ADHF/N-terminal pro-B-type natriuretic peptide (NT-proBNP) risk score with 90-day and in-hospital mortality in 701 patients admitted with advanced ADHF, defined as severe symptoms of worsening HF, severely depressed left ventricular ejection fraction, and the need for i.v. diuretic and/or inotropic drugs. A total of 15.7% of the patients died within 90 days of admission and 5.2% underwent ventricular assist device (VAD) implantation or urgent heart transplantation (UHT). The C-statistic of the ADHF/NT-proBNP risk score for 90-day mortality was 0.810 (95% CI: 0.769-0.852). Predicted and observed mortality rates were in close agreement. When the composite outcome of death/VAD/UHT at 90 days was considered, the C-statistic decreased to 0.741. During hospitalization, 7.6% of the patients died. The C-statistic for in-hospital mortality was 0.815 (95% CI: 0.761-0.868) and Hosmer-Lemeshow χ(2)=3.71 (P=0.716). The updated ADHF/NT-proBNP risk score outperformed the Acute Decompensated Heart Failure National Registry, the Organized Program to Initiate Lifesaving Treatment in Patients Hospitalized for Heart Failure, and the American Heart Association Get with the Guidelines Program predictive models. Updated ADHF/NT-proBNP risk score is a valuable tool for predicting short-term mortality in severe ADHF, outperforming existing inpatient predictive models.

The role of n terminal - probrain natriuretic peptide in the diagnosis of hemodynamic persistent asrteriosus ductus in premature neonates patient

NASA Astrophysics Data System (ADS)

Dasraf, D.; Djer, M. M.; Advani, N.

2017-08-01

Persistent ductus arteriosus is one of the most frequent congenital heart diseases found in infants, mainly in preterms. Echocardiography is the gold standard for the diagnosis of hemodynamically significant patent ductus arteriosus (hs-PDA) in preterm neonates. A few studies have suggested that the use of a simple blood assay to detect N-terminal pro-brain natriuretic peptide (NT-proBNP) may be useful in determining the diagnosis and management of hs-PDA. No such studies have been conducted in Indonesia, although the assay kit and characteristics of the patient (gestational age and chronological age) influence the accuracy of NT-proBNP levels in determining hs-PDA. The aim of this study was to determine the association between the NT-proBNP level and the prevalence of hs-PDA in an Indonesian patient population. A cross-sectional study was conducted at Dr. Cipto Mangunkusumo Hospital. PDA was determined using echocardiography in 49 preterm neonates (gestational age <37 weeks and birthweight <2000 g). Subsequently, these patients were divided into three groups: non-PDA, non-hsPDA, and hs-PDA. The blood NT-proBNP level was then determined in the non-hsPDA and hs-PDA groups, and between-group differences were compared. Among the 49 neonates, 33 patients had PDA, and 16 of these had hs-PDA. The results revealed a significant association between the NT-proBNP level and hs-PDA (p < 0.001).

Rapid autocatalytic activation of the M4 metalloprotease aureolysin is controlled by a conserved N-terminal fungalysin-thermolysin-propeptide domain.

PubMed

Nickerson, Nicholas N; Joag, Vineet; McGavin, Martin J

2008-09-01

The Staphylococcus aureus proteolytic cascade consists of a metalloprotease aureolysin (Aur), which activates a serine protease zymogen proSspA, which in turn activates the SspB cysteine protease. As with other M4 metalloproteases, including elastase of Pseudomonas aeruginosa, the propeptide of proAur contains an N-terminal fungalysin-thermolysin-propeptide (FTP) domain. Autocatalytic activation of proAur was initiated by processing at T85 downward arrowL(86) in the FTP domain. This differed from the mechanism described for proElastase, where the FTP domain has an RY motif in place of TL(86), and processing occurred at the junction of the propeptide and metalloprotease domains, which remained as an inactive complex during passage across the outer membrane. When TL(86) in the FTP domain was replaced with RY, an intact N-terminal propeptide was secreted, but the M4 metalloprotease domain was degraded. Consequently, this segment of the FTP domain promotes intramolecular processing of proAur while bestowing a chaperone function, but discourages processing within the FTP domain of proElastase, where activation must be co-ordinated with passage across a second membrane. We conclude that the FTP domain of proAur is adapted to facilitate a rapid autocatalytic activation mechanism, consistent with the role or proAur as initiator of the staphylococcal proteolytic cascade.

Prognostic value of N-terminal prohormone brain natriuretic peptide for in-hospital and long-term outcomes in patients with infective endocarditis.

PubMed

Wei, Xue-Biao; Liu, Yuan-Hui; He, Peng-Cheng; Yu, Dan-Qing; Zhou, Ying-Ling; Tan, Ning; Chen, Ji-Yan

2017-05-01

Background Limited research studies with a large sample size were performed to evaluate the prognostic value of N-terminal pro-B-type natriuretic peptide (NT-proBNP) for in-hospital or long-term poor outcomes in patients with infective endocarditis. Methods A total of 703 patients with infective endocarditis were enrolled and divided into four groups according to admission NT-pro-BNP (pg/mL) quartiles: Q1 (<258), Q2 (258-1054), Q3 (1055-3522) and Q4 (>3522). Multivariate regression was used to determine independent risk of NT-proBNP for in-hospital and one-year death. Results In-hospital death occurred in 9.0% of patients. The in-hospital mortality was increased from the lowest to the highest NT-proBNP quartiles (1.1%, 3.4%, 9.1% and 22.3%, P < 0.001, respectively). During the one-year follow-up period, 29 patients died: 0 in Q1, 7 (4.6%) in Q2, 8 (5.7%) in Q3 and 14 (12.0%) in Q4 ( P < 0.001). Log-transformed (lg) NT-proBNP had a linear correlation with lg C-reactive protein ( r = 0.308, P < 0.001). Multivariate analysis showed lgNT-proBNP was an independent predictor for both in-hospital (odds ratio 4.59, 95% confidence interval (CI) 2.45-8.61, P < 0.001) and one-year mortality (hazard ratio 3.11, 95% CI 1.65-5.87, P < 0.001). In addition, NT-proBNP had a higher predictive power for in-hospital death than C-reactive protein (area under the curve 0.797 vs. 0.670, P = 0.005). NT-proBNP > 2260 pg/mL had 76.2% sensitivity and 69.1% specificity for predicting in-hospital death. Kaplan-Meier analysis showed that patients with NT-proBNP > 2260 pg/ml had a worse prognosis than those without (log-rank test 18.84, P < 0.001). Conclusion Increased NT-proBNP was independently associated with in-hospital and one-year mortality in patients with infective endocarditis.

Insufficiency of pro-heparin-binding epidermal growth factor-like growth factor shedding enhances hypoxic cell death in H9c2 cardiomyoblasts via the activation of caspase-3 and c-Jun N-terminal kinase.

PubMed

Uetani, Teruyoshi; Nakayama, Hironao; Okayama, Hideki; Okura, Takafumi; Higaki, Jitsuo; Inoue, Hirofumi; Higashiyama, Shigeki

2009-05-01

Heparin-binding epidermal growth factor-like growth factor (HB-EGF) is a cardiogenic and cardiohypertrophic growth factor. ProHB-EGF, a product of the Hb-egf gene and the precursor of HB-EGF, is anchored to the plasma membrane. Its ectodomain region is shed by a disintegrin and metalloproteases (ADAMs) when activated by various stimulations. It has been reported that an uncleavable mutant of Hb-egf, uc-Hb-egf, produces uc-proHB-EGF, which is not cleaved by ADAMs and causes dilation of the heart in knock-in mice. This suggests that the shedding of proHB-EGF is essential for the development and survival of cardiomyocytes: however, the molecular mechanism involved has remained unclear. In this study, we investigated the relationship between uc-proHB-EGF expression and cardiomyocyte survival. Human uc-proHB-EGF was adenovirally introduced into the rat cardiomyoblast cell line H9c2, and the cells were cultured under normoxic and hypoxic conditions. Uc-proHB-EGF-expressing H9c2 cells underwent apoptosis under normoxic conditions, which distinctly increased under hypoxic conditions. Furthermore, we observed an increased Caspase-3 activity, reactive oxygen species accumulation, and an increased c-Jun N-terminal kinase (JNK) activity in the uc-proHB-EGF-expressing H9c2 cells. Treatment of the uc-proHB-EGF transfectants with inhibitors of Caspase-3, reactive oxygen species, and JNK, namely, Z-VAD-fmk, N-acetylcysteine, and SP600125, respectively, significantly reduced hypoxic cell death. These data indicate that insufficiency of proHB-EGF shedding under hypoxic stress leads to cardiomyocyte apoptosis via Caspase-3- and JNK-dependent pathways.

Combined Measurement of Soluble ST2 and Amino-Terminal Pro-B-Type Natriuretic Peptide Provides Early Assessment of Severity in Cardiogenic Shock Complicating Acute Coronary Syndrome.

PubMed

Tolppanen, Heli; Rivas-Lasarte, Mercedes; Lassus, Johan; Sadoune, Malha; Gayat, Etienne; Pulkki, Kari; Arrigo, Mattia; Krastinova, Evguenia; Sionis, Alessandro; Parissis, John; Spinar, Jindrich; Januzzi, James; Harjola, Veli-Pekka; Mebazaa, Alexandre

2017-07-01

Mortality in cardiogenic shock complicating acute coronary syndrome is high, and objective risk stratification is needed for rational use of advanced therapies such as mechanical circulatory support. Traditionally, clinical variables have been used to judge risk in cardiogenic shock. The aim of this study was to assess the added value of serial measurement of soluble ST2 and amino-terminal pro-B-type natriuretic peptide to clinical parameters for risk stratification in cardiogenic shock. CardShock (www.clinicaltrials.gov NCT01374867) is a prospective European multinational study of cardiogenic shock. The main study introduced CardShock risk score, which is calculated from seven clinical variables at baseline, and was associated with short-term mortality. Nine tertiary care university hospitals. Patients with cardiogenic shock caused by acute coronary syndrome (n=145). In this substudy, plasma samples from the study patients were analyzed at eight time points during the ICU or cardiac care unit stay. Additional prognostic value of the biomarkers was assessed with incremental discrimination improvement. The combination of soluble ST2 and amino-terminal pro-B-type natriuretic peptide showed excellent discrimination for 30-day mortality (area under the curve, 0.77 at 12 hr up to 0.93 at 5-10 d after cardiogenic shock onset). At 12 hours, patients with both biomarkers elevated (soluble ST2, ≥ 500 ng/mL and amino-terminal pro-B-type natriuretic peptide, ≥ 4,500 ng/L) had higher 30-day mortality (79%) compared to those with one or neither biomarkers elevated (31% or 10%, respectively; p < 0.001). Combined measurement of soluble ST2 and amino-terminal pro-B-type natriuretic peptide at 12 hours added value to CardShock risk score, correctly reclassifying 11% of patients. The combination of results for soluble ST2 and amino-terminal pro-B-type natriuretic peptide provides early risk assessment beyond clinical variables in patients with acute coronary syndrome

Regional Brain Shrinkage over Two Years: Individual Differences and Effects of Pro-Inflammatory Genetic Polymorphisms

PubMed Central

Persson, N.; Ghisletta, P.; Dahle, C.L.; Bender, A.R.; Yang, Y.; Yuan, P.; Daugherty, A.M.; Raz, N.

2014-01-01

We examined regional changes in brain volume in healthy adults (N = 167, age 19-79 years at baseline; N = 90 at follow-up) over approximately two years. With latent change score models, we evaluated mean change and individual differences in rates of change in 10 anatomically-defined and manually-traced regions of interest (ROIs): lateral prefrontal cortex (LPFC), orbital frontal cortex (OF), prefrontal white matter (PFw), hippocampus (HC), parahippocampal gyrus (PhG), caudate nucleus (Cd), putamen (Pt), insula (In), cerebellar hemispheres (CbH), and primary visual cortex (VC). Significant mean shrinkage was observed in the HC, CbH, In, OF, and the PhG, and individual differences in change were noted in all regions, except the OF. Pro-inflammatory genetic variants mediated shrinkage in PhG and CbH. Carriers of two T alleles of interleukin-1β (IL-1βC-511T, rs16944) and a T allele of methylenetetrahydrofolate reductase (MTHFRC677T, rs1801133) polymorphisms showed increased PhG shrinkage. No effects of a pro-inflammatory polymorphism for C-reactive protein (CRP-286C>A>T, rs3091244) or apolipoprotein (APOE) ε4 allele were noted. These results replicate the pattern of brain shrinkage observed in previous studies, with a notable exception of the LPFC thus casting doubt on the unique importance of prefrontal cortex in aging. Larger baseline volumes of CbH and In were associated with increased shrinkage, in conflict with the brain reserve hypothesis. Contrary to previous reports, we observed no significant linear effects of age and hypertension on regional brain shrinkage. Our findings warrant further investigation of the effects of neuroinflammation on structural brain change throughout the lifespan. PMID:25264227

N-terminal pro brain natriuretic peptide-guided management in patients with heart failure and preserved ejection fraction: findings from the Trial of Intensified versus standard medical therapy in elderly patients with congestive heart failure (TIME-CHF).

PubMed

Maeder, Micha T; Rickenbacher, Peter; Rickli, Hans; Abbühl, Heidi; Gutmann, Marc; Erne, Paul; Vuilliomenet, André; Peter, Martin; Pfisterer, Matthias; Brunner-La Rocca, Hans-Peter

2013-10-01

To assess the effects of an NT-proBNP-guided medical management on 18-month outcomes in patients with heart failure (HF) and preserved LVEF ( HFpEF). Patients with HFpEF (LVEF >45%; n = 123) and HF with reduced LVEF (HFrEF; LVEF ≤45%; n = 499) with age ≥60 years, NYHA class ≥ II, and elevated NT-proBNP (>400 ng/L or >800 ng/L depending on age) were randomized to medical therapy titrated only to reduce symptoms to NYHA ≤II (symptom-guided) or also to reduce NT-proBNP below the inclusion threshold (NT-proBNP-guided) during a 6-month period. Patients were followed for an additional 12 months. Despite similar treatment escalation, NT-proBNP reduction and symptom relief were less in HFpEF than in HFrEF. Hospitalization-free survival at 18 months was worse in HFpEF than in HFrEF (P = 0.02), while survival and HF hospitalization-free survival did not differ. Among HFpEF patients, NT-proBNP reduction and symptom relief were similar in the symptom-guided (n = 59) and NT-proBNP-guided (n = 64) group despite more aggressive treatment in the NT-proBNP-guided group. In contrast to effects in HFrEF, NT-proBNP-guided management tended to worsen 18-month outcomes in HFpEF, with P-values for the interactions between LVEF stratum and management strategy of 0.2 for hospitalization-free survival, 0.03 for survival, and 0.01 for HF hospitalization-free survival. Outcomes in HFpEF were not better than in HFrEF, and opposite effects of NT-proBNP-guided management were observed in HFpEF compared with HFrEF. These preliminary findings suggest that, in contrast to HFrEF, NT-proBNP-guided therapy may not be beneficial in HFpEF. Trial registration ISRCTN43596477.

Systematic review of the effect of aerobic and resistance exercise training on systemic brain natriuretic peptide (BNP) and N-terminal BNP expression in heart failure patients.

PubMed

Smart, N A; Steele, M

2010-04-30

BNP and the N-terminal portion (NT-pro-BNP) have emerged as powerful tools in the diagnosis and prognosis of heart failure on acute presentation. The aim of this work was to systematically review the effect of exercise training on BNP and NT-pro-BNP levels in patients with left ventricular dysfunction. A systematic search was conducted of Medline (Ovid) (1950-July 2008), Embase.com (1974-current), Cochrane Central Register of Controlled Trials, CINAHL (1981-current) and Web of Science (2000-current) to identify randomized controlled trials of aerobic and/or resistance exercise training in heart failure patients that measured BNP and/or pro-BNP. Primary outcome measures were changes in BNP and NT-pro-BNP. Secondary outcomes were changes in functional capacity and energy expenditure, measures of study quality were also recorded. Nine randomized controlled studies measuring BNP or NT-pro-BNP met our eligibility criteria. Exercise training had a favourable effect on BNP (mean difference -79 pg/ml 95% C.I. -141 to - 17 pg/ml, P=0.01) and NT-pro-BNP (mean difference -621 pg/ml, 95% C.I. -844 to -398 pg/ml, P=<0.00001). Moreover the trials that showed a significant change in NT-pro-BNP all had a weekly exercise energy expenditure of more than 400 Kcal. Data from nine published studies, suggest exercise training has a favorable effect on BNP and NT-pro-BNP in heart failure patients. Copyright (c) 2009 Elsevier Ireland Ltd. All rights reserved.

Value of serum N-terminal B-type natriuretic peptide in asymptomatic structural heart disease in Taiwanese population: Comparisons with current ESC Guidelines.

PubMed

Hung, Ta-Chuan; Wang, Kuang-Te; Yun, Chun-Ho; Kuo, Jen-Yuan; Hou, Charles Jia-Yin; Liu, Chia-Yuan; Wu, Tung-Hsin; Bezerra, Hiram G; Cheng, Hsiao-Yang; Hung, Chung-Lieh; Yeh, Hung-I

2017-03-15

The relationship between N-terminal pro-brain natriuretic peptide (NT-proBNP) and cardiac structural or functional anomalies in pre-clinical, asymptomatic Asian populations has not been well identified. From October 2005 to March 2008, we enrolled consecutive asymptomatic adults with preserved global left ventricular (LV) function (ejection fraction>50%) who underwent annual cardiovascular health survey. Circulating NT-proBNP was used to identify echo-defined cardiac structural/functional anomalies and compared to current recommended cut-off from the European Society of Heart Failure. Among 976 eligible subjects, 371 (38%) had structural heart diseases. Echocardiography-based left atrial diameter (Coef: 71.2), diastolic dysfunction (Coef: 35.4), and presence of pulmonary hypertension (Coef: 83.1) or valvular heart disease (Coef: 56.1, all p<0.05) of any form independently predicted circulating NT-ProBNP. NT-ProBNP cut-off values of 32.8 and 115.4pg/ml for subjects aged ≤ and >75years, respectively, demonstrated areas under the receiver operating characteristic curve of 0.76 (95% CI: 0.73-0.80) and 0.70 (95% CI: 0.52-0.88) for predicting structural or functional anomaly. We examined the feasibility of NT-ProBNP for identifying cardiac structural and functional anomaly in an asymptomatic ethnic Taiwanese population with a relatively lower cut-off value, indicating its potential role for pre-clinical screening of Asian patients. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Direct Immunochemiluminescent Assay for proBNP and Total BNP in Human Plasma proBNP and Total BNP Levels in Normal and Heart Failure

PubMed Central

Nishikimi, Toshio; Okamoto, Hiroyuki; Nakamura, Masahiro; Ogawa, Naoko; Horii, Kazukiyo; Nagata, Kiyoshi; Nakagawa, Yasuaki; Kinoshita, Hideyuki; Yamada, Chinatsu; Nakao, Kazuhiro; Minami, Takeya; Kuwabara, Yoshihiro; Kuwahara, Koichiro; Masuda, Izuru; Kangawa, Kenji; Minamino, Naoto; Nakao, Kazuwa

2013-01-01

Background Recent studies have shown that in addition to brain (or B-type) natriuretic peptide (BNP) and the N-terminal proBNP fragment, levels of intact proBNP are also increased in heart failure. Moreover, present BNP immunoassays also measure proBNP, as the anti-BNP antibody cross-reacts with proBNP. It is important to know the exact levels of proBNP in heart failure, because elevation of the low-activity proBNP may be associated with the development of heart failure. Methodology/Principal Findings We therefore established a two-step immunochemiluminescent assay for total BNP (BNP+proBNP) and proBNP using monoclonal antibodies and glycosylated proBNP as a standard. The assay enables measurement of plasma total BNP and proBNP within only 7 h, without prior extraction of the plasma. The detection limit was 0.4 pmol/L for a 50-µl plasma sample. Within-run CVs ranged from 5.2%–8.0% in proBNP assay and from 7.0%–8.4% in total BNP assay, and between-run CVs ranged from 5.3–7.4% in proBNP assay and from 2.9%–9.5% in total BNP assay, respectively. The dilution curves for plasma samples showed good linearity (correlation coefficients = 0.998–1.00), and analytical recovery was 90–101%. The mean total BNP and proBNP in plasma from 116 healthy subjects were 1.4±1.2 pM and 1.0±0.7 pM, respectively, and were 80±129 pM and 42±70 pM in 32 heart failure patients. Plasma proBNP levels significantly correlate with age in normal subjects. Conclusions/Significance Our immunochemiluminescent assay is sufficiently rapid and precise for routine determination of total BNP and proBNP in human plasma. PMID:23365636

Correlates of N-Terminal Prohormone Brain Natriuretic Peptides in African Americans with Hypertensive Chronic Kidney Disease: The African American Study of Kidney Disease and Hypertension

PubMed Central

Yi, S.; Contreras, G.; Miller, E.R.; Appel, L.J.; Astor, B.C.

2009-01-01

Background/Aims The N-amino-terminal fragment of the prohormone B-type natriuretic peptide (NT-proBNP) is a marker of cardiac stress and elevated levels are indicative of heart failure. Few correlates of NT-proBNP levels have been identified in persons with moderate chronic kidney disease (CKD), and data from those without heart failure and from African Americans are especially limited. Methods The African American Study of Kidney Disease and Hypertension (AASK) enrolled nondiabetic African Americans with hypertensive kidney disease (glomerular filtration rate [GFR] = 20–65 ml/min/1.73 m2) and no evidence of clinical heart failure. NT-proBNP was measured in 982 AASK participants. Results In unadjusted analyses, GFR (r = −0.39; p < 0.001), hematocrit (r = −0.21; p < 0.001) and body mass index (BMI; r = −0.07; p = 0.04) were inversely correlated, and systolic blood pressure (r = 0.30; p < 0.001) and log UPCR (r = 0.32; p < 0.001) were positively correlated with log NT-proBNP levels. After adjustment for potential confounders, lower GFR and hematocrit and higher systolic blood pressure and protein:creatinine ratio remained significantly associated with higher NT-proBNP. Conclusion Lower GFR and hematocrit, and higher urinary protein excretion may be associated with volume expansion in CKD. These results suggest that these processes are associated with increased NT-proBNP in CKD and may play a role in the development of heart failure. PMID:18824845

Evaluation by N-terminal prohormone of brain natriuretic peptide concentrations and ross scoring of the efficacy of digoxin in the treatment of heart failure secondary to congenital heart disease with left-to-right shunts.

PubMed

Elkiran, Ozlem; Sandikkaya, Ayse; Kocak, Gulendam; Karakurt, Cemsit; Taskapan, Cagatay; Yologlu, Saim

2013-10-01

This study aimed to evaluate the effectiveness of digoxin in children with heart failure secondary to left-to-right shunt lesions and normal left ventricular systolic function. The study registered 37 such patients (ages 10 days to 24 months, groups 1 and 2) and used 20 healthy children as a control group (group 3). Left ventricular systolic function, as assessed by conventional echocardiography, was normal in all the subjects. Congestive heart failure was diagnosed by clinical evaluation and modified Ross scoring. Plasma N-terminal prohormone of brain natriuretic peptide (NT-proBNP) concentrations and complete blood counts were assessed in all the children. Group 1 was treated with digoxin, enalapril, and furosemide and group 2 with enalapril and furosemide. Approximately 1 month after starting treatment, the patients were reevaluated by physical and echocardiographic examinations, modified Ross scoring, plasma NT-proBNP concentrations, and complete blood counts. The pre- and posttreatment Ross scores of group 1 (p = 0.377) and group 2 (p = 0.616) did not differ significantly. The NT-proBNP values in both groups decreased after treatment (p = 0.0001). The pre- and posttreatment NT-proBNP values did not differ significantly in group 1 (p = 0.094)) and group 2 (p = 0.372). The pretreatment NT-proBNP values in groups 1 and 2 (p = 0.0001) were significantly higher than in the control group (p = 0.003). A smaller difference was observed between posttreatment NT-proBNP values in group 1 and the control group (p = 0.045). We found no significant difference between the posttreatment NT-proBNP values of group 2 and those of the control group (p = 0.271). The study showed that both treatments currently used to treat heart failure secondary to congenital heart disease with left-to-right shunts and preserved left ventricular systolic function are effective and do not differ significantly. Thus, digoxin does not provide any extra benefit in the treatment of such patients.

Frequency of and Prognostic Significance of Cardiac Involvement at Presentation in Hereditary Transthyretin-Derived Amyloidosis and the Value of N-Terminal Pro-B-Type Natriuretic Peptide.

PubMed

Klaassen, Sebastiaan H C; Tromp, Jasper; Nienhuis, Hans L A; van der Meer, Peter; van den Berg, Maarten P; Blokzijl, Hans; van Veldhuisen, Dirk J; Hazenberg, Bouke P C

2018-01-01

The aim of this study is to assess the prevalence of cardiac involvement in hereditary transthyretin-derived (ATTRm) amyloidosis at the time of diagnosis and to determine the diagnostic and clinical value of N-terminal pro-B-type natriuretic peptide (NT-proBNP). The University Medical Center Groningen is the national center of expertise for amyloidosis. All consecutive patients between 1994 and 2016 with ATTRm amyloidosis were followed prospectively. Baseline was set at the time of the first positive biopsy. All patients underwent a standard cardiac and neurologic work-up. Cardiac involvement was defined by otherwise unexplained left and/or right ventricular wall hypertrophy on cardiac ultrasound and/or advanced conduction disturbances. Seventy-seven patients had ATTRm amyloidosis and were included in the study. The TTR V30M mutation was present in 30 patients (39%). In both the V30M and the non-V30M groups, the neurologic presentation dominated (77% vs 51%), whereas cardiac presentation was infrequent (7% vs 15%). Clinical work-up showed that cardiac involvement was present at baseline in 51% of all patients irrespective of genotype and was associated with increased overall mortality (hazard ratio 5.95, 95% confidence interval 2.12 to 16.7), independent from clinical confounders. At a cutoff level of 125 ng/L, NT-proBNP had a sensitivity of 92% for establishing cardiac involvement. In conclusion, irrespective of the frequent noncardiac presentation of ATTRm amyloidosis, cardiac involvement is already present at diagnosis in half of the patients and is associated with increased mortality. NT-proBNP is a useful marker to determine cardiac involvement in this disease. Copyright © 2017 Elsevier Inc. All rights reserved.

Pro-oxidant effects of Ecstasy and its metabolites in mouse brain synaptosomes

PubMed Central

Barbosa, Daniel José; Capela, João Paulo; Oliveira, Jorge MA; Silva, Renata; Ferreira, Luísa Maria; Siopa, Filipa; Branco, Paula Sério; Fernandes, Eduarda; Duarte, José Alberto; de Lourdes Bastos, Maria; Carvalho, Félix

2012-01-01

BACKGROUND AND PURPOSE 3,4-Methylenedioxymethamphetamine (MDMA or ‘Ecstasy’) is a worldwide major drug of abuse known to elicit neurotoxic effects. The mechanisms underlying the neurotoxic effects of MDMA are not clear at present, but the metabolism of dopamine and 5-HT by monoamine oxidase (MAO), as well as the hepatic biotransformation of MDMA into pro-oxidant reactive metabolites is thought to contribute to its adverse effects. EXPERIMENTAL APPROACH Using mouse brain synaptosomes, we evaluated the pro-oxidant effects of MDMA and its metabolites, α-methyldopamine (α-MeDA), N-methyl-α-methyldopamine (N-Me-α-MeDA) and 5-(glutathion-S-yl)-α-methyldopamine [5-(GSH)-α-MeDA], as well as those of 5-HT, dopamine, l-DOPA and 3,4-dihydroxyphenylacetic acid (DOPAC). KEY RESULTS 5-HT, dopamine, l-DOPA, DOPAC and MDMA metabolites α-MeDA, N-Me-α-MeDA and 5-(GSH)-α-MeDA, concentration- and time-dependently increased H2O2 production, which was significantly reduced by the antioxidants N-acetyl-l-cysteine (NAC), ascorbic acid and melatonin. From experiments with MAO inhibitors, it was observed that H2O2 generation induced by 5-HT was totally dependent on MAO-related metabolism, while for dopamine, it was a minor pathway. The MDMA metabolites, dopamine, l-DOPA and DOPAC concentration-dependently increased quinoproteins formation and, like 5-HT, altered the synaptosomal glutathione status. Finally, none of the compounds modified the number of polarized mitochondria in the synaptosomal preparations, and the compounds’ pro-oxidant effects were unaffected by prior mitochondrial depolarization, excluding a significant role for mitochondrial-dependent mechanisms of toxicity in this experimental model. CONCLUSIONS AND IMPLICATIONS MDMA metabolites along with high levels of monoamine neurotransmitters can be major effectors of neurotoxicity induced by Ecstasy. PMID:21506960

C-Jun N-terminal kinase signalling pathway in response to cisplatin.

PubMed

Yan, Dong; An, GuangYu; Kuo, Macus Tien

2016-11-01

Cisplatin (cis diamminedichloroplatinum II, cDDP) is one of the most effective cancer chemotherapeutic agents and is used in the treatment of many types of human malignancies. However, inherent tumour resistance is a major barrier to effective cisplatin therapy. So far, the mechanism of cDDP resistance has not been well defined. In general, cisplatin is considered to be a cytotoxic drug, for damaging DNA and inhibiting DNA synthesis, resulting in apoptosis via the mitochondrial death pathway or plasma membrane disruption. cDDP-induced DNA damage triggers signalling pathways that will eventually decide between cell life and death. As a member of the mitogen-activated protein kinases family, c-Jun N-terminal kinase (JNK) is a signalling pathway in response to extracellular stimuli, especially drug treatment, to modify the activity of numerous proteins locating in the mitochondria or the nucleus. Recent studies suggest that JNK signalling pathway plays a major role in deciding the fate of the cell and inducing resistance to cDDP-induced apoptosis in human tumours. c-Jun N-terminal kinase regulates several important cellular functions including cell proliferation, differentiation, survival and apoptosis while activating and inhibiting substrates for phosphorylation transcription factors (c-Jun, ATF2: Activating transcription factor 2, p53 and so on), which subsequently induce pro-apoptosis and pro-survival factors expression. Therefore, it is suggested that JNK signal pathway is a double-edged sword in cDDP treatment, simultaneously being a significant pro-apoptosis factor but also being associated with increased resistance to cisplatin-based chemotherapy. This review focuses on current knowledge concerning the role of JNK in cell response to cDDP, as well as their role in cisplatin resistance. © 2016 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.

Combination of Acute Physiology and Chronic Health Evaluation II score, early lactate area, and N-terminal prohormone of brain natriuretic peptide levels as a predictor of mortality in geriatric patients with septic shock.

PubMed

Wang, Hao; Li, Zhong; Yin, Mei; Chen, Xiao-Mei; Ding, Shi-Fang; Li, Chen; Zhai, Qian; Li, Yuan; Liu, Han; Wu, Da-Wei

2015-04-01

Given the high mortality rates in elderly patients with septic shock, the early recognition of patients at greatest risk of death is crucial for the implementation of early intervention strategies. Serum lactate and N-terminal prohormone of brain natriuretic peptide (NT-proBNP) levels are often elevated in elderly patients with septic shock and are therefore important biomarkers of metabolic and cardiac dysfunction. We hypothesized that a risk stratification system that incorporates the Acute Physiology and Chronic Health Evaluation (APACHE) II score and lactate and NT-proBNP biomarkers would better predict mortality in geriatric patients with septic shock than the APACHE II score alone. A single-center prospective study was conducted from January 2012 to December 2013 in a 30-bed intensive care unit of a triservice hospital. The lactate area score was defined as the sum of the area under the curve of serial lactate levels measured during the 24 hours following admission divided by 24. The NT-proBNP score was assigned based on NT-proBNP levels measured at admission. The combined score was calculated by adding the lactate area and NT-proBNP scores to the APACHE II score. Multivariate logistic regression analyses and receiver operating characteristic curves were used to evaluate which variables and scoring systems served as the best predictors of mortality in elderly septic patients. A total of 115 patients with septic shock were included in the study. The overall 28-day mortality rate was 67.0%. When compared to survivors, nonsurvivors had significantly higher lactate area scores, NT-proBNP scores, APACHE II scores, and combined scores. In the multivariate regression model, the combined score, lactate area score, and mechanical ventilation were independent risk factors associated with death. Receiver operating characteristic curves indicated that the combined score had significantly greater predictive power when compared to the APACHE II score or the NT-proBNP score

ProBDNF and mature BDNF as punishment and reward signals for synapse elimination at mouse neuromuscular junctions.

PubMed

Je, H Shawn; Yang, Feng; Ji, Yuanyuan; Potluri, Srilatha; Fu, Xiu-Qing; Luo, Zhen-Ge; Nagappan, Guhan; Chan, Jia Pei; Hempstead, Barbara; Son, Young-Jin; Lu, Bai

2013-06-12

During development, mammalian neuromuscular junctions (NMJs) transit from multiple-innervation to single-innervation through axonal competition via unknown molecular mechanisms. Previously, using an in vitro model system, we demonstrated that the postsynaptic secretion of pro-brain-derived neurotrophic factor (proBDNF) stabilizes or eliminates presynaptic axon terminals, depending on its proteolytic conversion at synapses. Here, using developing mouse NMJs, we obtained in vivo evidence that proBDNF and mature BDNF (mBDNF) play roles in synapse elimination. We observed that exogenous proBDNF promoted synapse elimination, whereas mBDNF infusion substantially delayed synapse elimination. In addition, pharmacological inhibition of the proteolytic conversion of proBDNF to mBDNF accelerated synapse elimination via activation of p75 neurotrophin receptor (p75(NTR)). Furthermore, the inhibition of both p75(NTR) and sortilin signaling attenuated synapse elimination. We propose a model in which proBDNF and mBDNF serve as potential "punishment" and "reward" signals for inactive and active terminals, respectively, in vivo.

Association of N-terminal pro-B-type natriuretic peptide with contrast-induced nephropathy and long-term outcomes in patients with chronic kidney disease and relative preserved left ventricular function.

PubMed

Liu, Yuan-hui; Liu, Yong; Zhou, Ying-ling; Yu, Dan-qing; He, Peng-cheng; Xie, Nian-jin; Li, Hua-long; Wei-Guo; Chen, Ji-yan; Tan, Ning

2015-04-01

The aim of the present article was to evaluate the association of N-terminal pro-B-type natriuretic peptide (NT-pro-BNP) with contrast-induced nephropathy (CIN) and long-term outcomes in patients with chronic kidney disease (CKD) and relative preserved left ventricular function (LVF) undergoing percutaneous coronary intervention (PCI). We prospectively enrolled 1203 consecutive patients with CKD and preserved LVF undergoing elective PCI. The primary end point was the development of CIN, defined as an absolute increase in serum creatinine (SCr) ≥0.5 mg/dL, from baseline within 48 to 72 hours after contrast medium exposure. CIN incidence varied from 2.2% to 5.2%. Univariate logistic analysis showed that lg-NT-pro-BNP was significantly associated with CIN (odds ratio [OR] = 3.93, 95% confidence interval [CI], 2.22-6.97, P < 0.001). Furthermore, lg-NT-pro-BNP remained a significant predictor of CIN (OR = 3.30, 95% CI, 1.57-6.93, P = 0.002), even after adjusting for potential confounding risk factors. These results were confirmed by using other CIN criteria, which were defined as elevations of the SCr by 25% or 0.5 and 0.3 mg/dL from the baseline. The best cutoff value of lg-NT-pro-BNP for detecting CIN was 2.73 pg/mL (537 pg/mL) with 73.1% sensitivity and 70.0% specificity according to the receiver operating characteristic (ROC) analysis (C statistic = 0.754, 95% CI, 0.67-0.84, P < 0.001). In addition, NT-pro-BNP ≥537 pg/mL (2.73 pg/mL, lg-NT-pro-BNP) was associated with an increased risk of all-cause mortality and composite end points during 2.5 years of follow-up. NT-pro-BNP ≥537 pg/mL is independently associated with an increased risk of CIN with different definitions and poor clinical outcomes in patients with CKD and relative preserved LVF undergoing PCI.

The C- and N-Terminal Residues of Synthetic Heptapeptide Ion Channels Influence Transport Efficacy Through Phospholipid Bilayers

PubMed Central

Djedovič, Natasha; Ferdani, Riccardo; Harder, Egan; Pajewska, Jolanta; Pajewski, Robert; Weber, Michelle E.; Schlesinger, Paul H.; Gokel, George W.

2008-01-01

The synthetic peptide, R2N-COCH2OCH2CO-Gly-Gly-Gly-Pro-Gly-Gly-Gly-OR’, was shown to be selective for Cl- over K+ when R is n-octadecyl and R’ is benzyl. Nineteen heptapeptides have now been prepared in which the N-terminal and C-terminal residues have been varied. All of the N-terminal residues are dialkyl but the C-terminal chains are esters, 2° amides, or 3° amides. The compounds having varied N-terminal anchors and C-terminal benzyl groups are as follows: 1, R = n-propyl; 2, R = n-hexyl; 3, R = n-octyl; 4, R = n-decyl; 5, R = n-dodecyl; 6, R = n-tetradecyl; 7, R = n-hexadecyl; 8, R = n-octadecyl. Compounds 9-19 have R = n-octadecyl and C-terminal residues as follows: 9, OR’ = OCH2CH3; 10, OR’ = OCH(CH3)2; 11, OR’ = O(CH2)6CH3; 12, OR’ = OCH2-c-C6H11; 13, OR’ = O(CH2)9CH3; 14, OR’ = O (CH2)17CH3; 15, NR’2 = N[(CH2)6CH3]2; 16, NHR’ = NH(CH2)9CH3; 17, NR’2 = N[(CH2)9CH3]2; 18, NHR’ = NH(CH2)17CH3; 19, NR’2 = N[(CH2)17CH3]2. The highest anion transport activities were observed as follows. For the benzyl esters whose N-terminal residues were varied, i.e. 1-8, compound 3 was most active. For the C18 anchored esters 10-14, n-heptyl ester 11 was most active. For the C18 anchored, C-terminal amides 15-19, di-n-decylamide 17 was most active. It was concluded that both the C- and N-terminal anchors were important for channel function in the bilayer but that activity was lost unless only one of the two anchoring groups was dominant. PMID:19633728

Inactivation of neurotensin by rat brain synaptic membranes. Cleavage at the Pro10-Tyr11 bond by endopeptidase 24.11 (enkephalinase) and a peptidase different from proline-endopeptidase.

PubMed

Checler, F; Emson, P C; Vincent, J P; Kitabgi, P

1984-11-01

It was shown previously that the tridecapeptide neurotensin is inactivated by rat brain synaptic membranes and that one of the primary inactivating cleavages occurs at the Pro10-Try11 peptide bond, leading to the formation of NT1-10 and NT11-13. The present study was designed to investigate the possibility that this cleavage was catalyzed by proline endopeptidase and/or endopeptidase 24.11 (enkephalinase). Purified rat brain synaptic membranes were found to contain a N-benzyloxycarbonyl-Gly-Pro-4-methyl-coumarinyl-7-amide-hydrolyzin g activity that was markedly inhibited (93%) by the proline endopeptidase inhibitor N-benzyloxycarbonyl-Pro-Prolinal and partially blocked (25%) by an antiproline endopeptidase antiserum. In contrast, the cleavage of neurotensin at the Pro10-Tyr11 bond by synaptic membranes was not affected by N-benzyloxycarbonyl-Pro-Prolinal and the antiserum. When the conversion of NT1-10 to NT1-8 by angiotensin converting enzyme was blocked by captopril and when the processing of NT11-13 by aminopeptidase(s) was inhibited by bestatin, it was found that thiorphan, a potent endopeptidase 24.11 inhibitor, partially decreased the formation of NT1-10 and NT11-13 by synaptic membranes. (1) proline endopeptidase, although it is present in synaptic membranes, is not involved in the cleavage of neurotensin at the Pro10-Tyr11 bond; (2) endopeptidase 24.11 only partially contributes to this cleavage; (3) there exists in rat brain synaptic membranes a peptidase different from proline endopeptidase and endopeptidase 24.11 that is mainly responsible for inactivating neurotensin by cleaving at the Pro10-Tyr11 bond.

Brain-derived neurotrophic factor (BDNF) and its precursor (proBDNF) in genetically defined fear-induced aggression.

PubMed

Ilchibaeva, Tatiana V; Kondaurova, Elena M; Tsybko, Anton S; Kozhemyakina, Rimma V; Popova, Nina K; Naumenko, Vladimir S

2015-09-01

The brain-derived neurotrophic factor (BDNF), its precursor (proBDNF) and BDNF mRNA levels were studied in the brain of wild rats selectively bred for more than 70 generations for either high level or for the lack of affective aggressiveness towards man. Significant increase of BDNF mRNA level in the frontal cortex and increase of BDNF level in the hippocampus of aggressive rats was revealed. In the midbrain and hippocampus of aggressive rats proBDNF level was increased, whereas BDNF/proBDNF ratio was reduced suggesting the prevalence and increased influence of proBDNF in highly aggressive rats. In the frontal cortex, proBDNF level in aggressive rats was decreased. Thus, considerable structure-specific differences in BDNF and proBDNF levels as well as in BDNF gene expression between highly aggressive and nonaggressive rats were shown. The data suggested the implication of BDNF and its precursor proBDNF in the mechanism of aggressiveness and in the creation of either aggressive or nonaggressive phenotype. Copyright © 2015 Elsevier B.V. All rights reserved.

Cardiac Troponin I and Amino-Terminal Pro B-Type Natriuretic Peptide in Dogs With Stable Chronic Kidney Disease.

PubMed

Pelander, L; Häggström, J; Ley, C J; Ljungvall, I

2017-05-01

Increased concentrations of N-terminal pro B-type natriuretic peptide (NT-proBNP) and cardiac troponin I (cTnI) in dogs with azotemia have been documented. Knowledge of mechanisms behind increased concentrations of cardiac biomarkers in dogs with azotemia is warranted for correct interpretation of test results. The aim of the article was to investigate possible associations between plasma concentrations of cTnI and NT-proBNP, respectively, and patient characteristics, glomerular filtration rate (GFR), a plasma volume factor (PVF) derived from scintigraphic examination (PVf), systolic blood pressure (SBP), selected hematologic and biochemical variables, and echocardiographic measurements in dogs with stable chronic kidney disease (CKD) and in healthy dogs. Fifty student-, staff-, and client-owned dogs were included. Twenty-three of the dogs were healthy and 27 were diagnosed with CKD. In this cross-sectional observational study, dogs with a previous diagnosis of CKD and healthy control dogs were included. At inclusion, all dogs were characterized by physical examination, repeated blood pressure measurements, complete urinalysis, hematology and biochemistry panel, echocardiography, abdominal ultrasound examination of the entire urinary tract, and scintigraphic examination for measurement of GFR. Plasma volume factor and PCV were independently associated with NT-proBNP (Radj2 = 0.42; P < .0001). Age, body weight (BW), and SBP were independently associated with cTnI (Radj2 = 0.50; P < .0001). Neither NT-proBNP nor cTnI concentrations were independently associated with measured GFR. Thus, findings were not suggestive of passive accumulation of either marker, suggesting that increased circulating concentrations of cTnI and NT-proBNP can be interpreted similarly in dogs with stable CKD as in dogs without CKD. Copyright © 2017 The Authors. Journal of Veterinary Internal Medicine published by Wiley Periodicals, Inc. on behalf of the American College of Veterinary

NT-pro-BNP is associated with inducible myocardial ischemia in mildly symptomatic type 2 diabetic patients.

PubMed

Wiersma, Jacobijne J; van der Zee, P Marc; van Straalen, Jan P; Fischer, Johan C; van Eck-Smit, Berthe L F; Tijssen, Jan G P; Trip, Mieke D; Piek, Jan J; Verberne, Hein J

2010-11-19

Baseline levels of N-terminal fragment of the brain natriuretic peptide prohormone (NT-pro-BNP) are associated with myocardial ischemia in non-diabetic patients with stable angina pectoris. A total of 281 patients with diabetes mellitus type 2 and stable angina pectoris underwent myocardial perfusion scintigraphy (MPS). Myocardial ischemia on MPS was present in 140 (50%) patients. These ischemic patients had significantly higher NT-pro-BNP levels compared with patients without ischemia: 183 pg/ml (64-324 pg/ml) vs. 88 pg/ml (34-207 pg/ml), respectively (p<0.001). In addition, NT-pro-BNP ≥180 pg/ml was an independent predictor of the presence of myocardial ischemia (OR 2.36, 95%CI 1.40-3.97, p=0.001). Possible confounding factors such as age and creatinine clearance were of no influence on the predictive value in this specific patient population. These findings strengthen the idea that NT-pro-BNP may be of value in the early detection of diabetic patients with hemodynamic significant coronary artery disease. Copyright © 2009 Elsevier Ireland Ltd. All rights reserved.

Early Discharge After Primary Percutaneous Coronary Intervention: The Added Value of N‐Terminal Pro–Brain Natriuretic Peptide to the Zwolle Risk Score

PubMed Central

Schellings, Dirk A. A. M.; Adiyaman, Ahmet; Giannitsis, Evangelos; Hamm, Christian; Suryapranata, Harry; ten Berg, Jurrien M.; Hoorntje, Jan C. A.; van‘t Hof, Arnoud W. J.

2014-01-01

Background The Zwolle Risk Score (ZRS) identifies ST‐elevation myocardial infarction (STEMI) patients treated with primary percutaneous coronary intervention (PPCI) eligible for early discharge. We aimed to investigate whether baseline N‐terminal pro–brain natriuretic peptide (NT‐proBNP) is also able to identify these patients and could improve future risk strategies. Methods and Results PPCI patients included in the Ongoing Tirofiban in Myocardial Infarction Evaluation (On‐TIME) II study were candidates (N=861). We analyzed whether ZRS and baseline NT‐proBNP predicted 30‐day mortality and assessed the occurrence of major adverse cardiac events (MACEs) and major bleeding. Receiver operating characteristic curve analysis was used to assess discriminative accuracy for ZRS, NT‐pro‐BNP, and their combination. After multiple imputation, 845 patients were included. Both ZRS >3 (hazard ratio [HR]=9.42; P<0.001) and log NT‐pro‐BNP (HR=2.61; P<0.001) values were associated with 30‐day mortality. On multivariate analysis, both the ZRS (HR=1.41; 95% confidence interval [CI]=1.27 to 1.56; P<0.001) and log NT‐proBNP (HR=2.09; 95% CI=1.59 to 2.74; P<0.001) independently predicted death at 30 days. The area under the curve for 30‐day mortality for combined ZRS/NT‐proBNP was 0.94 (95% CI=0.90 to 0.99), with optimal predictive values of a ZRS ≥2 and a NT‐proBNP value of ≥200 pg/mL. Using these cut‐off values, 64% of the study population could be identified as very low risk with zero mortality at 30 days follow‐up and low occurrence of MACEs and major bleeding between 48 hours and 10 days (1.3% and 0.6%, respectively). Conclusion Baseline NT‐proBNP identifies a large group of low‐risk patients who may be eligible for early (48‐ to 72‐hour) discharge, whereas optimal predictive accuracy is reached by the combination of both baseline NT‐proBNP and ZRS. PMID:25389283

An antibody reactive to the Gly63–Lys68 epitope of NT-proBNP exhibits O-glycosylation-independent binding

PubMed Central

Lee, Yujean; Kim, Hyori; Chung, Junho

2014-01-01

The N-terminal fragment of prohormone brain natriuretic peptide (NT-proBNP) is a commonly used biomarker for the diagnosis of congestive heart failure, although its biological function is not well known. NT-proBNP exhibits heavy O-linked glycosylation, and it is quite difficult to develop an antibody that exhibits glycosylation-independent binding. We developed an antibody that binds to the recombinant NT-proBNP protein and its deglycosylated form with similar affinities in an enzyme immunoassay. The epitope was defined as Gly63–Lys68 based on mimetic peptide screening, site-directed mutagenesis and a competition assay with a peptide mimotope. The nearest O-glycosylation residues are Thr58 and Thr71; therefore, four amino acid residues intervene between the epitope and those residues in both directions. In conclusion, we report that an antibody reactive to Gly63–Lys68 of NT-proBNP exhibits O-glycosylation-independent binding. PMID:25236766

Influence of atrial fibrillation on plasma von willebrand factor, soluble E-selectin, and N-terminal pro B-type natriuretic peptide levels in systolic heart failure.

PubMed

Freestone, Bethan; Gustafsson, Finn; Chong, Aun Yeong; Corell, Pernille; Kistorp, Caroline; Hildebrandt, Per; Lip, Gregory Y H

2008-05-01

Endothelial dysfunction is present in patients with heart failure (HF) due to left ventricular systolic dysfunction, as well as in patients with atrial fibrillation (AF) who have normal cardiac function. It is unknown whether AF influences the degree of endothelial dysfunction in patients with systolic HF. We measured levels of plasma von Willebrand factor (vWF) and E-selectin (as indexes of endothelial damage/dysfunction and endothelial activation, respectively; both enzyme-linked immunosorbent assay) in patients with AF and HF (AF-HF), who were compared to patients with sinus rhythm and HF (SR-HF), as well as in age-matched, healthy, control subjects. We also assessed the relationship of vWF and E-selectin to plasma N-terminal pro B-type natriuretic peptide (NTpro-BNP), a marker for HF severity and prognosis. One hundred ninety patients (73% men; mean age, 69.0 +/- 10.1 years [+/- SD]) with systolic HF were studied, who were compared to 117 healthy control subjects: 52 subjects (27%) were in AF, while 138 subjects (73%) were in sinus rhythm. AF-HF patients were older than SR-HF patients (p = 0.046), but left ventricular ejection fraction and New York Heart Association class were similar. There were significant differences in NT-proBNP (p < 0.0001) and plasma vWF (p = 0.003) between patients and control subjects. On Tukey post hoc analysis, AF-HF patients had significantly increased NT-proBNP (p < 0.001) and vWF (p = 0.0183) but not E-selectin (p = 0.071) levels when compared to SR-HF patients. On multivariate analysis, the presence of AF was related to plasma vWF levels (p = 0.018). Plasma vWF was also significantly correlated with NT-proBNP levels (Spearman r = 0.139; p = 0.017). There is evidence of greater endothelial damage/dysfunction in AF-HF patients when compared to SR-HF patients. The clinical significance of this is unclear but may have prognostic value.

A Novel c-Jun N-terminal Kinase (JNK) Signaling Complex Involved in Neuronal Migration during Brain Development.

PubMed

Zhang, Feng; Yu, Jingwen; Yang, Tao; Xu, Dan; Chi, Zhixia; Xia, Yanheng; Xu, Zhiheng

2016-05-27

Disturbance of neuronal migration may cause various neurological disorders. Both the transforming growth factor-β (TGF-β) signaling and microcephaly-associated protein WDR62 are important for neuronal migration during brain development; however, the underlying molecular mechanisms involved remain unclear. We show here that knock-out or knockdown of Tak1 (TGFβ-activated kinase 1) and Jnk2 (c-Jun N-terminal kinase 2) perturbs neuronal migration during cortical development and that the migration defects incurred by knock-out and/or knockdown of Tβr2 (type II TGF-β receptor) or Tak1 can be partially rescued by expression of TAK1 and JNK2, respectively. Furthermore, TAK1 forms a protein complex with RAC1 and two scaffold proteins of the JNK pathway, the microcephaly-associated protein WDR62 and the RAC1-interacting protein POSH (plenty of Src homology). Components of the complex coordinate with each other in the regulation of TAK1 as well as JNK activities. We suggest that unique JNK protein complexes are involved in the diversified biological and pathological functions during brain development and pathogenesis of diseases. © 2016 by The American Society for Biochemistry and Molecular Biology, Inc.

Association of N-Terminal Pro-B-Type Natriuretic Peptide With Contrast-Induced Nephropathy and Long-Term Outcomes in Patients With Chronic Kidney Disease and Relative Preserved Left Ventricular Function

PubMed Central

Liu, Yuan-hui; Liu, Yong; Zhou, Ying-ling; Yu, Dan-qing; He, Peng-cheng; Xie, Nian-Jin; Li, Hua-long; Wei-Guo; Chen, Ji-yan; Tan, Ning

2015-01-01

Abstract The aim of the present article was to evaluate the association of N-terminal pro-B-type natriuretic peptide (NT-pro-BNP) with contrast-induced nephropathy (CIN) and long-term outcomes in patients with chronic kidney disease (CKD) and relative preserved left ventricular function (LVF) undergoing percutaneous coronary intervention (PCI). We prospectively enrolled 1203 consecutive patients with CKD and preserved LVF undergoing elective PCI. The primary end point was the development of CIN, defined as an absolute increase in serum creatinine (SCr) ≥0.5 mg/dL, from baseline within 48 to 72 hours after contrast medium exposure. CIN incidence varied from 2.2% to 5.2%. Univariate logistic analysis showed that lg-NT-pro-BNP was significantly associated with CIN (odds ratio [OR] = 3.93, 95% confidence interval [CI], 2.22–6.97, P < 0.001). Furthermore, lg-NT-pro-BNP remained a significant predictor of CIN (OR = 3.30, 95% CI, 1.57–6.93, P = 0.002), even after adjusting for potential confounding risk factors. These results were confirmed by using other CIN criteria, which were defined as elevations of the SCr by 25% or 0.5 and 0.3 mg/dL from the baseline. The best cutoff value of lg-NT-pro-BNP for detecting CIN was 2.73 pg/mL (537 pg/mL) with 73.1% sensitivity and 70.0% specificity according to the receiver operating characteristic (ROC) analysis (C statistic = 0.754, 95% CI, 0.67–0.84, P < 0.001). In addition, NT-pro-BNP ≥537 pg/mL (2.73 pg/mL, lg-NT-pro-BNP) was associated with an increased risk of all-cause mortality and composite end points during 2.5 years of follow-up. NT-pro-BNP ≥537 pg/mL is independently associated with an increased risk of CIN with different definitions and poor clinical outcomes in patients with CKD and relative preserved LVF undergoing PCI. PMID:25837748

Amino-Terminal Pro-B-Type Natriuretic Peptide and B-Type Natriuretic Peptide

PubMed Central

McKie, Paul M.; Rodeheffer, Richard J.; Cataliotti, Alessandro; Martin, Fernando L.; Urban, Lynn H.; Mahoney, Douglas W.; Jacobsen, Steven J.; Redfield, Margaret M.; Burnett, John C.

2007-01-01

Recent studies report that, in the absence of heart failure and renal failure, plasma B-type natriuretic peptide (BNP) has prognostic value for mortality. We sought to confirm and extend these previous studies to assess BNP, measured by 3 distinct assays, as a biomarker for mortality in a strategy to enhance efforts at primary prevention and to better understand the clinical phenotype of such subjects at risk. We used a community-based cohort of 2042 subjects from Olmsted County, Minn, and individuals with heart or renal failure were excluded. BNP was assessed using 3 assays including Biosite and Shionogi for mature, biologically active BNP and the Roche assay for apparently nonbiologically active amino-terminal pro-BNP (NT-proBNP). Thorough echocardiographic and clinical data were recorded for all of the participants. Median follow-up for mortality was 5.6 years. BNP by all 3 of the assays was predictive of mortality. NT-proBNP and Biosite assays remained significant even after adjustment for traditional clinical risk factors and echocardiographic abnormalities including left ventricular hypertrophy and diastolic dysfunction. Echocardiography documented widespread structural changes in those with increasing BNP levels yet below levels observed in heart failure. We report in a large, well-characterized community-based cohort, free of heart failure, the first study to compare 3 distinct BNP assays as biomarkers for mortality in the same cohort. Our findings confirm the potential use of NT-proBNP and BNP biomarkers for future events and underscore that these peptides may also serve as biomarkers for underlying cardiac remodeling secondary to diverse cardiovascular disease entities. PMID:16585413

Glial Modulation by N-acylethanolamides in Brain Injury and Neurodegeneration

PubMed Central

Herrera, María I.; Kölliker-Frers, Rodolfo; Barreto, George; Blanco, Eduardo; Capani, Francisco

2016-01-01

Neuroinflammation involves the activation of glial cells and represents a key element in normal aging and pathophysiology of brain damage. N-acylethanolamides (NAEs), naturally occurring amides, are known for their pro-homeostatic effects. An increase in NAEs has been reported in vivo and in vitro in the aging brain and in brain injury. Treatment with NAEs may promote neuroprotection and exert anti-inflammatory actions via PPARα activation and/or by counteracting gliosis. This review aims to provide an overview of endogenous and exogenous properties of NAEs in neuroinflammation and to discuss their interaction with glial cells. PMID:27199733

Glial Modulation by N-acylethanolamides in Brain Injury and Neurodegeneration.

PubMed

Herrera, María I; Kölliker-Frers, Rodolfo; Barreto, George; Blanco, Eduardo; Capani, Francisco

2016-01-01

Neuroinflammation involves the activation of glial cells and represents a key element in normal aging and pathophysiology of brain damage. N-acylethanolamides (NAEs), naturally occurring amides, are known for their pro-homeostatic effects. An increase in NAEs has been reported in vivo and in vitro in the aging brain and in brain injury. Treatment with NAEs may promote neuroprotection and exert anti-inflammatory actions via PPARα activation and/or by counteracting gliosis. This review aims to provide an overview of endogenous and exogenous properties of NAEs in neuroinflammation and to discuss their interaction with glial cells.

Activation of a synapse weakening pathway by human Val66 but not Met66 pro-brain-derived neurotrophic factor (proBDNF)

PubMed Central

Kailainathan, Sumangali; Piers, Thomas M.; Yi, Jee Hyun; Choi, Seongmin; Fahey, Mark S.; Borger, Eva; Gunn-Moore, Frank J.; O’Neill, Laurie; Lever, Michael; Whitcomb, Daniel J.; Cho, Kwangwook; Allen, Shelley J.

2016-01-01

This study describes a fundamental functional difference between the two main polymorphisms of the pro-form of brain-derived neurotrophic factor (proBDNF), providing an explanation as to why these forms have such different age-related neurological outcomes. Healthy young carriers of the Met66 form (present in ∼30% Caucasians) have reduced hippocampal volume and impaired hippocampal-dependent memory function, yet the same polymorphic population shows enhanced cognitive recovery after traumatic brain injury, delayed cognitive dysfunction during aging, and lower risk of late-onset Alzheimer’s disease (AD) compared to those with the more common Val66 polymorphism. To examine the differences between the protein polymorphisms in structure, kinetics of binding to proBDNF receptors and in vitro function, we generated purified cleavage-resistant human variants. Intriguingly, we found no statistical differences in those characteristics. As anticipated, exogenous application of proBDNF Val66 to rat hippocampal slices dysregulated synaptic plasticity, inhibiting long-term potentiation (LTP) and facilitating long-term depression (LTD). We subsequently observed that this occurred via the glycogen synthase kinase 3β (GSK3β) activation pathway. However, surprisingly, we found that Met66 had no such effects on either LTP or LTD. These novel findings suggest that, unlike Val66, the Met66 variant does not facilitate synapse weakening signaling, perhaps accounting for its protective effects with aging. PMID:26687096

TIR-domain-containing adapter-inducing interferon-β (TRIF) forms filamentous structures, whose pro-apoptotic signalling is terminated by autophagy.

PubMed

Gentle, Ian E; McHenry, Kevin T; Weber, Arnim; Metz, Arlena; Kretz, Oliver; Porter, Dale; Häcker, Georg

2017-07-01

The formation of amyloid-like protein structures has recently emerged as a feature in signal transduction, particularly in innate immunity. These structures appear to depend on defined domains for their formation but likely also require dedicated ways to terminate signalling. We, here, define the innate immunity protein/Toll-like receptor adaptor TIR-domain-containing adapter-inducing interferon-β (TRIF) as a novel platform of fibril formation and probe signal initiation through TRIF as well as its termination in Toll-like receptor 3 (TLR3)-stimulated melanoma cells. A main signalling pathway triggered by TLR3 caused apoptosis, which was controlled by inhibitor of apoptosis proteins and was dependent on RIPK1 and independent of TNF. Using correlative electron/fluorescence microscopy, we visualised fibrillar structures formed through both Toll/interleukin-1 receptor and RIP homotypic interacting motif regions of TRIF. We provide evidence that these fibrillary structures are active signalling platforms whose activity is terminated by autophagy. TRIF-signalling enhanced autophagy, and fibrillary structures were partly contained within autophagosomes. Inhibition of autophagy increased levels of pro-apoptotic TRIF complexes, leading to the accumulation of active caspase-8 and enhanced apoptosis while stimulation of autophagy reduced TRIF-dependent death. We conclude that pro-death signals through TRIF are regulated by autophagy and propose that pro-apoptotic signalling through TRIF/RIPK1/caspase-8 occurs in fibrillary platforms. © 2017 Federation of European Biochemical Societies.

The prognostic value of individual NT-proBNP values in chronic heart failure does not change with advancing age.

PubMed

Frankenstein, L; Clark, A L; Goode, K; Ingle, L; Remppis, A; Schellberg, D; Grabs, F; Nelles, M; Cleland, J G F; Katus, H A; Zugck, C

2009-05-01

It is unclear whether age-related increases in N-terminal pro-brain natriuretic peptide (NT-proBNP) represent a normal physiological process-possibly affecting the prognostic power-of NT-proBNP-or reflect age-related subclinical pathological changes. To determine the effect of age on the short-term prognostic value of NT-proBNP in patients with chronic heart failure (CHF). Prospective observational study with inclusion and matching of consecutive patients aged >65 years (mean (SD) 73.1 (6.0) years) to patients <65 years (53.7 (8.6) years) with respect to NT-proBNP, New York Heart Association stage, sex and aetiology of CHF (final n = 443). University hospital outpatient departments in the UK and Germany. Chronic stable heart failure due to systolic left ventricular dysfunction. None. All-cause mortality. In both age groups, NT-proBNP was a significant univariate predictor of mortality, and independent of age, sex and other established risk markers. The prognostic information given by NT-proBNP was comparable between the two groups, as reflected by the 1-year mortality of 9% in both groups. The prognostic accuracy of NT-proBNP as judged by the area under the receiver operating characteristics curve for the prediction of 1-year mortality was comparable for elderly and younger patients (0.67 vs 0.71; p = 0.09). NT-proBNP reflects disease severity in elderly and younger patients alike. In patients with chronic stable heart failure, the NT-proBNP value carries the same 1-year prognostic information regardless of the age of the patient.

A structural model for the osmosensor, transporter, and osmoregulator ProP of Escherichia coli.

PubMed

Wood, Janet M; Culham, Doreen E; Hillar, Alexander; Vernikovska, Yaroslava I; Liu, Feng; Boggs, Joan M; Keates, Robert A B

2005-04-19

Transporter ProP of Escherichia coli, a member of the major facilitator superfamily (MFS), acts as an osmosensor and an osmoregulator in cells and after purification and reconstitution in proteoliposomes. H(+)-osmoprotectant symport via ProP is activated when medium osmolality is elevated with membrane impermeant osmolytes. The three-dimensional structure of ProP was modeled with the crystal structure of MFS member GlpT as a template. This GlpT structure represents the inward (or cytoplasm)-facing conformation predicted by the alternating access model for transport. LacZ-PhoA fusion analysis and site-directed fluorescence labeling substantiated the membrane topology and orientation predicted by this model and most hydropathy analyses. The model predicts the presence of a proton pathway within the N-terminal six-helix bundle of ProP (as opposed to the corresponding pathway found within the C-terminal helix bundle of its paralogue, LacY). Replacement of residues within the N-terminal helix bundle impaired the osmotic activation of ProP, providing the first indication that residues outside the C-terminal domain are involved in osmosensing. Some residues that were accessible from the periplasmic side, as predicted by the structural model, were more susceptible to covalent labeling in permeabilized membrane fractions than in intact bacteria. These residues may be accessible from the cytoplasmic side in structures not represented by our current model, or their limited exposure in vivo may reflect constraints on transporter structure that are related to its osmosensory mechanism.

Early metabolic/cellular-level resuscitation following terminal brain stem herniation: implications for organ transplantation.

PubMed

Arbour, Richard B

2013-01-01

Patients with terminal brain stem herniation experience global physiological consequences and represent a challenging population in critical care practice as a result of multiple factors. The first factor is severe depression of consciousness, with resulting compromise in airway stability and lung ventilation. Second, with increasing severity of brain trauma, progressive brain edema, mass effect, herniation syndromes, and subsequent distortion/displacement of the brain stem follow. Third, with progression of intracranial pathophysiology to terminal brain stem herniation, multisystem consequences occur, including dysfunction of the hypothalamic-pituitary axis, depletion of stress hormones, and decreased thyroid hormone bioavailability as well as biphasic cardiovascular state. Cardiovascular dysfunction in phase 1 is a hyperdynamic and hypertensive state characterized by elevated systemic vascular resistance and cardiac contractility. Cardiovascular dysfunction in phase 2 is a hypotensive state characterized by decreased systemic vascular resistance and tissue perfusion. Rapid changes along the continuum of hyperperfusion versus hypoperfusion increase risk of end-organ damage, specifically pulmonary dysfunction from hemodynamic stress and high-flow states as well as ischemic changes consequent to low-flow states. A pronounced inflammatory state occurs, affecting pulmonary function and gas exchange and contributing to hemodynamic instability as a result of additional vasodilatation. Coagulopathy also occurs as a result of consumption of clotting factors as well as dilution of clotting factors and platelets consequent to aggressive crystalloid administration. Each consequence of terminal brain stem injury complicates clinical management within this patient demographic. In general, these multisystem consequences are managed with mechanism-based interventions within the context of caring for the donor's organs (liver, kidneys, heart, etc.) after death by neurological

N-terminal pro-B-type natriuretic peptide for risk assessment in patients with atrial fibrillation: insights from the ARISTOTLE Trial (Apixaban for the Prevention of Stroke in Subjects With Atrial Fibrillation).

PubMed

Hijazi, Ziad; Wallentin, Lars; Siegbahn, Agneta; Andersson, Ulrika; Christersson, Christina; Ezekowitz, Justin; Gersh, Bernard J; Hanna, Michael; Hohnloser, Stefan; Horowitz, John; Huber, Kurt; Hylek, Elaine M; Lopes, Renato D; McMurray, John J V; Granger, Christopher B

2013-06-04

This study sought to assess the prognostic value of N-terminal pro-B-type natriuretic peptide (NT-proBNP) in patients with atrial fibrillation (AF) enrolled in the ARISTOTLE (Apixaban for the Prevention of Stroke in Subjects With Atrial Fibrillation) trial, and the treatment effect of apixaban according to NT-proBNP levels. Natriuretic peptides are associated with mortality and cardiovascular events in several cardiac diseases. In the ARISTOTLE trial, 18,201 patients with AF were randomized to apixaban or warfarin. Plasma samples at randomization were available from 14,892 patients. The association between NT-proBNP concentrations and clinical outcomes was evaluated using Cox proportional hazard models, after adjusting for established cardiovascular risk factors. Quartiles of NT-proBNP were: Q1, ≤363 ng/l; Q2, 364 to 713 ng/l; Q3, 714 to 1,250 ng/l; and Q4, >1,250 ng/l. During 1.9 years, the annual rates of stroke or systemic embolism ranged from 0.74% in the bottom NT-proBNP quartile to 2.21% in the top quartile, an adjusted hazard ratio of 2.35 (95% confidence interval [CI]: 1.62 to 3.40; p < 0.0001). Annual rates of cardiac death ranged from 0.86% in Q1 to 4.14% in Q4, with an adjusted hazard ratio of 2.50 (95% CI: 1.81 to 3.45; p < 0.0001). Adding NT-proBNP levels to the CHA2DS2VASc score improved C-statistics from 0.62 to 0.65 (p = 0.0009) for stroke or systemic embolism and from 0.59 to 0.69 for cardiac death (p < 0.0001). Apixaban reduced stroke, mortality, and bleeding regardless of the NT-proBNP level. NT-proBNP levels are often elevated in AF and independently associated with an increased risk of stroke and mortality. NT-proBNP improves risk stratification beyond the CHA2DS2VASc score and might be a novel tool for improved stroke prediction in AF. The efficacy of apixaban compared with warfarin is independent of the NT-proBNP level. (Apixaban for the Prevention of Stroke in Subjects With Atrial Fibrillation [ARISTOTLE]; NCT00412984). Copyright �

Serum potassium decline during hospitalization for acute decompensated heart failure is a predictor of 6-month mortality, independent of N-terminal pro-B-type natriuretic peptide levels: An individual patient data analysis.

PubMed

Salah, Khibar; Pinto, Yigal M; Eurlings, Luc W; Metra, Marco; Stienen, Susan; Lombardi, Carlo; Tijssen, Jan G; Kok, Wouter E

2015-09-01

Limited data exist for the role of serum potassium changes during hospitalization for acute decompensated heart failure (ADHF). The present study investigated the long-term prognostic value of potassium changes during hospitalization in patients admitted for ADHF. Our study is a pooled individual patient data analysis assembled from 3 prospective cohorts comprising 754 patients hospitalized for ADHF. The endpoint was all-cause mortality within 180 days after discharge. Serum potassium levels and N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels were measured at admission and at discharge. A percentage decrease >15% in serum potassium levels occurred in 96 (13%) patients, and an absolute decrease of >0.7 mmol/L in serum potassium levels occurred in 85 (12%) patients; and both were predictors of poor outcome independent of admission or discharge serum potassium. After the addition of other strong predictors of mortality-a 30% change in NT-proBNP during hospitalization, discharge levels of NT-proBNP, renal markers, and other relevant clinical variables-the multivariate hazard ratio of serum potassium percentage reduction of >15% remained an independent predictor of 180-day mortality (hazard ratio 2.06, 95% CI 1.14-3.73). A percentage serum potassium decline of >15% is an independent predictor of 180-day all-cause mortality on top of baseline potassium levels, NT-proBNP levels, renal variables, and other relevant clinical variables. This suggest that patients hospitalized for ADHF with a decline of >15% in serum potassium levels are at risk and thus monitoring and regulating of serum potassium level during hospitalization are needed in these patients. Copyright © 2015 Elsevier Inc. All rights reserved.

The Effects of Super-Flux (High Performance) Dialyzer on Plasma Glycosylated Pro-B-Type Natriuretic Peptide (proBNP) and Glycosylated N-Terminal proBNP in End-Stage Renal Disease Patients on Dialysis

PubMed Central

Nakagawa, Yasuaki; Nishikimi, Toshio; Kuwahara, Koichiro; Yasuno, Shinji; Kinoshita, Hideyuki; Kuwabara, Yoshihiro; Nakao, Kazuhiro; Minami, Takeya; Yamada, Chinatsu; Ueshima, Kenji; Ikeda, Yoshihiro; Okamoto, Hiroyuki; Horii, Kazukiyo; Nagata, Kiyoshi; Kangawa, Kenji; Minamino, Naoto; Nakao, Kazuwa

2014-01-01

Background Plasma BNP levels are predictive of prognosis in hemodialysis patients. However, recent studies showed that the current BNP immunoassay cross-reacts with glycosylated proBNP, and the NT-proBNP assay underestimates glycosylated NT-proBNP. In addition, the recently developed high performance dialyzer removes medium-sized molecular solutes such as β2-microgloburin. We therefore investigated the effects of high performance dialysis on measured levels of glycosylated proBNP, glycosylated NT-proBNP and other BNP-related peptides in end-stage renal disease (ESRD) patients on hemodialysis. Method The relationships between clinical parameters and BNP-related molecule were also investigated. We used our newly developed immunoassay to measure plasma total BNP and proBNP in 105 normal subjects and 36 ESRD patients before and after hemodialysis. Plasma NT-proBNP was measured using Elecsys II after treatment with or without deglycosylating enzymes. We also measured plasma ANP and cGMP using radioimmunoassays. Results All the measured BNP-related peptides were significantly higher in ESRD patients than healthy subjects. Total BNP (−38.9%), proBNP (−29.7%), glycoNT-proBNP (−45.5%), nonglycoNT-proBNP (−53.4%), ANP (−50.4%) and cGMP (−72.1%) were all significantly reduced after hemodialysis, and the magnitude of the reduction appeared molecular weight- dependent. Both the proBNP/total BNP and glycoNT-proBNP/nonglycoNT-proBNP ratios were increased after hemodialysis. The former correlated positively with hemodialysis vintage and negatively with systolic blood pressure, while the latter correlated positively with parathyroid hormone levels. Conclusion These results suggest that hemodialysis using super-flux dialyzer removes BNP-related peptides in a nearly molecular weight-dependent manner. The ProBNP/total BNP and glycoNT-proBNP/nonglycoNT-proBNP ratios appear to be influenced by hemodialysis-related parameters in ESRD patients on hemodialysis. PMID:24667631

Reliability of N-terminal proBNP assay in diagnosis of left ventricular systolic dysfunction within representative and high risk populations.

PubMed

Hobbs, F D R; Davis, R C; Roalfe, A K; Hare, R; Davies, M K

2004-08-01

To determine the performance of a new NT-proBNP assay in comparison with brain natriuretic peptide (BNP) in identifying left ventricular systolic dysfunction (LVSD) in randomly selected community populations. Blood samples were taken prospectively in the community from 591 randomly sampled individuals over the age of 45 years, stratified for age and socioeconomic status and divided into four cohorts (general population; clinically diagnosed heart failure; patients on diuretics; and patients deemed at high risk of heart failure). Definite heart failure (left ventricular ejection fraction (LVEF) < 40%) was identified in 33 people. Samples were handled as though in routine clinical practice. The laboratories undertaking the assays were blinded. Using NT-proBNP to diagnose LVEF < 40% in the general population, a level of > 40 pmol/l had 80% sensitivity, 73% specificity, 5% positive predictive value (PPV), 100% negative predictive value (NPV), and an area under the receiver-operator characteristic curve (AUC) of 76% (95% confidence interval (CI) 46% to 100%). For BNP to diagnose LVSD, a cut off level of > 33 pmol/l had 80% sensitivity, 88% specificity, 10% PPV, 100% NPV, and AUC of 88% (95% CI 75% to 100%). Similar NPVs were found for patients randomly screened from the three other populations. Both NT-proBNP and BNP have value in diagnosing LVSD in a community setting, with similar sensitivities and specificities. Using a high cut off for positivity will confirm the diagnosis of LVSD but will miss cases. At lower cut off values, positive results will require cardiac imaging to confirm LVSD.

Neurotensin and neuromedin N are differentially processed from a common precursor by prohormone convertases in tissues and cell lines.

PubMed

Kitabgi, Patrick

2010-01-01

Neurotensin (NT) is synthesized as part of a larger precursor that also contains neuromedin N (NN), a six amino acid NT-like peptide. NT and NN are located in the C-terminal region of the precursor (pro-NT/NN) where they are flanked and separated by three Lys-Arg sequences. A fourth dibasic sequence is present in the middle of the precursor. Dibasics are the consensus sites recognized and cleaved by specialized endoproteases that belong to the family of proprotein convertases (PCs). In tissues that express pro-NT/NN, the three C-terminal Lys-Arg sites are differentially processed, whereas the middle dibasic is poorly cleaved. Processing gives rise mainly to NT and NN in the brain, NT and a large peptide with a C-terminal NN moiety (large NN) in the gut, and NT, large NN, and a large peptide with a C-terminal NT moiety (large NT) in the adrenals. Recent evidence indicates that PC1, PC2, and PC5-A are the prohormone convertases responsible for the processing patterns observed in the gut, brain, and adrenals, respectively. As NT, NN, large NT, and large NN are all endowed with biological activity, the evidence reviewed here supports the idea that posttranslational processing of pro-NT/NN in tissues may generate biological diversity of pathophysiological relevance.

The TDP-43 N-terminal domain structure at high resolution.

PubMed

Mompeán, Miguel; Romano, Valentina; Pantoja-Uceda, David; Stuani, Cristiana; Baralle, Francisco E; Buratti, Emanuele; Laurents, Douglas V

2016-04-01

Transactive response DNA-binding protein 43 kDa (TDP-43) is an RNA transporting and processing protein whose aberrant aggregates are implicated in neurodegenerative diseases. The C-terminal domain of this protein plays a key role in mediating this process. However, the N-terminal domain (residues 1-77) is needed to effectively recruit TDP-43 monomers into this aggregate. In the present study, we report, for the first time, the essentially complete (1) H, (15) N and (13) C NMR assignments and the structure of the N-terminal domain determined on the basis of 26 hydrogen-bond, 60 torsion angle and 1058 unambiguous NOE structural restraints. The structure consists of an α-helix and six β-strands. Two β-strands form a β-hairpin not seen in the ubiquitin fold. All Pro residues are in the trans conformer and the two Cys are reduced and distantly separated on the surface of the protein. The domain has a well defined hydrophobic core composed of F35, Y43, W68, Y73 and 17 aliphatic side chains. The fold is topologically similar to the reported structure of axin 1. The protein is stable and no denatured species are observed at pH 4 and 25 °C. At 4 kcal·mol(-1) , the conformational stability of the domain, as measured by hydrogen/deuterium exchange, is comparable to ubiquitin (6 kcal·mol(-1) ). The β-strands, α-helix, and three of four turns are generally rigid, although the loop formed by residues 47-53 is mobile, as determined by model-free analysis of the (15) N{(1) H}NOE, as well as the translational and transversal relaxation rates. Structural data have been deposited in the Protein Data Bank under accession code: 2n4p. The NMR assignments have been deposited in the BMRB database under access code: 25675. © 2016 Federation of European Biochemical Societies.

Posttraumatic Propofol Neurotoxicity Is Mediated via the Pro-Brain-Derived Neurotrophic Factor-p75 Neurotrophin Receptor Pathway in Adult Mice.

PubMed

Sebastiani, Anne; Granold, Matthias; Ditter, Anja; Sebastiani, Philipp; Gölz, Christina; Pöttker, Bruno; Luh, Clara; Schaible, Eva-Verena; Radyushkin, Konstantin; Timaru-Kast, Ralph; Werner, Christian; Schäfer, Michael K; Engelhard, Kristin; Moosmann, Bernd; Thal, Serge C

2016-02-01

The gamma-aminobutyric acid modulator propofol induces neuronal cell death in healthy immature brains by unbalancing neurotrophin homeostasis via p75 neurotrophin receptor signaling. In adulthood, p75 neurotrophin receptor becomes down-regulated and propofol loses its neurotoxic effect. However, acute brain lesions, such as traumatic brain injury, reactivate developmental-like programs and increase p75 neurotrophin receptor expression, probably to foster reparative processes, which in turn could render the brain sensitive to propofol-mediated neurotoxicity. This study investigates the influence of delayed single-bolus propofol applications at the peak of p75 neurotrophin receptor expression after experimental traumatic brain injury in adult mice. Randomized laboratory animal study. University research laboratory. Adult C57BL/6N and nerve growth factor receptor-deficient mice. Sedation by IV propofol bolus application delayed after controlled cortical impact injury. Propofol sedation at 24 hours after traumatic brain injury increased lesion volume, enhanced calpain-induced αII-spectrin cleavage, and increased cell death in perilesional tissue. Thirty-day postinjury motor function determined by CatWalk (Noldus Information Technology, Wageningen, The Netherlands) gait analysis was significantly impaired in propofol-sedated animals. Propofol enhanced pro-brain-derived neurotrophic factor/brain-derived neurotrophic factor ratio, which aggravates p75 neurotrophin receptor-mediated cell death. Propofol toxicity was abolished both by pharmacologic inhibition of the cell death domain of the p75 neurotrophin receptor (TAT-Pep5) and in mice lacking the extracellular neurotrophin binding site of p75 neurotrophin receptor. This study provides first evidence that propofol sedation after acute brain lesions can have a deleterious impact and implicates a role for the pro-brain-derived neurotrophic factor-p75 neurotrophin receptor pathway. This observation is important as sedation

The Prognostic Value of Serum Levels of Heart-Type Fatty Acid Binding Protein and High Sensitivity C-Reactive Protein in Patients With Increased Levels of Amino-Terminal Pro-B Type Natriuretic Peptide.

PubMed

Jeong, Ji Hun; Seo, Yiel Hea; Ahn, Jeong Yeal; Kim, Kyung Hee; Seo, Ja Young; Kim, Moon Jin; Lee, Hwan Tae; Park, Pil Whan

2016-09-01

Amino-terminal pro-B type natriuretic peptide (NT-proBNP) is a well-established prognostic factor in heart failure (HF). However, numerous causes may lead to elevations in NT-proBNP, and thus, an increased NT-proBNP level alone is not sufficient to predict outcome. The aim of this study was to evaluate the utility of two acute response markers, high sensitivity C-reactive protein (hsCRP) and heart-type fatty acid binding protein (H-FABP), in patients with an increased NT-proBNP level. The 278 patients were classified into three groups by etiology: 1) acute coronary syndrome (ACS) (n=62), 2) non-ACS cardiac disease (n=156), and 3) infectious disease (n=60). Survival was determined on day 1, 7, 14, 21, 28, 60, 90, 120, and 150 after enrollment. H-FABP (P<0.001), NT-proBNP (P=0.006), hsCRP (P<0.001) levels, and survival (P<0.001) were significantly different in the three disease groups. Patients were divided into three classes by using receiver operating characteristic curves for NT-proBNP, H-FABP, and hsCRP. Patients with elevated NT-proBNP (≥3,856 pg/mL) and H-FABP (≥8.8 ng/mL) levels were associated with higher hazard ratio for mortality (5.15 in NT-proBNP and 3.25 in H-FABP). Area under the receiver operating characteristic curve analysis showed H-FABP was a better predictor of 60-day mortality than NT-proBNP. The combined measurement of H-FABP with NT-proBNP provides a highly reliable means of short-term mortality prediction for patients hospitalized for ACS, non-ACS cardiac disease, or infectious disease.

Brain natriuretic peptide and insulin resistance in older adults.

PubMed

Kim, F; Biggs, M L; Kizer, J R; Brutsaert, E F; de Filippi, C; Newman, A B; Kronmal, R A; Tracy, R P; Gottdiener, J S; Djoussé, L; de Boer, I H; Psaty, B M; Siscovick, D S; Mukamal, K J

2017-02-01

Higher levels of brain natriuretic peptide (BNP) have been associated with a decreased risk of diabetes in adults, but whether BNP is related to insulin resistance in older adults has not been established. N-terminal of the pro hormone brain natriuretic peptide (NT-pro BNP) was measured among Cardiovascular Health Study participants at the 1989-1990, 1992-1993 and 1996-1997 examinations. We calculated measures of insulin resistance [homeostatic model assessment of insulin resistance (HOMA-IR), quantitative insulin sensitivity check index (QUICKI), Gutt index, Matsuda index] from fasting and 2-h concentrations of glucose and insulin among 3318 individuals with at least one measure of NT-proBNP and free of heart failure, coronary heart disease and chronic kidney disease, and not taking diabetes medication. We used generalized estimating equations to assess the cross-sectional association of NT-proBNP with measures of insulin resistance. Instrumental variable analysis with an allele score derived from nine genetic variants (single nucleotide polymorphisms) within or near the NPPA and NPPB loci was used to estimate an un-confounded association of NT-proBNP levels on insulin resistance. Lower NT-proBNP levels were associated with higher insulin resistance even after adjustment for BMI, waist circumference and other risk factors (P < 0.001 for all four indices). Although the genetic score was strongly related to measured NT-proBNP levels amongst European Americans (F statistic = 71.08), we observed no association of genetically determined NT-proBNP with insulin resistance (P = 0.38; P = 0.01 for comparison with the association of measured levels of NT-proBNP). In older adults, lower NT-proBNP is associated with higher insulin resistance, even after adjustment for traditional risk factors. Because related genetic variants were not associated with insulin resistance, the causal nature of this association will require future study. © 2016 Diabetes UK.

Intracerebroventricular infusion of the (Pro)renin receptor antagonist PRO20 attenuates deoxycorticosterone acetate-salt-induced hypertension.

PubMed

Li, Wencheng; Sullivan, Michelle N; Zhang, Sheng; Worker, Caleb J; Xiong, Zhenggang; Speth, Robert C; Feng, Yumei

2015-02-01

We previously reported that binding of prorenin to the (pro)renin receptor (PRR) plays a major role in brain angiotensin II formation and the development of deoxycorticosterone acetate (DOCA)-salt hypertension. Here, we designed and developed an antagonistic peptide, PRO20, to block prorenin binding to the PRR. Fluorescently labeled PRO20 bound to both mouse and human brain tissues with dissociation constants of 4.4 and 1.8 nmol/L, respectively. This binding was blocked by coincubation with prorenin and was diminished in brains of neuron-specific PRR-knockout mice, indicating specificity of PRO20 for PRR. In cultured human neuroblastoma cells, PRO20 blocked prorenin-induced calcium influx in a concentration- and AT(1) receptor-dependent manner. Intracerebroventricular infusion of PRO20 dose-dependently inhibited prorenin-induced hypertension in C57Bl6/J mice. Furthermore, acute intracerebroventricular infusion of PRO20 reduced blood pressure in both DOCA-salt and genetically hypertensive mice. Chronic intracerebroventricular infusion of PRO20 attenuated the development of hypertension and the increase in brain hypothalamic angiotensin II levels induced by DOCA-salt. In addition, chronic intracerebroventricular infusion of PRO20 improved autonomic function and spontaneous baroreflex sensitivity in mice treated with DOCA-salt. In summary, PRO20 binds to both mouse and human PRRs and decreases angiotensin II formation and hypertension induced by either prorenin or DOCA-salt. Our findings highlight the value of the novel PRR antagonist, PRO20, as a lead compound for a novel class of antihypertensive agents and as a research tool to establish the validity of brain PRR antagonism as a strategy for treating hypertension. © 2014 American Heart Association, Inc.

Intracerebroventricular Infusion of the (Pro)renin Receptor Antagonist PRO20 Attenuates Deoxycorticosterone Acetate-Salt–Induced Hypertension

PubMed Central

Li, Wencheng; Sullivan, Michelle N.; Zhang, Sheng; Worker, Caleb J.; Xiong, Zhenggang; Speth, Robert C.; Feng, Yumei

2016-01-01

We previously reported that binding of prorenin to the (pro)renin receptor (PRR) plays a major role in brain angiotensin II formation and the development of deoxycorticosterone acetate (DOCA)-salt hypertension. Here, we designed and developed an antagonistic peptide, PRO20, to block prorenin binding to the PRR. Fluorescently labeled PRO20 bound to both mouse and human brain tissues with dissociation constants of 4.4 and 1.8 nmol/L, respectively. This binding was blocked by coincubation with prorenin and was diminished in brains of neuron-specific PRR-knockout mice, indicating specificity of PRO20 for PRR. In cultured human neuroblastoma cells, PRO20 blocked prorenin-induced calcium influx in a concentration- and AT1 receptor–dependent manner. Intracerebroventricular infusion of PRO20 dose-dependently inhibited prorenin-induced hypertension in C57Bl6/J mice. Furthermore, acute intracerebroventricular infusion of PRO20 reduced blood pressure in both DOCA-salt and genetically hypertensive mice. Chronic intracerebroventricular infusion of PRO20 attenuated the development of hypertension and the increase in brain hypothalamic angiotensin II levels induced by DOCA-salt. In addition, chronic intracerebroventricular infusion of PRO20 improved autonomic function and spontaneous baroreflex sensitivity in mice treated with DOCA-salt. In summary, PRO20 binds to both mouse and human PRRs and decreases angiotensin II formation and hypertension induced by either prorenin or DOCA-salt. Our findings highlight the value of the novel PRR antagonist, PRO20, as a lead compound for a novel class of antihypertensive agents and as a research tool to establish the validity of brain PRR antagonism as a strategy for treating hypertension. PMID:25421983

Superior performance of N-terminal pro brain natriuretic peptide for diagnosis of acute decompensated heart failure in an Asian compared with a Western setting.

PubMed

Ibrahim, Irwani; Kuan, Win Sen; Frampton, Chris; Troughton, Richard; Liew, Oi Wah; Chong, Jenny Pek Ching; Chan, Siew Pang; Tan, Li Ling; Lin, Wei Qin; Pemberton, Chris J; Ooi, Shirley Beng Suat; Richards, A Mark

2017-02-01

This study was conducted to test the diagnostic performance of NT-proBNP for discrimination of acute decompensated heart failure (ADHF) among breathless patients presenting in an Asian compared with a Western centre. Patients with breathlessness were prospectively and contemporaneously recruited in Emergency Departments in Singapore and New Zealand (NZ). The diagnosis of ADHF was adjudicated by two clinician specialists. A total of 606 patients were recruited in Singapore and 500 in NZ. The discriminative power of NT-proBNP for ADHF was superior in Singapore compared with NZ [area under the curve (AUC) 0.926 vs. 0.866; P = 0.012] both overall and among selected subgroups stratified according to age, renal function, body mass index, and presence or absence of AF or diabetes. Previously established cut-off point values of plasma NT-proBNP yielded comparable sensitivity and negative predictive values, but superior specificity and accuracy in Singapore compared with NZ. The difference in test performance was driven by the younger age (median age 56 years vs. 73 years; P < 0.001), associated with better renal function (estimated glomerular filtration rate 89 vs. 62 mL/min/1.73 m 2 ; P < 0.001), and lower prevalence of AF (9.7% vs. 25.7%; P < 0.001) in acutely breathless patients in Singapore. Considering emerging evidence of a lower average age of presentation with ADHF over most of Asia compared with Western countries, NT-proBNP is likely to be more accurate when applied in Asian centres than in the West. © 2016 The Authors. European Journal of Heart Failure © 2016 European Society of Cardiology.

Specific inhibition of c-Jun N-terminal kinase delays preterm labour and reduces mortality

PubMed Central

Pirianov, Grisha; MacIntyre, David A; Lee, Yun; Waddington, Simon N; Terzidou, Vasso; Mehmet, Huseyin; Bennett, Phillip R

2015-01-01

Preterm labour (PTL) is commonly associated with infection and/or inflammation. Lipopolysaccharide (LPS) from different bacteria can be used to independently or mutually activate Jun N-terminal kinase (JNK)/AP1- or NF-κB-driven inflammatory pathways that lead to PTL. Previous studies using Salmonella abortus LPS, which activates both JNK/AP-1 and NF-κB, showed that selective inhibition of NF-κB delays labour and improves pup outcome. Where labour is induced using Escherichia coli LPS (O111), which upregulates JNK/AP-1 but not NF-κB, inhibition of JNK/AP-1 activation also delays labour. In this study, to determine the potential role of JNK as a therapeutic target in PTL, we investigated the specific contribution of JNK signalling to S. Abortus LPS-induced PTL in mice. Intrauterine administration of S. Abortus LPS to pregnant mice resulted in the activation of JNK in the maternal uterus and fetal brain, upregulation of pro-inflammatory proteins COX-2, CXCL1, and CCL2, phosphorylation of cPLA2 in myometrium, and induction of PTL. Specific inhibition of JNK by co-administration of specific D-JNK inhibitory peptide (D-JNKI) delayed LPS-induced preterm delivery and reduced fetal mortality. This is associated with inhibition of myometrial cPLA2 phosphorylation and proinflammatory proteins synthesis. In addition, we report that D-JNKI inhibits the activation of JNK/JNK3 and caspase-3, which are important mediators of neural cell death in the neonatal brain. Our data demonstrate that specific inhibition of TLR4-activated JNK signalling pathways has potential as a therapeutic approach in the management of infection/inflammation-associated PTL and prevention of the associated detrimental effects to the neonatal brain. PMID:26183892

Crystal Structure of the Full-Length Feline Immunodeficiency Virus Capsid Protein Shows an N-Terminal β-Hairpin in the Absence of N-Terminal Proline

PubMed Central

Folio, Christelle; Sierra, Natalia; Dujardin, Marie; Alvarez, Guzman

2017-01-01

Feline immunodeficiency virus (FIV) is a member of the Retroviridae family. It is the causative agent of an acquired immunodeficiency syndrome (AIDS) in cats and wild felines. Its capsid protein (CA) drives the assembly of the viral particle, which is a critical step in the viral replication cycle. Here, the first atomic structure of full-length FIV CA to 1.67 Å resolution is determined. The crystallized protein exhibits an original tetrameric assembly, composed of dimers which are stabilized by an intermolecular disulfide bridge induced by the crystallogenesis conditions. The FIV CA displays a standard α-helical CA topology with two domains, separated by a linker shorter than other retroviral CAs. The β-hairpin motif at its amino terminal end, which interacts with nucleotides in HIV-1, is unusually long in FIV CA. Interestingly, this functional β-motif is formed in this construct in the absence of the conserved N-terminal proline. The FIV CA exhibits a cis Arg–Pro bond in the CypA-binding loop, which is absent in known structures of lentiviral CAs. This structure represents the first tri-dimensional structure of a functional, full-length FIV CA. PMID:29120364

Elevated NT-Pro-Brain Natriuretic Peptide Level Is Independently Associated with All-Cause Mortality in HIV-Infected Women in the Early and Recent HAART Eras in the Women’s Interagency HIV Study Cohort

PubMed Central

Gingo, Matthew R.; Zhang, Yingze; Ghebrehawariat, Kidane B.; Jeong, Jong-Hyeon; Chu, Yanxia; Yang, Quanwei; Lucht, Lorrie; Hanna, David B.; Lazar, Jason M.; Gladwin, Mark T.; Morris, Alison

2015-01-01

Background HIV-infected individuals are at increased risk of right and left heart dysfunction. N-terminal-pro-brain natriuretic peptide (NT-proBNP), a marker of cardiac ventricular strain and systolic dysfunction, may be associated with all-cause mortality in HIV-infected women. The aim of this study was to determine if elevated levels of NT-proBNP is associated with increased mortality in HIV-infected women. Design Prospective cohort study. Methods and Results We measured NT-proBNP in 936 HIV-infected and 387 age-matched HIV-uninfected women early (10/11/94 to 7/17/97) and 1082 HIV-infected and 448 HIV-uninfected women late (4/1/08 to 10/7/08) in the highly active antiretroviral therapy (HAART) periods in the Women’s Interagency HIV Study. An NT-proBNP >75th percentile was more likely in HIV-infected persons, but only statistically significant in the late period (27% vs. 21%, unadjusted p = 0.03). In HIV-infected participants, NT-proBNP>75th percentile was independently associated with worse 5-year survival in the early HAART period (HR 1.8, 95% CI 1.3–2.4, p<0.001) and remained a predictor of mortality in the late HAART period (HR 2.8, 95% CI 1.4–5.5, p = 0.002) independent of other established risk covariates (age, race/ethnicity, body mass index, smoking, hepatitis C serostatus, hypertension, renal function, and hemoglobin). NT-proBNP level was not associated with mortality in HIV-uninfected women. Conclusion NT-proBNP is a novel independent marker of mortality in HIV-infected women both when HAART was first introduced and currently. As NT-proBNP is often associated with both pulmonary hypertension and left ventricular dysfunction, these findings suggest that these conditions may contribute significantly to adverse outcomes in this population, requiring further definition of causes and treatments of elevated NT-proBNP in HIV-infected women. PMID:25811188

Regulation of presynaptic Ca2+, synaptic plasticity and contextual fear conditioning by a N-terminal β-amyloid fragment.

PubMed

Lawrence, James L M; Tong, Mei; Alfulaij, Naghum; Sherrin, Tessi; Contarino, Mark; White, Michael M; Bellinger, Frederick P; Todorovic, Cedomir; Nichols, Robert A

2014-10-22

Soluble β-amyloid has been shown to regulate presynaptic Ca(2+) and synaptic plasticity. In particular, picomolar β-amyloid was found to have an agonist-like action on presynaptic nicotinic receptors and to augment long-term potentiation (LTP) in a manner dependent upon nicotinic receptors. Here, we report that a functional N-terminal domain exists within β-amyloid for its agonist-like activity. This sequence corresponds to a N-terminal fragment generated by the combined action of α- and β-secretases, and resident carboxypeptidase. The N-terminal β-amyloid fragment is present in the brains and CSF of healthy adults as well as in Alzheimer's patients. Unlike full-length β-amyloid, the N-terminal β-amyloid fragment is monomeric and nontoxic. In Ca(2+) imaging studies using a model reconstituted rodent neuroblastoma cell line and isolated mouse nerve terminals, the N-terminal β-amyloid fragment proved to be highly potent and more effective than full-length β-amyloid in its agonist-like action on nicotinic receptors. In addition, the N-terminal β-amyloid fragment augmented theta burst-induced post-tetanic potentiation and LTP in mouse hippocampal slices. The N-terminal fragment also rescued LTP inhibited by elevated levels of full-length β-amyloid. Contextual fear conditioning was also strongly augmented following bilateral injection of N-terminal β-amyloid fragment into the dorsal hippocampi of intact mice. The fragment-induced augmentation of fear conditioning was attenuated by coadministration of nicotinic antagonist. The activity of the N-terminal β-amyloid fragment appears to reside largely in a sequence surrounding a putative metal binding site, YEVHHQ. These findings suggest that the N-terminal β-amyloid fragment may serve as a potent and effective endogenous neuromodulator. Copyright © 2014 the authors 0270-6474/14/3414210-09$15.00/0.

NT-pro-BNP is an independent predictor of mortality in patients with end-stage renal disease.

PubMed

Svensson, M; Gorst-Rasmussen, A; Schmidt, E B; Jorgensen, K A; Christensen, J H

2009-04-01

Patients with end-stage renal disease (ESRD) have an increased mortality from cardiovascular disease (CVD). N-terminal pro-brain natriuretic peptide (NT-pro-BNP) is an independent predictor of mortality in patients with ischemic heart disease and congestive heart failure. Previous data have shown markedly elevated levels of NT-pro-BNP in patients with ESRD, while the prognostic value of elevated levels of NT-pro-BNP in patients with ESRD is largely unknown. The aim of the present study was to examine if the level of NT-pro-BNP predicts mortality in patients with ERSD and CVD. We prospectively followed 206 patients with ESRD and documented CVD. Levels of NT-pro-BNP were measured at baseline, and patients were followed for 2 years or until they reached the predefined endpoint of all-cause mortality. During follow-up, the total mortality was 44% (90/206). Patients who died were followed for a median of 314 days (interquartile range 179 - 530). Using Cox regression analysis, age, female sex, systolic blood pressure, dialysis efficiency and plasma levels of NT-pro-BNP were independent prognostic risk factors of mortality. In receiver operating characteristic curve analysis a cut off value for NT-pro-BNP was determined. Patients with values of NT-pro-BNP above 12.200 pg/ml had a 3 times higher risk of death than patients below the cut-off value (HR 3.05 95% CI 1.96 - 4.77, p < 0.0001). In spite of generally elevated levels of NT-pro-BNP, NT-pro-BNP is still an independent predictor of mortality and might add prognostic information in patients with ESRD and documented CVD.

The Pro-inflammatory Effects of Glucocorticoids in the Brain

PubMed Central

Duque, Erica de Almeida; Munhoz, Carolina Demarchi

2016-01-01

Glucocorticoids are a class of steroid hormones derived from cholesterol. Their actions are mediated by the glucocorticoid and mineralocorticoid receptors, members of the superfamily of nuclear receptors, which, once bound to their ligands, act as transcription factors that can directly modulate gene expression. Through protein–protein interactions with other transcription factors, they can also regulate the activity of many genes in a composite or tethering way. Rapid non-genomic signaling was also demonstrated since glucocorticoids can act through membrane receptors and activate signal transduction pathways, such as protein kinases cascades, to modulate other transcriptions factors and activate or repress various target genes. By all these different mechanisms, glucocorticoids regulate numerous important functions in a large variety of cells, not only in the peripheral organs but also in the central nervous system during development and adulthood. In general, glucocorticoids are considered anti-inflammatory and protective agents due to their ability to inhibit gene expression of pro-inflammatory mediators and other possible damaging molecules. Nonetheless, recent studies have uncovered situations in which these hormones can act as pro-inflammatory agents depending on the dose, chronicity of exposure, and the structure/organ analyzed. In this review, we will provide an overview of the conditions under which these phenomena occur, a discussion that will serve as a basis for exploring the mechanistic foundation of glucocorticoids pro-inflammatory gene regulation in the brain. PMID:27445981

Comparison of Abbott AxSYM and Roche Elecsys 2010 for measurement of BNP and NT-proBNP.

PubMed

Chien, Tzu-I; Chen, Hui-Hou; Kao, Jau-Tsuen

2006-07-15

B-type natriuretic peptide (BNP) and N-terminal pro-brain natriuretic peptide (NT-proBNP) are small cardiac hormones released from the heart. They can be used as an important aid to diagnose congestive heart failure (CHF). We compared the performances of the Abbott AxSYM and Roche Elecsys 2010 for the measurement of BNP and NT-proBNP. The first method uses a microparticle enzyme-linked immunoassay, whereas the other uses chemiluminescent immunometric assay. The CVs using pooled sera ranged from 3.7% to 12.7% for the AxSYM and 0.9% to 2.2% for the Elecsys 2010. The Passing and Bablok regression was Elecsys 2010 NT-proBNP=7.23xAxSYM BNP+2.53. The BNP in EDTA plasma was more stable than in serum. The immunoreactivity difference of NT-proBNP in serum or EDTA plasma was within 10% when stored at 4 degrees Celsius or 25 degrees Celsius for 72 h. Receiver operating characteristic (ROC) curves were different for both assays, and the areas under the curves were 0.704 and 0.841 for the AxSYM and Elecsys 2010 method, respectively. Both assays were not entirely specific for heart failure. The precision and stability for NT-proBNP was better than for BNP in serum. It is important to use method-appropriate reference ranges (or cutoff) for the BNP and NT-proBNP, respectively, in the assessment of CHF.

Interaction of Body Mass Index on the Association Between N-Terminal-Pro-b-Type Natriuretic Peptide and Morbidity and Mortality in Patients With Acute Heart Failure: Findings From ASCEND-HF (Acute Study of Clinical Effectiveness of Nesiritide in Decompensated Heart Failure).

PubMed

Bhatt, Ankeet S; Cooper, Lauren B; Ambrosy, Andrew P; Clare, Robert M; Coles, Adrian; Joyce, Emer; Krishnamoorthy, Arun; Butler, Javed; Felker, G Michael; Ezekowitz, Justin A; Armstrong, Paul W; Hernandez, Adrian F; O'Connor, Christopher M; Mentz, Robert J

2018-02-03

Higher body mass index (BMI) is associated with lower circulating levels of N-terminal-pro-b-type natriuretic peptide (NT-proBNP). The Interaction between BMI and NT-proBNP with respect to clinical outcomes is not well characterized in patients with acute heart failure. A total of 686 patients from the biomarker substudy of the ASCEND-HF (Acute Study of Clinical Effectiveness of Nesiritide in Decompensated HF ) clinical trial with documented NT-proBNP levels at baseline were included in the present analysis. Patients were classified by the World Health Organization obesity classification (nonobese: BMI <30 kg/m 2 , Class I obesity: BMI 30-34.9 kg/m 2 , Class II obesity BMI 35-39.9 kg/m 2 , and Class III obesity BMI ≥40 kg/m 2 ). We assessed baseline characteristics and 30- and 180-day outcomes by BMI class and explored the interaction between BMI and NT-proBNP for these outcomes. Study participants had a median age of 67 years (55, 78) and 71% were female. NT-proBNP levels were inversely correlated with BMI ( P <0.001). Higher NT-proBNP levels were associated with higher 180-day mortality (adjusted hazard ratio for each doubling of NT-proBNP, 1.40; 95% confidence interval, 1.16, 1.71; P <0.001), but not 30-day outcomes. The effect of NT-proBNP on 180-day death was not modified by BMI class (interaction P =0.24). The prognostic value of NT-proBNP was not modified by BMI in this acute heart failure population. NT-proBNP remains a useful prognostic indicator of long-term mortality in acute heart failure even in the obese patient. URL: http://www.clinicaltrials.gov. Unique identifier: NCT00475852. © 2018 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley.

SARS-CoV 3CL protease cleaves its C-terminal autoprocessing site by novel subsite cooperativity.

PubMed

Muramatsu, Tomonari; Takemoto, Chie; Kim, Yong-Tae; Wang, Hongfei; Nishii, Wataru; Terada, Takaho; Shirouzu, Mikako; Yokoyama, Shigeyuki

2016-11-15

The 3C-like protease (3CL pro ) of severe acute respiratory syndrome coronavirus (SARS-CoV) cleaves 11 sites in the polyproteins, including its own N- and C-terminal autoprocessing sites, by recognizing P4-P1 and P1'. In this study, we determined the crystal structure of 3CL pro with the C-terminal prosequence and the catalytic-site C145A mutation, in which the enzyme binds the C-terminal prosequence of another molecule. Surprisingly, Phe at the P3' position [Phe(P3')] is snugly accommodated in the S3' pocket. Mutations of Phe(P3') impaired the C-terminal autoprocessing, but did not affect N-terminal autoprocessing. This difference was ascribed to the P2 residue, Phe(P2) and Leu(P2), in the C- and N-terminal sites, as follows. The S3' subsite is formed by Phe(P2)-induced conformational changes of 3CL pro and the direct involvement of Phe(P2) itself. In contrast, the N-terminal prosequence with Leu(P2) does not cause such conformational changes for the S3' subsite formation. In fact, the mutation of Phe(P2) to Leu in the C-terminal autoprocessing site abolishes the dependence on Phe(P3'). These mechanisms explain why Phe is required at the P3' position when the P2 position is occupied by Phe rather than Leu, which reveals a type of subsite cooperativity. Moreover, the peptide consisting of P4-P1 with Leu(P2) inhibits protease activity, whereas that with Phe(P2) exhibits a much smaller inhibitory effect, because Phe(P3') is missing. Thus, this subsite cooperativity likely exists to avoid the autoinhibition of the enzyme by its mature C-terminal sequence, and to retain the efficient C-terminal autoprocessing by the use of Phe(P2).

Cardiac and Carotid Markers Link With Accelerated Brain Atrophy: The AGES-Reykjavik Study (Age, Gene/Environment Susceptibility-Reykjavik).

PubMed

Sabayan, Behnam; van Buchem, Mark A; Sigurdsson, Sigurdur; Zhang, Qian; Meirelles, Osorio; Harris, Tamara B; Gudnason, Vilmundur; Arai, Andrew E; Launer, Lenore J

2016-11-01

Pathologies in the heart-brain axis might, independently or in combination, accelerate the process of brain parenchymal loss. We aimed to investigate the association of serum N-terminal brain natriuretic peptide (NT-proBNP), as a marker of cardiac dysfunction, and carotid intima media thickness (CIMT), as a marker of carotid atherosclerosis burden, with structural brain changes. In the longitudinal population-based AGES-Reykjavik study (Age, Gene/Environment Susceptibility-Reykjavik), we included 2430 subjects (mean age, 74.6 years; 41.4% men) with baseline data on NT-proBNP and CITM (assessed by ultrasound imaging). Participants underwent a high-resolution brain magnetic resonance imaging at baseline and 5 years later to assess total brain (TBV), gray matter, and white matter volumes. Each unit higher log-transformed NT-proBNP was associated with 3.6 mL (95% confidence interval [CI], -6.0 to -1.1) decline in TBV and 3.5 mL (95% CI, -5.7 to -1.3) decline in gray matter volume. Likewise, each millimeter higher CIMT was associated with 10.8 mL (95% CI, -17.3 to -4.2) decline in TBV and 8.6 mL (95% CI, -14.4 to -2.8) decline in gray matter volume. There was no association between NT-proBNP and CIMT and changes in white matter volume. Compared with participants with low NT-proBNP and CIMT, participants with both high NT-proBNP and CIMT had 3.8 mL (95% CI, -6.0 to -1.6) greater decline in their TBV and 4 mL (95% CI, -6.0 to -2.0) greater decline in GMW. These associations were independent of sociodemographic and cardiovascular factors. Older subjects with both cardiac dysfunction and carotid atherosclerosis are at an increased risk for brain parenchymal loss. Accumulated pathologies in the heart-brain axis might accelerate brain atrophy. © 2016 American Heart Association, Inc.

Pro-region engineering for improved yeast display and secretion of brain derived neurotrophic factor.

PubMed

Burns, Michael L; Malott, Thomas M; Metcalf, Kevin J; Puguh, Arthya; Chan, Jonah R; Shusta, Eric V

2016-03-01

Brain derived neurotrophic factor (BDNF) is a promising therapeutic candidate for a variety of neurological diseases. However, it is difficult to produce as a recombinant protein. In its native mammalian context, BDNF is first produced as a pro-protein with subsequent proteolytic removal of the pro-region to yield mature BDNF protein. Therefore, in an attempt to improve yeast as a host for heterologous BDNF production, the BDNF pro-region was first evaluated for its effects on BDNF surface display and secretion. Addition of the wild-type pro-region to yeast BDNF production constructs improved BDNF folding both as a surface-displayed and secreted protein in terms of binding its natural receptors TrkB and p75, but titers remained low. Looking to further enhance the chaperone-like functions provided by the pro-region, two rounds of directed evolution were performed, yielding mutated pro-regions that further improved the display and secretion properties of BDNF. Subsequent optimization of the protease recognition site was used to control whether the produced protein was in pro- or mature BDNF forms. Taken together, we have demonstrated an effective strategy for improving BDNF compatibility with yeast protein engineering and secretion platforms. Copyright © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Employment status and termination among survivors of pediatric brain tumors: a cross-sectional survey.

PubMed

Sato, Iori; Higuchi, Akiko; Yanagisawa, Takaaki; Murayama, Shiho; Kumabe, Toshihiro; Sugiyama, Kazuhiko; Mukasa, Akitake; Saito, Nobuhito; Sawamura, Yutaka; Terasaki, Mizuhiko; Shibui, Soichiro; Takahashi, Jun; Nishikawa, Ryo; Ishida, Yasushi; Kamibeppu, Kiyoko

2018-04-30

Some childhood cancer survivors experience employment difficulties. This study aimed to describe pediatric brain-tumor survivors' employment status. A cross-sectional, observational study was conducted, with questionnaires distributed to 101 pediatric brain-tumor survivors (aged 15 years or older) and their attending physicians from nine institutions in Japan. We compared category and time-series histories for participants' first-time employment using national census information. Factors related to delayed employment or early employment termination were examined using survival-time analyses. Excluding students and homemakers, 38 brain-tumor survivors (median age 27 years, with 15 years since diagnosis) were of working age. Of these, 12 (32%) were unemployed and 9 (24%) had never been employed. First-time employment occurred later for brain-tumor survivors than the general population, particularly in those with lower educational levels. The number of brain-tumor survivors whose first job was terminated within the first year was higher than that for the general population, particularly in male survivors and germ cell-tumor survivors. Brain-tumor survivors described their working patterns (irregular), job types (specialist or professional), reasons for early termination (unsuitable job), and thoughts about working (they wished to serve their communities but lacked confidence). Brain-tumor survivors are associated with high unemployment rates and multiple unemployment-related factors. Education and welfare systems should identify individual methods of social participation for this group.

Diagnostic value of analysis of H-FABP, NT-proBNP, and cTnI in heart function in children with congenital heart disease and pneumonia.

PubMed

Zhou, F-J; Zhou, C-Y; Tian, Y-J; Xiao, A-J; Li, P-L; Wang, Y-H; Jia, J-W

2014-01-01

To analyze the expression of heart-fatty acid-binding protein (H-FABP), N-terminal pro-brain natriuretic peptide (NT-proBNP), and cTnI in children with congenital heart disease (CHD) and pneumonia, and evaluate its diagnostic value in heart failure (HF). The levels of serum H-FABP, NT-proBNP, and cardiac troponin 1 (cTnI) were measured by immunoassays in 22 children with CHD, pneumonia, and HF (group I), 25 children with CHD and pneumonia (group II), and 25 healthy children without CHD or pneumonia (control group). The concentration and positive rate of serum H-FABP, NT-proBNP, and cTnI were significantly higher in group I than those in group II. Compared to control group, these indexes were increased in both group I and group II. There were statistical significant differences in the positive rate of NT-proBNP and cTnI but not H-FABP between groups of patients with different classes of heart function. The levels of H-FABP, NT-proBNP, and cTnI were correlated with heart function, and can be used for the diagnosis of early-stage HF in children with CHD.

Deletion of the N-terminal Domain (NTD) Alters the Ethanol Inhibition of NMDA Receptors in a Subunit-Dependent Manner

PubMed Central

Smothers, C. Thetford; Jin, Chun; Woodward, John J.

2013-01-01

Background Ethanol inhibition of NMDA receptors is poorly understood due in part to the organizational complexity of the receptor that provides ample locations for sites of action. Among these the N-terminal domain of NMDA receptor subunits contains binding sites for a variety of modulatory agents including zinc, protons and GluN2B selective antagonists such as ifenprodil or Ro-25–6981. Ethanol inhibition of neuronal NMDA receptors expressed in some brain areas has been reported to be occluded by the presence of ifenprodil or similar compounds suggesting that the N-terminal domain may be important in regulating the ethanol sensitivity of NMDA receptors. Methods Wild-type GluN1 and GluN2 subunits and those in which the coding sequence for the N-terminal domain was deleted were expressed in HEK293 cells. Whole-cell voltage-clamp recording was used to assess ethanol inhibition of wild-type and mutant receptors lacking the N-terminal domain. Results As compared to wild-type GluN1/GluN2A receptors, ethanol inhibition was slightly greater in cells expressing GluN2A subunits lacking the N-terminal domain. In contrast, GluN2B N-terminal deletion mutants showed normal ethanol inhibition while those lacking the N-terminal domain in both GluN1 and GluN2B subunits had decreased ethanol inhibition as compared to wild-type receptors. N-terminal domain lacking GluN2B receptors were insensitive to ifenprodil but retained normal sensitivity to ethanol. Conclusions These findings indicate that the N-terminal domain modestly influences the ethanol sensitivity of NMDA receptors in a subunit-dependent manner. They also show that ifenprodil’s actions on GluN2B containing receptors can be dissociated from those of ethanol. These results suggest that while the N-terminal domain is not a primary site of action for ethanol on NMDA receptors, it likely affects sensitivity via actions on intrinsic channel properties. PMID:23905549

NT-proBNP and Heart Failure Risk Among Individuals With and Without Obesity: The ARIC Study

PubMed Central

Ndumele, Chiadi E.; Matsushita, Kunihiro; Sang, Yingying; Lazo, Mariana; Agarwal, Sunil K.; Nambi, Vijay; Deswal, Anita; Blumenthal, Roger S.; Ballantyne, Christie M.; Coresh, Josef; Selvin, Elizabeth

2016-01-01

Background Obesity is a risk factor for heart failure (HF), but is associated with lower N-terminal of pro-Brain Natriuretic Peptide (NT-proBNP) levels. It is unclear whether the prognostic value and implications of NT-proBNP levels for HF risk differ across body mass index (BMI) categories. Methods and Results We followed 12,230 ARIC participants free of prior HF at baseline (visit 2, 1990–1992) with BMI ≥18.5 kg/m2. We quantified and compared the relative and absolute risk associations of NT-proBNP with incident HF across BMI categories. There were 1,861 HF events during a median 20.6 years of follow-up. Despite increased HF risk in obesity, a weak inverse association was seen between baseline BMI and NT-proBNP levels (r = −0.10). Nevertheless, higher baseline NT-proBNP was associated with increased HF risk in all BMI categories. NT-proBNP improved HF risk prediction overall and even among those with severe obesity (BMI ≥35 kg/m2; improvement in c-statistic +0.032 [95% CI 0.011–0.053]). However, given higher HF rates among those with obesity, at each NT-proBNP level, higher BMI was associated with greater absolute HF risk. Indeed, among those with NT-proBNP 100 to < 200 pg/ml, the average 10-year HF risk was <5% among normal weight individuals but >10% if severely obese. Conclusions Despite its inverse relationship with BMI, NT-proBNP provides significant prognostic information regarding the risk of developing HF even among individuals with obesity. Given the higher baseline HF risk among persons with obesity, even slight elevations in NT-proBNP may have implications for increased absolute HF risk in this population. PMID:26746175

Value of Combining Left Atrial Diameter and Amino-terminal Pro-brain Natriuretic Peptide to the CHA2DS2-VASc Score for Predicting Stroke and Death in Patients with Sick Sinus Syndrome after Pacemaker Implantation.

PubMed

Mo, Bin-Feng; Lu, Qiu-Fen; Lu, Shang-Biao; Xie, Yu-Quan; Feng, Xiang-Fei; Li, Yi-Gang

2017-08-20

The CHA2DS2-VASc score is used clinically for stroke risk stratification in patients with atrial fibrillation (AF). We sought to investigate whether the CHA2DS2-VASc score predicts stroke and death in Chinese patients with sick sinus syndrome (SSS) after pacemaker implantation and to evaluate whether the predictive power of the CHA2DS2-VASc score could be improved by combining it with left atrial diameter (LAD) and amino-terminal pro-brain natriuretic peptide (NT-proBNP). A total of 481 consecutive patients with SSS who underwent pacemaker implantation from January 2004 to December 2014 in our department were included. The CHA2DS2-VASc scores were retrospectively calculated according to the hospital medical records before pacemaker implantation. The outcome data (stroke and death) were collected by pacemaker follow-up visits and telephonic follow-up until December 31, 2015. During 2151 person-years of follow-up, 46 patients (9.6%) suffered stroke and 52 (10.8%) died. The CHA2DS2-VASc score showed a significant association with the development of stroke (hazard ratio [HR] 1.45, 95% confidence interval [CI] 1.20-1.75, P< 0.001) and death (HR 1.45, 95% CI 1.22-1.71, P< 0.001). The combination of increased LAD and the CHA2DS2-VASc score improved the predictive power for stroke (C-stat 0.69, 95% CI 0.61-0.77 vs. C-stat 0.66, 95% CI 0.57-0.74, P= 0.013), and the combination of increased NT-proBNP and the CHA2DS2-VASc score improved the predictive power for death (C-stat 0.70, 95% CI 0.64-0.77 vs. C-stat 0.67, 95% CI 0.60--0.75, P= 0.023). CHA2DS2-VASc score is valuable for predicting stroke and death risk in patients with SSS after pacemaker implantation. The addition of LAD and NT-proBNP to the CHA2DS2-VASc score improved its predictive power for stroke and death, respectively, in this patient cohort. Future prospective studies are warranted to validate the benefit of adding LAD and NT-proBNP to the CHA2DS2-VASc score for predicting stroke and death risk in non

Crystal Structures of Copper-depleted and Copper-bound Fungal Pro-tyrosinase

PubMed Central

Fujieda, Nobutaka; Yabuta, Shintaro; Ikeda, Takuya; Oyama, Takuji; Muraki, Norifumi; Kurisu, Genji; Itoh, Shinobu

2013-01-01

Tyrosinase, a dinuclear copper monooxygenase/oxidase, plays a crucial role in the melanin pigment biosynthesis. The structure and functions of tyrosinase have so far been studied extensively, but the post-translational maturation process from the pro-form to the active form has been less explored. In this study, we provide the crystal structures of Aspergillus oryzae full-length pro-tyrosinase in the holo- and the apo-forms at 1.39 and 2.05 Å resolution, respectively, revealing that Phe513 on the C-terminal domain is accommodated in the substrate-binding site as a substrate analog to protect the dicopper active site from substrate access (proteolytic cleavage of the C-terminal domain or deformation of the C-terminal domain by acid treatment transforms the pro-tyrosinase to the active enzyme (Fujieda, N., Murata, M., Yabuta, S., Ikeda, T., Shimokawa, C., Nakamura, Y., Hata, Y., and Itoh, S. (2012) ChemBioChem. 13, 193–201 and Fujieda, N., Murata, M., Yabuta, S., Ikeda, T., Shimokawa, C., Nakamura, Y., Hata, Yl, and Itoh, S. (2013) J. Biol. Inorg. Chem. 18, 19–26). Detailed crystallographic analysis and structure-based mutational studies have shown that the copper incorporation into the active site is governed by three cysteines as follows: Cys92, which is covalently bound to His94 via an unusual thioether linkage in the holo-form, and Cys522 and Cys525 of the CXXC motif located on the C-terminal domain. Molecular mechanisms of the maturation processes of fungal tyrosinase involving the accommodation of the dinuclear copper unit, the post-translational His-Cys thioether cross-linkage formation, and the proteolytic C-terminal cleavage to produce the active tyrosinase have been discussed on the basis of the detailed structural information. PMID:23749993

N-terminal nesprin-2 variants regulate β-catenin signalling

DOE Office of Scientific and Technical Information (OSTI.GOV)

Zhang, Qiuping; Minaisah, Rose-Marie; Ferraro, Elisa

2016-07-15

The spatial compartmentalisation of biochemical signalling pathways is essential for cell function. Nesprins are a multi-isomeric family of proteins that have emerged as signalling scaffolds, herein, we investigate the localisation and function of novel nesprin-2 N-terminal variants. We show that these nesprin-2 variants display cell specific distribution and reside in both the cytoplasm and nucleus. Immunofluorescence microscopy revealed that nesprin-2 N-terminal variants colocalised with β-catenin at cell-cell junctions in U2OS cells. Calcium switch assays demonstrated that nesprin-2 and β-catenin are lost from cell-cell junctions in low calcium conditions whereas emerin localisation at the NE remained unaltered, furthermore, an N-terminal fragmentmore » of nesprin-2 was sufficient for cell-cell junction localisation and interacted with β-catenin. Disruption of these N-terminal nesprin-2 variants, using siRNA depletion resulted in loss of β-catenin from cell-cell junctions, nuclear accumulation of active β-catenin and augmented β-catenin transcriptional activity. Importantly, we show that U2OS cells lack nesprin-2 giant, suggesting that the N-terminal nesprin-2 variants regulate β-catenin signalling independently of the NE. Together, these data identify N-terminal nesprin-2 variants as novel regulators of β-catenin signalling that tether β-catenin to cell-cell contacts to inhibit β-catenin transcriptional activity. - Highlights: • N-terminal nesprin-2 variants display cell specific expression patterns. • N-terminal spectrin repeats of nesprin-2 interact with β-catenin. • N-terminal nesprin-2 variants scaffold β-catenin at cell-cell junctions.. • Nesprin-2 variants play multiple roles in β-catenin signalling.« less

Evidence that PC2 is the endogenous pro-neurotensin convertase in rMTC 6-23 cells and that PC1- and PC2-transfected PC12 cells differentially process pro-neurotensin.

PubMed

Rovère, C; Barbero, P; Kitabgi, P

1996-05-10

The neuropeptide precursor proneurotensin/neuromedin N (pro-NT/NN) is mainly expressed and differentially processed in the brain and in the small intestine. We showed previously that rMTC 6-23 cells process pro-NT/NN with a pattern similar to brain tissue and increase pro-NT/NN expression in response to dexamethasone, and that PC12 cells also produce pro-NT/NN but are virtually unable to process it. In addition, PC12 cells were reported to be devoid of the prohormone convertases PC1 and PC2. The present study was designed to identify the proprotein convertase(s) (PC) involved in pro-NT/NN processing in rMTC 6-23 cells and to compare PC1- and PC2-transfected PC12 cells for their ability to process pro-NT/NN. rMTC 6-23 cells were devoid of PC1, PC4, and PC5 but expressed furin and PC2. Stable expression of antisense PC2 RNA in rMTC 6-23 cells led to a 90% decrease in PC2 protein levels that correlated with a > 80% reduction of pro-NT/NN processing. PC2 expression was stimulated by dexamethasone in a time- and concentration-dependent manner. Stable PC12/PC2 transfectants processed pro-NT/NN with a pattern similar to that observed in the brain and in rMTC 6-23 cells. In contrast, stable PC12/PC1 transfectants reproduced the pro-NT/NN processing pattern seen in the gut. We conclude that (i) PC2 is the major pro-NT/NN convertase in rMTC 6-23 cells; (ii) its expression is coregulated with that of pro-NT/NN in this cell line; and (iii) PC2 and PC1 differentially process pro-NT/NN with brain and intestinal phenotype, respectively.

Brain correlates of pro-social personality traits: a voxel-based morphometry study.

PubMed

Coutinho, Joana F; Sampaio, Adriana; Ferreira, Miguel; Soares, José M; Gonçalves, Oscar F

2013-09-01

Of the five personality dimensions described by the Big Five Personality Model (Costa and McCrae 1992), Extraversion and Agreeableness are the traits most commonly associated with a pro-social orientation. In this study we tested whether a pro-social orientation, as expressed in terms of Extraversion and Agreeableness, is associated with a specific grey matter phenotype. Fifty-two healthy participants underwent magnetic resonance imaging (MRI) and completed the NEO-Five Factor Inventory (NEO-FFI), a self-report measure of the Big Five personality traits. Voxel-based morphometry (VBM) was used to investigate the correlation between brain structure and the personality traits of Agreeableness and Extraversion. We found that Extraversion was negatively correlated with grey matter density in the middle frontal and orbitofrontal gyri while Agreeableness was negatively correlated with grey matter density in the inferior parietal, middle occipital and posterior cingulate gyri. No positive correlations were found. These results suggest that pro-social personality traits seem to be associated with decreases in grey matter density in more frontal regions for Extraversion, and more posterior regions for Agreeableness.

Selective Activation of N,N'-Diacyl Rhodamine Pro-fluorophores Paired with Releasing Enzyme, Porcine Liver Esterase (PLE).

PubMed

Abney, Kristopher K; Ramos-Hunter, Susan J; Romaine, Ian M; Godwin, J Shawn; Sulikowski, Gary A; Weaver, Charles David

2018-04-21

This study reports the synthesis and testing of a family of rhodamine pro-fluorophores and an enzyme capable of converting pro-fluorophores to Rhodamine 110. We prepared a library of simple N,N'-diacyl rhodamines and investigated Porcine Liver Esterase (PLE) as an enzyme to activate rhodamine-based pro-fluorophores. A PLE-expressing cell line generated an increase in fluorescence rapidly upon pro-fluorophore addition demonstrating the rhodamine pro-fluorophores are readily taken up and fluorescent upon PLE-mediated release. Rhodamine pro-fluorophore amides trifluoroacetamide (TFAm) and proponamide (PAm) appeared to be the best substrates using a cell-based assay using PLE expressing HEK293. Our pro-fluorophore series showed diffusion into live cells and resisted endogenous hydrolysis. The use of our engineered cell line containing the exogenous enzyme PLE demonstrated the rigorousness of amide masking when compared to cells not containing PLE. This simple and selective pro-fluorophore rhodamine pair with PLE offers the potential to be used in vitro and in vivo fluorescence based assays. © 2018 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Human IgG is produced in a pro-form that requires clipping of C-terminal lysines for maximal complement activation

PubMed Central

van den Bremer, Ewald TJ; Beurskens, Frank J; Voorhorst, Marleen; Engelberts, Patrick J; de Jong, Rob N; van der Boom, Burt G; Cook, Erika M; Lindorfer, Margaret A; Taylor, Ronald P; van Berkel, Patrick HC; Parren, Paul WHI

2015-01-01

Human IgG is produced with C-terminal lysines that are cleaved off in circulation. The function of this modification was unknown and generally thought not to affect antibody function. We recently reported that efficient C1q binding and complement-dependent cytotoxicity (CDC) requires IgG hexamerization at the cell surface. Here we demonstrate that C-terminal lysines may interfere with this process, leading to suboptimal C1q binding and CDC of cells opsonized with C-terminal lysine-containing IgG. After we removed these lysines with a carboxypeptidase, maximal complement activation was observed. Interestingly, IgG1 mutants containing either a negative C-terminal charge or multiple positive charges lost CDC almost completely; however, CDC was fully restored by mixing C-terminal mutants of opposite charge. Our data indicate a novel post-translational control mechanism of human IgG: human IgG molecules are produced in a pro-form in which charged C-termini interfere with IgG hexamer formation, C1q binding and CDC. To allow maximal complement activation, C-terminal lysine processing is required to release the antibody's full cytotoxic potential. PMID:26037225

A rapid and cost-effective method of producing recombinant proBNP and NT-proBNP variants in Escherichia coli for immunoassay of heart failure.

PubMed

Soleh, Muhammad Tarmizi; Foo, Jared Yong Yang; Bailey, Ulla-Maja; Tan, Nikki Yi; Wan, Yunxia; Cooper-White, Justin; Schulz, Benjamin Luke; Punyadeera, Chamindie

2014-01-01

The measurements of plasma natriuretic peptides (NT-proBNP, proBNP and BNP) are used to diagnose heart failure but these are expensive to produce. We describe a rapid, cheap and facile production of proteins for immunoassays of heart failure. DNA encoding N-terminally His-tagged NT-proBNP and proBNP were cloned into the pJexpress404 vector. ProBNP and NT-proBNP peptides were expressed in Escherichia coli, purified and refolded in vitro. The analytical performance of these peptides were comparable with commercial analytes (NT-proBNP EC50 for the recombinant is 2.6 ng/ml and for the commercial material is 5.3 ng/ml) and the EC50 for recombinant and commercial proBNP, are 3.6 and 5.7 ng/ml respectively). Total yield of purified refolded NT-proBNP peptide was 1.75 mg/l and proBNP was 0.088 mg/l. This approach may also be useful in expressing other protein analytes for immunoassay applications. To develop a cost effective protein expression method in E. coli to obtain high yields of NT-proBNP (1.75 mg/l) and proBNP (0.088 mg/l) peptides for immunoassay use.

Prohormone convertase 1 (PC1) when expressed with pro cholecystokinin (pro CCK) in L cells performs three endoproteolytic cleavages which are observed in rat brain and in CCK-expressing endocrine cells in culture, including the production of glycine and arginine extended CCK8.

PubMed

Wang, W; Birch, N P; Beinfeld, M C

1998-07-30

Pro CCK was expressed in an L cell line engineered to express PC1 and the products secreted into the media were characterized by a combination of RIA, gel filtration and HPLC. PC1 released from L cells, cleaved pro CCK generating the amino terminal pro peptide. PC1 also generated a peptide which after carboxypeptidase B treatment, was detected with an antiserum specific for CCK Gly. Neither of these peptides was found in media from L cells expressing pro CCK alone. This CCK Gly immunoreactive peptide was similar in size to CCK 8, and after treatment with arylsulfatase and carboxypeptidase B, it co-eluted on HPLC with unsulfated CCK 8 Gly. These results agree with previous studies which support a role for PC1 in generation of CCK 8. This is the first demonstration that PC1 acting alone is able to cleave pro CCK liberating the amino terminal pro peptide and a glycine and arginine extended CCK 8 which is the immediate precursor of CCK 8 amide.

The Prorenin and (Pro)renin Receptor: New Players in the Brain Renin-Angiotensin System?

PubMed Central

Li, Wencheng; Peng, Hua; Seth, Dale M.; Feng, Yumei

2012-01-01

It is well known that the brain renin-angiotensin (RAS) system plays an essential role in the development of hypertension, mainly through the modulation of autonomic activities and vasopressin release. However, how the brain synthesizes angiotensin (Ang) II has been a debate for decades, largely due to the low renin activity. This paper first describes the expression of the vasoconstrictive arm of RAS components in the brain as well as their physiological and pathophysiological significance. It then focus on the (pro)renin receptor (PRR), a newly discovered component of the RAS which has a high level in the brain. We review the role of prorenin and PRR in peripheral organs and emphasize the involvement of brain PRR in the pathogenesis of hypertension. Some future perspectives in PRR research are heighted with respect to novel therapeutic target for the treatment of hypertension and other cardiovascular diseases. PMID:23316344

24 CFR 266.608 - Mortgage insurance premium: Pro rata refund.

Code of Federal Regulations, 2010 CFR

2010-04-01

... 24 Housing and Urban Development 2 2010-04-01 2010-04-01 false Mortgage insurance premium: Pro... PROJECT LOANS Contract Rights and Obligations Mortgage Insurance Premiums § 266.608 Mortgage insurance premium: Pro rata refund. If the Contract of Insurance is terminated by payment in full or is terminated...

24 CFR 266.608 - Mortgage insurance premium: Pro rata refund.

Code of Federal Regulations, 2011 CFR

2011-04-01

... 24 Housing and Urban Development 2 2011-04-01 2011-04-01 false Mortgage insurance premium: Pro... PROJECT LOANS Contract Rights and Obligations Mortgage Insurance Premiums § 266.608 Mortgage insurance premium: Pro rata refund. If the Contract of Insurance is terminated by payment in full or is terminated...

Towards Understanding the Tandem Mass Spectra of Protonated Oligopeptides. 2: The Proline Effect in Collision-Induced Dissociation of Protonated Ala-Ala-Xxx-Pro-Ala (Xxx = Ala, Ser, Leu, Val, Phe, and Trp)

NASA Astrophysics Data System (ADS)

Bleiholder, Christian; Suhai, Sándor; Harrison, Alex G.; Paizs, Béla

2011-06-01

The product ion spectra of proline-containing peptides are commonly dominated by y n ions generated by cleavage at the N-terminal side of proline residues. This proline effect is investigated in the current work by collision-induced dissociation (CID) of protonated Ala-Ala-Xxx-Pro-Ala (Xxx includes Ala, Ser, Leu, Val, Phe, and Trp) in an electrospray/quadrupole/time-of-flight (QqTOF) mass spectrometer and by quantum chemical calculations on protonated Ala-Ala-Ala-Pro-Ala. The CID spectra of all investigated peptides show a dominant y 2 ion (Pro-Ala sequence). Our computational results show that the proline effect mainly arises from the particularly low threshold energy for the amide bond cleavage N-terminal to the proline residue, and from the high proton affinity of the proline-containing C-terminal fragment produced by this cleavage. These theoretical results are qualitatively supported by the experimentally observed y 2 / b 3 abundance ratios for protonated Ala-Ala-Xxx-Pro-Ala (Xxx = Ala, Ser, Leu, Val, Phe, and Trp). In the post-cleavage phase of fragmentation the N-terminal oxazolone fragment with the Ala-Ala-Xxx sequence and Pro-Ala compete for the ionizing proton for these peptides. As the proton affinity of the oxazolone fragment increases, the y 2 / b 3 abundance ratio decreases.

Towards understanding the tandem mass spectra of protonated oligopeptides. 2: The proline effect in collision-induced dissociation of protonated Ala-Ala-Xxx-Pro-Ala (Xxx = Ala, Ser, Leu, Val, Phe, and Trp).

PubMed

Bleiholder, Christian; Suhai, Sándor; Harrison, Alex G; Paizs, Béla

2011-06-01

The product ion spectra of proline-containing peptides are commonly dominated by y(n) ions generated by cleavage at the N-terminal side of proline residues. This proline effect is investigated in the current work by collision-induced dissociation (CID) of protonated Ala-Ala-Xxx-Pro-Ala (Xxx includes Ala, Ser, Leu, Val, Phe, and Trp) in an electrospray/quadrupole/time-of-flight (QqTOF) mass spectrometer and by quantum chemical calculations on protonated Ala-Ala-Ala-Pro-Ala. The CID spectra of all investigated peptides show a dominant y(2) ion (Pro-Ala sequence). Our computational results show that the proline effect mainly arises from the particularly low threshold energy for the amide bond cleavage N-terminal to the proline residue, and from the high proton affinity of the proline-containing C-terminal fragment produced by this cleavage. These theoretical results are qualitatively supported by the experimentally observed y(2)/b(3) abundance ratios for protonated Ala-Ala-Xxx-Pro-Ala (Xxx = Ala, Ser, Leu, Val, Phe, and Trp). In the post-cleavage phase of fragmentation the N-terminal oxazolone fragment with the Ala-Ala-Xxx sequence and Pro-Ala compete for the ionizing proton for these peptides. As the proton affinity of the oxazolone fragment increases, the y(2)/b(3) abundance ratio decreases.

Patients’ Perspectives of Enrollment in Research Without Consent- The Patients’ Experiences in Emergency Research- ProTECT Study (PEER-ProTECT)

PubMed Central

Dickert, Neal W; Scicluna, Victoria M; Baren, Jill M; Biros, Michelle H; Fleischman, Ross J; Govindarajan, Prasanthi R; Jones, Elizabeth B; Pancioli, Arthur M; Wright, David W; Pentz, Rebecca D

2016-01-01

Objective Research in acute illness often requires an exception from informed consent (EFIC). Few studies have assessed the views of patients enrolled in EFIC trials. This study was designed to assess the views of patients and their surrogates of EFIC enrollment in a randomized, placebo-controlled trial of an investigational agent for traumatic brain injury. Design Interactive interview study. Setting Nested within the Progesterone for the Treatment of Traumatic Brain Injury (ProTECT III) trial, a Phase III randomized controlled trial in acute traumatic brain injury (TBI). Participants Patients and surrogates (for patients incapable of being interviewed) enrolled in ProTECT III under EFIC at 12 sites. Measurements Interviews focused on respondents’ acceptance of EFIC enrollment in ProTECT, use of placebo and randomization, understanding of major study elements, and views regarding regulatory protections. Descriptive statistical analysis was performed; textual data were analyzed thematically. Main Results 85 individuals were interviewed. 84% had positive attitudes toward ProTECT III inclusion. 78% found their inclusion under EFIC acceptable, and 72% found use of EFIC in ProTECT III acceptable in general. Only 2 respondents clearly disagreed with both personal and general EFIC enrollment. The most common concerns (26%) related to absence of consent. 80% and 92% were accepting of placebo use and randomization, respectively. Though there were few black respondents (n=11), they were less accepting of personal EFIC enrollment than white respondents (55% vs 83%, p= 0.0494). Conclusions Acceptance of EFIC in this placebo-controlled trial of an investigational agent was high and exceeded acceptance among community consultation participants. EFIC enrollment appears generally consistent with patients’ preferences. PMID:25574795

Plasma NT-proBNP mirrors the deleterious cardiovascular and renal continuum in hypertension.

PubMed

Courand, Pierre-Yves; Harbaoui, Brahim; Bècle, Clément; Mouly-Bertin, Carine; Lantelme, Pierre

2017-03-01

Background The aims of this study were (a) to test the ability of N-terminal pro-brain natriuretic peptide (NT-proBNP) to detect subclinical target organ damage (TOD) denoted by left ventricular hypertrophy (LVH), aortic stiffness or renal damage and (b) to test its reproducibility in two different conditions in an ancillary study. Methods The study included 837 patients (50.9% men) with hypertension aged 50 ± 24 years with a median 24-h ambulatory blood pressure (BP) of 148/90 mmHg. LVH was assessed by transthoracic echocardiography and echocardiography, aortic stiffness was assessed by carotid-femoral pulse wave (PWV) measurements and renal dysfunction by measurements of the estimated glomerular filtration rate (eGFR) and microalbuminuria. Results After the exclusion of patients with a history of heart failure, NT-proBNP was independently correlated with sex, systolic BP, primary hypertension, PWV, LVH and eGFR, but not with microalbuminuria. The median (interquartile range) NT-proBNP increased gradually according to the number of target organs damaged: 42 (24-70), 77 (39-151), 141 (81-250) and 334 (177-556) pg/mL, for damage to 0, 1, 2 and 3 target organs, respectively ( p < 0.001). . For the same number of target organs damaged, NT-proBNP was higher in women and for secondary hypertension. A threshold at 90 pg/mL for men and 142 pg/mL in women had a specificity of 95% to detect at least one TOD (areas under ROC curve 0.790 and 0.783, respectively). The reproducibility of NT-proBNP was fairly good in this setting ( r = 0.952, p < 0.001, N = 325) Conclusion This study demonstrates that NT-proBNP mirrors the harmful effect of high BP on TOD. NT-proBNP could be used as an integrative tool for risk stratification in hypertension.

B-type and N-terminal pro-B-type natriuretic peptides are equally useful in assessing patent ductus arteriosus in very preterm infants.

PubMed

König, Kai; Guy, Katelyn J; Drew, Sandra M; Barfield, Charles P

2015-04-01

B-type natriuretic peptide (BNP) and N-terminal pro-BNP (NTproBNP) have been shown to correlate with the size of the patent ductus arteriosus (PDA) in preterm infants. We investigated whether BNP or NTproBNP was more closely correlated with PDA size. This prospective observational study included preterm infants born <32 weeks' gestation who had an echocardiogram performed within the first four days of life. Blood samples were taken simultaneously for BNP and NTproBNP measurements prior to echocardiographic examination. Of the 60 infants recruited, 58 had complete data sets. The cohort's mean and standard deviation (SD) gestational age was 27(+3) (2(+2)) weeks, the mean (SD) birthweight was 1032 (315) grams, and 46 (79.3%) infants had a PDA with a mean (SD) diameter of 3.2 (0.9) mm. Median and interquartile range (IQR) BNP levels were 486.5 (219-1316) pg/mL for infants with a PDA and 190 (95.5-514.5) pg/mL for infants without a PDA. Median (IQR) NTproBNP levels were 10 858.5 (6319-42 108) pg/mL for infants with a PDA and 7488 (3363-14 227.5) pg/mL for infants without a PDA. Both BNP (R = 0.35, p = 0.0066) and NTproBNP (R = 0.31, p = 0.018) were significantly correlated with PDA size. BNP and NTproBNP are similarly useful for assessing PDA size in preterm infants. ©2014 Foundation Acta Paediatrica. Published by John Wiley & Sons Ltd.

N-terminal RASSF family

PubMed Central

Underhill-Day, Nicholas; Hill, Victoria

2011-01-01

Epigenetic inactivation of tumor suppressor genes is a hallmark of cancer development. RASSF1A (Ras Association Domain Family 1 isoform A) tumor suppressor gene is one of the most frequently epigenetically inactivated genes in a wide range of adult and children's cancers and could be a useful molecular marker for cancer diagnosis and prognosis. RASSF1A has been shown to play a role in several biological pathways, including cell cycle control, apoptosis and microtubule dynamics. RASSF2, RASSF4, RASSF5 and RASSF6 are also epigenetically inactivated in cancer but have not been analyzed in as wide a range of malignancies as RASSF1A. Recently four new members of the RASSF family were identified these are termed N-Terminal RASSF genes (RASSF7–RASSF10). Molecular and biological analysis of these newer members has just begun. This review highlights what we currently know in respects to structural, functional and molecular properties of the N-Terminal RASSFs. PMID:21116130

The association between disease activity and NT-proBNP in 238 patients with rheumatoid arthritis: a 10-year longitudinal study

PubMed Central

Provan, Sella A; Angel, Kristin; Ødegård, Sigrid; Mowinckel, Petter; Atar, Dan; Kvien, Tore K

2008-01-01

Introduction Disease activity in patients with rheumatoid arthritis (RA) is associated with increased cardiovascular morbidity and mortality, of which N-terminal pro-brain natriuretic peptide (NT-proBNP) is a predictor. Our objective was to examine the cross-sectional and longitudinal associations between markers of inflammation, measures of RA disease activity, medication used in the treatment of RA, and NT-proBNP levels (dependent variable). Methods Two hundred thirty-eight patients with RA of less than 4 years in duration were followed longitudinally with three comprehensive assessments of clinical and radiographic data over a 10-year period. Serum samples were frozen and later batch-analyzed for NT-proBNP levels and other biomarkers. Bivariate, multivariate, and repeated analyses were performed. Results C-reactive protein (CRP) levels at baseline were cross-sectionally associated with NT-proBNP levels after adjustment for age and gender (r2 adjusted = 0.23; P < 0.05). At the 10-year follow-up, risk factors for cardiovascular disease were recorded. Duration of RA and CRP levels were independently associated with NT-proBNP in the final model that was adjusted for gender, age, and creatinine levels (r2 adjusted = 0.38; P < 0.001). In the longitudinal analyses, which adjusted for age, gender, and time of follow-up, we found that repeated measures of CRP predicted NT-proBNP levels (P < 0.001). Conclusion CRP levels are linearly associated with levels of NT-proBNP in cross-sectional and longitudinal analyses of patients with RA. The independent associations of NT-proBNP levels and markers of disease activity with clinical cardiovascular endpoints need to be further investigated. PMID:18573197

The predictive value of plasma biomarkers in discharged heart failure patients: role of plasma NT-proBNP.

PubMed

Leto, Laura; Testa, Marzia; Feola, Mauro

2016-04-01

Natriuretic peptides (NPs) have demonstrated their value to support clinical diagnosis of heart failure (HF); furthermore they are also studied for their prognostic role using them to guide appropriate management strategies. The present review gathers available evidence on prognostic role of N-terminal pro-B-type natriuretic peptide (NT-proBNP) in patients hospitalized for acute decompensated heart failure (ADHF). We searched Medline for English-language studies with the sequent key-words: "acute heart failure/acute decompensated heart failure", "NT-proBNP/N-terminal pro-B type natriuretic peptide" and "prognosis/mortality/readmission". Almost 30 studies were included. NT-proBNP plasma levels at admission are strongly associated with all-cause short-term mortality (2-3 months), mid-term (6-11 months) or long- term mortality (more than one year) of follow-up. Regarding the prognostic power on cardiac death fewer data are available with uncertain results. NT-proBNP at discharge demonstrated its prognostic role for all-cause mortality at mid and long-term follow-up. The relation between NT-proBNP at discharge and cardiovascular mortality or composite end-point is under investigation. A decrease in NT-proBNP values during hospitalization provided prognostic prospects mainly for cardiovascular mortality and HF readmission. A 30% variation in NT-proBNP levels during in-hospital stay seemed to be an optimal cut-off for prognostic role. SNT-proBNP plasma levels proved to have a strong correlation with all-cause mortality, cardiovascular mortality, morbidity and composite outcomes in patients discharged after an ADHF. A better definition of the correct time of serial measurements and the cut-off values might be the challenge for the future investigations.

NT-proBNP in severe chronic heart failure: rationale, design and preliminary results of the COPERNICUS NT-proBNP substudy.

PubMed

Hartmann, Franz; Packer, Milton; Coats, Andrew J S; Fowler, Michael B; Krum, Henry; Mohacsi, Paul; Rouleau, Jean L; Tendera, Michal; Castaigne, Alain; Trawinski, Jürgen; Amann-Zalan, Ildiko; Hoersch, Silke; Katus, Hugo A

2004-03-15

Neither profiles nor prognostic value of cardiac N-terminal proBNP (NT-proBNP) have been prospectively evaluated in a sufficient number of patients with severe chronic heart failure (CHF) treated with carvedilol or placebo. Baseline and follow-up plasma concentrations of NT-proBNP were measured in the European part of the COPERNICUS Trial. This study enrolled patients with an ejection fraction <25% and symptoms of CHF at rest or on minimal exertion, equally randomized to placebo or carvedilol. NT-proBNP concentrations were increased at baseline (mean+/-S.D.=579+/-822 pmol/l, median=322.5 pmol/l) with a marked decrease during follow-up in the carvedilol, but not in the placebo group. One-year mortality rates were 3.9, 12 and 27.9% in the lower, middle and upper tertiles of NT-proBNP, respectively. When mortality was calculated separately in the placebo and carvedilol group, rates were 0.8, 6.3 and 19.1% in the carvedilol treated but 6.7, 17.9 and 36.9% in the placebo treated patients. NT-proBNP was a powerful predictor of subsequent all-cause mortality in patients with severe CHF. This marker should therefore be further evaluated for risk stratification and monitoring of therapy in CHF.

Chromogranin A promotes peptide hormone sorting to mobile granules in constitutively and regulated secreting cells: role of conserved N- and C-terminal peptides.

PubMed

Montero-Hadjadje, Maité; Elias, Salah; Chevalier, Laurence; Benard, Magalie; Tanguy, Yannick; Turquier, Valérie; Galas, Ludovic; Yon, Laurent; Malagon, Maria M; Driouich, Azeddine; Gasman, Stéphane; Anouar, Youssef

2009-05-01

Chromogranin A (CgA) has been proposed to play a major role in the formation of dense-core secretory granules (DCGs) in neuroendocrine cells. Here, we took advantage of unique features of the frog CgA (fCgA) to assess the role of this granin and its potential functional determinants in hormone sorting during DCG biogenesis. Expression of fCgA in the constitutively secreting COS-7 cells induced the formation of mobile vesicular structures, which contained cotransfected peptide hormones. The fCgA and the hormones coexpressed in the newly formed vesicles could be released in a regulated manner. The N- and C-terminal regions of fCgA, which exhibit remarkable sequence conservation with their mammalian counterparts were found to be essential for the formation of the mobile DCG-like structures in COS-7 cells. Expression of fCgA in the corticotrope AtT20 cells increased pro-opiomelanocortin levels in DCGs, whereas the expression of N- and C-terminal deletion mutants provoked retention of the hormone in the Golgi area. Furthermore, fCgA, but not its truncated forms, promoted pro-opiomelanocortin sorting to the regulated secretory pathway. These data demonstrate that CgA has the intrinsic capacity to induce the formation of mobile secretory granules and to promote the sorting and release of peptide hormones. The conserved terminal peptides are instrumental for these activities of CgA.

Association of NT-proBNP and Multiple Biomarkers with Severity of Angiographic Coronary Artery Disease in Diabetic and Pre-Diabetic Chinese Patients

PubMed Central

Fang, Zhou; Bao, Yuanyuan; Ding, Wei; Luo, Xinping; Hu, Renming

2011-01-01

Background Little is known about the plasma levels of N-terminal pro-brain natriuretic peptide (NT-proBNP), and the relationship between the severity of coronary heart disease (CHD) with NT-proBNP and multiple biomarkers in diabetic and pre-diabetic patients, compared to individuals with normal glucose levels. Methods Four hundred and fifteen consecutive Chinese patients of both sexes were assigned to three groups on the basis of the new hemoglobin (Hb) A1c (HbA1c) cut-off points for diagnosis of diabetes and pre-diabetes. The three groups were divided into tertiles according to NT-proBNP, hs-CRP, cystatin C, and troponin T levels. Gensini scores were compared among the three groups and biomarker tertiles. Receiver operating characteristic (ROC) curves were used to obtain the angiographic CHD cut-off points for each biomarker. Stepwise multivariate linear correlation analysis was applied to examine the association between the severity of CHD and biomarker levels. Results Gensini scores increased with increasing biomarker tertile levels and HbA1c. Gensini scores were significantly different in the middle and upper NT-proBNP tertiles of the diabetic, pre-diabetic and control groups. NT-proBNP had the highest positive and negative predictive values and area under the curve for CHD. Only NT-proBNP was identified as an independent variable for Gensini score. Conclusions Plasma NT-proBNP may be an important biomarker to evaluate the severity of CHD and screen for CHD in diabetic or pre-diabetic patients. PMID:21857933

Rise and fall of NT-proBNP in aortic valve intervention.

PubMed

Hultkvist, Henrik; Holm, Jonas; Svedjeholm, Rolf; Vánky, Farkas

2018-01-01

To describe the dynamics of N-terminal pro-B-type natriuretic peptide (NT-proBNP) from preoperative evaluation to 6-month follow-up in patients undergoing aortic valve intervention, and to evaluate NT-proBNP with regard to 1-year mortality. At preoperative evaluation, we prospectively included 462 patients accepted for aortic valve intervention. The median time to surgical aortic valve replacement (SAVR; n=336) or transcatheter aortic valve implantation (TAVI; n=126) was 4 months. NT-proBNP was measured at enrolment for preoperative evaluation, on the day of surgery, postoperatively on day 1, day 3 and at the 6-month follow-up. Subgroups of patients undergoing SAVR with aortic regurgitation and aortic stenosis with and without coronary artery bypass were also analysed. NT-proBNP remained stable in all subgroups during the preoperative waiting period, but displayed a substantial transient early postoperative increase with a peak on day 3 except in the TAVI group, which peaked on day 1. At the 6-month follow-up, NT-proBNP had decreased to or below the preoperative level in all groups. In the SAVR group, NT-proBNP preoperatively and on postoperative days 1 and 3 revealed significant discriminatory power with regard to 1-year mortality (area under the curve (AUC)=0.79, P=0.0001; AUC=0.71, P=0.03; and AUC=0.79, P=0.002, respectively). This was not found in the TAVI group, which had higher levels of NT-proBNP both preoperatively and at the 6-month follow-up compared with the SAVR group. The dynamic profile of NT-proBNP differed between patients undergoing TAVI and SAVR. NT-proBNP in the perioperative course was associated with increased risk of 1-year mortality in SAVR but not in TAVI.

Globular adiponectin induces a pro-inflammatory response in human astrocytic cells

DOE Office of Scientific and Technical Information (OSTI.GOV)

Wan, Zhongxiao; Mah, Dorrian; Simtchouk, Svetlana

Highlights: • Adiponectin receptors are expressed in human astrocytes. • Globular adiponectin induces secretion of IL-6 and MCP-1 from cultured astrocytes. • Adiponectin may play a pro-inflammatory role in astrocytes. - Abstract: Neuroinflammation, mediated in part by activated brain astrocytes, plays a critical role in the development of neurodegenerative disorders, including Alzheimer’s disease (AD). Adiponectin is the most abundant adipokine secreted from adipose tissue and has been reported to exert both anti- and pro-inflammatory effects in peripheral tissues; however, the effects of adiponectin on astrocytes remain unknown. Shifts in peripheral concentrations of adipokines, including adiponectin, could contribute to the observedmore » link between midlife adiposity and increased AD risk. The aim of the present study was to characterize the effects of globular adiponectin (gAd) on pro-inflammatory cytokine mRNA expression and secretion in human U373 MG astrocytic cells and to explore the potential involvement of nuclear factor (NF)-κB, p38 mitogen-activated protein kinase (MAPK), extracellular signal-regulated kinase (ERK)1/2, c-Jun N-terminal kinase (JNK) and phosphatidylinositide 3-kinases (PI3 K) signaling pathways in these processes. We demonstrated expression of adiponectin receptor 1 (adipoR1) and adipoR2 in U373 MG cells and primary human astrocytes. gAd induced secretion of interleukin (IL)-6 and monocyte chemoattractant protein (MCP)-1, and gene expression of IL-6, MCP-1, IL-1β and IL-8 in U373 MG cells. Using specific inhibitors, we found that NF-κB, p38MAPK and ERK1/2 pathways are involved in gAd-induced induction of cytokines with ERK1/2 contributing the most. These findings provide evidence that gAd may induce a pro-inflammatory phenotype in human astrocytes.« less

The additive value of N-terminal pro-B-type natriuretic peptide testing at the emergency department in patients with acute dyspnoea.

PubMed

van der Burg-de Graauw, N; Cobbaert, C M; Middelhoff, C J F M; Bantje, T A; van Guldener, C

2009-05-01

B-type natriuretic peptide (BNP) and its inactive counterpart NT-proBNP can help to identify or rule out heart failure in patients presenting with acute dyspnoea. It is not well known whether measurement of these peptides can be omitted in certain patient groups. We conducted a prospective observational study of 221 patients presenting with acute dyspnoea at the emergency department. The attending physicians estimated the probability of heart failure by clinical judgement. NT-proBNP was measured, but not reported. An independent panel made a final diagnosis of all available data including NT-proBNP level and judged whether and how NT-proBNP would have altered patient management. NT-proBNP levels were highest in patients with heart failure, alone or in combination with pulmonary failure. Additive value of NT-proBNP was present in 40 of 221 (18%) of the patients, and it mostly indicated that a more intensive treatment for heart failure would have been needed. Clinical judgement was an independent predictor of additive value of NT-proBNP with a maximum at a clinical probability of heart failure of 36%. NT-proBNP measurement has additive value in a substantial number of patients presenting with acute dyspnoea, but can possibly be omitted in patients with a clinical probability of heart failure of >70%.

Brain natriuretic peptide is not predictive of dilated cardiomyopathy in Becker and Duchenne muscular dystrophy patients and carriers.

PubMed

Schade van Westrum, Steven; Dekker, Lukas; de Haan, Rob; Endert, Erik; Ginjaar, Ieke; de Visser, Marianne; van der Kooi, Anneke

2013-07-16

Cardiomyopathy is reported in Duchenne and Becker muscle dystrophy patients and female carriers. Brain Natriuretic peptide (BNP) is a hormone produced mainly by ventricular cardiomyocytes and its production is up regulated in reaction to increased wall stretching. N-terminal-proBNP (NT-proBNP) has been shown to be a robust laboratory parameter to diagnose and monitor cardiac failure, and it may be helpful to screen for asymptomatic left ventricular dysfunction. Therefore we tested whether NT-proBNP can distinguish patients with Duchenne or Becker muscular dystrophy patients and carriers of a dystrophin mutation with a dilated cardiomyopathy from those without. In a cohort of Duchenne and Becker muscle dystrophy patients (n = 143) and carriers (n = 219) NT-proBNP was measured, and echocardiography was performed to diagnose dilated cardiomyopathy (DCM). In total sixty-one patients (17%) fulfilled the criteria for DCM, whereas 283 patients (78%) had an elevated NT-pro BNP. The sensitivity of NT-proBNP for DCM in patients or carriers was 85%, the specificity 23%, area under the ROC-curve = 0.56. In the specified subgroups there was also no association. Measurement of NT-pro BNP in patients suffering from Duchenne or Becker muscular dystrophy and carriers does not distinguish between those with and without dilated cardiomyopathy.

Pro-2-PAM Therapy for Central and Peripheral Cholinesterases

PubMed Central

DeMar, James C.; Clarkson, Edward D.; Ratcliffe, Ruthie H.; Campbell, Amy J.; Thangavelu, Sonia G.; Herdman, Christine A.; Leader, Haim; Schulz, Susan M.; Marek, Elizabeth; Medynets, Marie A.; Ku, Theresa C.; Evans, Sarah A.; Khan, Farhat A.; Owens, Roberta R.; Nambiar, Madhusoodana P.; Gordon, Richard K.

2010-01-01

Novel therapeutics to overcome the toxic effects of organophosphorus (OP) chemical agents are needed due to the documented use of OPs in warfare (e.g. 1980–1988 Iran/Iraq war) and terrorism (e.g. 1995 Tokyo subway attacks). Standard OP exposure therapy in the United States consists of atropine sulfate (to block muscarinic receptors), the acetylcholinesterase (AChE) reactivator (oxime) pralidoxime chloride (2-PAM), and a benzodiazepine anticonvulsant to ameliorate seizures. A major disadvantage is that quaternary nitrogen charged oximes, including 2-PAM, do not cross the blood brain barrier (BBB) to treat brain AChE. Therefore, we have synthesized and evaluated pro-2-PAM (a lipid permeable 2-PAM derivative) that can enter the brain and reactivate CNS AChE, preventing seizures in guinea pigs after exposure to OPs. The protective effects of the pro-2-PAM after OP exposure were shown using a) surgically-implanted radiotelemetry probes for electroencephalogram (EEG) b) neurohistopathology of brain, c) cholinesterase activities in the PNS and CNS, and d) survivability. The PNS oxime 2-PAM was ineffective at reducing seizures/status epilepticus (SE) in diisopropyl-fluorophosphate (DFP)-exposed animals. In contrast, pro-2-PAM significantly suppressed and then eliminated seizure activity. In OP-exposed guinea pigs, there was a significant reduction in neurological damage with pro-2-PAM, but not 2-PAM. Distinct regional areas of the brains showed significantly higher AChE activity 1.5 h after OP exposure in pro-2-PAM treated animals compared to the 2-PAM treated ones. However, blood and diaphragm showed similar AChE activities in animals treated with either oxime, as both 2-PAM and pro 2-PAM are PNS active oximes. In conclusion, pro-2-PAM can cross the BBB, is rapidly metabolized inside the brain to 2-PAM, and protects against OP-induced SE through restoration of brain AChE activity. Pro-2-PAM represents the first non-invasive means of administering a CNS therapeutic for

Structural basis for substrate recognition by the human N-terminal methyltransferase 1

DOE PAGES

Dong, Cheng; Mao, Yunfei; Tempel, Wolfram; ...

2015-11-05

α-N-terminal methylation represents a highly conserved and prevalent post-translational modification, yet its biological function has remained largely speculative. The recent discovery of α-N-terminal methyltransferase 1 (NTMT1) and its physiological substrates propels the elucidation of a general role of α-N-terminal methylation in mediating DNA-binding ability of the modified proteins. The phenotypes, observed from both NTMT1 knockdown in breast cancer cell lines and knockout mouse models, suggest the potential involvement of α-N-terminal methylation in DNA damage response and cancer development. In this study, we report the first crystal structures of human NTMT1 in complex with cofactor S-adenosyl-L-homocysteine (SAH) and six substrate peptides,more » respectively, and reveal that NTMT1 contains two characteristic structural elements (a β hairpin and an N-terminal extension) that contribute to its substrate specificity. Our complex structures, coupled with mutagenesis, binding, and enzymatic studies, also present the key elements involved in locking the consensus substrate motif XPK (X indicates any residue type other than D/E) into the catalytic pocket for α-N-terminal methylation and explain why NTMT1 prefers an XPK sequence motif. We propose a catalytic mechanism for α-N-terminal methylation. Overall, this study gives us the first glimpse of the molecular mechanism of α-N-terminal methylation and potentially contributes to the advent of therapeutic agents for human diseases associated with deregulated α-N-terminal methylation.« less

The Multi-Biomarker Approach for Heart Failure in Patients with Hypertension

PubMed Central

Bielecka-Dabrowa, Agata; Gluba-Brzózka, Anna; Michalska-Kasiczak, Marta; Misztal, Małgorzata; Rysz, Jacek; Banach, Maciej

2015-01-01

We assessed the predictive ability of selected biomarkers using N-terminal pro-brain natriuretic peptide (NT-proBNP) as the benchmark and tried to establish a multi-biomarker approach to heart failure (HF) in hypertensive patients. In 120 hypertensive patients with or without overt heart failure, the incremental predictive value of the following biomarkers was investigated: Collagen III N-terminal propeptide (PIIINP), cystatin C (CysC), lipocalin-2/NGAL, syndecan-4, tumor necrosis factor-α (TNF-α), interleukin 1 receptor type I (IL1R1), galectin-3, cardiotrophin-1 (CT-1), transforming growth factor β (TGF-β) and N-terminal pro-brain natriuretic peptide (NT-proBNP). The highest discriminative value for HF was observed for NT-proBNP (area under the receiver operating characteristic curve (AUC) = 0.873) and TGF-β (AUC = 0.878). On the basis of ROC curve analysis we found that CT-1 > 152 pg/mL, TGF-β < 7.7 ng/mL, syndecan > 2.3 ng/mL, NT-proBNP > 332.5 pg/mL, CysC > 1 mg/L and NGAL > 39.9 ng/mL were significant predictors of overt HF. There was only a small improvement in predictive ability of the multi-biomarker panel including the four biomarkers with the best performance in the detection of HF—NT-proBNP, TGF-β, CT-1, CysC—compared to the panel with NT-proBNP, TGF-β and CT-1 only. Biomarkers with different pathophysiological backgrounds (NT-proBNP, TGF-β, CT-1, CysC) give additive prognostic value for incident HF in hypertensive patients compared to NT-proBNP alone. PMID:25984599

NT-proBNP concentrations in mountain marathoners.

PubMed

Banfi, Giuseppe; Lippi, Giuseppe; Susta, Daniele; Barassi, Alessandra; D'Eril, Gianvico Melzi; Dogliotti, Giada; Corsi, Massimiliano M

2010-05-01

The 76 amino acid N-terminal proB-type natriuretic peptide (NT-proBNP) is proposed for evaluating and monitoring heart pathologies characterized by myocardial wall stress. Strenuous exercise might generate transitory ischemia, myocardial stress, and diastolic left ventricular dysfunction, possibly inducing an increase of some biochemical parameter concentrations. An alert has been claimed owing to biochemical and instrumental signs of heart dysfunction in recreational athletes during marathon races. We studied the behaviour of NT-proBNP in 15 mountain marathoners before and after a race. The concentrations of the parameter were lower than that observed in controls at rest and were similar to that observed in professional soccer and rugby players. The concentrations significantly increased after the race. NT-proBNP is low at rest in professional athletes, and the increase after physical exercise is physiological. The marathoners, even when performing races in a high-altitude environment, show NT-proBNP concentrations similar to those of athletes from other sports disciplines, characterized by low levels of effort and by a mix of aerobic and anaerobic metabolism. The increase of NT-proBNP is linked to strenuous physical exercise and to heavy heart effort, testified also by an increase of troponin I. However, the role of the NT-proBNP could be important to screen recreational and professional marathoners to avoid possible heart problems and sudden cardiac death in subjects with occult heart disease. The results of the present study are relevant to the design and evaluation of training programs for improving strength and function of professional marathoners.

Oxidative Folding and N-terminal Cyclization of Onconase+

PubMed Central

Welker, Ervin; Hathaway, Laura; Xu, Guoqiang; Narayan, Mahesh; Pradeep, Lovy; Shin, Hang-Cheol; Scheraga, Harold A.

2008-01-01

Cyclization of the N-terminal glutamine residue to pyroglutamic acid in onconase, an anti-cancer chemotherapeutic agent, increases the activity and stability of the protein. Here, we examine the correlated effects of the folding/unfolding process and the formation of this N-terminal pyroglutamic acid. The results in this study indicate that cyclization of the N-terminal glutamine has no significant effect on the rate of either reductive unfolding or oxidative folding of the protein. Both the cyclized and uncyclized proteins seem to follow the same oxidative folding pathways; however, cyclization altered the relative flux of the protein in these two pathways by increasing the rate of formation of a kinetically trapped intermediate. Glutaminyl cyclase (QC) catalyzed the cyclization of the unfolded, reduced protein, but had no effect on the disulfide-intact, uncyclized, folded protein. The structured intermediates of uncyclized onconase were also resistant to QC-catalysis, consistent with their having a native-like fold. These observations suggest that, in vivo, cyclization takes place during the initial stages of oxidative folding, specifically, before the formation of structured intermediates. The competition between oxidative folding and QC-mediated cyclization suggests that QC-catalyzed cyclization of the N-terminal glutamine in onconase occurs in the endoplasmic reticulum, probably co-translationally. PMID:17439243

The diagnostic significance of NT-proBNP and troponin I in emergency department patients presenting with palpitations

PubMed Central

Ocak, Tarık; Erdem, Alim; Duran, Arif; Tekelioğlu, Ümit Yaşar; Öztürk, Serkan; Ayhan, Suzi Selim; Özlü, Mehmet Fatih; Tosun, Mehmet; Koçoğlu, Hasan; Yazıcı, Mehmet

2013-01-01

OBJECTIVE: This prospective study investigated the diagnostic significance of the N-terminal pro-brain natriuretic (NT-proBNP) and troponin I peptides in emergency department patients presenting with palpitations. METHODS: Two groups of patients with palpitations but without documented supraventricular tachycardia were compared: a group with supraventricular tachycardia (n = 49) and a control group (n = 47). Both groups were diagnosed using electrophysiological studies during the study period. Blood samples were obtained from all of the patients to determine the NT-proBNP and troponin I levels within the first hour following arrival in the emergency department. RESULT: The mean NT-proBNP levels were 207.74±197.11 in supraventricular tachyarrhythmia group and 39.99±32.83 pg/mL in control group (p<0.001). To predict supraventricular tachycardia, the optimum NT-proBNP threshold was 61.15 pg/mL, as defined by the receiver operating characteristic (ROC) curve, with a non-significant area under the ROC curve of 0.920 (95% CI, 0.86-0.97, p<0.001). The NT-proBNP cut-off for diagnosing supraventricular tachycardia had 81.6% sensitivity and 91.5% specificity. Supraventricular tachycardia was significantly more frequent in the patients with NT-proBNP levels ≥61.15 pg/mL (n = 44, 90.9%, p>0.001). The mean troponin I levels were 0.17±0.56 and 0.01±0.06 pg/mL for the patients with and without supraventricular tachycardia, respectively (p<0.05). Of the 96 patients, 21 (21.87%) had troponin I levels ≥0.01: 2 (4.25%) in the control group and 19 (38.77%) in the supraventricular tachycardia group (p<0.001). CONCLUSION: Troponin I and, in particular, NT-proBNP peptide were helpful for differentiating supraventricular tachycardia from non- supraventricular tachycardia palpitations. Further randomized, large, multicenter trials are needed to define the benefit and diagnostic role of NT-proBNP and troponin I in the management algorithm of patients presenting with

N-terminal galanin-(1-16) fragment is an agonist at the hippocampal galanin receptor

DOE Office of Scientific and Technical Information (OSTI.GOV)

Fisone, G.; Berthold, M.; Bedecs, K.

1989-12-01

The galanin N-terminal fragment (galanin-(1-16)) has been prepared by solid-phase synthesis and by enzymic cleavage of galanin by endoproteinase Asp-N. This peptide fragment displaced {sup 125}I-labeled galanin in receptor autoradiography experiments on rat forebrain and spinal cord and in equilibrium binding experiments from high-affinity binding sites in the ventral hippocampus with an IC50 of approximately 3 nM. In tissue slices of the same brain area, galanin-(1-16), similarly to galanin, inhibited the muscarinic agonist-stimulated breakdown of inositol phospholipids. Upon intracerebroventricular administration, galanin-(1-16) (10 micrograms/15 microliters) also inhibited the scopolamine (0.3 mg/kg, s.c.)-evoked release of acetylcholine, as studied in vivo by microdialysis.more » Substitution of (L-Trp2) for (D-Trp2) resulted in a 500-fold loss in affinity as compared with galanin-(1-16). It is concluded that, in the ventral hippocampus, the N-terminal galanin fragment (galanin-(1-16)) is recognized by the galanin receptors controlling acetylcholine release and muscarinic agonist-stimulated inositol phospholipid breakdown as a high-affinity agonist and that amino acid residue (Trp2) plays an important role in the receptor-ligand interactions.« less

The role of N-terminal PRO-brain natriuretic peptide and echocardiography for screening asymptomatic left ventricular dysfunction in a population at high risk for heart failure. The PROBE-HF study.

PubMed

Betti, Irene; Castelli, Gabriele; Barchielli, Alessandro; Beligni, Cinzia; Boscherini, Vittorio; De Luca, Leonardo; Messeri, Gianni; Gheorghiade, Mihai; Maisel, Alan; Zuppiroli, Alfredo

2009-06-01

Screening for asymptomatic left ventricular dysfunction (ALVD) in subjects at risk for heart failure (HF) can affect clinical management. The aim of the present study is to examine the role of NT-pro BNP in the diagnosis of ALVD in subjects with hypertension and diabetes from primary care. A total of 1012 subjects with hypertension and/or diabetes and no symptoms or signs of HF were assessed by B-type natriuretic peptide (NT-proBNP) assay and echocardiography. Diastolic dysfunction was present in 368/1012 subjects (36.4%): 327 (32.4%) with mild diastolic dysfunction and 41 (4%) with a moderate-to-severe diastolic dysfunction. Systolic dysfunction was present in 11/1012 (1.1%). NT-proBNP levels were 170 +/- 206 and 859 +/- 661 pg/mL, respectively, in diastolic and systolic dysfunction and 92 +/- 169 in normal subjects (P < .0001). Pooling moderate-to-severe diastolic with systolic dysfunction, a total of 52 subjects (5.1 %) were obtained: best cutoff value of NT-proBNP was 125 pg/mL (males <67 years: sensitivity [Sens] 87.5%, specificity [Spec] 92.7%, negative predictive value [NPV] 99.5%, positive predictive value [PPV] 33.3%; females <67 years: Sens 100%, Spec 84.1%, NPV 100%, PPV 33.3%; males >or=67 years: Sens 100%, Spec 77.1%, NPV 100%, PPV 32.5%; females >or=67 years: Sens 100%, Spec 59.9%, NPV 100%, PPV 23%). The prevalence of ALVD in subjects at risk for HF is 5.1%. Because of its excellent NPV, NT-proBNP can be used by general practitioners to rule out ALVD in hypertensive or diabetic patients.

The N-terminal strand modulates immunoglobulin light chain fibrillogenesis

DOE Office of Scientific and Technical Information (OSTI.GOV)

Pozo-Yauner, Luis del, E-mail: ldelpozo@inmegen.gob.mx; Wall, Jonathan S.; González Andrade, Martín

2014-01-10

Highlights: •We evaluated the impact of mutations in the N-terminal strand of 6aJL2 protein. •Mutations destabilized the protein in a position-dependent manner. •Destabilizing mutations accelerated the fibrillogenesis by shortening the lag time. •The effect on the kinetic of fibril elongation by seeding was of different nature. •The N-terminal strand is buried in the fibrillar state of 6aJL2 protein. -- Abstract: It has been suggested that the N-terminal strand of the light chain variable domain (V{sub L}) protects the molecule from aggregation by hindering spurious intermolecular contacts. We evaluated the impact of mutations in the N-terminal strand on the thermodynamic stabilitymore » and kinetic of fibrillogenesis of the V{sub L} protein 6aJL2. Mutations in this strand destabilized the protein in a position-dependent manner, accelerating the fibrillogenesis by shortening the lag time; an effect that correlated with the extent of destabilization. In contrast, the effect on the kinetics of fibril elongation, as assessed in seeding experiments was of different nature, as it was not directly dependant on the degree of destabilization. This finding suggests different factors drive the nucleation-dependent and elongation phases of light chain fibrillogenesis. Finally, taking advantage of the dependence of the Trp fluorescence upon environment, four single Trp substitutions were made in the N-terminal strand, and changes in solvent exposure during aggregation were evaluated by acrylamide-quenching. The results suggest that the N-terminal strand is buried in the fibrillar state of 6aJL2 protein. This finding suggest a possible explanation for the modulating effect exerted by the mutations in this strand on the aggregation behavior of 6aJL2 protein.« less

The Association of Menopausal Age and NT-proBrain Natriuretic Peptide: The Multi-Ethnic Study of Atherosclerosis

PubMed Central

Ebong, Imo A.; Watson, Karol E.; Goff, David C.; Bluemke, David A.; Srikanthan, Preethi; Horwich, Tamara; Bertoni, Alain G.

2014-01-01

Objective Menopausal age could affect the risk of developing cardiovascular disease (CVD). The purpose of this study was to investigate the associations of early menopause (menopause occurring before 45 years of age) and menopausal age with NT-pro brain natriuretic peptide (NT-proBNP), a potential risk marker of CVD and heart failure (HF). Methods Our cross-sectional study included 2275 postmenopausal women, aged 45–85 years, without clinical CVD (2000–2002), from the Multi-Ethnic Study of Atherosclerosis. Participants were classified as having or not having early menopause. NT-proBNP was log-transformed. Multivariable linear regression was used for analysis. Results There were 561 women with early menopause. The median NT-proBNP value was 79.0 (41.1–151.6) pg/ml for all participants with values of 83.4 (41.4–164.9) pg/ml and 78.0 (40.8–148.3) pg/ml for women with and without early menopause respectively. The mean (SD) age was 65 (10.1) and 65 (8.9) years for women with and without early menopause respectively. There were no significant interactions between menopausal age and ethnicity. In multivariable analysis, early menopause was associated with a 10.7% increase in NT-proBNP while each year increase in menopausal age was associated with a 0.7% decrease in NT-proBNP. Conclusion Early menopause is associated with greater NT-proBNP levels while each year increase in menopausal age is associated with lower NT-proBNP levels in postmenopausal women. PMID:25290536

Anatomical Variability in the Termination of the Basilar Artery in the Human Cadaveric Brain.

PubMed

Gunnal, Sandhya; Farooqui, Mujeebuddin; Wabale, Rajendra

2015-01-01

The basilar artery (BA) is the prominent median vessel of the vertebrobasilar circulation and usually terminates into two posterior cerebral arteries forming the posterior angle of the Circle of Willis (CW). To tackle different variations of CW, basilar artery acts as a guideline for neuroradiologists and neurosurgeons. Basilar termination is the most frequent site of aneurysm. Abnormalities at the site of termination may compress the oculomotor nerve. Variations at the termination may complicate surgeries at the base of brain. The present study aims to add to the knowledge regarding the termination pattern of the BA. 170 BA terminations were studied. Morphological variations in the termination pattern were noted. Frequency of variations in termination patterns was recorded. Dimensions of BA were measured. Data were analyzed. Morphological variations in termination were seen in 17.64%. Bifurcation, Trifurcation, Quadrifurcation, Pentafurcation and Nonfurcation of BA was seen in 82.35%, 5.29%, 5.88%, 3.52% and 2.94% respectively. BA associated with aneurysm and Fenestration was seen in 3.52% and 1.17% respectively. Mean length and diameter of BA was 30.27 mm and 4.8 mm respectively. Awareness of these anatomical variations in termination patterns of BA is important in neurovascular procedures.

Identification and Functional Characterization of N-Terminally Acetylated Proteins in Drosophila melanogaster

PubMed Central

Gerrits, Bertran; Roschitzki, Bernd; Mohanty, Sonali; Niederer, Eva M.; Laczko, Endre; Timmerman, Evy; Lange, Vinzenz; Hafen, Ernst; Aebersold, Ruedi; Vandekerckhove, Joël; Basler, Konrad; Ahrens, Christian H.; Gevaert, Kris; Brunner, Erich

2009-01-01

Protein modifications play a major role for most biological processes in living organisms. Amino-terminal acetylation of proteins is a common modification found throughout the tree of life: the N-terminus of a nascent polypeptide chain becomes co-translationally acetylated, often after the removal of the initiating methionine residue. While the enzymes and protein complexes involved in these processes have been extensively studied, only little is known about the biological function of such N-terminal modification events. To identify common principles of N-terminal acetylation, we analyzed the amino-terminal peptides from proteins extracted from Drosophila Kc167 cells. We detected more than 1,200 mature protein N-termini and could show that N-terminal acetylation occurs in insects with a similar frequency as in humans. As the sole true determinant for N-terminal acetylation we could extract the (X)PX rule that indicates the prevention of acetylation under all circumstances. We could show that this rule can be used to genetically engineer a protein to study the biological relevance of the presence or absence of an acetyl group, thereby generating a generic assay to probe the functional importance of N-terminal acetylation. We applied the assay by expressing mutated proteins as transgenes in cell lines and in flies. Here, we present a straightforward strategy to systematically study the functional relevance of N-terminal acetylations in cells and whole organisms. Since the (X)PX rule seems to be of general validity in lower as well as higher eukaryotes, we propose that it can be used to study the function of N-terminal acetylation in all species. PMID:19885390

Serum A-FABP is increased and closely associated with elevated NT-proBNP levels in type 2 diabetic patients treated with rosiglitazone.

PubMed

Zhou, Mi; Bao, Yuqian; Lu, Junxi; Zhou, Jian; Jia, Weiping

2011-01-01

Adipocyte fatty acid-binding protein (A-FABP) has been shown to play important roles in the development of metabolic syndrome, diabetes, and cardiovascular diseases. In this study we investigated the possible role of A-FABP in the development of cardiac dysfunction related to rosiglitazone treatment. A total of 84 patients with newly diagnosed type 2 diabetes were treated with rosiglitazone for 48 weeks. Circulating A-FABP and N-terminal pro-brain natriuretic peptide (NT-proBNP) levels were determined at baseline and repeated at 24 and 48 weeks. After the 48-week rosiglitazone treatment period, serum levels of both A-FABP and NT-proBNP increased progressively and significantly (P<0.01). Serum levels of A-FABP were demonstrated to be positively correlated with gender and waist circumference both at baseline and the end of the study, and with age, body mass index (BMI), total cholesterol (TC), triglyceride (TG), low-density lipoprotein cholesterol (LDL-C), and NT-proBNP at 48 weeks (all P<0.05). In addition, changes in A-FABP were significantly and positively correlated with changes in NT-proBNP (r = 0.239, P = 0.039). Furthermore, multiple stepwise regression analysis showed that the changes in A-FABP were independently and positively associated with changes in NT-proBNP after adjusting for confounding factors (β = 0.320, P = 0.007). Rosiglitazone-mediated increase of A-FABP is closely associated with the elevation of NT-proBNP, a well-established marker of cardiac dysfunction. The findings of our study imply that A-FABP may mediate the cross-talk between heart and adipose tissue.

N-Terminal Acetylation Inhibits Protein Targeting to the Endoplasmic Reticulum

PubMed Central

Forte, Gabriella M. A.; Pool, Martin R.; Stirling, Colin J.

2011-01-01

Amino-terminal acetylation is probably the most common protein modification in eukaryotes with as many as 50%–80% of proteins reportedly altered in this way. Here we report a systematic analysis of the predicted N-terminal processing of cytosolic proteins versus those destined to be sorted to the secretory pathway. While cytosolic proteins were profoundly biased in favour of processing, we found an equal and opposite bias against such modification for secretory proteins. Mutations in secretory signal sequences that led to their acetylation resulted in mis-sorting to the cytosol in a manner that was dependent upon the N-terminal processing machinery. Hence N-terminal acetylation represents an early determining step in the cellular sorting of nascent polypeptides that appears to be conserved across a wide range of species. PMID:21655302

Quantification of VGF- and pro-SAAS-derived peptides in endocrine tissues and the brain, and their regulation by diet and cold stress.

PubMed

Chakraborty, Tandra R; Tkalych, Oleg; Nanno, Daniela; Garcia, Angelo L; Devi, Lakshmi A; Salton, Stephen R J

2006-05-17

Two novel granin-like polypeptides, VGF and pro-SAAS, which are stored in and released from secretory vesicles and are expressed widely in nervous, endocrine, and neuroendocrine tissues, play roles in the regulation of body weight, feeding, and energy expenditure. Both VGF and pro-SAAS are cleaved into peptide fragments, several of which are biologically active. We utilized a highly sensitive and specific radioimmunoassay (RIA) to immunoreactive, pro-SAAS-derived PEN peptides, developed another against immunoreactive, VGF-derived AQEE30 peptides, and quantified these peptides in various mouse tissues and brain regions. Immunoreactive AQEE30 was most abundant in the pituitary, while brain levels were highest in hypothalamus, striatum, and frontal cortex. Immunoreactive PEN levels were highest in the pancreas and spinal cord, and in brain, PEN was most abundant in striatum, hippocampus, pons and medulla, and cortex. Since both peptides were expressed in hypothalamus, a region of the brain that controls feeding and energy expenditure, double label immunofluorescence studies were employed. These demonstrated that 42% of hypothalamic arcuate neurons coexpress VGF and SAAS peptides, and that the intracellular distributions of these peptides in arcuate neurons differed. By RIA, cold stress increased immunoreactive AQEE30 and PEN peptide levels in female but not male hypothalamus, while a high fat diet increased AQEE30 and PEN peptide levels in female but not male hippocampus. VGF and SAAS-derived peptides are therefore widely expressed in endocrine, neuroendocrine, and neural tissues, can be accurately quantified by RIA, and are differentially regulated in the brain by diet and cold stress.

A Stereomicroscopic Evaluation of Dentinal Cracks at Different Instrumentation Lengths by Using Different Rotary Files (ProTaper Universal, ProTaper Next, and HyFlex CM): An Ex Vivo Study

PubMed Central

Shankarappa, Pushpa; Misra, Abhinav; Sawhney, Asheesh; Sridevi, Nandamuri; Singh, Anu

2016-01-01

Introduction. The aim of the present study was to evaluate the dentinal cracks after root canal preparation with rotary files: Gates Glidden, ProTaper Universal, ProTaper Next, and HyFlex CM at different instrumentation lengths. Methodology. Sixty-five mandibular premolars were mounted in the acrylic tube with simulated periodontal ligaments and the apex was exposed. The root canals were instrumented with different rotary files, namely, ProTaper Universal, ProTaper Next, and HyFlex CM, to the major apical foramen (AF), short AF, and beyond AF. The root apex was stained with 1% methylene blue dye and digital images of apical surface of every tooth were taken and development of dentinal defects was determined by using stereomicroscope. Multinomial logistic regression test was performed to identify influencing factors. Results. Instrumentation with rotary files terminated 2 mm short AF and did not cause any cracks. Significantly less cracks were seen when instrumentation with rotary files terminated 1 mm short apical foramen when compared with the instrumentation terminated at or beyond apical foramen (p < 0.05). Conclusion. ProTaper Universal rotary files caused more dentinal cracks than ProTaper Next and HyFlex CM. Instrumentation short AF reduced the risk of dentinal defects. PMID:27446636

N-terminal fragment of probrain natriuretic peptide is associated with diabetes microvascular complications in type 2 diabetes.

PubMed

Hamano, Kumiko; Nakadaira, Ikue; Suzuki, Jun; Gonai, Megumi

2014-01-01

Circulating levels of N-terminal fragment of probrain natriuretic peptide (NT-proBNP) are established as a risk factor for cardiovascular disease and mortality in patients with diabetes, as well as in the general population. We sought to examine the possibility of NT-proBNP as a biomarker of microvascular complications in patients with type 2 diabetes. In total, 277 outpatients with type 2 diabetes were consecutively enrolled as a hospital cohort. Two hundred and seventeen of these patients (132 males; mean age, 63.4 years) were designated as cases with any of the diabetic complications (retinopathy, neuropathy, nephropathy, ischemic heart disease, strokes, peripheral artery disease), and 60 (42 males; mean age, 54.1 years) were set as controls without clinical evidence of diabetic complications. Diabetic complications were evaluated by medical record and routine laboratory examinations. NT-proBNP was measured and investigated with regard to the associations with diabetic complications. Mean NT-proBNP levels were significantly higher in patients with any of the diabetic complications (59 versus 33 pg/mL; P<0.0001). In logistic regression analysis, NT-proBNP levels >79 pg/mL, which was the highest tertile, were independently associated with a 5.04 fold increased risk of all complications (P<0.0051) compared to the lowest tertile (NT-proBNP levels <31 pg/mL). Odd ratios of cardiovascular disease and nephropathy, neuropathy, and retinopathy were 9.33, 6.23, 6.6 and 13.78 respectively, in patients with NT-proBNP values in the highest tertile (>79 pg/mL), independently of age, sex, duration of diabetes or other risk factors, such as body mass index or hemoglobin A1c. In addition, NT-proBNP levels were associated with surrogate markers of atherosclerosis, such as brachial-ankle pulse wave velocity (r=0.449, P<0.0001) and left ventricular hypertrophy (r=0.212, P<0.001). In this hospital-based cohort of type 2 diabetes, the NT-proBNP levels were associated with systemic

Structure of the EMMPRIN N-terminal domain 1: Dimerization via [beta]-strand swapping

DOE Office of Scientific and Technical Information (OSTI.GOV)

Luo, Jinquan; Teplyakov, Alexey; Obmolova, Galina

2010-09-27

Extracellular matrix metalloproteinase inducer (EMMPRIN), also known as Hab18G, CD147, Basigin, M6, and neurothelin, is a membrane glycoprotein expressed on the surface of various cell types and many cancer cells. EMMPRIN stimulates adjacent fibroblasts and tumor cells to produce matrix metalloproteinases and plays an important role in tumor invasion and metastasis, angiogenesis, spermatogensis and fertilization, cell-cell adhesion and communication, and other biological processes (reviewed in Ref. 1 and references therein). It was demonstrated that the EMMPRIN extracellular domain (ECD), which structurally belongs to the IgG superfamily, can form homo-oligomers in a cis dependent manner and the N-terminal domain 1 (residuesmore » 22-101) was necessary and sufficient to mediate this interaction. The crystal structure of the ECD of recombinant human EMMPRIN (Hab18G/CD147) expressed in E. coli was reported at 2.8 {angstrom} resolution (Yu et al. 2008). The construct consists of residues 22-205 of the mature protein and has both an N-terminal IgC2 domain (ND1, residues 22-101) and a C-terminal IgC2 domain (ND2, residues 107-205). The two domains are joined by a five amino acid residue linker that constitutes a flexible hinge between the two domains. The crystal form has four copies of the molecule in the asymmetric unit, each of which has a different inter-domain angle that varies from 121{sup o} to 144{sup o}. The two domains each have a conserved disulfide bridge and both are comprised of two {beta}-sheets formed by strands EBA and GFCC, and DEBA and AGFCC for ND1 and ND2, respectively. Based on the crystal packing in this structure, the authors proposed that lateral packing between the two IgG domains of EMMPRIN ECD represents a potential mechanism for cell adhesion. Here we report the 2.0-{angstrom} crystal structure of the N-terminal domain of EMMPRIN ECD (ND1) expressed in mammalian cells. The overall structure of the domain is very similar to that in the full

Neurospora tryptophan synthase: N-terminal analysis and the sequence of the pyridoxal phosphate active site peptide

DOE Office of Scientific and Technical Information (OSTI.GOV)

Pratt, M.L.; Hsu, P.Y.; DeMoss, J.A.

1986-05-01

Tryptophan synthase (TS), which catalyzes the final step of tryptophan biosynthesis, is a multifunctional protein requiring pyridoxal phosphate (B6P) for two of its three distinct enzyme activities. TS from Neurospora has a blocked N-terminal, is a homodimer of 150 KDa and binds one mole of B6P per mole of subunit. The authors shown the N-terminal residue to be acyl-serine. The B6P-active site of holoenzyme was labelled by reduction of the B6P-Schiff base with (/sup 3/H)-NaBH/sub 4/, and resulted in a proportionate loss of activity in the two B6P-requiring reactions. SDS-polyacrylamide gel electrophoresis of CNBr-generated peptides showed the labelled, active sitemore » peptide to be 6 KDa. The sequence of this peptide, purified to apparent homogeneity by a combination of C-18 reversed phase and TSK gel filtration HPLC is: gly-arg-pro-gly-gln-leu-his-lys-ala-glu-arg-leu-thr-glu-tyr-ala-gly-gly-ala-gln-ile-xxx-leu-lys-arg-glu-asp-leu-asn-his-xxx-gly-xxx-his-/sub ***/-ile-asn-asn-ala-leu. Although four residues (xxx, /sub ***/) are unidentified, this peptide is minimally 78% homologous with the corresponding peptide from yeast TS, in which residue (/sub ***/) is the lysine that binds B6P.« less

Effects of the nuclear localization of the N(pro) protein of classical swine fever virus on its virulence in pigs.

PubMed

Li, Yongfeng; Shen, Liang; Sun, Yuan; Wang, Xiao; Li, Chao; Huang, Junhua; Chen, Jianing; Li, Lianfeng; Zhao, Bibo; Luo, Yuzi; Li, Su; Qiu, Hua-Ji

2014-12-05

The N(pro) protein of classical swine fever virus (CSFV) is localized in the cytoplasm and nucleus. However, it is unknown whether the nuclear localization of N(pro) correlates with the virulence of CSFV in the host. Previously, we showed that the N(pro) protein fused with interferon regulatory factor 3 (IRF3) was present only in the cytoplasm. Here, we generated and evaluated a recombinant CSFV vSM-IRF3 harboring the IRF3 gene inserted into the N(pro) gene of the highly virulent CSFV Shimen strain. Compared to the even nuclear and cytoplasmic distribution of the enhanced green fluorescent protein (EGFP)-N(pro) fusion expressed by the recombinant CSFV EGFP-CSFV, vSM-IRF3 expressed an IRF3-N(pro) fusion protein that only was localized in the cytoplasm. vSM-IRF3 was markedly attenuated in vitro and in vivo, and the inoculated pigs were completely protected from lethal CSFV challenge, whereas the parental virus as well as EGFP-CSFV exhibited a typical virulent phenotype. Taken together, the nuclear localization of N(pro) plays a significant role in the CSFV replication and virulence. Copyright © 2014 Elsevier B.V. All rights reserved.

The Gain-of-Function Integrin β3 Pro33 Variant Alters the Serotonin System in the Mouse Brain.

PubMed

Dohn, Michael R; Kooker, Christopher G; Bastarache, Lisa; Jessen, Tammy; Rinaldi, Capria; Varney, Seth; Mazalouskas, Matthew D; Pan, Hope; Oliver, Kendra H; Velez Edwards, Digna R; Sutcliffe, James S; Denny, Joshua C; Carneiro, Ana M D

2017-11-15

Engagement of integrins by the extracellular matrix initiates signaling cascades that drive a variety of cellular functions, including neuronal migration and axonal pathfinding in the brain. Multiple lines of evidence link the ITGB3 gene encoding the integrin β3 subunit with the serotonin (5-HT) system, likely via its modulation of the 5-HT transporter (SERT). The ITGB3 coding polymorphism Leu33Pro (rs5918, Pl A2 ) produces hyperactive αvβ3 receptors that influence whole-blood 5-HT levels and may influence the risk for autism spectrum disorder (ASD). Using a phenome-wide scan of psychiatric diagnoses, we found significant, male-specific associations between the Pro33 allele and attention-deficit hyperactivity disorder and ASDs. Here, we used knock-in (KI) mice expressing an Itgb3 variant that phenocopies the human Pro33 variant to elucidate the consequences of constitutively enhanced αvβ3 signaling to the 5-HT system in the brain. KI mice displayed deficits in multiple behaviors, including anxiety, repetitive, and social behaviors. Anatomical studies revealed a significant decrease in 5-HT synapses in the midbrain, accompanied by decreases in SERT activity and reduced localization of SERTs to integrin adhesion complexes in synapses of KI mice. Inhibition of focal adhesion kinase (FAK) rescued SERT function in synapses of KI mice, demonstrating that constitutive active FAK signaling downstream of the Pro32Pro33 integrin αvβ3 suppresses SERT activity. Our studies identify a complex regulation of 5-HT homeostasis and behaviors by integrin αvβ3, revealing an important role for integrins in modulating risk for neuropsychiatric disorders. SIGNIFICANCE STATEMENT The integrin β3 Leu33Pro coding polymorphism has been associated with autism spectrum disorders (ASDs) within a subgroup of patients with elevated blood 5-HT levels, linking integrin β3, 5-HT, and ASD risk. We capitalized on these interactions to demonstrate that the Pro33 coding variation in the murine

The change in NT-pro-BNP and post-PTMC echocardiography parameters in patients with mitral stenosis. A pilot study.

PubMed

Safi, Morteza; Bayat, Fariba; Ahmadi, Zahra; Shekarchizadeh, Masood; Khaheshi, Isa; Naderian, Mohammadreza

2017-06-01

The change in the level of NT-pro-BNP (N-terminal-pro-Brain Natriuretic Peptide) is now considered as a reflection of the hemodynamic alterations and its circulatory reductions reported early after successful PTMC (percutaneous transvenous mitral commissurotomy). The present study aims to assess the change in the level of NT-pro BNP following PTMC in patients with mitral stenosis and also to determine the association between circulatory NT-pro-BNP reduction and post-PTMC echocardiography parameters. Twenty five symptomatic consecutive patients with severe MS undergoing elective PTMC were prospectively enrolled. All patients underwent echocardiography before and also 24 to 48 hours after PTMC. Peripheral blood samples were taken for measurement of NT-pro-BNP before as well as 24 to 48 hours after PTMC. The patients were also classified in group with normal sinus rhythm or having atrial fibrillation (AF) based on their 12-lead electrocardiogram. It was shown a significant decrease in the parameters of PPG (Peak Pressure Gradient), MPG (Mean Pressure Gradient), PHT (Pressure Half Time), PAP (Pulmonary Arterial Pressure), LAV (Left Atrial Volume), and also a significant increase in MVA (Mitral Valve Area) RVS (Right Ventricular S velocity), and strains of lateral, septal, inferior and anterior walls of LA following PTMC. The mean LVEF remained unchanged after PTMC. The mean NT-pro-BNP before PTMC was 309.20 ± 17.97 pg/lit that significantly diminished after PTMC to 235.72 ± 22.46 pg/lit (p = 0.009). Among all echocardiography parameters, only MPG was positively associated with the change in NT-pro-BNP after PTMC. Comparing the change in echocardiography indices between the patients with normal rhythm and those with AF, lower change in PAP was shown in the group with AF. However, more change in the level of NT-pro-BNP after PTMC was shown in the patients with AF compared to those without this arrhythmia. PTMC procedure leads to reduce the level of NT-pro-BNP. The

The N-terminal strand modulates immunoglobulin light chain fibrillogenesis.

PubMed

del Pozo-Yauner, Luis; Wall, Jonathan S; González Andrade, Martín; Sánchez-López, Rosana; Rodríguez-Ambriz, Sandra L; Pérez Carreón, Julio I; Ochoa-Leyva, Adrián; Fernández-Velasco, D Alejandro

2014-01-10

It has been suggested that the N-terminal strand of the light chain variable domain (V(L)) protects the molecule from aggregation by hindering spurious intermolecular contacts. We evaluated the impact of mutations in the N-terminal strand on the thermodynamic stability and kinetic of fibrillogenesis of the V(L) protein 6aJL2. Mutations in this strand destabilized the protein in a position-dependent manner, accelerating the fibrillogenesis by shortening the lag time; an effect that correlated with the extent of destabilization. In contrast, the effect on the kinetics of fibril elongation, as assessed in seeding experiments was of different nature, as it was not directly dependant on the degree of destabilization. This finding suggests different factors drive the nucleation-dependent and elongation phases of light chain fibrillogenesis. Finally, taking advantage of the dependence of the Trp fluorescence upon environment, four single Trp substitutions were made in the N-terminal strand, and changes in solvent exposure during aggregation were evaluated by acrylamide-quenching. The results suggest that the N-terminal strand is buried in the fibrillar state of 6aJL2 protein. This finding suggest a possible explanation for the modulating effect exerted by the mutations in this strand on the aggregation behavior of 6aJL2 protein. Copyright © 2013 Elsevier Inc. All rights reserved.

The role of NT-proBNP in explaining the variance in anaerobic threshold and VE/VCO(2) slope.

PubMed

Athanasopoulos, Leonidas V; Dritsas, Athanasios; Doll, Helen A; Cokkinos, Dennis V

2011-01-01

We investigated whether anaerobic threshold (AT) and ventilatory efficiency (minute ventilation/carbon dioxide production slope, VE/VCO2 slope), both significantly associated with mortality, can be predicted by questionnaire scores and/or other laboratory measurements. Anaerobic threshold and VE/VCO(2) slope, plasma N-terminal pro-brain natriuretic peptide (NT-proBNP), and the echocardiographic markers left ventricular ejection fraction (LVEF) and left atrial (LA) diameter were measured in 62 patients with heart failure (HF), who also completed the Minnesota Living with Heart Failure Questionnaire (MLHF), and the Specific Activity Questionnaire (SAQ). Linear regression models, adjusting for age and gender, were fitted. While the etiology of HF, SAQ score, MLHF score, LVEF, LA diameter, and logNT-proBNP were each significantly predictive of both AT and VE/VCO2 slope on stepwise multiple linear regression, only SAQ score (P < .001) and logNT-proBNP (P = .001) were significantly predictive of AT, explaining 56% of the variability (adjusted R(2) = 0.525), while logNT-proBNP (P < .001) and etiology of HF (P = .003) were significantly predictive of VE/VCO(2) slope, explaining 49% of the variability (adjusted R(2) = 0.45). The area under the ROC curve for NT-proBNP to identify patients with a VE/VCO(2) slope greater than 34 and AT less than 11 mL · kg(-1) · min(-1) was 0.797; P < .001 and 0.712; P = .044, respectively. A plasma concentration greater than 429.5 pg/mL (sensitivity: 78%; specificity: 70%) and greater than 674.5 pg/mL (sensitivity: 77.8%; specificity: 65%) identified a VE/VCO(2) slope greater than 34 and AT lower than 11 mL · kg(-1) · min(-1), respectively. NT-proBNP is independently related to both AT and VE/VCO(2) slope. Specific Activity Questionnaire score is independently related only to AT and the etiology of HF only to VE/VCO(2) slope.

Rationale, application and clinical qualification for NT-proBNP as a surrogate end point in pivotal clinical trials in patients with AL amyloidosis.

PubMed

Merlini, G; Lousada, I; Ando, Y; Dispenzieri, A; Gertz, M A; Grogan, M; Maurer, M S; Sanchorawala, V; Wechalekar, A; Palladini, G; Comenzo, R L

2016-10-01

Amyloid light-chain (LC) amyloidosis (AL amyloidosis) is a rare and fatal disease for which there are no approved therapies. In patients with AL amyloidosis, LC aggregates progressively accumulate in organs, resulting in organ failure that is particularly lethal when the heart is involved. A significant obstacle in the development of treatments for patients with AL amyloidosis, as well as for those with any disease that is rare, severe and heterogeneous, has been satisfying traditional clinical trial end points (for example, overall survival or progression-free survival). It is for this reason that many organizations, including the United States Food and Drug Administration through its Safety and Innovation Act Accelerated Approval pathway, have recognized the need for biomarkers as surrogate end points. The international AL amyloidosis expert community is in agreement that the N-terminal fragment of the pro-brain natriuretic peptide (NT-proBNP) is analytically validated and clinically qualified as a biomarker for use as a surrogate end point for survival in patients with AL amyloidosis. Underlying this consensus is the demonstration that NT-proBNP is an indicator of cardiac response in all interventional studies in which it has been assessed, despite differences in patient population, treatment type and treatment schedule. Furthermore, NT-proBNP expression is directly modulated by amyloidogenic LC-elicited signal transduction pathways in cardiomyocytes. The use of NT-proBNP will greatly facilitate the development of targeted therapies for AL amyloidosis. Here, we review the data supporting the use of NT-proBNP, a biomarker that is analytically validated, clinically qualified, directly modulated by LC and universally accepted by AL amyloidosis specialists, as a surrogate end point for survival.

Rationale, application and clinical qualification for NT-proBNP as a surrogate end point in pivotal clinical trials in patients with AL amyloidosis

PubMed Central

Merlini, G; Lousada, I; Ando, Y; Dispenzieri, A; Gertz, M A; Grogan, M; Maurer, M S; Sanchorawala, V; Wechalekar, A; Palladini, G; Comenzo, R L

2016-01-01

Amyloid light-chain (LC) amyloidosis (AL amyloidosis) is a rare and fatal disease for which there are no approved therapies. In patients with AL amyloidosis, LC aggregates progressively accumulate in organs, resulting in organ failure that is particularly lethal when the heart is involved. A significant obstacle in the development of treatments for patients with AL amyloidosis, as well as for those with any disease that is rare, severe and heterogeneous, has been satisfying traditional clinical trial end points (for example, overall survival or progression-free survival). It is for this reason that many organizations, including the United States Food and Drug Administration through its Safety and Innovation Act Accelerated Approval pathway, have recognized the need for biomarkers as surrogate end points. The international AL amyloidosis expert community is in agreement that the N-terminal fragment of the pro-brain natriuretic peptide (NT-proBNP) is analytically validated and clinically qualified as a biomarker for use as a surrogate end point for survival in patients with AL amyloidosis. Underlying this consensus is the demonstration that NT-proBNP is an indicator of cardiac response in all interventional studies in which it has been assessed, despite differences in patient population, treatment type and treatment schedule. Furthermore, NT-proBNP expression is directly modulated by amyloidogenic LC-elicited signal transduction pathways in cardiomyocytes. The use of NT-proBNP will greatly facilitate the development of targeted therapies for AL amyloidosis. Here, we review the data supporting the use of NT-proBNP, a biomarker that is analytically validated, clinically qualified, directly modulated by LC and universally accepted by AL amyloidosis specialists, as a surrogate end point for survival. PMID:27416985

NT-pro-BNP levels in patients with acute pulmonary embolism are correlated to right but not left ventricular volume and function.

PubMed

Pasha, Sharif M; Klok, Frederikus A; van der Bijl, Noortje; de Roos, Albert; Kroft, Lucia J M; Huisman, Menno V

2012-08-01

N-terminal pro-Brain Natriuretic Peptide (NT-pro-BNP) is primarily secreted by left ventricular (LV) stretch and wall tension. Notably, NT-pro-BNP is a prognostic marker in acute pulmonary embolism (PE), which primarily stresses the right ventricle (RV). We sought to evaluate the relative contribution of the RV to NT-pro-BNP levels during PE. A post-hoc analysis of an observational prospective outcome study in 113 consecutive patients with computed tomography (CT)-proven PE and 226 patients in whom PE was clinically suspected but ruled out by CT. In all patients RV and LV function was established by assessing ECG-triggered-CT measured ventricular end-diastolic-volumes and ejection fraction (EF). NT-pro-BNP was assessed in all patients. The correlation between RV and LV end-diastolic-volumes and systolic function was evaluated by multiple linear regression corrected for known confounders. In the PE cohort increased RVEF (β-coefficient (95% confidence interval [CI]) -0.044 (± -0.011); p<0.001) and higher RV end-diastolic-volume (β-coefficient 0.005 (± 0.001); p<0.001) were significantly correlated to NT-pro-BNP, while no correlation was found with LVEF (β-coefficient 0.005 (± 0.010); p=0.587) and LV end-diastolic-volume (β-coefficient -0.003 (± 0.002); p=0.074). In control patients without PE we found a strong correlation between NT-pro-BNP levels and LVEF (β-coefficient -0.027 (± -0.006); p<0.001) although not LV end-diastolic-volume (β-coefficient 0.001 (± 0.001); p=0.418). RVEF (β-coefficient -0.002 (± -0.006); p=0.802) and RV end-diastolic-volume (β-coefficient <0.001 (± 0.001); p=0.730) were not correlated in patients without PE. In PE patients, lower RVEF and higher RV end-diastolic-volume were significantly correlated to NT-pro-BNP levels as compared to control patients without PE. These observations provide pathophysiological ground for the well-known prognostic value of NT-pro-BNP in acute PE.

NMR assignments of the N-terminal domain of Nephila clavipes spidroin 1

PubMed Central

Parnham, Stuart; Gaines, William A.; Duggan, Brendan M.; Marcotte, William R.

2011-01-01

The building blocks of spider dragline silk are two fibrous proteins secreted from the major ampullate gland named spidroins 1 and 2 (MaSp1, MaSp2). These proteins consist of a large central domain composed of approximately 100 tandem copies of a 35–40 amino acid repeat sequence. Non-repetitive N and C-terminal domains, of which the C-terminal domain has been implicated to transition from soluble and insoluble states during spinning, flank the repetitive core. The N-terminal domain until recently has been largely unknown due to difficulties in cloning and expression. Here, we report nearly complete assignment for all 1H, 13C, and 15N resonances in the 14 kDa N-terminal domain of major ampullate spidroin 1 (MaSp1-N) of the golden orb-web spider Nephila clavipes. PMID:21152998

Prognostic utility of the Seattle Heart Failure Score and amino terminal pro B-type natriuretic peptide in varying stages of systolic heart failure.

PubMed

Adlbrecht, Christopher; Hülsmann, Martin; Neuhold, Stephanie; Strunk, Guido; Pacher, Richard

2013-05-01

Cardiac transplantation represents the best procedure to improve long-term clinical outcome in advanced chronic heart failure (CHF), if pre-selection criteria are sufficient to outweigh the risk of the failing heart over the risk of transplantation. Although the cornerstone of success, risk assessment in heart transplant candidates is still under-investigated. Amino terminal pro B-type natriuretic peptide (NT-proBNP) is regarded as the best predictor of outcome in CHF, and the Seattle Heart Failure Score (SHFS), including clinical markers, is widely used if NT-proBNP is unavailable. The present study assessed the predictive value for all-cause death of the SHFS in CHF patients and compared it with NT-proBNP in a multivariate model including established baseline parameters known to predict survival. A total of 429 patients receiving stable HF-specific pharmacotherapy were included and monitored for 53.4 ± 20.6 months. Of these, 133 patients (31%) died during follow-up. Several established predictors of death on univariate analysis proved significant for the total study cohort. Systolic pulmonary arterial pressure (hazard ratio [HR], 1.03; 95% confidence interval [CI], 1.02-1.05); p < 0.001, Wald 15.1), logNT-proBNP (HR, 1.51; 95% CI, 1.22-1.86; p < 0.001, Wald 14.9), and the SHFS (HR, 0.99; 95% CI, 0.99-1.00; p < 0.001, Wald 12.6) remained within the stepwise multivariate Cox regression model as independent predictors of all-cause death. Receiver operating characteristic curve analysis revealed an area under the curve of 0.802 for logNT-proBNP and 0.762 for the SHFS. NT-proBNP is a more potent marker to identify patients at the highest risk. If the NT-proBNP measurement is unavailable, the SHFS may serve as an adequate clinical surrogate to predict all-cause death. Copyright © 2013 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.

Plasma pro-brain natriuretic peptide and electrocardiographic changes in combination improve risk prediction in persons without known heart disease.

PubMed

Jørgensen, Peter G; Jensen, Jan S; Appleyard, Merete; Jensen, Gorm B; Mogelvang, Rasmus

2015-12-15

Though the electrocardiogram(ECG) and plasma pro-brain-natriuretic-peptide (pro-BNP) are widely used markers of subclinical cardiac injury and can be used to predict future cardiovascular disease(CVD), they could merely be markers of the same underlying pathology. We aimed to determine if ECG changes and pro-BNP are independent predictors of CVD and if the combination improves risk prediction in persons without known heart disease. Pro-BNP and ECG were obtained on 5454 persons without known heart disease from the 4th round of the Copenhagen City Heart Study, a prospective cohort study. Median follow-up was 10.4 years. High pro-BNP was defined as above 90th percentile of age and sex adjusted levels. The end-points were all-cause mortality and the combination of admission with ischemic heart disease, heart failure or CVD death. ECG changes were present in 907 persons and were associated with high levels of pro-BNP. In a fully adjusted model both high pro-BNP and ECG changes remained significant predictors: all-cause mortality(high pro-BNP, no ECG changes: HR: 1.43(1.12-1.82);P=0.005, low pro-BNP, ECG changes: HR: 1.22(1.05-1.42);P=0.009, and both high pro-BNP and ECG changes: HR: 1.99(1.54-2.59);P<0.001), CVD event(high pro-BNP, no ECG changes: HR: 1.94(1.45-2.58);P<0.001, low pro-BNP, ECG changes: HR: 1.55(1.29-1.87);P<0.001, and both high pro-BNP and ECG changes: HR: 3.86(2.94-5.08);P<0.001). Adding the combination of pro-BNP and ECG changes to a fully adjusted model correctly reclassified 33.9%(26.5-41.3);P<0.001 on the continuous net reclassification scale for all-cause mortality and 49.7%(41.1-58.4);P<0.001 for CVD event. Combining ECG changes and pro-BNP improves risk prediction in persons without known heart disease. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

N-terminal Proteomics Assisted Profiling of the Unexplored Translation Initiation Landscape in Arabidopsis thaliana *

PubMed Central

Ndah, Elvis; Jonckheere, Veronique

2017-01-01

Proteogenomics is an emerging research field yet lacking a uniform method of analysis. Proteogenomic studies in which N-terminal proteomics and ribosome profiling are combined, suggest that a high number of protein start sites are currently missing in genome annotations. We constructed a proteogenomic pipeline specific for the analysis of N-terminal proteomics data, with the aim of discovering novel translational start sites outside annotated protein coding regions. In summary, unidentified MS/MS spectra were matched to a specific N-terminal peptide library encompassing protein N termini encoded in the Arabidopsis thaliana genome. After a stringent false discovery rate filtering, 117 protein N termini compliant with N-terminal methionine excision specificity and indicative of translation initiation were found. These include N-terminal protein extensions and translation from transposable elements and pseudogenes. Gene prediction provided supporting protein-coding models for approximately half of the protein N termini. Besides the prediction of functional domains (partially) contained within the newly predicted ORFs, further supporting evidence of translation was found in the recently released Araport11 genome re-annotation of Arabidopsis and computational translations of sequences stored in public repositories. Most interestingly, complementary evidence by ribosome profiling was found for 23 protein N termini. Finally, by analyzing protein N-terminal peptides, an in silico analysis demonstrates the applicability of our N-terminal proteogenomics strategy in revealing protein-coding potential in species with well- and poorly-annotated genomes. PMID:28432195

N-terminal Proteomics Assisted Profiling of the Unexplored Translation Initiation Landscape in Arabidopsis thaliana.

PubMed

Willems, Patrick; Ndah, Elvis; Jonckheere, Veronique; Stael, Simon; Sticker, Adriaan; Martens, Lennart; Van Breusegem, Frank; Gevaert, Kris; Van Damme, Petra

2017-06-01

Proteogenomics is an emerging research field yet lacking a uniform method of analysis. Proteogenomic studies in which N-terminal proteomics and ribosome profiling are combined, suggest that a high number of protein start sites are currently missing in genome annotations. We constructed a proteogenomic pipeline specific for the analysis of N-terminal proteomics data, with the aim of discovering novel translational start sites outside annotated protein coding regions. In summary, unidentified MS/MS spectra were matched to a specific N-terminal peptide library encompassing protein N termini encoded in the Arabidopsis thaliana genome. After a stringent false discovery rate filtering, 117 protein N termini compliant with N-terminal methionine excision specificity and indicative of translation initiation were found. These include N-terminal protein extensions and translation from transposable elements and pseudogenes. Gene prediction provided supporting protein-coding models for approximately half of the protein N termini. Besides the prediction of functional domains (partially) contained within the newly predicted ORFs, further supporting evidence of translation was found in the recently released Araport11 genome re-annotation of Arabidopsis and computational translations of sequences stored in public repositories. Most interestingly, complementary evidence by ribosome profiling was found for 23 protein N termini. Finally, by analyzing protein N-terminal peptides, an in silico analysis demonstrates the applicability of our N-terminal proteogenomics strategy in revealing protein-coding potential in species with well- and poorly-annotated genomes. © 2017 by The American Society for Biochemistry and Molecular Biology, Inc.

The novel ER membrane protein PRO41 is essential for sexual development in the filamentous fungus Sordaria macrospora.

PubMed

Nowrousian, Minou; Frank, Sandra; Koers, Sandra; Strauch, Peter; Weitner, Thomas; Ringelberg, Carol; Dunlap, Jay C; Loros, Jennifer J; Kück, Ulrich

2007-05-01

The filamentous fungus Sordaria macrospora develops complex fruiting bodies (perithecia) to propagate its sexual spores. Here, we present an analysis of the sterile mutant pro41 that is unable to produce mature fruiting bodies. The mutant carries a deletion of 4 kb and is complemented by the pro41 open reading frame that is contained within the region deleted in the mutant. In silico analyses predict PRO41 to be an endoplasmic reticulum (ER) membrane protein, and a PRO41-EGFP fusion protein colocalizes with ER-targeted DsRED. Furthermore, Western blot analysis shows that the PRO41-EGFP fusion protein is present in the membrane fraction. A fusion of the predicted N-terminal signal sequence of PRO41 with EGFP is secreted out of the cell, indicating that the signal sequence is functional. pro41 transcript levels are upregulated during sexual development. This increase in transcript levels was not observed in the sterile mutant pro1 that lacks a transcription factor gene. Moreover, microarray analysis of gene expression in the mutants pro1, pro41 and the pro1/41 double mutant showed that pro41 is partly epistatic to pro1. Taken together, these data show that PRO41 is a novel ER membrane protein essential for fruiting body formation in filamentous fungi.

24 CFR 220.806 - Pro rata refund of insurance premium.

Code of Federal Regulations, 2010 CFR

2010-04-01

... refund of insurance premium. Upon termination of loan insurance contract by a payment in full or by a... equal to the pro rata portion of the current annual loan insurance premium theretofore paid which is... 24 Housing and Urban Development 2 2010-04-01 2010-04-01 false Pro rata refund of insurance...

24 CFR 220.806 - Pro rata refund of insurance premium.

Code of Federal Regulations, 2011 CFR

2011-04-01

... refund of insurance premium. Upon termination of loan insurance contract by a payment in full or by a... equal to the pro rata portion of the current annual loan insurance premium theretofore paid which is... 24 Housing and Urban Development 2 2011-04-01 2011-04-01 false Pro rata refund of insurance...

Meprin A and meprin {alpha} generate biologically functional IL-1{beta} from pro-IL-1{beta}

DOE Office of Scientific and Technical Information (OSTI.GOV)

Herzog, Christian; University of Arkansas for Medical Sciences, Department of Medicine, Little Rock, AR 72205; Haun, Randy S.

The present study demonstrates that both oligomeric metalloendopeptidase meprin A purified from kidney cortex and recombinant meprin {alpha} are capable of generating biologically active IL-1{beta} from its precursor pro-IL-1{beta}. Amino-acid sequencing analysis reveals that meprin A and meprin {alpha} cleave pro-IL-1{beta} at the His{sup 115}-Asp{sup 116} bond, which is one amino acid N-terminal to the caspase-1 cleavage site and five amino acids C-terminal to the meprin {beta} site. The biological activity of the pro-IL-1{beta} cleaved product produced by meprin A, determined by proliferative response of helper T-cells, was 3-fold higher to that of the IL-1{beta} product produced by meprin {beta}more » or caspase-1. In a mouse model of sepsis induced by cecal ligation puncture that results in elevated levels of serum IL-1{beta}, meprin inhibitor actinonin significantly reduces levels of serum IL-1{beta}. Meprin A and meprin {alpha} may therefore play a critical role in the production of active IL-1{beta} during inflammation and tissue injury.« less

Opposite Roles of Furin and PC5A in N-Cadherin Processing12

PubMed Central

Maret, Deborah; Sadr, Mohamad Seyed; Sadr, Emad Seyed; Colman, David R; Del Maestro, Rolando F; Seidah, Nabil G

2012-01-01

We recently demonstrated that lack of Furin-processing of the N-cadherin precursor (proNCAD) in highly invasive melanoma and brain tumor cells results in the cell-surface expression of a nonadhesive protein favoring cell migration and invasion in vitro. Quantitative polymerase chain reaction analysis of malignant human brain tumor cells revealed that of all proprotein convertases (PCs) only the levels of Furin and PC5A are modulated, being inversely (Furin) or directly (PC5A) correlated with brain tumor invasive capacity. Intriguingly, the N-terminal sequence following the Furin-activated NCAD site (RQKR↓DW161, mouse nomenclature) reveals a second putative PC-processing site (RIRSDR↓DK189) located in the first extracellular domain. Cleavage at this site would abolish the adhesive functions of NCAD because of the loss of the critical Trp161. This was confirmed upon analysis of the fate of the endogenous prosegment of proNCAD in human malignant glioma cells expressing high levels of Furin and low levels of PC5A (U343) or high levels of PC5A and negligible Furin levels (U251). Cellular analyses revealed that Furin is the best activating convertase releasing an ∼17-kDa prosegment, whereas PC5A is the major inactivating enzyme resulting in the secretion of an ∼20-kDa product. Like expression of proNCAD at the cell surface, cleavage of the NCAD molecule at RIRSDR↓DK189 renders the U251 cancer cells less adhesive to one another and more migratory. Our work modifies the present view on posttranslational processing and surface expression of classic cadherins and clarifies how NCAD possesses a range of adhesive potentials and plays a critical role in tumor progression. PMID:23097623

Assessment of N-terminal prohormone B-type natriuretic peptide as a measure of vascular and ventricular function in pediatric pulmonary arterial hypertension

PubMed Central

Dunning, Jamie; Truong, Uyen; Ivy, D. Dunbar; Hunter, Kendall A.; Shandas, Robin

2015-01-01

Abstract Pulmonary arterial hypertension (PAH) is a progressive disease that puts excessive mechanical loads on the ventricle due to a gradual increase in pulmonary vascular impedance. We hypothesize that the increase in right ventricular (RV) afterload is reflected in the concentration of circulating biochemical markers of ventricular strain and stress (B-type natriuretic peptide [BNP] and N-terminal prohormone BNP [NT-proBNP]). We retrospectively analyzed right heart catheterization (RHC) and serum biochemical analysis data () for a pediatric PAH cohort with no sign of left ventricular dysfunction. Using RHC data, we computed an estimate of pulmonary vascular resistance (PVR), compliance, and ventricular-vascular coupling. We also compared how the early onset of interventricular decoupling (characterized as septal flattening) impacts serum NT-proBNP concentrations. Our data revealed correlated NT-proBNP expression with both the resistive and reactive components of RV afterload, an estimate of ventricular-vascular coupling, and a significant increase in biomarker expression in patients with a flattened interventricular septum. Furthermore, the strong correlation between PVR and NT-proBNP appears to break down under flat septum morphology. Over 80% of resistive RV afterload variance is reflected in serum NT-proBNP concentration in pediatric patients with PAH with no sign of left ventricular dysfunction. Reactive afterload appears to contribute to myocardial NT-proBNP release at advanced stages of PAH. Therefore, in mild-to-moderate PAH, resistive afterload is likely the greatest contributor to RV wall stress. These findings could also be used to estimate invasive RHC measurements from serum biochemical analysis, but more work is needed to improve correlations and overcome the issue of interventricular decoupling. PMID:26697173

Nerve growth factor metabolic dysfunction in Down’s syndrome brains

PubMed Central

Iulita, M. Florencia; Do Carmo, Sonia; Ower, Alison K.; Fortress, Ashley M.; Aguilar, Lisi Flores; Hanna, Michael; Wisniewski, Thomas; Granholm, Ann-Charlotte; Buhusi, Mona; Busciglio, Jorge

2014-01-01

Basal forebrain cholinergic neurons play a key role in cognition. This neuronal system is highly dependent on NGF for its synaptic integrity and the phenotypic maintenance of its cell bodies. Basal forebrain cholinergic neurons progressively degenerate in Alzheimer’s disease and Down’s syndrome, and their atrophy contributes to the manifestation of dementia. Paradoxically, in Alzheimer’s disease brains, the synthesis of NGF is not affected and there is abundance of the NGF precursor, proNGF. We have shown that this phenomenon is the result of a deficit in NGF’s extracellular metabolism that compromises proNGF maturation and exacerbates its subsequent degradation. We hypothesized that a similar imbalance should be present in Down’s syndrome. Using a combination of quantitative reverse transcription-polymerase chain reaction, enzyme-linked immunosorbent assay, western blotting and zymography, we investigated signs of NGF metabolic dysfunction in post-mortem brains from the temporal (n = 14), frontal (n = 34) and parietal (n = 20) cortex obtained from subjects with Down’s syndrome and age-matched controls (age range 31–68 years). We further examined primary cultures of human foetal Down’s syndrome cortex (17–21 gestational age weeks) and brains from Ts65Dn mice (12–22 months), a widely used animal model of Down’s syndrome. We report a significant increase in proNGF levels in human and mouse Down’s syndrome brains, with a concomitant reduction in the levels of plasminogen and tissue plasminogen activator messenger RNA as well as an increment in neuroserpin expression; enzymes that partake in proNGF maturation. Human Down’s syndrome brains also exhibited elevated zymogenic activity of MMP9, the major NGF-degrading protease. Our results indicate a failure in NGF precursor maturation in Down’s syndrome brains and a likely enhanced proteolytic degradation of NGF, changes which can compromise the trophic support of basal forebrain cholinergic

24 CFR 232.825 - Pro rata refund of insurance premium.

Code of Federal Regulations, 2010 CFR

2010-04-01

... ASSISTED LIVING FACILITIES Contract Rights and Obligations Premiums § 232.825 Pro rata refund of insurance premium. Upon termination of a loan insurance contract by a payment in full or by a voluntary termination... rata portion of the current annual loan insurance premium theretofore paid which is applicable to the...

24 CFR 232.825 - Pro rata refund of insurance premium.

Code of Federal Regulations, 2011 CFR

2011-04-01

... ASSISTED LIVING FACILITIES Contract Rights and Obligations Premiums § 232.825 Pro rata refund of insurance premium. Upon termination of a loan insurance contract by a payment in full or by a voluntary termination... rata portion of the current annual loan insurance premium theretofore paid which is applicable to the...

The tetrapeptide N-acetyl-Pro-Pro-Tyr-Leu in skin care formulations-Physicochemical and release studies.

PubMed

Olejnik, Anna; Schroeder, Grzegorz; Nowak, Izabela

2015-08-15

Recently there has been a growth of interest in the novel skin care formulations containing active ingredients such as low molecular weight peptides. In this paper we present new skincare formulations such as hydrogels, oil-in-water emulsions and water-in-oil emulsion containing a tetrapeptide (N-acetyl-Pro-Pro-Tyr-Leu). These formulations were characterized in terms of physicochemical parameters (pH, viscosity), stability and particle size distribution. Additionally, the diffusion parameters of the peptide in the obtained formulations were calculated based on the Einstein-Smoluchowski equation. Furthermore, in order to determine the penetration of the tetrapeptide through membranes its release kinetics were investigated. On the basis of release curves, the release rate constants were determined. The results proved that the properties of the formulations strongly determined the release rate of the tetrapeptide. The higher viscosity of the semisolid, the slower was the permeation through the membrane. Copyright © 2015 Elsevier B.V. All rights reserved.

Blocking an N-terminal acetylation–dependent protein interaction inhibits an E3 ligase

DOE Office of Scientific and Technical Information (OSTI.GOV)

Scott, Daniel C.; Hammill, Jared T.; Min, Jaeki

N-terminal acetylation is an abundant modification influencing protein functions. Because ~80% of mammalian cytosolic proteins are N-terminally acetylated, this modification is potentially an untapped target for chemical control of their functions. Structural studies have revealed that, like lysine acetylation, N-terminal acetylation converts a positively charged amine into a hydrophobic handle that mediates protein interactions; hence, this modification may be a druggable target. We report the development of chemical probes targeting the N-terminal acetylation–dependent interaction between an E2 conjugating enzyme (UBE2M or UBC12) and DCN1 (DCUN1D1), a subunit of a multiprotein E3 ligase for the ubiquitin-like protein NEDD8. The inhibitors aremore » highly selective with respect to other protein acetyl-amide–binding sites, inhibit NEDD8 ligation in vitro and in cells, and suppress anchorage-independent growth of a cell line with DCN1 amplification. Overall, our data demonstrate that N-terminal acetyl-dependent protein interactions are druggable targets and provide insights into targeting multiprotein E2–E3 ligases.« less

Pro-Brain Natriuretic Peptide and Troponin T-Hypersensitivity Levels Correlate With the Severity of Liver Dysfunction in Liver Cirrhosis.

PubMed

Zhao, Jiancheng; Li, Sai; Ren, Linan; Guo, Xiaozhong; Qi, Xingshun

2017-08-01

Increased pro-brain natriuretic peptide (pro-BNP) or troponin T-hypersensitivity (TnT-HSST) levels are common in liver cirrhosis. We conducted a retrospective observational study aimed to evaluate the correlation of pro-BNP and TnT-HSST levels with the clinical characteristics, laboratory data and in-hospital outcomes of patients with liver cirrhosis. We selected cirrhotic patients admitted to our hospital between January 2011 and June 2014. All eligible patients had pro-BNP or TnT-HSST data, or both. The pro-BNP and TnT-HSST data were further divided according to the presence of cardiac diseases. The prevalence of pro-BNP level >900pg/mL was 41.72% (63 of 151 patients). The prevalence of TnT-HSST level >0.05ng/mL was 11.22% (45 of 401 patients). In the overall analysis, pro-BNP level significantly correlated with red blood cell (RBC), platelet, ascites, blood urea nitrogen (BUN), creatinine (Cr), Child-Pugh score, model for end-stage liver disease (MELD) score and in-hospital death; TnT-HSST level significantly correlated with white blood cell, ascites, albumin (ALB), BUN, Cr, Child-Pugh score, MELD score and in-hospital death. In patients with cardiac diseases, pro-BNP level significantly correlated with RBC, ascites, BUN, Cr, Child-Pugh score and MELD score; TnT-HSST level significantly correlated with sex, ascites, white blood cell, ALB, BUN, Cr, Child-Pugh score, MELD score and in-hospital death. In patients without cardiac diseases, pro-BNP level significantly correlated with ascites, RBC, platelet, BUN, Cr, MELD score and in-hospital death; TnT-HSST level significantly correlated with age, ascites, RBC, ALB, BUN, Cr, Child-Pugh score, MELD score and in-hospital death. Pro-BNP and TnT-HSST levels significantly correlated with the severity of liver dysfunction and in-hospital mortality in cirrhosis. Copyright © 2017 Southern Society for Clinical Investigation. Published by Elsevier Inc. All rights reserved.

Cell surface chondroitin sulfate glycosaminoglycan in melanoma: role in the activation of pro-MMP-2 (pro-gelatinase A)

PubMed Central

Iida, Joji; Wilhelmson, Krista L.; Ng, Janet; Lee, Peter; Morrison, Charlotte; Tam, Eric; Overall, Christopher M.; McCarthy, James B.

2007-01-01

We previously reported that CS (chondroitin sulfate) GAG (glycosaminoglycan), expressed on MCSP (melanoma-specific CS proteoglycan), is important for regulating MT3-MMP [membrane-type 3 MMP (matrix metalloproteinase)]-mediated human melanoma invasion and gelatinolytic activity in vitro. In the present study, we sought to determine if CS can directly enhance MT3-MMP-mediated activation of pro-MMP-2. Co-immunoprecipitation studies suggest that MCSP forms a complex with MT3-MMP and MMP-2 on melanoma cell surface. When melanoma cells were treated with βDX (p-nitro-β-D-xylopyranoside) to inhibit coupling of CS on the core protein, both active form and proform of MMP-2 were no longer co-immunoprecipitated with either MCSP or MT3-MMP, suggesting a model in which CS directly binds to MMP-2 and presents the gelatinase to MT3-MMP to be activated. By using recombinant proteins, we determined that MT3-MMP directly activates pro-MMP-2 and that this activation requires the interaction of the C-terminal domain of pro-MMP-2 with MT3-MMP. Activation of pro-MMP-2 by suboptimal concentrations of MT3-MMP is also significantly enhanced in the presence of excess C4S (chondroitin 4-sulfate), whereas C6S (chondroitin 6-sulfate) or low-molecular-mass hyaluronan was ineffective. Affinity chromatography studies using CS isolated from aggrecan indicate that the catalytic domain of MT3-MMP and the C-terminal domain of MMP-2 directly bind to the GAG. Thus the direct binding of pro-MMP-2 with CS through the C-domain would present the catalytic domain of pro-MMP-2 to MT3-MMP, which facilitates the generation of the active form of MMP-2. These results suggest that C4S, which is expressed on tumour cell surface, can function to bind to pro-MMP-2 and facilitate its activation by MT3-MMP-expressing tumour cells to enhance invasion and metastasis. PMID:17217338

Myocardial 2D strain echocardiography and cardiac biomarkers in children during and shortly after anthracycline therapy for acute lymphoblastic leukaemia (ALL): a prospective study.

PubMed

Mavinkurve-Groothuis, Annelies M C; Marcus, Karen A; Pourier, Milanthy; Loonen, Jacqueline; Feuth, Ton; Hoogerbrugge, Peter M; de Korte, Chris L; Kapusta, Livia

2013-06-01

The aim of this study was to investigate myocardial 2D strain echocardiography and cardiac biomarkers in the assessment of cardiac function in children with acute lymphoblastic leukaemia (ALL) during and shortly after treatment with anthracyclines. Cardiac function of 60 children with ALL was prospectively studied with measurements of cardiac troponin T (cTnT) and N-terminal-pro-brain natriuretic peptide (NT-pro-BNP) and conventional and myocardial 2D strain echocardiography before start (T = 0), after 3 months (T = 1), and after 1 year (T = 2), and were compared with 60 healthy age-matched controls. None of the patients showed clinical signs of cardiac failure or abnormal fractional shortening. Cardiac function decreased significantly during treatment and was significantly decreased compared with normal controls. Cardiac troponin T levels were abnormal in 11% of the patients at T = 1 and were significantly related to increased time to global peak systolic longitudinal strain at T = 2 (P = 0.003). N-terminal-pro-brain natriuretic peptide levels were abnormal in 13% of patients at T = 1 and in 20% at T = 2, absolute values increased throughout treatment in 59%. Predictors for abnormal NT-pro-BNP at T = 2 were abnormal NT-pro-BNP at T = 0 and T = 1, for abnormal myocardial 2D strain parameters at T = 2 cumulative anthracycline dose and z-score of the diastolic left ventricular internal diameter at baseline. Children with newly diagnosed ALL showed decline of systolic and diastolic function during treatment with anthracyclines using cardiac biomarkers and myocardial 2D strain echocardiography. N-terminal-pro-brain natriuretic peptide levels were not related to echocardiographic strain parameters and cTnT was not a predictor for abnormal strain at T = 2.Therefore, the combination of cardiac biomarkers and myocardial 2D strain echocardiography is important in the assessment of cardiac function of children with ALL treated with anthracyclines.

Individual patient meta-analysis of exercise training effects on systemic brain natriuretic peptide expression in heart failure.

PubMed

Smart, N A; Meyer, T; Butterfield, J A; Faddy, S C; Passino, C; Malfatto, G; Jonsdottir, S; Sarullo, F; Wisloff, U; Vigorito, C; Giallauria, F

2012-06-01

Brain natriuretic peptide (BNP) predicts exercise performance and exercise training may modulate BNP and its N-terminal portion (NT-pro-BNP), we therefore conducted an individual patient analysis of exercise training effects on BNP and NT-pro-BNP. To use an individual patient meta-analysis to relate changes in BNP, NT-pro-BNP, and peak VO(2); to link these changes to volume parameters of exercise training programmes (intensity etc.); and to identify patient characteristics likely to lead to greater improvements in BNP, NT-pro-BNP, and peak VO(2). Individual patient meta-analysis. A systematic search was conducted of Medline (Ovid), Embase.com, Cochrane Central Register of Controlled Trials, and CINAHL (until July 2008) to identify randomized controlled trials of aerobic and/or resistance exercise training in systolic heart failure patients measuring BNP and/or NT-pro-BNP. Primary outcome measures were change in BNP, NT-pro-BNP, and peak VO2. Subanalyses were conducted to identify (1) patient groups that benefit most and (2) exercise programme parameters enhancing favourable changes in primary outcome measures. Ten randomized controlled studies measuring BNP or NT-pro-BNP met eligibility criteria, authors provided individual patient data for 565 patients (313 exercise and 252 controls). Exercise training had favourable effects on BNP (-28.3%, p < 0.0001), NT-pro-BNP (-37.4%, p = < 0.0001), and peak VO(2) (17.8%, p < 0.0001). The analysis showed a significant change in primary outcome measures; moreover, change in BNP (r = -0.31, p < 0.0001) and NT-pro-BNP (r = -0.22, p < 0.0001) were correlated with peak VO(2) change. Exercise training has favourable effects on BNP, NT-pro-BNP, and peak VO(2) in heart failure patients and BNP/NT-pro-BNP changes were correlated with peak VO(2) changes.

Precursor N-cadherin mediates glial cell line-derived neurotrophic factor-promoted human malignant glioma

PubMed Central

Zhu, Shuang; Zhang, Baole; Qin, Yuxia; Yao, Ruiqin; Zhou, Hao; Gao, Dian Shuai

2017-01-01

As the most prevalent primary brain tumor, gliomas are highly metastatic, invasive and are characteristic of high levels of glial cell-line derived neurotrophic factor (GDNF). GDNF is an important factor for invasive glioma cell growth; however, the underlying mechanism involved is unclear. In this study, we affirm a significantly higher expression of the precursor of N-cadherin (proN-cadherin) in most gliomas compared with normal brain tissues. Our findings reveal that GDNF interacts with the extracellular domain of proN-cadherin, which suggests that proN-cadherin mediates GDNF-induced glioma cell migration and invasion. We hypothesize that proN-cadherin might cause homotypic adhesion loss within neighboring cells and at the same time promote heterotypic adhesion within the extracellular matrix (ECM) through a certain mechanism. This study also demonstrates that the interaction between GDNF and proN-cadherin activates specific intracellular signaling pathways; furthermore, GDNF promoted the secretion of matrix metalloproteinase-9 (MMP-9), which degrades the ECM via proN-cadherin. To reach the future goal of developing novel therapies of glioma, this study, reveals a unique mechanism of glioma cell migration and invasion. PMID:28212546

Precursor N-cadherin mediates glial cell line-derived neurotrophic factor-promoted human malignant glioma.

PubMed

Xiong, Ye; Liu, Liyun; Zhu, Shuang; Zhang, Baole; Qin, Yuxia; Yao, Ruiqin; Zhou, Hao; Gao, Dian Shuai

2017-04-11

As the most prevalent primary brain tumor, gliomas are highly metastatic, invasive and are characteristic of high levels of glial cell-line derived neurotrophic factor (GDNF). GDNF is an important factor for invasive glioma cell growth; however, the underlying mechanism involved is unclear. In this study, we affirm a significantly higher expression of the precursor of N-cadherin (proN-cadherin) in most gliomas compared with normal brain tissues. Our findings reveal that GDNF interacts with the extracellular domain of proN-cadherin, which suggests that proN-cadherin mediates GDNF-induced glioma cell migration and invasion. We hypothesize that proN-cadherin might cause homotypic adhesion loss within neighboring cells and at the same time promote heterotypic adhesion within the extracellular matrix (ECM) through a certain mechanism. This study also demonstrates that the interaction between GDNF and proN-cadherin activates specific intracellular signaling pathways; furthermore, GDNF promoted the secretion of matrix metalloproteinase-9 (MMP-9), which degrades the ECM via proN-cadherin. To reach the future goal of developing novel therapies of glioma, this study, reveals a unique mechanism of glioma cell migration and invasion.

N-Terminal Truncated UCH-L1 Prevents Parkinson's Disease Associated Damage

PubMed Central

Kim, Hee-Jung; Kim, Hyun Jung; Jeong, Jae-Eun; Baek, Jeong Yeob; Jeong, Jaeho; Kim, Sun; Kim, Young-Mee; Kim, Youhwa; Nam, Jin Han; Huh, Sue Hee; Seo, Jawon; Jin, Byung Kwan; Lee, Kong-Joo

2014-01-01

Ubiquitin C-terminal hydrolase-L1 (UCH-L1) has been proposed as one of the Parkinson's disease (PD) related genes, but the possible molecular connection between UCH-L1 and PD is not well understood. In this study, we discovered an N-terminal 11 amino acid truncated variant UCH-L1 that we called NT-UCH-L1, in mouse brain tissue as well as in NCI-H157 lung cancer and SH-SY5Y neuroblastoma cell lines. In vivo experiments and hydrogen-deuterium exchange (HDX) with tandem mass spectrometry (MS) studies showed that NT-UCH-L1 is readily aggregated and degraded, and has more flexible structure than UCH-L1. Post-translational modifications including monoubiquitination and disulfide crosslinking regulate the stability and cellular localization of NT-UCH-L1, as confirmed by mutational and proteomic studies. Stable expression of NT-UCH-L1 decreases cellular ROS levels and protects cells from H2O2, rotenone and CCCP-induced cell death. NT-UCH-L1-expressing transgenic mice are less susceptible to degeneration of nigrostriatal dopaminergic neurons seen in the MPTP mouse model of PD, in comparison to control animals. These results suggest that NT-UCH-L1 may have the potential to prevent neural damage in diseases like PD. PMID:24959670

Endothelial immunomediated reactivity in acute cardiac ischaemia: Role of endothelin 1, interleukin 8 and NT-proBNP in patients affected by unstable angina pectoris

PubMed Central

Caroselli, Costantino; De Rosa, Rosario; Tanzi, Pietro; Rigatelli, Alberto; Bruno, Guglielmo

2016-01-01

The role of endothelium in the progression of atheromasic disease has already been demonstrated. Endothelin-1 (ET-1) is released from endothelial cells during acute and chronic vascular damage and it appears to be the strongest vasoconstrictor agent known. The aim of this study is to investigate the amount of endothelial damage in patients with unstable angina (UA), as defined by serum levels of ET-1, to verify a possible correlation with increased ischaemic damage by evaluation of serum N-terminal pro-brain natriuretic peptide (NT-proBNP) and interleukin 8 (IL-8) levels. Serum levels of ET-1, IL-8 and NT-proBNP obtained from 10 patients affected by low-risk UA were compared to those belonging to eight healthy subjects. In order to compare the laboratory data pertaining to the two populations, a Student’s t-test and a Mann-Whitney U test were performed. Levels of ET-1, IL-8 and NT-proBNP in samples of peripheral blood of patients affected by UA were significantly elevated, compared with those of the control group. The linear correlation analysis demonstrated a positive and significant correlation between levels of ET-1 and IL-8, between levels of ET-1 and NT-proBNP, and between levels of IL-8 and NT-proBNP in subjects affected by UA. Early elevated levels of ET-1, IL-8 and NT-proBNP in patients with UA show a coexistence between ischaemic insults and endothelial damages. A positive and significant linear correlation between levels of ET-1 and IL-8, between levels of ET-1 and NT-proBNP, and between levels of IL-8 and NT-proBNP confirms that an increased ischaemic insult is correlated to inflammation signs and endothelium damage signs. In patients with UA, ischaemia is always associated with a systemic immuno-mediated activity induced by acute endothelial damage. We suggest early administration of ET-1-selective receptor blockers and anti-inflammatory drugs. PMID:26684625

Endothelial immunomediated reactivity in acute cardiac ischaemia: Role of endothelin 1, interleukin 8 and NT-proBNP in patients affected by unstable angina pectoris.

PubMed

Caroselli, Costantino; De Rosa, Rosario; Tanzi, Pietro; Rigatelli, Alberto; Bruno, Guglielmo

2016-09-01

The role of endothelium in the progression of atheromasic disease has already been demonstrated. Endothelin-1 (ET-1) is released from endothelial cells during acute and chronic vascular damage and it appears to be the strongest vasoconstrictor agent known.The aim of this study is to investigate the amount of endothelial damage in patients with unstable angina (UA), as defined by serum levels of ET-1, to verify a possible correlation with increased ischaemic damage by evaluation of serum N-terminal pro-brain natriuretic peptide (NT-proBNP) and interleukin 8 (IL-8) levels.Serum levels of ET-1, IL-8 and NT-proBNP obtained from 10 patients affected by low-risk UA were compared to those belonging to eight healthy subjects. In order to compare the laboratory data pertaining to the two populations, a Student's t-test and a Mann-Whitney U test were performed.Levels of ET-1, IL-8 and NT-proBNP in samples of peripheral blood of patients affected by UA were significantly elevated, compared with those of the control group. The linear correlation analysis demonstrated a positive and significant correlation between levels of ET-1 and IL-8, between levels of ET-1 and NT-proBNP, and between levels of IL-8 and NT-proBNP in subjects affected by UA.Early elevated levels of ET-1, IL-8 and NT-proBNP in patients with UA show a coexistence between ischaemic insults and endothelial damages. A positive and significant linear correlation between levels of ET-1 and IL-8, between levels of ET-1 and NT-proBNP, and between levels of IL-8 and NT-proBNP confirms that an increased ischaemic insult is correlated to inflammation signs and endothelium damage signs.In patients with UA, ischaemia is always associated with a systemic immuno-mediated activity induced by acute endothelial damage. We suggest early administration of ET-1-selective receptor blockers and anti-inflammatory drugs. © The Author(s) 2015.

Donor Preconditioning After the Onset of Brain Death With Dopamine Derivate n-Octanoyl Dopamine Improves Early Posttransplant Graft Function in the Rat.

PubMed

Li, S; Korkmaz-Icöz, S; Radovits, T; Ruppert, M; Spindler, R; Loganathan, S; Hegedűs, P; Brlecic, P; Theisinger, B; Theisinger, S; Höger, S; Brune, M; Lasitschka, F; Karck, M; Yard, B; Szabó, G

2017-07-01

Heart transplantation is the therapy of choice for end-stage heart failure. However, hemodynamic instability, which has been demonstrated in brain-dead donors (BDD), could also affect the posttransplant graft function. We tested the hypothesis that treatment of the BDD with the dopamine derivate n-octanoyl-dopamine (NOD) improves donor cardiac and graft function after transplantation. Donor rats were given a continuous intravenous infusion of either NOD (0.882 mg/kg/h, BDD+NOD, n = 6) or a physiological saline vehicle (BDD, n = 9) for 5 h after the induction of brain death by inflation of a subdural balloon catheter. Controls were sham-operated (n = 9). In BDD, decreased left-ventricular contractility (ejection fraction; maximum rate of rise of left-ventricular pressure; preload recruitable stroke work), relaxation (maximum rate of fall of left-ventricular pressure; Tau), and increased end-diastolic stiffness were significantly improved after the NOD treatment. Following the transplantation, the NOD-treatment of BDD improved impaired systolic function and ventricular relaxation. Additionally, after transplantation increased interleukin-6, tumor necrosis factor TNF-α, NF-kappaB-p65, and nuclear factor (NF)-kappaB-p105 gene expression, and increased caspase-3, TNF-α and NF-kappaB protein expression could be significantly downregulated by the NOD treatment compared to BDD. BDD postconditioning with NOD through downregulation of the pro-apoptotic factor caspase-3, pro-inflammatory cytokines, and NF-kappaB may protect the heart against the myocardial injuries associated with brain death and ischemia/reperfusion. © 2017 The American Society of Transplantation and the American Society of Transplant Surgeons.

Relative role of NT-pro BNP and cardiac troponin T at 96 hours for estimation of infarct size and left ventricular function after acute myocardial infarction.

PubMed

Steen, Henning; Futterer, Simon; Merten, Constanze; Jünger, Claus; Katus, Hugo A; Giannitsis, Evangelos

2007-01-01

N-terminal brain-type natriuretic peptide (NT-pro BNP) and cardiac troponin T (cTnT) after acute myocardial infarction (AMI) have proven useful for prediction of prognosis and may be valuable for assessment of left ventricular function and infarct size. The aim of the present study was to correlate infarct size and left ventricular function determined by cine and late gadolinium enhanced CMR with plasma levels of TNT and NT-pro BNP levels after AMI. We studied 44 patients (pts) with first ST- and non-ST-segment elevation myocardial infarction (STEMI=23 pts.,NSTEMI=21 pts.). We measured NT-pro BNP and cTnT on a single occasion at 96 hours after onset of symptoms. There was a moderate inverse correlation between NT-pro BNP and LV-EF in STEMI (r=-0.67, p=0.0009) and NSTEMI (r=-0.85, p<0.0001). Likewise, cTnT showed a significant inverse correlation with LV-EF in STEMI (r=-0.54, p=0.014) but not in NSTEMI. With cTnT there was a strong linear correlation with infarct mass and relative infarct size in STEMI (r=0.92, p<0.0001) and NSTEMI (r=0.59, p<0.0093). NT-pro BNP demonstrated a good relationship with infarct mass (r=0.79, p<0.0001) and relative infarct size (r=0.75, p<0.0001) in STEMI, but not in NSTEMI. A single NT-pro BNP and cTnT value at 96 hours after onset of symptoms proved useful for estimation of LV-EF and infarct size. In direct comparison, NT-pro BNP disclosed a better performance for estimation of LV-EF whereas cTnT was superior for assessment of infarct mass and relative infarct size, suggesting an implementation of a dual marker strategy for diagnostic and prognostic work-up.

Protective effects of recombinant human brain natriuretic peptide in perioperative period during open heart surgery.

PubMed

Xu, Yunbin; Li, Yong; Bao, Weiguo; Qiu, Shi

2018-03-01

The aim of the present study was to evaluate the protective effects and safety aspects of recombinant human brain natriuretic peptide (rhBNP) on cardiac functions of patients undergoing open-heart surgery during perioperative period. In total, 150 patients undergoing open heart surgery in the Second Hospital of Shandong Universty from August 2015 to July 2016 were randomly divided into control group and observation group each with 75 cases. Patients in control group were treated by routine rehabilitation while patients in the observation group were treated by both the routine rehabilitation and rhBNP. All the observations were made before operation, after operation and 7 days after operation. The changes of N-terminal pro-brain natriuretic peptide (NT-proBNP) of patients, the left ventricular ejection fraction (LVEF), cardiac function [Cardiac output (CO), pulmonary capillary wedge pressure (PAWP) and central venous pressure (CVP)] of patients were measured. Further, respirator support time, ICU stay time, incidence of complications and vital signs (BP, HR, SaO2) of patients in the two groups were also compared. NT-proBNP levels of all patients improved after operation but it decreased in both groups after 7 days of operation. The decrease of NT-proBNP levels in observation group was significantly higher than that of control group. Whereas, LVEF, CO, PAWP and CVP of patients in both the groups increased after operation but effects were significantly higher in the observation group after 7 days of medication. Respirator support time and ICU stay time of patients in observation group were significantly shorter than those in control group, and the incidence of postoperative complications of patients in the observation group were significantly lower than the control group. Moreover, BP, HR and SaO2 of patients in observation group were significantly elevated in comparison to control group (P<0.05). Recombinant human brain natriuretic peptide (rhBNP) could significantly

In-hospital and long-term outcomes of congestive heart failure: Predictive value of B-type and amino-terminal pro-B-type natriuretic peptides and their ratio.

PubMed

Dai, Yuxiang; Yang, Jun; Takagi, Atsutoshi; Konishi, Hakuoh; Miyazaki, Tetsuro; Masuda, Hiroshi; Shimada, Kazunori; Miyauchi, Katsumi; Daida, Hiroyuki

2017-08-01

Relative changes in B-type natriuretic peptide (BNP) and amino terminal pro-BNP (NT-proBNP) levels may help to assess the risk of congestive heart failure (CHF). However, whether these levels at the time of admission enable the prediction of outcomes with acute exacerbation remains unknown. The current study determined the abilities of BNP, NT-proBNP and their ratio to predict in-hospital and long-term outcomes of patients with CHF. Patients who were admitted to the cardiac care unit of Juntendo University Hospital (Tokyo, Japan) with acute CHF onset were consecutively enrolled into the present observational study. Serum levels of BNP and NT-proBNP were immediately measured on admission, and other biomarkers and clinical data were also investigated. Of 195 enrolled patients, 16 (8.2%) succumbed to CHF in hospital and 124 (69.3%) reached the endpoint of mortality or readmission following a median follow-up of 14 months. Multiple linear regression analysis revealed body mass index, low density lipoprotein cholesterol, hemoglobin, estimated glomerular filtration rate and C-reactive protein as independent predictors of the NT-proBNP/BNP ratio. BNP, NT-proBNP and their ratio were significantly higher among those who succumbed to CHF than in those who remained alive in hospital (P<0.05). Logistic regression analysis indicated that the ratio was an independent predictor for in-hospital mortality and long-term outcomes. In conclusion, the ratio of NT-proBNP to BNP more effectively predicts in-hospital outcomes than either factor alone and it may also help to predict outcomes among patients with acute exacerbation of HF.

Targeted mass spectrometric analysis of N-terminally truncated isoforms generated via alternative translation initiation.

PubMed

Kobayashi, Ryuji; Patenia, Rebecca; Ashizawa, Satoshi; Vykoukal, Jody

2009-07-21

Alternative translation initiation is a mechanism whereby functionally altered proteins are produced from a single mRNA. Internal initiation of translation generates N-terminally truncated protein isoforms, but such isoforms observed in immunoblot analysis are often overlooked or dismissed as degradation products. We identified an N-terminally truncated isoform of human Dok-1 with N-terminal acetylation as seen in the wild-type. This Dok-1 isoform exhibited distinct perinuclear localization whereas the wild-type protein was distributed throughout the cytoplasm. Targeted analysis of blocked N-terminal peptides provides rapid identification of protein isoforms and could be widely applied for the general evaluation of perplexing immunoblot bands.

Nitrous oxide discretely up-regulates nNOS and p53 in neonatal rat brain.

PubMed

Cattano, D; Valleggi, S; Abramo, A; Forfori, F; Maze, M; Giunta, F

2010-06-01

Animal studies suggest that neuronal cell death often results from anesthetic administration during synaptogenesis. Volatile anesthetics are strongly involved in triggering neuronal apoptosis, whereas other inhalational agents (xenon) demonstrate protective effects. Nitrous oxide (N2O) has modest pro-apoptotic effects on its own and potent, synergistic toxic effects when combined with volatile agents. Recent findings suggest that, during periods of rapid brain development, the enhanced neurodegeneration triggered by anesthetic drugs may be caused by a compensatory increase in intracellular free calcium, a potent activator of neuronal nitric oxide synthase (nNOS). Anesthesia-induced neuro-apoptosis is also activated via the intrinsic and the extrinsic apoptotic pathways because both pathways involve p53, a key regulatory gene. The molecular events related to neuronal cell apoptosis are not completely understood. To gain further insight into the events underlying neuro-apoptosis, we analyzed the transcriptional consequences of N2O exposure on nNOS, iNOS and p53 mRNA levels. The study used 2 groups of postnatal day seven Sprague/Dawley rats (N=6 each) that were exposed for 120 minutes to air (75% N2, 25% O2) or N2O (75% N2O, 25% O2; this N2O concentration is commonly used to induce anesthesia and has been demonstrated to trigger neurodegeneration in postnatal day seven rats). Total RNA was isolated from each brain and expression analyses on iNOS and nNOS transcripts were performed using relative Real-Time C-reactive protein PCR (using G3PDH as a housekeeping gene). A semi-quantitative RT-PCR analysis was performed on the p53 transcript (using Ciclophylin A as a housekeeping gene). Statistical analysis (REST 2005) revealed a significant, 11-fold up-regulation (P=0.026) of the nNOS transcript but no significant changes in iNOS transcription. The p53 mRNA was up-regulated almost 2-fold (P=0.0002; Student's t-Test; GraphPad Prism 4.00) in N2O-treated samples relative to

Identification of a novel amyloid precursor protein processing pathway that generates secreted N-terminal fragments.

PubMed

Vella, Laura J; Cappai, Roberto

2012-07-01

Alzheimer's disease (AD) is a neurodegenerative disorder of the central nervous system. The proteolytic processing of the amyloid precursor protein (APP) into the β-amyloid (Aβ) peptide is a central event in AD. While the pathway that generates Aβ is well described, many questions remain concerning general APP metabolism and its metabolites. It is becoming clear that the amino-terminal region of APP can be processed to release small N-terminal fragments (NTFs). The purpose of this study was to investigate the occurrence and generation of APP NTFs in vivo and in cell culture (SH-SY5Y) in order to delineate the cellular pathways implicated in their generation. We were able to detect 17- to 28-kDa APP NTFs in human and mouse brain tissue that are distinct from N-APP fragments previously reported. We show that the 17- to 28-kDa APP NTFs were highly expressed in mice from the age of 2 wk to adulthood. SH-SY5Y studies indicate the generation of APP NTFs involves a novel APP processing pathway, regulated by protein kinase C, but independent of α-secretase or β-secretase 1 (BACE) activity. These results identify a novel, developmentally regulated APP processing pathway that may play an important role in the physiological function of APP.

Influencing factors of NT-proBNP level inheart failure patients with different cardiacfunctions and correlation with prognosis.

PubMed

Xu, Liang; Chen, Yanchun; Ji, Yanni; Yang, Song

2018-06-01

Factors influencing N-terminal pro-brain natriuretic peptide (NT-proBNP) level in heart failure patients with different cardiac functions were identified to explore the correlations with prognosis. Eighty heart failure patients with different cardiac functions treated in Yixing People's Hospital from January 2016 to June 2017 were selected, and divided into two groups (group with cardiac function in class II and below and group with cardiac function in class III and above), according to the cardiac function classification established by New York Heart Association (NYHA). Blood biochemical test and outcome analysis were conducted to measure serum NT-proBNP and matrix metalloproteinase-9 (MMP-9) levels in patients with different cardiac functions, and correlations between levels of NT-proBNP and MMP-9 and left ventricular ejection fraction (LVEF) level were analyzed in patients with different cardiac functions at the same time. In addition, risk factors for heart failure in patients with different cardiac functions were analyzed. Compared with the group with cardiac function in class III and above, the group with cardiac function in class II and below had significantly lower serum NT-proBNP and MMP-9 levels (p<0.05). For echocardiogram indexes, left ventricular end-diastolic diameter (LVEDD) and left ventricular end-systolic diameter (LVESD) in the group with cardiac function in class II and below were obviously lower than those in the group with cardiac function in class III and above (p<0.05), while LVEF was higher in group with cardiac function in class II and below than that in group with cardiac function in class III and above (p<0.05). NT-proBNP and MMP-9 levels were negatively correlated with LVEF level [r=-0.8517 and -0.8517, respectively, p<0.001 (<0.05)]. Cardiac function in class III and above, increased NT-proBNP, increased MMP-9 and decreased LVEF were relevant risk factors and independent risk factors for heart failure in patients with different cardiac

Determination of the enthalpy of vaporization and prediction of surface tension for ionic liquid 1-alkyl-3-methylimidazolium propionate [C(n)mim][Pro](n = 4, 5, 6).

PubMed

Tong, Jing; Yang, Hong-Xu; Liu, Ru-Jing; Li, Chi; Xia, Li-Xin; Yang, Jia-Zhen

2014-11-13

With the use of isothermogravimetrical analysis, the enthalpies of vaporization, Δ(g)lH(o)m(T(av)), at the average temperature, T(av) = 445.65 K, for the ionic liquids (ILs) 1-alkyl-3-methylimidazolium propionate [C(n)mim][Pro](n = 4, 5, 6) were determined. Using Verevkin's method, the difference of heat capacities between the vapor phase and the liquid phase, Δ(g)lC(p)(o)m, for [C(n)mim][Pro](n = 2, 3, 4, 5, 6), were calculated based on the statistical thermodynamics. Therefore, with the use of Δ(g)lC(p)(o)m, the values of Δ(g)lH(o)m(T(av)) were transformed into Δ(g)lH(o)m(298), 126.8, 130.3, and 136.5 for [C(n)mim][Pro](n = 4, 5, 6), respectively. In terms of the new scale of polarity for ILs, the order of the polarity of [C(n)mim][Pro](n = 2, 3, 4, 5, 6) was predicted, that is, the polarity decreases with increasing methylene. A new model of the relationship between the surface tension and the enthalpy of vaporization for aprotic ILs was put forward and used to predict the surface tension for [C(n)mim][Pro](n = 2, 3, 4, 5, 6) and others. The predicted surface tension for the ILs is in good agreement with the experimental one.

Design and methodology of the NorthStar Study: NT-proBNP stratified follow-up in outpatient heart failure clinics -- a randomized Danish multicenter study.

PubMed

Schou, Morten; Gustafsson, Finn; Videbaek, Lars; Markenvard, John; Ulriksen, Hans; Ryde, Henrik; Jensen, Jens C H; Nielsen, Tonny; Knudsen, Anne S; Tuxen, Christian D; Handberg, Jens; Sørensen, Per J; Espersen, Geert; Lind-Rasmussen, Søren; Keller, Niels; Egstrup, Kenneth; Nielsen, Olav W; Abdulla, Jawdat; Nyvad, Ole; Toft, Jens; Hildebrandt, Per R

2008-10-01

Randomized clinical trials have shown that newly discharged and symptomatic patients with chronic heart failure (CHF) benefit from follow-up in a specialized heart failure clinic (HFC). Clinical stable and educated patients are usually discharged from the HFC when on optimal therapy. It is unknown if risk stratification using natriuretic peptides could identify patients who would benefit from longer-term follow-up. Furthermore, data on the use of natriuretic peptides for monitoring of stable patients with CHF are sparse. The aims of this study are to test the hypothesis that clinical stable, educated, and medical optimized patients with CHF with N-terminal pro-brain natriuretic peptide (NT-proBNP) levels > or = 1,000 pg/mL benefit from long-term follow-up in an HFC and to assess the efficacy of NT-proBNP monitoring. A total of 1,250 clinically stable, medically optimized, and educated patients with CHF will be enrolled from 18 HFCs in Denmark. The patients will be randomized to treatment in general practice, to a standard follow-up program in the HFC, or to NT-proBNP monitoring in the HFC. The patients will be followed for 30 months (median). Data will be collected from 2006 to 2009. At present (March 2008), 720 patients are randomized. Results expect to be presented in the second half of 2010. This article outlines the design of the NorthStar study. If our hypotheses are confirmed, the results will help cardiologists and nurses in HFCs to identify patients who may benefit from long-term follow-up. Our results may also indicate whether patients with CHF will benefit from adding serial NT-proBNP measurements to usual clinical monitoring.

The novel ER membrane protein PRO41 is essential for sexual development in the filamentous fungus Sordaria macrospora

PubMed Central

Nowrousian, Minou; Frank, Sandra; Koers, Sandra; Strauch, Peter; Weitner, Thomas; Ringelberg, Carol; Dunlap, Jay C.; Loros, Jennifer J.; Kück, Ulrich

2013-01-01

Summary The filamentous fungus Sordaria macrospora develops complex fruiting bodies (perithecia) to propagate its sexual spores. Here, we present an analysis of the sterile mutant pro41 that is unable to produce mature fruiting bodies. The mutant carries a deletion of 4 kb and is complemented by the pro41 open reading frame that is contained within the region deleted in the mutant. In silico analyses predict PRO41 to be an endoplasmic reticulum (ER) membrane protein, and a PRO41–EGFP fusion protein colocalizes with ER-targeted DsRED. Furthermore, Western blot analysis shows that the PRO41–EGFP fusion protein is present in the membrane fraction. A fusion of the predicted N-terminal signal sequence of PRO41 with EGFP is secreted out of the cell, indicating that the signal sequence is functional. pro41 transcript levels are upregulated during sexual development. This increase in transcript levels was not observed in the sterile mutant pro1 that lacks a transcription factor gene. Moreover, microarray analysis of gene expression in the mutants pro1, pro41 and the pro1/41 double mutant showed that pro41 is partly epistatic to pro1. Taken together, these data show that PRO41 is a novel ER membrane protein essential for fruiting body formation in filamentous fungi. PMID:17501918

Evaluation of CA125 and NT-proBNP values in patients undergoing transcatheter aortic valve implantation

PubMed Central

Ayhan, Hüseyin; Kasapkara, Hacı Ahmet; Durmaz, Tahir; Keleş, Telat; Sarı, Cenk; Baştuğ, Serdal; Erdoğan, Kemal Eşref; Bayram, Nihal Akar; Bilen, Emine; Akçay, Murat; Bozkurt, Engin

2015-01-01

Background Transcatheter aortic valve implantation (TAVI) is a minimally invasive, emerging therapy in surgically high risk, or inoperable patients. Parameters used for risk classification have some deficiencies in the selection of patients. The objective of this study is to evaluate the impact of TAVI on carbohydrate antigen 125 (CA125) and N-Terminal pro Brain-type Natriuretic Peptide (NT-proBNP) as biomarkers that have been used frequently in recent years, and also the relationship of these biomarkers to prognosis. Methods & Results Transcatheter aortic valve implantation was practiced on 31 patients in this study. Then, CA125 and NT-proBNP levels studied in patients prior to and after the TAVI were evaluated. The patients were also grouped in accordance with their left ventricular ejection fraction (LVEF) and CA125 levels (LVEF ≥ 40% and < 40%; CA125 ≤ 35 U/L and > 35 U/L). The TAVI operation was successfully performed in all patients. There was no in-hospital mortality and substantial improvement in functional capacity was detected at follow ups. In addition, a statistically significant decrease was detected in post-TAVI CA125 and NT-proBNP levels of all patients (CA125 83.8 ± 18.1 U/L vs. 64.3 ± 14.2 U/L, P = 0.008; NT-proBNP: 4633.6 ± 627.6 pg/mL vs. 2866.3 ± 536.8 pg/mL, P < 0.001). In groups divided according to the CA125 levels, there was also statistically significant post-TAVI decline in CA125 levels. Within CA125 > 35 U/L and LVEF < 40% groups, the permanent need for a pacemaker was required in one (3.2%) patient and mortality was observed in two (6.4%) patients after TAVI at follow up. Conclusions The results show that TAVI can be performed effectively and reliably in patients with high baseline levels of CA125 and NT-proBNP. These biomarkers are reduced substantially with TAVI, while high biomarker levels are associated with undesired events, and certainly, these biomarkers can be used for risk classifications in patient selection for TAVI

Passive immunization targeting the N-terminal projection domain of tau decreases tau pathology and improves cognition in a transgenic mouse model of Alzheimer disease and tauopathies.

PubMed

Dai, Chun-ling; Chen, Xia; Kazim, Syed Faraz; Liu, Fei; Gong, Cheng-Xin; Grundke-Iqbal, Inge; Iqbal, Khalid

2015-04-01

Intraneuronal accumulation of abnormally hyperphosphorylated tau in the brain is a histopathological hallmark of Alzheimer's disease and a family of related neurodegenerative disorders collectively called tauopathies. At present there is no effective treatment available for these progressive neurodegenerative diseases which are clinically characterized by dementia in mid to old-age. Here we report the treatment of 14-17-months-old 3xTg-AD mice with tau antibodies 43D (tau 6-18) and 77E9 (tau 184-195) to the N-terminal projection domain of tau or mouse IgG as a control by intraperitoneal injection once a week for 4 weeks, and the effects of the passive immunization on reduction of hyperphosphorylated tau, Aβ accumulation and cognitive performance in these animals. We found that treatment with tau antibodies 43D and 77E9 reduced total tau level, decreased tau hyperphosphorylated at Ser199, Ser202/Thr205 (AT8), Thr205, Ser262/356 (12E8), and Ser396/404 (PHF-1) sites, and a trend to reduce Aβ pathology. Most importantly, targeting N-terminal tau especially by 43D (tau 6-18) improved reference memory in the Morris water maze task in 3xTg-AD mice. We did not observe any abnormality in general physical characteristics of the treated animals with either of the two antibodies during the course of this study. Taken together, our studies demonstrate for the first time (1) that passive immunization targeting normal tau can effectively clear the hyperphosphorylated protein and possibly reduce Aβ pathology from the brain and (2) that targeting N-terminal projection domain of tau containing amino acid 6-18 is especially beneficial. Thus, targeting selective epitopes of N-terminal domain of tau may present a novel effective therapeutic opportunity for Alzheimer disease and other tauopathies.

Neuron-specific (pro)renin receptor knockout prevents the development of salt-sensitive hypertension

PubMed Central

Li, Wencheng; Peng, Hua; Mehaffey, Eamonn P.; Kimball, Christie D.; Grobe, Justin L.; van Gool, Jeanette M.G.; Sullivan, Michelle N.; Earley, Scott; Danser, A.H. Jan; Ichihara, Atsuhiro; Feng, Yumei

2013-01-01

The (pro)renin receptor, which binds both renin and prorenin, is a newly discovered component of the renin angiotensin system that is highly expressed in the central nervous system. The significance of brain PRRs in mediating local angiotensin II formation and regulating blood pressure remains unclear. The current study was performed to test the hypothesis that PRR-mediated, non-proteolytic activation of prorenin is the main source of angiotensin II in the brain. Thus, PRR knockout in the brain is expected to prevent angiotensin II formation and development of deoxycorticosterone acetate salt induced hypertension. A neuron-specific PRR (ATP6AP2) knockout mouse model was generated using the Cre-LoxP system. Physiological parameters were recorded by telemetry. (Pro)renin receptor expression, detected by immunostaining and RT-PCR, was significantly decreased in the brains of knockout compared with wide-type mice. Intracerebroventricular infusion of mouse prorenin increased blood pressure and angiotensin II formation in wild type mice. This hypertensive response was abolished in (pro)renin receptor knockout mice in association with a reduction in angiotensin II levels. Deoxycorticosterone acetate salt increased (pro)renin receptor expression and angiotensin II formation in the brains of wild-type mice, an effect that was attenuated in (pro)renin receptor knockout mice. (Pro)renin receptor knockout in neurons prevented the development of Deoxycorticosterone acetate salt-induced hypertension as well as activation of cardiac and vasomotor sympathetic tone. In conclusion, non-proteolytic activation of prorenin through binding to the PRR mediates angiotensin II formation in the brain. Neuron-specific PRR knockout prevents the development of deoxycorticosterone acetate salt-induced hypertension, possibly through diminished angiotensin II formation. PMID:24246383

Structural Aspects of N-Glycosylations and the C-terminal Region in Human Glypican-1*

PubMed Central

Awad, Wael; Adamczyk, Barbara; Örnros, Jessica; Karlsson, Niclas G.; Mani, Katrin; Logan, Derek T.

2015-01-01

Glypicans are multifunctional cell surface proteoglycans involved in several important cellular signaling pathways. Glypican-1 (Gpc1) is the predominant heparan sulfate proteoglycan in the developing and adult human brain. The two N-linked glycans and the C-terminal domain that attach the core protein to the cell membrane are not resolved in the Gpc1 crystal structure. Therefore, we have studied Gpc1 using crystallography, small angle x-ray scattering, and chromatographic approaches to elucidate the composition, structure, and function of the N-glycans and the C terminus and also the topology of Gpc1 with respect to the membrane. The C terminus is shown to be highly flexible in solution, but it orients the core protein transverse to the membrane, directing a surface evolutionarily conserved in Gpc1 orthologs toward the membrane, where it may interact with signaling molecules and/or membrane receptors on the cell surface, or even the enzymes involved in heparan sulfate substitution in the Golgi apparatus. Furthermore, the N-glycans are shown to extend the protein stability and lifetime by protection against proteolysis and aggregation. PMID:26203194

Addition of N-terminal pro-B natriuretic peptide to soluble fms-like tyrosine kinase-1/placental growth factor ratio > 38 improves prediction of pre-eclampsia requiring delivery within 1 week: a longitudinal cohort study.

PubMed

Sabriá, E; Lequerica-Fernández, P; Lafuente-Ganuza, P; Eguia-Ángeles, E; Escudero, A I; Martínez-Morillo, E; Barceló, C; Álvarez, F V

2018-06-01

Short-term prediction of pre-eclampsia (PE) using the soluble fms-like tyrosine kinase-1 (sFlt-1)/placental growth factor (PlGF) ratio is characterized by frequent false-positive results. As such, no treatment can be recommended to test-positive patients and multiple measurements are often required. The aim of this study was to evaluate the effectiveness of N-terminal pro-B natriuretic peptide (NT-proBNP), uric acid and the sFlt-1/PlGF ratio for prediction of delivery with PE within 1 week in singleton pregnancies with suspected PE and sFlt-1/PlGF ratio > 38. This was a longitudinal prospective cohort study of singleton pregnancies presenting at 24 + 0 to 36 + 6 weeks of gestation with clinically suspected PE and sFlt-1/PlGF ratio > 38, enrolled between January 2015 and June 2017. Multiple samples per patient were allowed but were restricted to one sample per gestational week. From 495 enrolled patients, 270 blood samples from 134 patients were ultimately analyzed. By using generalized estimating equations (GEE), the best-fit model was selected for prediction of delivery with PE within 1 week. The predictive value of this model was then assessed using area under the paired-ROC curve (AUC) analysis. The best-fit model included the sFlt-1/PlGF ratio, NT-proBNP and the gestational week at the time of the measurement. This combined model was compared with the GEE model based on the sFlt-1/PlGF ratio and the gestational week at the time of the measurement (reduced model). The AUC for the combined model was 0.845 (95% CI, 0.787-0.896), which was significantly greater (P = 0.011) than that of the reduced model (0.786 (95% CI, 0.722-0.844)). The addition of NT-proBNP assessment improves the short-term prediction of delivery as a result of PE compared with sFlt-1/PlGF ratio alone, when the sFlt-1/PlGF ratio is > 38. This finding should be considered in future research on the assessment of short-term risk of delivery as a result of PE. Copyright �

A Convenient Approach to Synthesizing Peptide C-Terminal N-Alkyl Amides

PubMed Central

Fang, Wei-Jie; Yakovleva, Tatyana; Aldrich, Jane V.

2014-01-01

Peptide C-terminal N-alkyl amides have gained more attention over the past decade due to their biological properties, including improved pharmacokinetic and pharmacodynamic profiles. However, the synthesis of this type of peptide on solid phase by current available methods can be challenging. Here we report a convenient method to synthesize peptide C-terminal N-alkyl amides using the well-known Fukuyama N-alkylation reaction on a standard resin commonly used for the synthesis of peptide C-terminal primary amides, the PAL-PEG-PS (Peptide Amide Linker-polyethylene glycol-polystyrene) resin. The alkylation and oNBS deprotection were conducted under basic conditions and were therefore compatible with this acid labile resin. The alkylation reaction was very efficient on this resin with a number of different alkyl iodides or bromides, and the synthesis of model enkephalin N-alkyl amide analogs using this method gave consistently high yields and purities, demonstrating the applicability of this methodology. The synthesis of N-alkyl amides was more difficult on a Rink amide resin, especially the coupling of the first amino acid to the N-alkyl amine, resulting in lower yields for loading the first amino acid onto the resin. This method can be widely applied in the synthesis of peptide N-alkyl amides. PMID:22252422

Comparison of copeptin, B-type natriuretic peptide, and amino-terminal pro-B-type natriuretic peptide in patients with chronic heart failure: prediction of death at different stages of the disease.

PubMed

Neuhold, Stephanie; Huelsmann, Martin; Strunk, Guido; Stoiser, Brigitte; Struck, Joachim; Morgenthaler, Nils G; Bergmann, Andreas; Moertl, Deddo; Berger, Rudolf; Pacher, Richard

2008-07-22

This study sought to evaluate the predictive value of copeptin over the entire spectrum of heart failure (HF) and compare it to the current benchmark markers, B-type natriuretic peptide (BNP) and N-terminal pro-B-type natriuretic peptide (NT-proBNP). Vasopressin has been shown to increase with the severity of chronic HF. Copeptin is a fragment of pre-pro-vasopressin that is synthesized and secreted in equimolar amounts to vasopressin. Both hormones have a short lifetime in vivo, similar to BNPs, but in contrast to vasopressin, copeptin is very stable in vitro. The predictive value of copeptin has been shown in advanced HF, where it was superior to BNP for predicting 24-month mortality. This was a long-term observational study in 786 HF patients from the whole spectrum of heart failure (New York Heart Association [NYHA] functional class I to IV, BNP 688 +/- 948 pg/ml [range 3 to 8,536 pg/ml], left ventricular ejection fraction 25 +/- 10% [range 5% to 65%]). The NYHA functional class was the most potent single predictor of 24-month outcome in a stepwise Cox regression model. The BNP, copeptin, and glomerular filtration rate were related to NYHA functional class (p < 0.0001 for trend). Copeptin was the most potent single predictor of mortality in patients with NYHA functional class II (p < 0.0001) and class III (p < 0.0001). In NYHA functional class IV, the outcome of patients was best predicted by serum sodium, but again, copeptin added additional independent information. Increased levels of copeptin are linked to excess mortality, and this link is maintained irrespective of the clinical signs of severity of the disease. Copeptin was superior to BNP or NT-proBNP in this study, but the markers seem to be closely related.

N-terminal B-type natriuretic peptide concentrations are similarly increased by 30 minutes of moderate and brisk walking in patients with coronary artery disease.

PubMed

Scharhag, Jürgen; Herrmann, Markus; Weissinger, Melanie; Herrmann, Wolfgang; Kindermann, Wilfried

2007-04-01

Elevated concentrations of B-type natriuretic peptide (BNP) and N-terminal pro- BNP (NT-proBNP) reflect elevated myocardial wall stress due to volume or pressure overload in cardiac disease. Recently, exercise-induced elevations of (NT-pro)BNP in coronary artery disease (CAD) patients have been reported to result from exercise-induced ischemia associated regional wall abnormalities. Therefore, the study aimed to examine NT-proBNP concentrations in patients with CAD after moderate and brisk walking (MW, BW). We hypothesized that BW induces higher increases than MW. In randomized order 14 patients with stable CAD (12 male symbol/2 female symbol; 63 +/- 9 years; LV ejection fraction: 59+/-9%) of a out-patient rehabilitation group performed MW with 4.5 +/- 0.6 km/h (mean heart rate: 80 +/- 11/min) or BWat their allowed upper exercise heart rate of 102+/-9/min with a speed of 6.2 +/- 0.6 km/h for 30 min on a tartan track on two separate days. Blood samples were taken before, immediately, 1 h, 3 h and 1 day after exercise to determine NT-proBNP and cardiac troponin T (cTnT). Echocardiographic LV function was determined before and 1 h after exercise. Median concentrations of NT-proBNP significantly increased from 222 to 295 ng/l (MW) and from 222 to 296 ng/l (BW) without a difference between both modalities. cTnT remained below the detection limit of 0.01 microg/l. LV functions remained unchanged. A cutoff level of 250 ng/l distinguished CAD patients with elevated exercise-induced increases in NT-proBNP and a diminished LV ejection fraction at rest. BW and MW induce similar increases in NT-proBNP in CAD patients without myocardial damage, which have to be considered when NT-proBNP is determined. Derived from the exercise- induced increase in NTproBNP, the myocardial strain in BW is not elevated in comparison to MW.

Brain natriuretic peptide: Much more than a biomarker.

PubMed

Calzetta, Luigino; Orlandi, Augusto; Page, Clive; Rogliani, Paola; Rinaldi, Barbara; Rosano, Giuseppe; Cazzola, Mario; Matera, Maria Gabriella

2016-10-15

Brain natriuretic peptide (BNP) modulates several biological processes by activating the natriuretic peptide receptor A (NPR-A). Atria and ventricles secrete BNP. BNP increases natriuresis, diuresis and vasodilatation, thus resulting in a decreased cardiac workload. BNP and NT-proBNP, which is the biologically inactive N-terminal portion of its pro-hormone, are fast and sensitive biomarkers for diagnosing heart failure. The plasma concentrations of both BNP and NT-proBNP also correlate with left ventricular function in patients with acute exacerbation of COPD, even without history of heart failure. Several studies have been conducted in vitro and in vivo, both in animals and in humans, in order to assess the potential role of the NPR-A activation as a novel therapeutic approach for treating obstructive pulmonary disorders. Unfortunately, these studies have yielded conflicting results. Nevertheless, further recent specific studies, performed in ex vivo models of asthma and COPD, have confirmed the bronchorelaxant effect of BNP and its protective role against bronchial hyperresponsiveness in human airways. These studies have also clarified the intimate mechanism of action of BNP, represented by an autocrine loop elicited by the activation of NPR-A, localized on bronchial epithelium, and the relaxant response of the surrounding ASM, which does not expresses NPR-A. This review explores the teleological activities and paradoxical effects of BNP with regard to chronic obstructive respiratory disorders, and provides an excursus on the main scientific findings that explain why BNP should be considered much more than a biomarker. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Involvement of the N-terminal region in alpha-crystallin-lens membrane recognition

NASA Technical Reports Server (NTRS)

Ifeanyi, F.; Takemoto, L.; Spooner, B. S. (Principal Investigator)

1991-01-01

Previous studies have demonstrated that alpha-crystallin binds specifically, in a saturable manner, to lens membrane. To determine the region of the alpha-crystallin molecule that might be involved in this binding, native alpha-crystallin from the bovine lens has been treated by limited digestion with trypsin, to produce alpha-A molecules with an intact C-terminal region, and a nicked N-terminal region. Compared to intact alpha-crystallin, trypsin-treated alpha-crystallin binds less avidly to lens membrane, suggesting that the N-terminal region of the alpha-A molecule may play a key role in the recognition between lens membrane and crystallin.

In-Operando Spatial Imaging of Edge Termination Electric Fields in GaN Vertical p-n Junction Diodes

DOE PAGES

Leonard, Francois; Dickerson, J. R.; King, M. P.; ...

2016-05-03

Control of electric fields with edge terminations is critical to maximize the performance of high-power electronic devices. We proposed a variety of edge termination designs which makes the optimization of such designs challenging due to many parameters that impact their effectiveness. And while modeling has recently allowed new insight into the detailed workings of edge terminations, the experimental verification of the design effectiveness is usually done through indirect means, such as the impact on breakdown voltages. In this letter, we use scanning photocurrent microscopy to spatially map the electric fields in vertical GaN p-n junction diodes in operando. We alsomore » reveal the complex behavior of seemingly simple edge termination designs, and show how the device breakdown voltage correlates with the electric field behavior. Modeling suggests that an incomplete compensation of the p-type layer in the edge termination creates a bilayer structure that leads to these effects, with variations that significantly impact the breakdown voltage.« less

Releasing N-glycan from peptide N-terminus by N-terminal succinylation assisted enzymatic deglycosylation.

PubMed

Weng, Yejing; Sui, Zhigang; Jiang, Hao; Shan, Yichu; Chen, Lingfan; Zhang, Shen; Zhang, Lihua; Zhang, Yukui

2015-04-22

Due to the important roles of N-glycoproteins in various biological processes, the global N-glycoproteome analysis has been paid much attention. However, by current strategies for N-glycoproteome profiling, peptides with glycosylated Asn at N-terminus (PGANs), generated by protease digestion, could hardly be identified, due to the poor deglycosylation capacity by enzymes. However, theoretically, PGANs occupy 10% of N-glycopeptides in the typical tryptic digests. Therefore, in this study, we developed a novel strategy to identify PGANs by releasing N-glycans through the N-terminal site-selective succinylation assisted enzymatic deglycosylation. The obtained PGANs information is beneficial to not only achieve the deep coverage analysis of glycoproteomes, but also discover the new biological functions of such modification.

Molecular basis for subtype-specificity and high-affinity zinc inhibition in the GluN1-GluN2A NMDA receptor amino terminal domain

PubMed Central

Romero-Hernandez, Annabel; Simorowski, Noriko; Karakas, Erkan

2016-01-01

Summary Zinc is vastly present in the mammalian brain and controls functions of various cell surface receptors to regulate neurotransmission. A distinctive characteristic of N-methyl-D-aspartate (NMDA) receptors containing a GluN2A subunit is that their ion channel activity is allosterically inhibited by a nano-molar concentration of zinc that binds to an extracellular domain called an amino terminal domain (ATD). Despite physiological importance, the molecular mechanism underlying the high-affinity zinc inhibition has been incomplete due to lack of a GluN2A ATD structure. Here we show the first crystal structures of the heterodimeric GluN1-GluN2A ATD, which provide the complete map of the high-affinity zinc binding site and reveals distinctive features from the ATD of the GluN1-GluN2B subtype. Perturbation of hydrogen bond networks at the hinge of the GluN2A bi-lobe structure affects both zinc inhibition and open probability supporting the general model where the bi-lobe motion in ATD regulates the channel activity in NMDA receptors. PMID:27916457

The N-Terminal Residues 43 to 60 Form the Interface for Dopamine Mediated α-Synuclein Dimerisation

PubMed Central

Leong, Su Ling; Hinds, Mark G.; Connor, Andrea R.; Smith, David P.; Illes-Toth, Eva; Pham, Chi L. L.; Barnham, Kevin J.; Cappai, Roberto

2015-01-01

α-synuclein (α-syn) is a major component of the intracellular inclusions called Lewy bodies, which are a key pathological feature in the brains of Parkinson’s disease patients. The neurotransmitter dopamine (DA) inhibits the fibrillisation of α-syn into amyloid, and promotes α-syn aggregation into SDS-stable soluble oligomers. While this inhibition of amyloid formation requires the oxidation of both DA and the methionines in α-syn, the molecular basis for these processes is still unclear. This study sought to define the protein sequences required for the generation of oligomers. We tested N- (α-syn residues 43–140) and C-terminally (1–95) truncated α-syn, and found that similar to full-length protein both truncated species formed soluble DA:α-syn oligomers, albeit 1–95 had a different profile. Using nuclear magnetic resonance (NMR), and the N-terminally truncated α-syn 43–140 protein, we analysed the structural characteristics of the DA:α-syn 43–140 dimer and α-syn 43–140 monomer and found the dimerisation interface encompassed residues 43 to 60. Narrowing the interface to this small region will help define the mechanism by which DA mediates the formation of SDS-stable soluble DA:α-syn oligomers. PMID:25679387

14 CFR 1214.806 - Premature termination of Spacelab flights.

Code of Federal Regulations, 2011 CFR

2011-01-01

... dedicated-Shuttle Spacelab flight, a dedicated-pallet flight, or dedicated-FMDM/MPESS flight is prematurely terminated, NASA shall refund the optional services charges for planned, but unused, extra days on orbit. If a complete-pallet or shared-element flight is prematurely terminated, NASA shall refund a pro rata...

14 CFR 1214.806 - Premature termination of Spacelab flights.

Code of Federal Regulations, 2013 CFR

2013-01-01

... dedicated-Shuttle Spacelab flight, a dedicated-pallet flight, or dedicated-FMDM/MPESS flight is prematurely terminated, NASA shall refund the optional services charges for planned, but unused, extra days on orbit. If a complete-pallet or shared-element flight is prematurely terminated, NASA shall refund a pro rata...

14 CFR 1214.806 - Premature termination of Spacelab flights.

Code of Federal Regulations, 2012 CFR

2012-01-01

... dedicated-Shuttle Spacelab flight, a dedicated-pallet flight, or dedicated-FMDM/MPESS flight is prematurely terminated, NASA shall refund the optional services charges for planned, but unused, extra days on orbit. If a complete-pallet or shared-element flight is prematurely terminated, NASA shall refund a pro rata...

14 CFR 1214.806 - Premature termination of Spacelab flights.

Code of Federal Regulations, 2010 CFR

2010-01-01

... dedicated-Shuttle Spacelab flight, a dedicated-pallet flight, or dedicated-FMDM/MPESS flight is prematurely terminated, NASA shall refund the optional services charges for planned, but unused, extra days on orbit. If a complete-pallet or shared-element flight is prematurely terminated, NASA shall refund a pro rata...

Pro-neurotensin/neuromedin N expression and processing in human colon cancer cell lines.

PubMed

Rovère, C; Barbero, P; Maoret, J J; Laburthe, M; Kitabgi, P

1998-05-08

The regulatory peptide neurotensin NT has been proposed to exert an autocrine trophic effect on human colon cancers. In the present study, pro-neurotensin/neuromedin N (proNT/NN) expression and processing were investigated in 13 human colon cancer cell lines using a combination of radioimmunoassay and HPLC techniques. All 13 cell lines displayed low to moderate levels of proNT/NN ranging from 10 to 250 fmol/mg protein. However, only 6 (HCT8, LoVo, HT29, C119A, LS174T, and coloDM320) processed the precursor. Three of the latter (HCT8, LS174T, and coloDM320) were analysed in detail with regard to proNT/NN processing pattern and were found to produce NT and large precursor fragments ending with the NT or NN sequence. They had no detectable level of NN. Such a processing pattern resembles that generated by the prohormone convertase PC5. Northern and Western blot analysis of prohormone convertase expression in the 3 cell lines revealed that they were devoid of PC1 and PC2, whereas they all expressed PC5. These data indicate that proNT/NN is a good marker of human colon cancer cell lines while NT is found in only about half of the cell lines. They also suggest that, in addition to NT, several proNT/NN-derived products, possibly generated by PC5, might exert an autocrine positive effect on human colon cancer growth.

Active uptake of substance P carboxy-terminal heptapeptide (5-11) into rat brain and rabbit spinal cord slices.

PubMed

Nakata, Y; Kusaka, Y; Yajima, H; Segawa, T

1981-12-01

We previously reported that nerve terminals and glial cells lack an active uptake system capable of terminating transmitter action of substance P (SP). In the present study, we demonstrated the existence of an active uptake system for SP carboxy-terminal heptapeptide, (5-11)SP. When the slices from either rat brain or rabbit spinal cord were incubated with [3H](5-11)SP, the uptake of (5-11)SP into slices was observed. The uptake system has the properties of an active transport mechanism: it is dependent on temperature and sensitive to hypoosmotic treatment and is inhibited by ouabain and dinitrophenol (DNP). In the brain, (5-11)SP was accumulated by means of a high-affinity and a low-affinity uptake system. The Km and the Vmax values for the high-affinity system were 4.20 x 10(-8) M and 7.59 fmol/10 mg wet weight/min, respectively, whereas these values for the low-affinity system were 1.00 x 10(-6) M and 100 fmol/10 mg wet weight/min, respectively. In the spinal cord, there was only one uptake system, with a Km value of 2.16 x 10(-7) M and Vmax value of 26.2 fmol/10 mg wet weight/min. These results suggest that when SP is released from nerve terminals, it is hydrolysed into (5-11)SP before or after acting as a neurotransmitter, which is in turn accumulated into nerve terminals. Therefore, the uptake system may represent a possible mechanism for the inactivation of SP.

Brain BLAQ: Post-hoc thick-section histochemistry for localizing optogenetic constructs in neurons and their distal terminals

PubMed Central

Kupferschmidt, David A.; Cody, Patrick A.; Lovinger, David M.; Davis, Margaret I.

2015-01-01

Optogenetic constructs have revolutionized modern neuroscience, but the ability to accurately and efficiently assess their expression in the brain and associate it with prior functional measures remains a challenge. High-resolution imaging of thick, fixed brain sections would make such post-hoc assessment and association possible; however, thick sections often display autofluorescence that limits their compatibility with fluorescence microscopy. We describe and evaluate a method we call “Brain BLAQ” (Block Lipids and Aldehyde Quench) to rapidly reduce autofluorescence in thick brain sections, enabling efficient axon-level imaging of neurons and their processes in conventional tissue preparations using standard epifluorescence microscopy. Following viral-mediated transduction of optogenetic constructs and fluorescent proteins in mouse cortical pyramidal and dopaminergic neurons, we used BLAQ to assess innervation patterns in the striatum, a region in which autofluorescence often obscures the imaging of fine neural processes. After BLAQ treatment of 250–350 μm-thick brain sections, axons and puncta of labeled afferents were visible throughout the striatum using a standard epifluorescence stereomicroscope. BLAQ histochemistry confirmed that motor cortex (M1) projections preferentially innervated the matrix component of lateral striatum, whereas medial prefrontal cortex projections terminated largely in dorsal striosomes and distinct nucleus accumbens subregions. Ventral tegmental area dopaminergic projections terminated in a similarly heterogeneous pattern within nucleus accumbens and ventral striatum. Using a minimal number of easily manipulated and visualized sections, and microscopes available in most neuroscience laboratories, BLAQ enables simple, high-resolution assessment of virally transduced optogenetic construct expression, and post-hoc association of this expression with molecular markers, physiology and behavior. PMID:25698938

Prodomain–growth factor swapping in the structure of pro-TGF-β1

PubMed Central

Xu, Shutong; Dong, Xianchi; Lu, Chafen; Springer, Timothy A.

2018-01-01

TGF-β is synthesized as a proprotein that dimerizes in the endoplasmic reticulum. After processing in the Golgi to cleave the N-terminal prodomain from the C-terminal growth factor (GF) domain in each monomer, pro-TGF-β is secreted and stored in latent complexes. It is unclear which prodomain and GF monomer are linked before proprotein convertase cleavage and how much conformational change occurs following cleavage. We have determined a structure of pro-TGF-β1 with the proprotein convertase cleavage site mutated to mimic the structure of the TGF-β1 proprotein. Structure, mutation, and model building demonstrate that the prodomain arm domain in one monomer is linked to the GF that interacts with the arm domain in the other monomer in the dimeric structure (i.e. the prodomain arm domain and GF domain in each monomer are swapped). Swapping has important implications for the mechanism of biosynthesis in the TGF-β family and is relevant to the mechanism for preferential formation of heterodimers over homodimers for some members of the TGF-β family. Our structure, together with two previous ones, also provides insights into which regions of the prodomain–GF complex are highly structurally conserved and which are perturbed by crystal lattice contacts. PMID:29109152

Molecular dynamics simulations of trans- and cis- N-acetyl- N'-methylamides of XaaPro dipeptides

NASA Astrophysics Data System (ADS)

Hoon Choi, Seung; Yun Yu, Jeong; Kwang Shin, Jae; Shik Jhon, Mu

1994-07-01

The occurrence of cis imide bonds in proteins is much higher than that of cis amide bonds due to the unique properties of proline. In order to examine the relationship between the high occurrence of these cis imide bonds and the residues preceding the proline, we perform molecular dynamics simulations of trans- and cis- N-acetyl- N'-methylamides of XaaPro dipeptides (AcXaaProNHMe). We investigate the conformational energies and structures of trans- and cis-AcXaa where Xaa has 12 amino acids in the vacuum state and 5 amino acids in the solution state. It is found that the occurrence of the cis imide bonds is strongly affected by the residue preceding the proline, and the dihedral angles (φ,ψ) of the backbone in AcXaaProNHMe are influenced by the configuration of the imide bond. We also find that the equilibrium properties of XaaPro in solution simulations are more similar to the statistics of X-ray crystallographic data than are those in vacuum simulations and solvation causes a remarkable change in the conformation of the pyrrolidine ring from the endo to the exo form.

Evidence for ProTα-TLR4/MD-2 binding: molecular dynamics and gravimetric assay studies.

PubMed

Omotuyi, Olaposi; Matsunaga, Hayato; Ueda, Hiroshi

2015-01-01

During preconditioning, lipopolysaccharide (LPS) selectively activates TLR4/MD-2/Toll/IL-1 receptor-domain-containing adaptor inducing IFN-β (TRIF) pathway instead of pro-inflammatory myeloid differentiation protein-88 (MyD88)/MyD88-adaptor-like protein (MAL) pathway. Extracellular prothymosin alpha (ProTα) is also known to selectively activate the TLR4/MD2/TRIF-IRF3 pathway in certain diseased conditions. In the current study, biophysical evidence for ProTα/TLR4/MD-2 complex formation and its interaction dynamics have been studied. Gravimetric assay was used to investigate ProTα/TLR4/MD-2 complex formation while molecular dynamics (MD) simulation was used to study its interaction dynamics. Through electrostatic interaction, full-length ProTα (F-ProTα) C-terminal peptide (aa 91 - 111) superficially interacts with similar TLR4/MD-2 (KD = 273.36 nm vs 16.07 μg/ml [LPS]) conformation with LPS at an overlapping three-dimensional space while F-ProTα is hinged to the TLR4 scaffold by one-amino acid shift-Mosoian domain (aa-51 - 90). Comparatively, F-ProTα better stabilizes MD-2 metastable states transition and mediates higher TLR4/MD-2 interaction than LPS. ProTα via its C-terminal peptide (aa 91 - 111) exhibits in vitro biophysical contact with TLR4/MD-2 complex conformation recognized by LPS at overlapping LPS-binding positions.

c-jun-N-Terminal Kinase (JNK) for the Treatment of Amyotrophic Lateral Sclerosis

DTIC Science & Technology

2014-10-01

AWARD NUMBER: W81XWH-12-1-0431 TITLE: “c-jun-N-Terminal Kinase (JNK) for the Treatment of Amyotrophic Lateral Sclerosis ” PRINCIPAL INVESTIGATOR...TITLE AND SUBTITLE “c-jun-N-Terminal Kinase (JNK) for the Treatment of Amyotrophic Lateral Scelerosis” 5a. CONTRACT NUMBER 5b. GRANT NUMBER W81XWH

Characterization of an extensin-modifying metalloprotease: N-terminal processing and substrate cleavage pattern of Pectobacterium carotovorum Prt1.

PubMed

Feng, Tao; Nyffenegger, Christian; Højrup, Peter; Vidal-Melgosa, Silvia; Yan, Kok-Phen; Fangel, Jonatan Ulrik; Meyer, Anne S; Kirpekar, Finn; Willats, William G; Mikkelsen, Jørn D

2014-12-01

Compared to other plant cell wall-degrading enzymes, proteases are less well understood. In this study, the extracellular metalloprotease Prt1 from Pectobacterium carotovorum (formerly Erwinia carotovora) was expressed in Escherichia coli and characterized with respect to N-terminal processing, thermal stability, substrate targets, and cleavage patterns. Prt1 is an autoprocessing protease with an N-terminal signal pre-peptide and a pro-peptide which has to be removed in order to activate the protease. The sequential cleavage of the N-terminus was confirmed by mass spectrometry (MS) fingerprinting and N-terminus analysis. The optimal reaction conditions for the activity of Prt1 on azocasein were at pH 6.0, 50 °C. At these reaction conditions, K M was 1.81 mg/mL and k cat was 1.82 × 10(7) U M(-1). The enzyme was relatively stable at 50 °C with a half-life of 20 min. Ethylenediaminetetraacetic acid (EDTA) treatment abolished activity; Zn(2+) addition caused regain of the activity, but Zn(2+)addition decreased the thermal stability of the Prt1 enzyme presumably as a result of increased proteolytic autolysis. In addition to casein, the enzyme catalyzed degradation of collagen, potato lectin, and plant extensin. Analysis of the cleavage pattern of different substrates after treatment with Prt1 indicated that the protease had a substrate cleavage preference for proline in substrate residue position P1 followed by a hydrophobic residue in residue position P1' at the cleavage point. The activity of Prt1 against plant cell wall structural proteins suggests that this enzyme might become an important new addition to the toolbox of cell-wall-degrading enzymes for biomass processing.

Head-to-head comparison of B-type natriuretic peptide (BNP) and NT-proBNP in daily clinical practice.

PubMed

Mair, Johannes; Gerda, Falkensammer; Renate, Hiemetzberger; Ulmer, Hanno; Andrea, Griesmacher; Pachinger, Otmar

2008-02-29

B-type natriuretic peptide (BNP; Abbott Diagnostics) and N-terminal proBNP (NT-proBNP, Roche Diagnostics) were compared in consecutive samples of 458 patients (mean age 60 years+/-16 years; 159 female, 299 male) sent for NT-proBNP measurement to investigate influences on both markers. BNP and NT-proBNP showed a close correlation with each other (r=0.89, p<0.0001). Using age- and gender-adjusted upper reference values the inter-rater agreement of both parameters was satisfactory (83%, Cohen's kappa coefficient=0.7). The combination of normal BNP and elevated NT-proBNP was significantly more frequent than vice versa (61 vs. 16 patients), and a calculated glomerular filtration rate<60 ml/min/1.73 m(2) was found in 39% of these patients. Multiple linear regression analysis revealed a significant influence of a reduced ejection fraction (<50%), renal dysfunction (calculated glomerular filtration rate<60 ml/min/1.73 m(2)), anemia, hypertension, age, and gender on both BNP and NT-proBNP. In conclusion, despite a close correlation and a satisfactory agreement between both markers in classification, frequent discrepancies in individual patients demonstrate that both markers are clinically not completely equivalent.

N-linked oligosaccharides on the low density lipoprotein receptor homolog SorLA/LR11 are modified with terminal GalNAc-4-SO4 in kidney and brain.

PubMed

Fiete, Dorothy; Mi, Yiling; Oats, Edward L; Beranek, Mary C; Baenziger, Jacques U

2007-01-19

Sorting protein-related receptor (SorLA/LR11) is a highly conserved mosaic receptor that is expressed by cells in a number of different tissues including principal cells of the collecting ducts in the kidney and neurons in the central and peripheral nervous systems. SorLA/LR11 has features that indicate it serves as a sorting receptor shuttling between the plasma membrane, endosomes, and the Golgi. We have found that a fraction of SorLA/LR11 that is synthesized in the kidney and the brain bears N-linked oligosaccharides that are modified with terminal beta1,4-linked GalNAc-4-SO(4). Oligosaccharides located in the vacuolar sorting (Vps) 10p domain (Vps10p domain) are modified with beta1,4-linked GalNAc when the Vps10p domain is expressed in cells along with either of two recently cloned protein-specific beta1,4GalNAc-transferases, GalNAcTIII and GalNAcTIV. Either of two sequences with basic amino acids located within the Vps10p domain is able to mediate recognition by these beta1,4GalNAc-transferases. The highly specific modification of oligosaccharides in the Vps10p domain of SorLA/LR11 with terminal GalNAc-4-SO(4) suggests that this unusual modification may modulate the interaction of SorLA/LR11 with proteins and influence their trafficking.

Hsp90 N- and C-terminal double inhibition synergistically suppresses Bcr-Abl-positive human leukemia cells

PubMed Central

Chen, Xianling; Chen, Xiaole; Li, Ding; Fan, Yingjuan; Xu, Jianhua; Chen, Yuanzhong; Wu, Lixian

2017-01-01

Heat shock protein 90 (Hsp90) contains amino (N)–terminal domain, carboxyl(C)-terminal domain, and middle domains, which activate Hsp90 chaperone function cooperatively in tumor cells. One terminal occupancy might influence another terminal binding with inhibitor. The Bcr-Abl kinase is one of the Hsp90 clients implicated in the pathogenesis of chronic myeloid leukemia (CML). Present studies demonstrate that double inhibition of the N- and C-terminal termini can disrupt Hsp90 chaperone function synergistically, but not antagonistically, in Bcr-Abl-positive human leukemia cells. Furthermore, both the N-terminal inhibitor 17-AAG and the C-terminal inhibitor cisplatin (CP) have the capacity to suppress progenitor cells; however, only CP is able to inhibit leukemia stem cells (LSCs) significantly, which implies that the combinational treatment is able to suppress human leukemia in different mature states. PMID:28036294

A C69-family cysteine dipeptidase from Lactobacillus farciminis JCM1097 possesses strong Gly-Pro hydrolytic activity.

PubMed

Sakamoto, Takuma; Otokawa, Takuya; Kono, Ryosuke; Shigeri, Yasushi; Watanabe, Kunihiko

2013-11-01

Dipeptide Gly-Pro, a hard-to-degrade and collagenous peptide, is thought to be hydrolysed by prolidases that can work on various X-Pro dipeptides. Here, we found an entirely different type of dipeptidase from Lactobacillus farciminis JCM1097 that cleaves Gly-Pro far more efficiently and with higher specificity than prolidases, and then investigated its properties by use of a recombinant enzyme. Although L. farciminis dipeptidase was expressed in the form of an inclusion body in Escherichia coli at 37 °C, it was smoothly over-expressed in a soluble form at a lower temperature. The maximal Gly-Pro hydrolytic activity was attained in E. coli at 30 °C. In contrast to prolidases that are metallopeptidases showing the modest or marginal activity toward Gly-Pro, this L. farciminis dipeptidase belongs to the cysteine peptidase family C69. Lactobacillus farciminis dipeptidase occurs in cytoplasm and utilizes the side chain of an amino-terminal cysteine residue to perform the nucleophilic attack on the target amide bond between Gly-Pro after processing eight amino acid residues at the N-terminus. Furthermore, L. farciminis dipeptidase is potent enough to synthesize Gly-Pro from Gly and Pro by a reverse reaction. These novel properties could be revealed by virtue of the success in preparing recombinant enzymes in higher yield and in a stable form.

The diagnostic value of plasma N-terminal connective tissue growth factor levels in children with heart failure.

PubMed

Li, Gang; Song, Xueqing; Xia, Jiyi; Li, Jing; Jia, Peng; Chen, Pengyuan; Zhao, Jian; Liu, Bin

2017-01-01

The aim of this study was to assess the diagnostic value of plasma N-terminal connective tissue growth factor in children with heart failure. Methods and results Plasma N-terminal connective tissue growth factor was determined in 61 children, including 41 children with heart failure, 20 children without heart failure, and 30 healthy volunteers. The correlations between plasma N-terminal connective tissue growth factor levels and clinical parameters were investigated. Moreover, the diagnostic value of N-terminal connective tissue growth factor levels was evaluated. Compared with healthy volunteers and children without heart failure, plasma N-terminal connective tissue growth factor levels were significantly elevated in those with heart failure (p0.05), but it obviously improved the ability of diagnosing heart failure in children, as demonstrated by the integrated discrimination improvement (6.2%, p=0.013) and net re-classification improvement (13.2%, p=0.017) indices. Plasma N-terminal connective tissue growth factor is a promising diagnostic biomarker for heart failure in children.

NT-proBNP and exercise capacity in adult patients with congenital heart disease and a prosthetic valve: a multicentre PROSTAVA study.

PubMed

Schoonbeek, R C; Pieper, P G; van Slooten, Y J; Freling, H G; Sieswerda, G T; van Dijk, A P J; Jongbloed, M R M; Post, M C; Bouma, B J; Berger, R M F; Ebels, T; van Melle, J P

2016-11-01

N-terminal B‑type natriuretic peptide (NT-proBNP) is an important biomarker for the detection of heart failure. Adults with congenital heart disease (ACHD) and a prosthetic heart valve are at risk for heart failure. This study aimed to determine the value of NT-proBNP in ACHD patients with a prosthetic valve and investigate its relationship with cardiac function and exercise capacity. In this multi-centre cross-sectional observational study, data regarding medical history, echocardiography, exercise testing (VO 2 peak) and laboratory blood evaluation (including NT-proBNP) were collected in ACHD patients with a single prosthetic valve (either homografts, heterografts or mechanical valves). A total of 306 ACHD patients with pulmonary valve replacement (PVR, n = 139), aortic valve replacement (n = 141), mitral valve replacement (n = 21) or tricuspid valve replacement (n = 5) were investigated. The majority of patients (77 %) were in NYHA class I or II. Elevated NT-proBNP levels (cut-off ≥125 pg/ml) were found in 50 % of the patients, with the highest levels in patients with mitral valve replacements. In this study population, NT-proBNP levels were associated with gender (p = 0.029) and VO 2 max (p < 0.001). In PVR patients, NT-proBNP levels were associated with lower VO 2 peak, also after adjustment for age, gender and age at valve replacement in a multivariate model (p = 0.015). In patients with ACHD and a prosthetic valve, elevated NT-proBNP levels are frequently observed despite preserved NYHA class. In PVR patients, a higher NT-proBNP level was associated with a lower VO 2 peak. These results may be of importance in the ongoing discussion about the timing of valve replacement in patients with CHD.

14 CFR § 1214.806 - Premature termination of Spacelab flights.

Code of Federal Regulations, 2014 CFR

2014-01-01

.... If a dedicated-Shuttle Spacelab flight, a dedicated-pallet flight, or dedicated-FMDM/MPESS flight is prematurely terminated, NASA shall refund the optional services charges for planned, but unused, extra days on orbit. If a complete-pallet or shared-element flight is prematurely terminated, NASA shall refund a pro...

Altering the N-terminal arms of the polymerase manager protein UmuD modulates protein interactions.

PubMed

Murison, David A; Ollivierre, Jaylene N; Huang, Qiuying; Budil, David E; Beuning, Penny J

2017-01-01

Escherichia coli cells that are exposed to DNA damaging agents invoke the SOS response that involves expression of the umuD gene products, along with more than 50 other genes. Full-length UmuD is expressed as a 139-amino-acid protein, which eventually cleaves its N-terminal 24 amino acids to form UmuD'. The N-terminal arms of UmuD are dynamic and contain recognition sites for multiple partner proteins. Cleavage of UmuD to UmuD' dramatically affects the function of the protein and activates UmuC for translesion synthesis (TLS) by forming DNA Polymerase V. To probe the roles of the N-terminal arms in the cellular functions of the umuD gene products, we constructed additional N-terminal truncated versions of UmuD: UmuD 8 (UmuD Δ1-7) and UmuD 18 (UmuD Δ1-17). We found that the loss of just the N-terminal seven (7) amino acids of UmuD results in changes in conformation of the N-terminal arms, as determined by electron paramagnetic resonance spectroscopy with site-directed spin labeling. UmuD 8 is cleaved as efficiently as full-length UmuD in vitro and in vivo, but expression of a plasmid-borne non-cleavable variant of UmuD 8 causes hypersensitivity to UV irradiation, which we determined is the result of a copy-number effect. UmuD 18 does not cleave to form UmuD', but confers resistance to UV radiation. Moreover, removal of the N-terminal seven residues of UmuD maintained its interactions with the alpha polymerase subunit of DNA polymerase III as well as its ability to disrupt interactions between alpha and the beta processivity clamp, whereas deletion of the N-terminal 17 residues resulted in decreases in binding to alpha and in the ability to disrupt the alpha-beta interaction. We find that UmuD 8 mimics full-length UmuD in many respects, whereas UmuD 18 lacks a number of functions characteristic of UmuD.

Apolipoprotein CIII and N-terminal prohormone b-type natriuretic peptide as independent predictors for cardiovascular disease in type 2 diabetes.

PubMed

Colombo, Marco; Looker, Helen C; Farran, Bassam; Agakov, Felix; Brosnan, M Julia; Welsh, Paul; Sattar, Naveed; Livingstone, Shona; Durrington, Paul N; Betteridge, D John; McKeigue, Paul M; Colhoun, Helen M

2018-05-21

Developing sparse panels of biomarkers for cardiovascular disease in type 2 diabetes would enable risk stratification for clinical decision making and selection into clinical trials. We examined the individual and joint performance of five candidate biomarkers for incident cardiovascular disease (CVD) in type 2 diabetes that an earlier discovery study had yielded. Apolipoprotein CIII (apoCIII), N-terminal prohormone B-type natriuretic peptide (NT-proBNP), high sensitivity Troponin T (hsTnT), Interleukin-6, and Interleukin-15 were measured in baseline serum samples from the Collaborative Atorvastatin Diabetes trial (CARDS) of atorvastatin versus placebo. Among 2105 persons with type 2 diabetes and median age of 62.9 years (range 39.2-77.3), there were 144 incident CVD (acute coronary heart disease or stroke) cases during the maximum 5-year follow up. We used Cox Proportional Hazards models to identify biomarkers associated with incident CVD and the area under the receiver operating characteristic curves (AUROC) to assess overall model prediction. Three of the biomarkers were singly associated with incident CVD independently of other risk factors; NT-proBNP (Hazard Ratio per standardised unit 2.02, 95% Confidence Interval [CI] 1.63, 2.50), apoCIII (1.34, 95% CI 1.12, 1.60) and hsTnT (1.40, 95% CI 1.16, 1.69). When combined in a single model, only NT-proBNP and apoCIII were independent predictors of CVD, together increasing the AUROC using Framingham risk variables from 0.661 to 0.745. The biomarkers NT-proBNP and apoCIII substantially increment the prediction of CVD in type 2 diabetes beyond that obtained with the variables used in the Framingham risk score. Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.

NT-pro-BNP predicts worsening renal function in patients with chronic systolic heart failure.

PubMed

Pfister, R; Müller-Ehmsen, J; Hagemeister, J; Hellmich, M; Erdmann, E; Schneider, C A

2011-06-01

Worsening renal function (WRF) is frequently observed in patients with heart failure and is associated with worse outcome. The aim of this study was to examine the association of the cardiac serum marker N-terminal pro-B-type natriuretic peptide (NT-pro-BNP) and WRF. A total of 125 consecutive patients of a tertiary care outpatient clinic for heart failure prospectively underwent evaluation of renal function every 6 months. The association of baseline NT-pro-BNP with WRF was analysed during a follow up of 18 months. Twenty-eight (22.4%) patients developed WRF (increase in serum creatinine ≥0.3 mg/dL). Patients with WRF (2870 pg/mL, interquartile range (IQR) 1063-4765) had significantly higher baseline NT-pro-BNP values than patients without WRF (547 pg/mL, IQR 173-1454). The risk for WRF increased by 4.0 (95% CI 2.1-7.5) for each standard deviation of log NT-pro-BNP. In multivariable analysis including age, baseline renal function, ejection fraction, New York Heart Association class and diuretic dose, only NT-pro-BNP and diabetes were independent predictors of WRF. At a cut-off level of 696 pg/mL, NT-pro-BNP showed a sensitivity of 92.9% and a negative predictive value of 96.4% for WRF. NT-pro-BNP is a strong independent predictor of WRF within 18 months in patients with systolic heart failure with a high negative predictive value. Further studies are needed to evaluate reno-protective strategies in patients with elevated NT-pro-BNP. © 2011 The Authors. Internal Medicine Journal © 2011 Royal Australasian College of Physicians.

Role of B-Type Natriuretic Peptide and N-Terminal Prohormone BNP as Predictors of Cardiovascular Morbidity and Mortality in Patients With a Recent Coronary Event and Type 2 Diabetes Mellitus.

PubMed

Wolsk, Emil; Claggett, Brian; Pfeffer, Marc A; Diaz, Rafael; Dickstein, Kenneth; Gerstein, Hertzel C; Lawson, Francesca C; Lewis, Eldrin F; Maggioni, Aldo P; McMurray, John J V; Probstfield, Jeffrey L; Riddle, Matthew C; Solomon, Scott D; Tardif, Jean-Claude; Køber, Lars

2017-05-29

Natriuretic peptides are recognized as important predictors of cardiovascular events in patients with heart failure, but less is known about their prognostic importance in patients with acute coronary syndrome. We sought to determine whether B-type natriuretic peptide (BNP) and N-terminal prohormone B-type natriuretic peptide (NT-proBNP) could enhance risk prediction of a broad range of cardiovascular outcomes in patients with acute coronary syndrome and type 2 diabetes mellitus. Patients with a recent acute coronary syndrome and type 2 diabetes mellitus were prospectively enrolled in the ELIXA trial (n=5525, follow-up time 26 months). Best risk models were constructed from relevant baseline variables with and without BNP/NT-proBNP. C statistics, Net Reclassification Index, and Integrated Discrimination Index were analyzed to estimate the value of adding BNP or NT-proBNP to best risk models. Overall, BNP and NT-proBNP were the most important predictors of all outcomes examined, irrespective of history of heart failure or any prior cardiovascular disease. BNP significantly improved C statistics when added to risk models for each outcome examined, the strongest increments being in death (0.77-0.82, P <0.001), cardiovascular death (0.77-0.83, P <0.001), and heart failure (0.84-0.87, P <0.001). BNP or NT-proBNP alone predicted death as well as all other variables combined (0.77 versus 0.77). In patients with a recent acute coronary syndrome and type 2 diabetes mellitus, BNP and NT-proBNP were powerful predictors of cardiovascular outcomes beyond heart failure and death, ie, were also predictive of MI and stroke. Natriuretic peptides added as much predictive information about death as all other conventional variables combined. URL: http://www.clinicaltrials.gov. Unique identifier: NCT01147250. © 2017 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell.

The Neural Basis of and a Common Neural Circuitry in Different Types of Pro-social Behavior

PubMed Central

Luo, Jun

2018-01-01

Pro-social behaviors are voluntary behaviors that benefit other people or society as a whole, such as charitable donations, cooperation, trust, altruistic punishment, and fairness. These behaviors have been widely described through non self-interest decision-making in behavioral experimental studies and are thought to be increased by social preference motives. Importantly, recent studies using a combination of neuroimaging and brain stimulation, designed to reveal the neural mechanisms of pro-social behaviors, have found that a wide range of brain areas, specifically the prefrontal cortex, anterior insula, anterior cingulate cortex, and amygdala, are correlated or causally related with pro-social behaviors. In this review, we summarize the research on the neural basis of various kinds of pro-social behaviors and describe a common shared neural circuitry of these pro-social behaviors. We introduce several general ways in which experimental economics and neuroscience can be combined to develop important contributions to understanding social decision-making and pro-social behaviors. Future research should attempt to explore the neural circuitry between the frontal lobes and deeper brain areas. PMID:29922197

Membrane interaction of the N-terminal domain of chemokine receptor CXCR1.

PubMed

Haldar, Sourav; Raghuraman, H; Namani, Trishool; Rajarathnam, Krishna; Chattopadhyay, Amitabha

2010-06-01

The N-terminal domain of chemokine receptors constitutes one of the two critical ligand binding sites, and plays important roles by mediating binding affinity, receptor selectivity, and regulating function. In this work, we monitored the organization and dynamics of a 34-mer peptide of the CXC chemokine receptor 1 (CXCR1) N-terminal domain and its interaction with membranes by utilizing a combination of fluorescence-based approaches and surface pressure measurements. Our results show that the CXCR1 N-domain 34-mer peptide binds vesicles of 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC) and upon binding, the tryptophan residues of the peptide experience motional restriction and exhibit red edge excitation shift (REES) of 19nm. These results are further supported by increase in fluorescence anisotropy and mean fluorescence lifetime upon membrane binding. These results constitute one of the first reports demonstrating membrane interaction of the N-terminal domain of CXCR1 and gain relevance in the context of the emerging role of cellular membranes in chemokine signaling.

Location of alkali metal binding sites in endothelin A selective receptor antagonists, cyclo(D-Trp-D-Asp-Pro-D-Val-Leu) and cyclo(D-Trp-D-Asp-Pro-D-Ile-Leu), from multistep collisionally activated decompositions.

PubMed

Ngoka, L C; Gross, M L

2000-02-01

We previously showed by using mass spectrometry that endothelin A selective receptor antagonists BQ123 and JKC301 form novel coordination compounds with sodium ions. This property may underlie the ability of an ET(A) antagonist to induce net tubular sodium reabsorption in the proximal tubule cells and reverse acute renal failure induced by severe ischemia. We have now defined the metal binding sites on BQ123 and JKC301 by subjecting the metal-containing peptides to multiple stages of collisionally activated decomposition (CAD) in an ion trap mass spectrometer. When submitted to low-energy CAD, the ring opens at the Asp-Pro amide bond. The metal ion, which bonds, inter alia, to the carbonyl oxygen of the proline residue, acts as a fixed charge site, and directs a charge-remote, sequence-specific fragmentation of the ring-opened peptide. Amino acid residues are sequentially cleaved from the C-terminal end, and the terminal aziridinone structure moves one step toward the N-terminus with each C-terminal amino acid residue removed. These observations are the basis of a new method to sequence cyclic peptides. Amino acid residues are observed as sets of three ions, a*(n)PD, b*(n)PD and c*(n)PD where n is the number of amino acid residues in the peptide. Copyright 2000 John Wiley & Sons, Ltd.

Design, Synthesis, and Evaluation of N- and C-Terminal Protein Bioconjugates as G Protein-Coupled Receptor Agonists.

PubMed

Healey, Robert D; Wojciechowski, Jonathan P; Monserrat-Martinez, Ana; Tan, Susan L; Marquis, Christopher P; Sierecki, Emma; Gambin, Yann; Finch, Angela M; Thordarson, Pall

2018-02-21

A G protein-coupled receptor (GPCR) agonist protein, thaumatin, was site-specifically conjugated at the N- or C-terminus with a fluorophore for visualization of GPCR:agonist interactions. The N-terminus was specifically conjugated using a synthetic 2-pyridinecarboxyaldehyde reagent. The interaction profiles observed for N- and C-terminal conjugates were varied; N-terminal conjugates interacted very weakly with the GPCR of interest, whereas C-terminal conjugates bound to the receptor. These chemical biology tools allow interactions of therapeutic proteins:GPCR to be monitored and visualized. The methodology used for site-specific bioconjugation represents an advance in application of 2-pyridinecarboxyaldehydes for N-terminal specific bioconjugations.

Enhanced microglial pro-inflammatory response to lipopolysaccharide correlates with brain infiltration and blood-brain barrier dysregulation in a mouse model of telomere shortening.

PubMed

Raj, Divya D A; Moser, Jill; van der Pol, Susanne M A; van Os, Ronald P; Holtman, Inge R; Brouwer, Nieske; Oeseburg, Hisko; Schaafsma, Wandert; Wesseling, Evelyn M; den Dunnen, Wilfred; Biber, Knut P H; de Vries, Helga E; Eggen, Bart J L; Boddeke, Hendrikus W G M

2015-12-01

Microglia are a proliferative population of resident brain macrophages that under physiological conditions self-renew independent of hematopoiesis. Microglia are innate immune cells actively surveying the brain and are the earliest responders to injury. During aging, microglia elicit an enhanced innate immune response also referred to as 'priming'. To date, it remains unknown whether telomere shortening affects the proliferative capacity and induces priming of microglia. We addressed this issue using early (first-generation G1 mTerc(-/-) )- and late-generation (third-generation G3 and G4 mTerc(-/-) ) telomerase-deficient mice, which carry a homozygous deletion for the telomerase RNA component gene (mTerc). Late-generation mTerc(-/-) microglia show telomere shortening and decreased proliferation efficiency. Under physiological conditions, gene expression and functionality of G3 mTerc(-/-) microglia are comparable with microglia derived from G1 mTerc(-/-) mice despite changes in morphology. However, after intraperitoneal injection of bacterial lipopolysaccharide (LPS), G3 mTerc(-/-) microglia mice show an enhanced pro-inflammatory response. Nevertheless, this enhanced inflammatory response was not accompanied by an increased expression of genes known to be associated with age-associated microglia priming. The increased inflammatory response in microglia correlates closely with increased peripheral inflammation, a loss of blood-brain barrier integrity, and infiltration of immune cells in the brain parenchyma in this mouse model of telomere shortening. © 2015 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.

Histone-like DNA binding protein of Streptococcus intermedius induces the expression of pro-inflammatory cytokines in human monocytes via activation of ERK1/2 and JNK pathways.

PubMed

Liu, Dali; Yumoto, Hiromichi; Hirota, Katsuhiko; Murakami, Keiji; Takahashi, Kanako; Hirao, Kouji; Matsuo, Takashi; Ohkura, Kazuto; Nagamune, Hideaki; Miyake, Yoichiro

2008-01-01

Streptococcus intermedius is a commensal associated with serious, deep-seated purulent infections in major organs, such as the brain and liver. Histone-like DNA binding protein (HLP) is an accessory architectural protein in a variety of bacterial cellular processes. In this study, we investigated the mechanisms of pro-inflammatory cytokine inductions in THP-1 cells by stimulation with recombinant HLP of S. intermedius (rSi-HLP). rSi-HLP stimulation-induced production of pro-inflammatory cytokines (IL-8, IL-1 beta and TNF-alpha) occurred in a time- and dose-dependent manner. In contrast with the heat-stable activity of DNA binding, the induction activity of rSi-HLP was heat-unstable. In subsequent studies, rSi-HLP acted cooperatively with lipoteichoic acid, the synthetic Toll-like receptor 2 agonist, Pam3CSK4, and the cytosolic nucleotide binding oligomerization domain 2 receptor agonist, muramyldipeptide. Furthermore, Western blot and blocking assays with specific inhibitors showed that rSi-HLP stimulation induced the activation of cell signal transduction pathways, extracellular signal-regulated kinase 1/2 (ERK1/2) and c-Jun N-terminal kinase (JNK). In addition to its physiological role in bacterial growth through DNA binding, these results indicate that Si-HLP can trigger a cascade of events that induce pro-inflammatory responses via ERK1/2 and JNK signal pathways, and suggest that bacterial HLP may contribute to the activation of host innate immunity during bacterial infection.

Monitoring the response to pharmacologic therapy in patients with stable chronic heart failure: is BNP or NT-proBNP a useful assessment tool?

PubMed

Balion, Cynthia M; McKelvie, Robert S; Reichert, Sonja; Santaguida, Pasqualina; Booker, Lynda; Worster, Andrew; Raina, Parminder; McQueen, Matthew J; Hill, Stephen

2008-03-01

B-type natriuretic peptides are biomarkers of heart failure (HF) that can decrease following treatment. We sought to determine whether B-type natriuretic peptide (BNP) or N-terminal proBNP (NT-proBNP) concentration changes occurred in parallel to changes in other measures of heart failure following treatment. We conducted a systematic review of the literature for studies that assessed B-type natriuretic peptide measurements in treatment monitoring of patients with stable chronic heart failure. Selected studies had to include at least three consecutive measurements of BNP or NT-proBNP. Of 4338 citations screened, only 12 met all of the selection criteria. The selected studies included populations with a wide range of heart failure severity and therapy. BNP and NT-proBNP decreased following treatment in nine studies and was associated with improvement in clinical measures of HF. There was limited data to support using BNP or NT-proBNP to monitor therapy in patients with HF.

Distinctive functions of Syk N-terminal and C-terminal SH2 domains in the signaling cascade elicited by oxidative stress in B cells.

PubMed

Ding, J; Takano, T; Hermann, P; Gao, S; Han, W; Noda, C; Yanagi, S; Yamamura, H