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1.  Elevated NT-pro-BNP Levels Are Associated with Comorbidities among HIV-Infected Women 
AIDS research and human retroviruses  2009;25(10):997-1004.
HIV infection is associated with left ventricular (LV) dysfunction and accelerated atherosclerosis. These conditions result in elevation of plasma natriuretic peptide (NP) levels. The present study compares N-terminal-pro-BNP (NT-pro-BNP) levels in HIV-infected and -uninfected women and identifies factors influencing NT-pro-BNP levels in HIV-infected women. A total of 454 HIV-infected and 200 HIV-uninfected participants from the Women’s Interagency HIV Study (WIHS) had NT-pro-BNP determination. Elevated NT-pro-BNP level was defined using previously determined age stratified cut-off values of >164 ng/liter (age <60 years) and >225 (age ≥60 years). HIV-infected women were older (41.6 ± 8.9 vs. 38.9 ± 10.5 years, p <0.01) and were more likely to have anemia, hepatitis C virus (HCV) antibodies, and kidney dysfunction than HIV-uninfected women. HIV-infected women had significantly higher NT-pro-BNP levels (142.4 ± 524.8 vs. 73.6 ± 115.1 ng/liter, p = 0.01) and a higher prevalence of elevated NT-pro-BNP (12.1% vs. 7.5%; p = 0.08). In univariate analyses, elevated NT-pro-BNP was significantly associated with age, systolic BP, hypertension, anemia, triglyceride levels, kidney disease, and HCV seropositivity, but not HIV infection. In multivariate analysis, elevated NT-pro-BNP levels were significantly associated with anemia and kidney function, and had a borderline association with the presence of HCV antibodies. Among HIV-infected women, NT-pro-BNP levels were not independently associated with measures of severity of infection or with HAART use. Although HIV-infected women have higher NT-pro-BNP levels than HIV-uninfected women, the differences are due to non-HIV factors such as anemia, kidney disease, and HCV coinfection. These findings suggest that natriuretic peptide levels are a global marker of comorbidity in the setting of HIV infection.
PMCID: PMC2791362  PMID: 19803714
2.  Direct Immunochemiluminescent Assay for proBNP and Total BNP in Human Plasma proBNP and Total BNP Levels in Normal and Heart Failure 
PLoS ONE  2013;8(1):e53233.
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.
Our immunochemiluminescent assay is sufficiently rapid and precise for routine determination of total BNP and proBNP in human plasma.
PMCID: PMC3554706  PMID: 23365636
3.  N-terminal-proB-type natriuretic peptide predicts cardiovascular disease events in HIV-infected patients 
AIDS (London, England)  2011;25(5):651-657.
Cardiovascular disease (CVD) is increasing in HIV-infected patients. N-terminal pro-B-type natriuretic peptide (NT-proBNP) is a significant predictor of CVD in the general population. We aimed to quantify the risk of CVD events associated with NT-proBNP at baseline in the Strategies for Management of Anti-Retroviral Therapy study.
In a nested case–control study, NT-proBNP was measured at baseline in 186 patients who experienced a CVD event over an average of 2.8 years of follow-up and in 329 matched controls. Odds ratios (ORs) associated with baseline levels of NT-proBNP for CVD were estimated using conditional logistic regression.
At baseline median NT-proBNP [interquartile range (IQR)] was 48.1 (18.5, 112.9) pg/ml in patients who developed a CVD event and 25.7 (12.4, 50.2) pg/ml in controls. The unadjusted OR for the highest versus the lowest quartile was 3.7 [95% confidence interval (CI) 2.1–6.5, P < 0.0001]. After adjustment for baseline covariates and CVD risk factors, OR was 2.8 (95% CI 1.4–5.6, P = 0.003); with additional adjustment for IL-6, high-sensitivity C-reactive protein and D-dimer, OR was 2.3 (95% CI 1.1–4.9, P = 0.02).
Higher levels of NT-proBNP are associated with increased risk of CVD in HIV patients after considering established CVD risk factors and markers for inflammation and thrombosis.
PMCID: PMC3113476  PMID: 21245726
AIDS; antiretroviral therapy; cardiovascular disease events; HIV; NT-proBNP; SMART
4.  Role of the NT-proBNP level in the diagnosis of pediatric heart failure and investigation of novel combined diagnostic criteria 
The aim of this study was to investigate the modified Ross criteria score and the diagnostic cut-off level for plasmatic amino-terminal pro-brain natriuretic peptide (NT-proBNP) in the diagnosis of pediatric heart failure, by analyzing the receiver operating characteristic (ROC) curve. The plasma NT-proBNP level was measured in 80 children diagnosed with heart failure according to the modified Ross criteria, 80 children with non-cardiogenic dyspnea and 80 healthy children. The NT-proBNP levels were then compared using an F-test. The cut-off score for heart failure in the modified Ross criteria and the diagnostic cut-off level for plasmatic NT-proBNP in pediatric heart failure were determined by ROC curve analysis. The results demonstrated that the NT-proBNP level was markedly increased in 76 of the 80 children with heart failure, and the correlation with the modified Ross criteria was 95%. Based on ROC curve analysis, the diagnosis of pediatric heart failure was most accurate when the modified Ross criteria score was ≥4 and the plasmatic NT-proBNP level was ≥598 ng/l. The NT-proBNP level was normal (0–300 ng/l) in the children with non-cardiogenic dyspnea and the healthy children. Significant differences were observed in the comparison of the three groups (P<0.01). In conclusion, a NT-proBNP level of ≥598 ng/l, combined with a modified Ross criteria score ≥4, is highly diagnostic of heart failure in children.
PMCID: PMC3797316  PMID: 24137304
heart failure; amino-terminal pro-B-type natriuretic peptide; diagnostic criteria; children
5.  Association of Serum Carotenoid Levels With N-Terminal Pro-Brain-Type Natriuretic Peptide: A Cross-Sectional Study in Japan 
Journal of Epidemiology  2013;23(3):163-168.
Several epidemiologic studies have reported an inverse association between serum levels of carotenoids and cardiovascular disease risk. However, no studies have reported an association between serum carotenoids and N-terminal pro-brain-type natriuretic peptide (NT-proBNP) in the general population.
In this cross-sectional study, we investigated whether serum carotenoids were associated with serum NT-proBNP in 1056 Japanese subjects (390 men, 666 women) who attended a health examination. Serum levels of carotenoids were separately determined by high-performance liquid chromatography. Serum NT-proBNP level was measured by electrochemiluminescence immunoassay.
Serum NT-proBNP was elevated (≥55 pg/ml) in 31.8% of men and 48.2% of women. Multivariate logistic regression analyses adjusted for confounding factors showed a significant association between the highest quartile of serum α-carotene and elevated NT-proBNP in men (odds ratio [OR] = 0.40, 95% CI = 0.19–0.82, P for trend = 0.005) and women (OR = 0.62, 95% CI = 0.39–0.99, P for trend = 0.047). In women, moreover, elevated serum NT-proBNP was significantly associated with serum canthaxanthin (OR = 0.57, 95% CI = 0.36–0.90 for highest quartile, P for trend = 0.026) and β-cryptoxanthin (OR = 0.53, 95% CI = 0.32–0.85 for highest quartile, P for trend = 0.026), after adjusting for potential confounders.
Higher levels of serum carotenoids were associated with lower risk of elevated serum NT-proBNP levels after adjusting for possible confounders, which suggests that a diet rich in carotenoids could help prevent cardiac overload in the Japanese population.
PMCID: PMC3700260  PMID: 23474820
carotenoids; N-terminal pro-brain-type natriuretic peptide; cross-sectional study
6.  Left ventricular ejection fraction assessment in older adults: An adjunct to natriuretic peptide testing to identify risk of new onset heart failure and cardiovascular death? 
Determine whether assessment of left ventricular ejection fraction (LVEF) enhances prediction of new onset heart failure (HF) and cardiovascular mortality over and above N-terminal pro–B-type natriuretic peptide (NT-proBNP) level in older adults.
Elevated NT-proBNP levels are common in older adults and associated with increased risk of HF.
NT-proBNP and LVEF were measured in 4,137 older adults free of HF. Repeat measures of NT-proBNP were performed 2–3 years later and echocardiography was repeated 5 years later (n=2,375) with a median follow-up of 10.7 years. The addition of an abnormal (<55%) LVEF (n=317 [7.7%]) to initially elevated or rising NT-proBNP levels was evaluated to determine risk of HF or cardiovascular mortality. Change in NT-proBNP levels were also assessed for estimating the risk of conversion from a normal to abnormal LVEF.
For participants with a low baseline NT-proBNP level (<190 pg/mL) (n=2,918), addition of an abnormal LVEF didn’t improve the estimation of risk of HF and identified a moderate increase in adjusted risk for cardiovascular mortality (HR 1.69; 95%CI: 1.22 to 2.31). Among those whose NT-proBNP subsequently increased ≥ 25% to ≥190 pg/mL, an abnormal LVEF was likewise associated with an increased risk of cardiovascular mortality but not HF. Participants with an initially high NT-proBNP (≥190 pg/mL) were at greater risk overall for both outcomes, and those with an abnormal LVEF were at the highest risk. However, an abnormal LVEF did not improve model classification or risk stratification for either endpoint when added to demographic factors and change in NT-proBNP. An initially elevated NT-proBNP or rising level was associated with an increased risk of developing an abnormal LVEF.
Assessment of LVEF in HF free older adults based on NT-proBNP levels should be considered on an individual basis, as such assessments do not routinely improve prognostication.
PMCID: PMC3540778  PMID: 21939835
Elderly; heart failure; echocardiography; natriuretic peptides; outcomes
7.  Correlation of natriuretic peptides and inferior vena cava size in patients with congestive heart failure 
The inferior vena cava (IVC) diameter and degree of inspiratory collapse are used as echocardiographic indices in the estimation of right atrial pressure. Brain-natriuretic peptides (BNPs) are established biomarkers of myocardial wall stress. There is no information available regarding the association between the IVC diameter and BNPs in patients with heart failure and various degrees of systolic performance. The purpose of this investigation is to quantify the degree to which natriuretic peptides (BNP and N-terminal pro-B natriuretic peptide [NT-ProBNP]) and echocardiographic-derived indices of right atrial pressure correlate in this patient population.
We examined 77 patients (mean age 61 ± 17 years, 44% male) with decompensated heart failure who underwent transthoracic echocardiography and, within a timeframe of 24 hours, determination of BNP and NT-ProBNP levels in venous blood. BNP and NT-ProBNP were analyzed after log transformation. The degree of association was measured by the correlation coefficient using the Pearson’s method.
The mean ejection fraction was 50% ± 20%, and 33% of the study cohort had a remote history of heart failure. The mean IVC diameter was 1.85 cm ± 0.5, the mean BNP was 274 pg/mL, the confidence interval (CI) was 95% (95% CI: 197–382), and the mean NT-ProBNP was 1994 pg/mL (95% CI: 1331–2989). There was a positive, albeit small, association between IVC diameter and BNP (r = 0.24, 95% CI: 0.01–0.44; P = 0.03) and NT-ProBNP (r = 0.27, 95% CI: 0.05–0.47; P = 0.01). Among patients with different degrees of IVC collapse in response to inspiration, values for BNP and NT-ProBNP did not differ substantially (P = 0.36 and 0.46 for BNP and NT-ProBNP, respectively).
Natriuretic peptides correlate weakly with IVC size and do not predict changes in response to intrathoracic pressure.
PMCID: PMC3333469  PMID: 22536076
heart failure; inferior vena cava; natriuretic peptides
8.  Amino-Terminal Pro-B-Type Natriuretic Peptide and B-Type Natriuretic Peptide in the General Community Determinants and Detection of Left Ventricular Dysfunction 
This study sought to characterize factors influencing amino-terminal pro-B-type natriuretic peptide (NT-proBNP) and to evaluate the ability of NT-proBNP to detect left ventricular (LV) dysfunction in a large community sample.
Secretion of BNP increases in cardiac disease, making BNP an attractive biomarker. Amino-terminal proBNP, a fragment of the BNP prohormone, is a new biomarker. We evaluated factors influencing NT-proBNP in normal patients and compared the ability of NT-proBNP and BNP to detect LV dysfunction in a large community sample.
Amino-terminal pro-BNP was determined in plasma samples of a previously reported and clinically and echocardiographically characterized random sample (n = 1,869, age ≥ 45 years) of Olmsted County, Minnesota.
In normal patients (n = 746), female gender and older age were the strongest independent predictors of higher NT-proBNP. Test characteristics for detecting an LV ejection fraction ≤ 40% or ≤ 50% were determined in the total sample with receiver operating characteristic curves. Amino-terminal pro-BNP had significantly higher areas under the curve for detecting an LV ejection fraction ≤ 40% or ≤ 50% than BNP in the total population and in several male and age subgroups, whereas areas were equivalent in female subgroups. Age- and gender-adjusted cutpoints improved test characteristics of NT-proBNP. Both assays detected patients with systolic and/or moderate to severe diastolic dysfunction to a similar degree, which was less robust than the detection of LV systolic dysfunction alone.
Amino-terminal pro-BNP in normal patients is affected primarily by gender and age, which should be considered when interpreting values. Importantly, in the entire population sample NT-proBNP performed at least equivalently to BNP in detecting LV dysfunction and was superior in some subgroups in detecting LV systolic dysfunction.
PMCID: PMC2647136  PMID: 16412859
9.  Midregional pro-Adrenomedullin in addition to b-type natriuretic peptides in the risk stratification of patients with acute dyspnea: an observational study 
Critical Care  2009;13(4):R122.
The identification of patients at highest risk for adverse outcome who are presenting with acute dyspnea to the emergency department remains a challenge. This study investigates the prognostic value of the newly described midregional fragment of the pro-Adrenomedullin molecule (MR-proADM) alone and combined to B-type natriuretic peptide (BNP) or N-terminal proBNP (NT-proBNP) in patients with acute dyspnea.
We conducted a prospective, observational cohort study in the emergency department of a University Hospital and enrolled 287 unselected, consecutive patients (48% women, median age 77 (range 68 to 83) years) with acute dyspnea.
MR-proADM levels were elevated in non-survivors (n = 77) compared to survivors (median 1.9 (1.2 to 3.2) nmol/L vs. 1.1 (0.8 to 1.6) nmol/L; P < 0.001). The areas under the receiver operating characteristic curve (AUC) to predict 30-day mortality were 0.81 (95% CI 0.73 to 0.90), 0.76 (95% CI 0.67 to 0.84) and 0.63 (95% CI 0.53 to 0.74) for MR-proADM, NT-proBNP and BNP, respectively (MRproADM vs. NTproBNP P = 0.38; MRproADM vs. BNP P = 0.009). For one-year mortality the AUC were 0.75 (95% CI 0.69 to 0.81), 0.75 (95% CI 0.68 to 0.81), 0.69 (95% CI 0.62 to 0.76) for MR-proADM, NT-proBNP and BNP, respectively without any significant difference. Using multivariate linear regression analysis, MR-proADM strongly predicted one-year all-cause mortality independently of NT-proBNP and BNP levels (OR = 10.46 (1.36 to 80.50), P = 0.02 and OR = 24.86 (3.87 to 159.80) P = 0.001, respectively). Using quartile approaches, Kaplan-Meier curve analyses demonstrated a stepwise increase in one-year all-cause mortality with increasing plasma levels (P < 0.0001). Combined levels of MR-proADM and NT-proBNP did risk stratify acute dyspneic patients into a low (90% one-year survival rate), intermediate (72 to 82% one-year survival rate) or high risk group (52% one-year survival rate).
MR-proADM alone or combined to NT-proBNP has a potential to assist clinicians in risk stratifying patients presenting with acute dyspnea regardless of the underlying disease.
PMCID: PMC2750172  PMID: 19627611
10.  N-terminal pro-B-type Natriuretic Peptide is Associated with Sudden Cardiac Death Risk: the Cardiovascular Health Study 
Sudden cardiac death (SCD), the cause of 250,000-450,000 deaths per year, is a major public health problem. The majority of those affected do not have a prior cardiovascular diagnosis. Elevated B-type natriuretic peptide levels have been associated with the risk of heart failure and mortality, as well as sudden death in women.
To examine the relationship between N-terminal pro-B-type natriuretic peptide (NT-proBNP) and SCD in the Cardiovascular Health Study population.
The risk of SCD associated with baseline NT-proBNP was examined in 5447 participants. Covariate-adjusted Cox model regressions were used to estimate the hazard ratios of developing SCD as a function of baseline NT-proBNP
Over a median follow-up of 12.5 years (maximum of 16), there were 289 cases of SCD. Higher NT-proBNP levels were strongly associated with SCD, with an unadjusted hazard ratio of 4.2 (95% CI: 2.9, 6.1, p<0.001) in the highest quintile compared to the lowest. NT-proBNP remained associated with SCD even after adjustment for numerous clinical characteristics and risk-factors (age, sex, race, and other associated conditions), with an adjusted hazard ratio for the 5th versus the 1st quintile of 2.5 (95% CI: 1.6, 3.8, p<0.001).
NT-proBNP provides information regarding the risk of sudden cardiac death in a community based population of older adults, beyond other traditional risk factors. This biomarker may ultimately prove useful in targeting the population at risk with aggressive medical management of comorbid conditions.
PMCID: PMC3826546  PMID: 21044699
Sudden cardiac death; B-type natriuretic peptide; BNP; NT-proBNP
11.  Admission N‐terminal pro‐brain natriuretic peptide and its interaction with admission troponin T and ST segment resolution for early risk stratification in ST elevation myocardial infarction 
Heart  2005;92(6):735-740.
To assess the long term prognostic value of N‐terminal pro‐brain natriuretic peptide (NT‐proBNP) on admission and its prognostic interaction with both admission troponin T (TnT) concentrations and resolution of ST segment elevation in fibrinolytic treated ST elevation myocardial infarction (STEMI).
Design and setting
Substudy of the ASSENT (assessment of the safety and efficacy of a new thrombolytic) ‐2 and ASSENT‐PLUS trials.
NT‐proBNP and TnT concentrations were determined on admission in 782 patients. According to NT‐proBNP concentrations, patients were divided into three groups: normal concentration (for patients ⩽ 65 years, ⩽ 184 ng/l and ⩽ 268 ng/l and for those > 65 years, ⩽ 269 ng/l and ⩽ 391 ng/l in men and women, respectively); higher than normal but less than the median concentration (742 ng/l); and above the median concentration. For TnT, a cut off of 0.1 μg/l was used. Of the 782 patients, 456 had ST segment resolution (< 50% or ⩾ 50%) at 60 minutes calculated from ST monitoring.
Main outcome measures
All cause one year mortality.
One year mortality increased stepwise according to increasing concentrations of NT‐proBNP (3.4%, 6.5%, and 23.5%, respectively, p < 0.001). In receiver operating characteristic analysis, NT‐proBNP strongly trended to be associated more with mortality than TnT and time to 50% ST resolution (area under the curve 0.81, 95% confidence interval (CI) 0.72 to 0.9, 0.67, 95% CI 0.56 to 0.79, and 0.66, 95% CI 0.56 to 0.77, respectively). In a multivariable analysis adjusted for baseline risk factors and TnT, both raised NT‐proBNP and ST resolution < 50% were independently associated with higher one year mortality, whereas raised TnT contributed independently only before information on ST resolution was added to the model.
Admission NT‐proBNP is a strong independent predictor of mortality and gives, together with 50% ST resolution at 60 minutes, important prognostic information even after adjustment for TnT and baseline characteristics in STEMI.
PMCID: PMC1860646  PMID: 16251228
acute myocardial infarction; brain natriuretic peptide; prognosis; electrocardiography
12.  Cut‐off values of B‐type natriuretic peptide for the diagnosis of congestive heart failure in patients with dyspnoea visiting emergency departments: a study on Korean patients visiting emergency departments 
Emergency Medicine Journal : EMJ  2007;24(5):343-347.
To determine the optimal cut‐off values of B‐type natriuretic peptide (BNP) for the diagnosis of congestive heart failure (CHF) in 1040 Korean patients with dyspnoea visiting emergency departments.
BNP values were measured for 662 patients without CHF to examine whether significant relationships existed between the BNP values and age, gender or underlying disease. In 378 patients with CHF, a similar analysis was performed in addition to the examination of the relationship between the mean BNP values and CHF severity.
The optimal threshold for the detection of heart failure was a BNP concentration of 296.5 pg/mL, regardless of age, sex and underlying disease among the Korean study population. In the non‐CHF patients, women showed significantly higher mean BNP values than did men. Further, in these patients, the mean BNP values of men with underlying disease (hypertension, angina pectoris, chronic renal failure, chronic obstructive pulmonary disease) and those with at least two underlying diseases, one of which was hypertension, was higher than those without underlying disease, whereas no difference was observed between women with and without underlying disease. Based on the New York Heart Association classification, echocardiography findings and mortality rate of the CHF patients, the BNP value was found to be related to both the severity of heart failure and its prognosis.
The BNP concentration used for the diagnosis of CHF in Korean people is considerably higher than the normal cut‐off value of 100 pg/mL. In the non‐CHF patients, the BNP values of women were influenced less by underlying disease. This suggests that the factors that influence BNP values in women are different from those in men.
PMCID: PMC2658481  PMID: 17452702
natriuretic peptide; brain; heart failure; congestive; gender identity; Korea; prognosis
13.  Dynamic cardiovascular risk assessment in the elderly: The role of repeated amino terminal pro-B-type natriuretic peptide testing 
Determine if serial measurement of N-terminal pro B-type natriuretic peptide (NT-proBNP) in community dwelling elderly would provide additional prognostic information to traditional risk factors.
Accurate cardiovascular risk stratification is challenging in the elderly.
NT-proBNP was measured at baseline and 2-3 years later in 2,975 community-dwelling older adults free of heart failure in the longitudinal Cardiovascular Health Study. This investigation examined the risk of new-onset heart failure (HF) and death from cardiovascular (CV) causes associated with baseline NT-proBNP and changes in NT-proBNP levels, adjusting for potential confounders.
NT-proBNP levels in the highest quintile (>267.7 pg/mL) were independently associated with greater risks of HF (hazard ratio [HR] =3.05 (95%CI [confidence interval] 2.46-3.78) and CV death (HR=3.02, 95%CI 2.36-3.86) compared to the lowest quintile (<47.5 pg/mL). The inflection point for elevated risk occurred at NT-proBNP=190 pg/mL. Among participants with initially low NT-proBNP (<190 pg/mL), those who developed a >25% increase on follow-up to >190 pg/mL (21%) were at greater adjusted risk of HF (HR=2.13, 95%CI=1.68-2.71) and CV death (HR=1.91, 95%CI=1.43-2.53) compared to those with sustained low levels. Among participants with initially high NT-proBNP, those who developed >25% increase (40%) were at higher risk of HF (HR=2.06 95%CI 1.56 −2.72) and cardiovascular death (HR=1.88, 95%CI 1.37-2.57), whereas those who developed >25% decrease to ≤190pg/mL (15%) were at lower risk of HF (HR=0.58, 95%CI 0.36-0.93) and CV death (HR=0.57, 95%CI 0.32 −1.01) compared to those with unchanged high values.
NT-proBNP levels independently predict heart failure and cardiovascular death in older adults. NT-proBNP levels frequently change over time and these fluctuations reflect dynamic changes in cardiovascular risk.
PMCID: PMC2840257  PMID: 20117457
biomarkers; risk stratification; heart failure; elderly
14.  Reference Limits for N-terminal-pro-B-type Natriuretic Peptide in Healthy Individuals (From the Framingham Heart Study) 
The American journal of cardiology  2011;108(9):1341-1345.
N-terminal-pro-B-type natriuretic peptide (NT-proBNP) is a commonly measured cardiovascular biomarker in both ambulatory and hospital settings. Nonetheless, there are limited data regarding “normal” ranges for NT-proBNP in healthy individuals, despite the importance of such information for interpreting natriuretic peptide measurements. We examined a healthy reference sample free of cardiovascular disease from the Framingham Heart Study Generation 3 cohort; there were 2,285 subjects (mean age 38 years, 56% women). Plasma NT-proBNP levels were measured using the Roche Diagnostics Elecsys 2010 assay, and reference values (2.5, 50, 97.5 quantiles) were determined using empiric and quantile regression methods. Gender, age, and body mass index accounted for approximately 33% of the inter-individual variability in NT-proBNP in the reference sample. NT-proBNP values were substantially higher in women compared with men at every age, and levels increased with increasing age for both sexes. Using quantile regression, the upper reference values (97.5 quantile) for NT-proBNP were 42.5 pg/ml to 106.4 pg/ml in men (depending on age), and 111.0 pg/ml to 215.9 pg/ml in women. Intra-individual variability was assessed in an additional 12 healthy individuals, who had serial NT-proBNP measurements over a month. Intra-class correlation was 0.85, indicating that most of the variability in NT-proBNP concentrations was among-persons rather than within-persons. However, the reference change value was 100%, suggesting that small proportional differences in NT-proBNP could be attributable to analytic variability. In conclusion, the reference limits obtained from this large, healthy community-based sample may aid in the evaluation of NT-proBNP concentrations measured for both clinical and research purposes.
PMCID: PMC3209520  PMID: 21864812
Natriuretic peptides; Cardiac Biomarkers; Heart Failure
15.  B-Type Natriuretic Peptide and Ischemia in Patients With Stable Coronary Disease 
Circulation  2003;108(24):2987-2992.
In patients with symptoms of heart failure, elevations in B-type natriuretic peptide (BNP) accurately identify ventricular dysfunction. However, BNP levels are not specific for ventricular dysfunction in patients who do not have overt symptoms of heart failure, suggesting that other cardiac processes such as myocardial ischemia may also cause elevations in BNP.
Methods and Results
To determine whether BNP elevations are associated with myocardial ischemia, we measured plasma BNP levels before performing exercise treadmill testing with stress echocardiography in outpatients with stable coronary disease. Of the 355 participants, 113 (32%) had inducible ischemia. Compared with participants in the lowest BNP quartile (0 to 16.4 pg/mL), those in the highest quartile of BNP (≥105 pg/mL) had double the risk of inducible ischemia (adjusted relative risk, 2.0; 95% CI, 1.2 to 2.6; P=0.008). The relation between elevated BNP levels and inducible ischemia was especially evident in the 206 participants who had a history of myocardial infarction (adjusted relative risk, 2.6; 95% CI, 1.5 to 3.7, P=0.002) and was absent in those without a history of myocardial infarction (adjusted relative risk, 1.0; 95% CI, 0.3 to 2.2; P=0.9). This association between BNP levels and inducible ischemia remained strong after adjustment for measures of systolic and diastolic dysfunction.
Elevated levels of BNP are independently associated with inducible ischemia among outpatients with stable coronary disease, particularly among those with a history of myocardial infarction. The observed association between BNP levels and ischemia may explain why tests for BNP are not specific for ventricular dysfunction among patients with coronary disease.
PMCID: PMC2771188  PMID: 14662720
natriuretic peptides; ischemia; myocardial infarction; heart failure; coronary disease
16.  The ability of NT-proBNP to detect chronic heart failure and predict all-cause mortality is higher in elderly Chinese coronary artery disease patients with chronic kidney disease 
To analyze the relationship between N-terminal pro-brain natriuretic peptide (NT-proBNP) and renal function, and compare the ability and cut-off thresholds of NT-proBNP to detect chronic heart failure (CHF) and predict mortality in elderly Chinese coronary artery disease (CAD) patients with and without chronic kidney disease (CKD).
The study included 999 CAD patients older than 60 years. The endpoint was all-cause mortality over a mean follow-up period of 417 days.
The median age was 86 years (range: 60–104 years), and the median NT-proBNP level was 409.8 pg/mL. CKD was present in 358 patients. Three hundred and six patients were positive for CHF. One hundred and ten CKD patients and 105 non-CKD patients died. Not only CKD, but also estimated glomerular filtration rate independently affected NT-proBNP. NT-proBNP detected CHF with a cut-off value of 298.4 pg/mL in non-CKD patients and a cut-off value of 435.7 pg/mL in CKD patients. NT-proBNP predicted death with a cut-off value of 369.5 pg/mL in non-CKD patients and a cut-off value of 2584.1 pg/mL in CKD patients. The NT-proBNP level was significantly related to the prevalence of CHF and all-cause mortality in CAD patients with and without CKD; this effect persisted after adjustment. The crude and multiple adjusted hazard ratios of NT-proBNP to detect CHF and predict mortality were significantly higher in patients with CKD compared with the remainder of the population. The addition of NT-proBNP to the three-variable and six-variable models generated a significant increase in the C-statistic.
Amongst elderly Chinese CAD patients, there was an independently inverse association between NT-proBNP and renal function. With the higher cutoff points, NT-proBNP better detected CHF and better predicted mortality in CKD patients than in non-CKD patients.
PMCID: PMC3665499  PMID: 23723693
aged; coronary artery disease; chronic kidney disease; N-terminal pro-brain natriuretic peptide; prognosis
17.  Potential cardiovascular disease risk markers among HIV-infected women initiating antiretroviral treatment 
Inflammation and hemostasis perturbation may be involved in vascular complications of HIV infection. We examined atherogenic biomarkers and subclinical atherosclerosis in HIV-infected adults before and after beginning highly-active antiretroviral therapy (HAART).
In the Women's Interagency HIV Study (WIHS), 127 HIV-infected women studied pre- and post-HAART were matched to HIV-uninfected controls. Six semi-annual measurements of soluble CD14, tumor necrosis factor (TNF)-alpha, soluble interleukin (IL)-2 receptor, IL-6, IL-10, monocyte chemoattractant protein (MCP)-1, D-dimer, and fibrinogen were obtained. Carotid artery intima-media thickness (CIMT) was measured by B-mode ultrasound.
Relative to HIV-uninfected controls, HAART-naïve HIV-infected women had elevated levels of soluble CD14 (1945 vs 1662 ng/mL, Wilcoxon signed rank P<0.0001), TNF-alpha (6.3 vs 3.4 pg/mL, P<0.0001), soluble IL-2 receptor (1587 vs 949 pg/mL, P<0.0001), IL-10 (3.3 vs 1.9 pg/mL, P<0.0001), MCP-1 (190 vs 163 pg/mL, P<0.0001) and D-dimer (0.43 vs 0.31 µg/mL, P<0.01). Elevated biomarker levels declined after HAART. While most biomarkers normalized to HIV-uninfected levels, in women on effective HAART, TNF-alpha levels remained elevated compared to HIV-uninfected women (+0.8 pg/mL, P=0.0002). Higher post-HAART levels of soluble IL-2 receptor (P=0.02), IL-6 (P=0.05), and D-dimer (P=0.03) were associated with increased CIMT.
Untreated HIV infection is associated with abnormal hemostasis (e.g., D-dimer), and pro-atherogenic (e.g., TNF-alpha) and anti-atherogenic (e.g., IL-10) inflammatory markers. HAART reduces most inflammatory mediators to HIV-uninfected levels. Increased inflammation and hemostasis are associated with subclinical atherosclerosis in recently treated women. These findings have potential implications for long-term risk of cardiovascular disease in HIV-infected patients, even with effective therapy.
PMCID: PMC3400505  PMID: 22592585
antiretroviral therapy; cardiovascular diseases; cytokines; hemostasis; HIV; inflammation
18.  High circulating N-terminal pro-brain natriuretic peptide and tumor necrosis factor-α in mixed cryoglobulinemia 
AIM: To evaluate serum levels of N-terminal pro-brain natriuretic peptide (NTproBNP) and tumor necrosis factor α (TNF-α) in a large series of patients with hepatitis C associated with mixed cryoglobulinemia (MC+HCV).
METHODS: Serum NTproBNP and TNF-α levels were assayed in 50 patients with MC+HCV, and in 50 sex- and age-matched controls.
RESULTS: Cryoglobulinemic patients showed significantly higher mean NTproBNP and TNF-α levels than controls (P < 0.001; Mann-Whitney U test). By defining high NTproBNP level as a value higher than 125 pg/mL (the single cut-off point for outpatients under 75 years of age), 30% of MC+HCV and 6% of controls had high NTproBNP (χ2, P < 0.01). With a cut-off point of 300 pg/mL (used to rule out heart failure (HF) in patients under 75 years of age), 8% of MC+HCV and 0 controls had high NTproBNP (χ2, P < 0.04). With a cut-off point of 900 pg/mL (used for ruling in HF in patients aged 50-75 years; such as the patients of our study), 6% of MC+HCV and 0 controls had high NTproBNP (χ2, P = 0.08).
CONCLUSION: The study demonstrates high levels of circulating NTproBNP and TNF-α in MC+HCV patients. The increase of NTproBNP may indicate the presence of a subclinical cardiac dysfunction.
PMCID: PMC2768887  PMID: 19860001
NTProBNP; Tumor necrosis factor α; Hepatitis C; Mixed cryoglobulinemia; Heart failure
19.  B-type natriuretic peptide and N-terminal pro-B-type natriuretic peptide – Diagnostic role in stable coronary artery disease 
B-type natriuretic peptide (BNP) and its N-terminal fragment (NT-proBNP) are released from ventricular cardiomyocytes in response to an increase in ventricular wall stress and to myocardial ischemia. Both BNP and NT-proBNP have proven to be reliable diagnostic and prognostic biomarkers in patients with heart failure. Recently, the diagnostic roles of BNP and NT-proBNP in patients with coronary artery disease (CAD) have been investigated. For patients with acute coronary syndromes, data have been derived from a great number of studies, whereas in patients with stable CAD, only a limited amount of recent data is available; although limited, these data show that elevations in BNP and NT-proBNP levels are associated with the extent of CAD, thus providing prognostic information for an unfavourable clinical outcome. However, clinical and therapeutic implications are indistinct and need to be elucidated in further studies.
PMCID: PMC2274852  PMID: 18651043
Acute coronary syndromes; B-type natriuretic peptide; Coronary artery disease; Ischemic heart disease; Myocardial infarction; N-terminal B-type natriuretic peptide
20.  Marked elevations in N-terminal brain natriuretic peptide levels in septic shock 
Critical Care  2004;8(4):R248-R250.
N-terminal pro brain natriuretic peptide (NT-proBNP) is a cardiac biomarker that has recently shown to be of diagnostic value in a diagnosis of decompensated heart failure, acute coronary syndromes and other conditions resulting in myocardial stretch. We sought to study whether sepsis-induced myocardial dilation would result in an elevation of NT-proBNP.
Serum NT-proBNP measurements were made in six consecutive patients with septic shock within 6 hours of admission to the intensive care unit.
Markedly elevated levels of NT-proBNP were found in all six patients.
NT-proBNP levels can be markedly elevated in critically ill patients presenting with septic shock. An elevated NT-proBNP level in a critically ill patient is not specific for decompensated heart failure.
PMCID: PMC522851  PMID: 15312225
brain natriuretic peptide; N-terminal pro brain natriuretic peptide; septic shock
21.  Pulmonary symptoms and diagnoses are associated with HIV in the MACS and WIHS cohorts 
Several lung diseases are increasingly recognized as comorbidities with HIV; however, few data exist related to the spectrum of respiratory symptoms, diagnostic testing, and diagnoses in the current HIV era. The objective of the study is to determine the impact of HIV on prevalence and incidence of respiratory disease in the current era of effective antiretroviral treatment.
A pulmonary-specific questionnaire was administered yearly for three years to participants in the Multicenter AIDS Cohort Study (MACS) and Women’s Interagency HIV Study (WIHS). Adjusted prevalence ratios for respiratory symptoms, testing, or diagnoses and adjusted incidence rate ratios for diagnoses in HIV-infected compared to HIV-uninfected participants were determined. Risk factors for outcomes in HIV-infected individuals were modeled.
Baseline pulmonary questionnaires were completed by 907 HIV-infected and 989 HIV-uninfected participants in the MACS cohort and by 1405 HIV-infected and 571 HIV-uninfected participants in the WIHS cohort. In MACS, dyspnea, cough, wheezing, sleep apnea, and incident chronic obstructive pulmonary disease (COPD) were more common in HIV-infected participants. In WIHS, wheezing and sleep apnea were more common in HIV-infected participants. Smoking (MACS and WIHS) and greater body mass index (WIHS) were associated with more respiratory symptoms and diagnoses. While sputum studies, bronchoscopies, and chest computed tomography scans were more likely to be performed in HIV-infected participants, pulmonary function tests were no more common in HIV-infected individuals. Respiratory symptoms in HIV-infected individuals were associated with history of pneumonia, cardiovascular disease, or use of HAART. A diagnosis of asthma or COPD was associated with previous pneumonia.
In these two cohorts, HIV is an independent risk factor for several respiratory symptoms and pulmonary diseases including COPD and sleep apnea. Despite a higher prevalence of chronic respiratory symptoms, testing for non-infectious respiratory diseases may be underutilized in the HIV-infected population.
PMCID: PMC4021087  PMID: 24884738
AIDS; HIV; Pulmonary disease; Chronic obstructive; Respiratory tract diseases; Sleep apnea syndromes
22.  Amino-Terminal Fragment of the Prohormone Brain-type Natriuretic Peptide (NT-proBNP) in Rheumatoid Arthritis 
Arthritis and rheumatism  2008;58(9):2662-2669.
Increased concentrations of amino-terminal prohormone brain-type natriuretic peptide (NT-proBNP) are associated with cardiovascular morbidity and mortality, but little is known about their relationship to chronic inflammation. Patients with rheumatoid arthritis (RA) have chronic inflammation, increased arterial stiffness and accelerated coronary atherosclerosis. We tested the hypothesis that NT-proBNP concentrations are elevated in patients with RA, and are associated with coronary artery calcification and markers of inflammation.
In 159 subjects with RA (90 patients with early RA and 69 patients with longstanding RA) without heart failure and 88 control subjects, we measured serum concentrations of NT-proBNP, interleukin (IL)-6, and tumor necrosis factor-α (TNF-α), and coronary calcification.
NT-proBNP concentrations were elevated in patients with long-standing RA [median (IQR): 142.8 (54.8–270.5) pg/mL] and those with early RA [58.1 (19.4–157.6) pg/mL] compared to controls [18.1 (3.2–46.0) pg/mL, P<0.001]. In patients with RA, NT-proBNP concentrations were associated with age (ρ=0.35, P<0.001), IL-6 (ρ=0.33, P<0.001), TNF-α (ρ=0.23, P=0.003), CRP (ρ=0.21, P=0.01), coronary calcium score (ρ=0.30, P<0.001), systolic blood pressure (ρ=0.30, p<0.001), and disease activity (ρ=0.29, P<0.001). After adjustment for age, race and sex the associations between NT-proBNP concentrations and disease activity (P<0.001), TNF-α (P<0.001), IL-6 (P=0.04) and CRP concentrations (P=0.02) remained significant, but those with systolic blood pressure (P=0.10) and coronary calcium score (P=0.27) were attenuated.
NT-proBNP concentrations are increased in patients with RA without clinical heart failure and may indicate subclinical cardiovascular disease and a chronic inflammatory state.
PMCID: PMC2587412  PMID: 18759301
rheumatoid arthritis; inflammation; atherosclerosis; B-type natriuretic peptide; NT-proBNP
23.  New insight into the role of NT-proBNP in alcoholic liver cirrhosis as a noninvasive marker of esophageal varices 
Croatian Medical Journal  2012;53(4):374-378.
To investigate the association between plasma concentrations of N-terminal pro-B-type natriuretic peptide (NT-proBNP) and formation of esophageal varices.
Thirty-five patients with alcoholic cirrhosis were divided into three groups according to the Child-Pugh classification: grade A (n = 11, 32%), B (n = 12, 34%), and C (n = 12, 34%). System hemodynamic parameters were measured using sphygmomanometry, electrocardiography, and echocardiography. NT-proBNP was analyzed by using an electrochemiluminiscence sandwich immunoassay.
The presence of esophageal varices was associated with a higher serum NT-proBNP level, with a cut-off value of >101 pg/mL (sensitivity, 87.60% and specificity, 72.73%; P < 0.001).
NT-proBNP was found to be a marker of the presence of esophageal varices, but not a marker of progression of liver cirrhosis. In cirrhotic patients, NT-proBNP value >101 pg/mL was shown to be a valuable noninvasive parameter in predicting the presence of varices.
PMCID: PMC3428825  PMID: 22911531
24.  Increased circulating pro-brain natriuretic peptide (proBNP) and brain natriuretic peptide (BNP) in patients with cirrhosis: relation to cardiovascular dysfunction and severity of disease 
Gut  2003;52(10):1511-1517.
Background and aims: Cardiac dysfunction may be present in patients with cirrhosis. This study was undertaken to relate plasma concentrations of cardiac peptides reflecting early ventricular dysfunction (pro-brain natriuretic peptide (proBNP) and brain natriuretic peptide (BNP)) to markers of severity of liver disease, cardiac dysfunction, and hyperdynamic circulation in patients with cirrhosis.
Patients and methods: Circulating levels of proBNP and BNP were determined in 51 cirrhotic patients during a haemodynamic investigation.
Results: Plasma proBNP and BNP were significantly increased in cirrhotic patients (19 and 12 pmol/l, respectively) compared with age matched controls (14 and 6 pmol/l; p<0.02) and healthy subjects (<15 and <5.3 pmol/l; p<0.002). Circulating proBNP and BNP were closely correlated (r = 0.89, p<0.001), and the concentration ratio proBNP/BNP was similar to that of control subjects (1.8 v 2.3; NS). Circulating proBNP and BNP were related to severity of liver disease (Child score, serum albumin, coagulation factors 2, 7, and 10, and hepatic venous pressure gradient) and to markers of cardiac dysfunction (QT interval, heart rate, plasma volume) but not to indicators of the hyperdynamic circulation. Moreover, in multiple regression analysis, proBNP and BNP were also related to arterial carbon dioxide and oxygen tensions. The rate of hepatic disposal of proBNP and BNP was not significantly different in cirrhotic patients and controls.
Conclusion: Elevated circulating levels of proBNP and BNP in patients with cirrhosis most likely reflects increased cardiac ventricular generation of these peptides and thus indicates the presence of cardiac dysfunction, rather than being caused by the hyperdynamic circulatory changes found in these patients.
PMCID: PMC1773816  PMID: 12970147
brain natriuretic peptide; cardiac dysfunction; cirrhotic cardiomyopathy; pro-brain natriuretic peptide; QT interval; cardiac ventricular peptides
25.  Biomarkers of Cardiac Dysfunction and Mortality from Community-Acquired Pneumonia in Adults 
PLoS ONE  2013;8(5):e62612.
Cardiac dysfunction is common in acute respiratory diseases and may influence prognosis. We hypothesised that blood levels of N-terminal B-type natriuretic peptide (NT-proBNP) and high-sensitivity Troponin T would predict mortality in adults with community-acquired pneumonia.
Methods and Findings
A prospective cohort of 474 consecutive patients admitted with community-acquired pneumonia to two New Zealand hospitals over one year. Blood taken on admission was available for 453 patients and was analysed for NT-proBNP and Troponin T. Elevated levels of NT-proBNP (>220 pmol/L) were present in 148 (33%) and 86 (19%) of these patients respectively. Among the 26 patients who died within 30 days of admission, 23 (89%) had a raised NT-proBNP and 14 (53%) had a raised Troponin T level on admission compared to 125 (29%) and 72 (17%) of the 427 who survived (p values<0.001). Both NT-proBNP and Troponin T predicted 30-day mortality in age-adjusted analysis but after mutual adjustment for the other cardiac biomarker and the Pneumonia Severity Index, a raised N-terminal pro-brain natriuretic peptide remained a predictor of 30-day mortality (OR = 5.3, 95% CI 1.4–19.8, p = 0.013) but Troponin T did not (OR = 1.3, 95% CI 0.5–3.2, p = 0.630). The areas under the receiver-operating curves to predict 30-day mortality were similar for NT-proBNP (0.88) and the Pneumonia Severity Index (0.87).
Elevated N-terminal B-type natriuretic peptide is a strong predictor of mortality from community-acquired pneumonia independent of clinical prognostic indicators. The pathophysiological basis for this is unknown but suggests that cardiac involvement may be an under-recognised determinant of outcome in pneumonia and may require a different approach to treatment. In the meantime, measurement of B-type natriuretic peptides may help to assess prognosis.
PMCID: PMC3646835  PMID: 23667500

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