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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.
doi:10.1089/aid.2009.0038
PMCID: PMC2791362  PMID: 19803714
2.  Mendelian Randomization Study of B-Type Natriuretic Peptide and Type 2 Diabetes: Evidence of Causal Association from Population Studies 
PLoS Medicine  2011;8(10):e1001112.
Using mendelian randomization, Roman Pfister and colleagues demonstrate a potentially causal link between low levels of B-type natriuretic peptide (BNP), a hormone released by damaged hearts, and the development of type 2 diabetes.
Background
Genetic and epidemiological evidence suggests an inverse association between B-type natriuretic peptide (BNP) levels in blood and risk of type 2 diabetes (T2D), but the prospective association of BNP with T2D is uncertain, and it is unclear whether the association is confounded.
Methods and Findings
We analysed the association between levels of the N-terminal fragment of pro-BNP (NT-pro-BNP) in blood and risk of incident T2D in a prospective case-cohort study and genotyped the variant rs198389 within the BNP locus in three T2D case-control studies. We combined our results with existing data in a meta-analysis of 11 case-control studies. Using a Mendelian randomization approach, we compared the observed association between rs198389 and T2D to that expected from the NT-pro-BNP level to T2D association and the NT-pro-BNP difference per C allele of rs198389. In participants of our case-cohort study who were free of T2D and cardiovascular disease at baseline, we observed a 21% (95% CI 3%–36%) decreased risk of incident T2D per one standard deviation (SD) higher log-transformed NT-pro-BNP levels in analysis adjusted for age, sex, body mass index, systolic blood pressure, smoking, family history of T2D, history of hypertension, and levels of triglycerides, high-density lipoprotein cholesterol, and low-density lipoprotein cholesterol. The association between rs198389 and T2D observed in case-control studies (odds ratio = 0.94 per C allele, 95% CI 0.91–0.97) was similar to that expected (0.96, 0.93–0.98) based on the pooled estimate for the log-NT-pro-BNP level to T2D association derived from a meta-analysis of our study and published data (hazard ratio = 0.82 per SD, 0.74–0.90) and the difference in NT-pro-BNP levels (0.22 SD, 0.15–0.29) per C allele of rs198389. No significant associations were observed between the rs198389 genotype and potential confounders.
Conclusions
Our results provide evidence for a potential causal role of the BNP system in the aetiology of T2D. Further studies are needed to investigate the mechanisms underlying this association and possibilities for preventive interventions.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Worldwide, nearly 250 million people have diabetes, and this number is increasing rapidly. Diabetes is characterized by dangerous amounts of sugar (glucose) in the blood. Blood sugar levels are normally controlled by insulin, a hormone that the pancreas releases after meals (digestion of food produces glucose). In people with type 2 diabetes (the most common form of diabetes), blood sugar control fails because the fat and muscle cells that usually respond to insulin by removing sugar from the blood become insulin resistant. Type 2 diabetes can be controlled with diet and exercise, and with drugs that help the pancreas make more insulin or that make cells more sensitive to insulin. The long-term complications of diabetes, which include kidney failure and an increased risk of cardiovascular problems such as heart disease and stroke, reduce the life expectancy of people with diabetes by about 10 years compared to people without diabetes.
Why Was This Study Done?
Because the causes of type 2 diabetes are poorly understood, it is hard to devise ways to prevent the condition. Recently, B-type natriuretic peptide (BNP, a hormone released by damaged hearts) has been implicated in type 2 diabetes development in cross-sectional studies (investigations in which data are collected at a single time point from a population to look for associations between an illness and potential risk factors). Although these studies suggest that high levels of BNP may protect against type 2 diabetes, they cannot prove a causal link between BNP levels and diabetes because the study participants with low BNP levels may share some another unknown factor (a confounding factor) that is the real cause of both diabetes and altered BNP levels. Here, the researchers use an approach called “Mendelian randomization” to examine whether reduced BNP levels contribute to causing type 2 diabetes. It is known that a common genetic variant (rs198389) within the genome region that encodes BNP is associated with a reduced risk of type 2 diabetes. Because gene variants are inherited randomly, they are not subject to confounding. So, by investigating the association between BNP gene variants that alter NT-pro-BNP (a molecule created when BNP is being produced) levels and the development of type 2 diabetes, the researchers can discover whether BNP is causally involved in this chronic condition.
What Did the Researchers Do and Find?
The researchers analyzed the association between blood levels of NT-pro-BNP at baseline in 440 participants of the EPIC-Norfolk study (a prospective population-based study of lifestyle factors and the risk of chronic diseases) who subsequently developed diabetes and in 740 participants who did not develop diabetes. In this prospective case-cohort study, the risk of developing type 2 diabetes was associated with lower NT-pro-BNP levels. They also genotyped (sequenced) rs198389 in the participants of three case-control studies of type 2 diabetes (studies in which potential risk factors for type 2 diabetes were examined in people with type 2 diabetes and matched controls living in the East of England), and combined these results with those of eight similar published case-control studies. Finally, the researchers showed that the association between rs198389 and type 2 diabetes measured in the case-control studies was similar to the expected association calculated from the association between NT-pro-BNP level and type 2 diabetes obtained from the prospective case-cohort study and the association between rs198389 and BNP levels obtained from the EPIC-Norfolk study and other published studies.
What Do These Findings Mean?
The results of this Mendelian randomization study provide evidence for a causal, protective role of the BNP hormone system in the development of type 2 diabetes. That is, these findings suggest that low levels of BNP are partly responsible for the development of type 2 diabetes. Because the participants in all the individual studies included in this analysis were of European descent, these findings may not be generalizable to other ethnicities. Moreover, they provide no explanation of how alterations in the BNP hormone system might affect the development of type 2 diabetes. Nevertheless, the demonstration of a causal link between the BNP hormone system and type 2 diabetes suggests that BNP may be a potential target for interventions designed to prevent type 2 diabetes, particularly since the feasibility of altering BNP levels with drugs has already been proven in patients with cardiovascular disease.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001112.
The International Diabetes Federation provides information about all aspects of diabetes
The US National Diabetes Information Clearinghouse provides detailed information about diabetes for patients, health-care professionals, and the general public (in English and Spanish)
The UK National Health Service Choices website also provides information for patients and carers about type 2 diabetes and includes people's stories about diabetes
MedlinePlus provides links to further resources and advice about diabetes (in English and Spanish)
Wikipedia has pages on BNP and on Mendelian randomization (note: Wikipedia is a free online encyclopedia that anyone can edit; available in several languages)
The charity Healthtalkonline has interviews with people about their experiences of diabetes; the charity Diabetes UK has a further selection of stories from people with diabetes
doi:10.1371/journal.pmed.1001112
PMCID: PMC3201934  PMID: 22039354
3.  B-type natriuretic peptide versus amino terminal pro-B type natriuretic peptide: selecting the optimal heart failure marker in patients with impaired kidney function 
BMC Nephrology  2013;14:117.
Background
The effect of impaired kidney function on B-type natriuretic peptide (BNP) and N-terminal proBNP (NT-proBNP) is vague. This study was performed to examine the effect of kidney dysfunction on the afore-mentioned markers and determine appropriate cutoffs for systolic heart failure (SHF).
Methods
In this cross sectional study adults with estimated glomerular filtration rate (eGFR) <60 ml/min for ≥3 months were identified in consulting clinics from June 2009 to March 2010. SHF was defined as documented by a cardiologist with ejection fraction of < 40% and assessed by New York Heart Association classification (NYHA). Plasma was assayed for creatinine (Cr), BNP and NT-proBNP.
Results
A total of 190 subjects were enrolled in the study, 95 with and 95 without SHF. The mean age of patients was 58 (±15) years, 67.4% being males. Mean BNP levels showed a 2.5 fold and 1.5 fold increase from chronic kidney disease (CKD) stage 3 to stage 5 in patients with and without SHF respectively. NT-proBNP levels in non-heart failure group were 3 fold higher in CKD stage 5 compared to stage 3. Mean NT-proBNP levels were 4 fold higher in CKD stage 5 compared to stage 3 in patients with SHF. Optimal BNP and NT-proBNP cutoffs of SHF diagnosis for the entire CKD group were 300 pg/ml and 4502 pg/ml respectively.
Conclusion
BNP and NT-proBNP were elevated in kidney dysfunction even in the absence of SHF; however the magnitude of increase in NT-proBNP was greater than that of BNP. BNP and NT-proBNP can be useful in diagnosing SHF, nonetheless, by using higher cutoffs stratified according to kidney dysfunction. NT-proBNP appears to predict heart failure better than BNP.
doi:10.1186/1471-2369-14-117
PMCID: PMC3680180  PMID: 23725445
B-Type natriuretic peptide; Heart failure; NT-proBNP; Kidney
4.  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.
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.
doi:10.1371/journal.pone.0053233
PMCID: PMC3554706  PMID: 23365636
5.  Anemia is independently associated with NT-proBNP levels in asymptomatic predialysis patients with chronic kidney disease 
Hippokratia  2013;17(4):307-312.
Background: Although anemia and renal dysfunction are related to increased natriuretic peptides levels in heart failure patients, less is known about this relationship in asymptomatic predialysis patients with chronic kidney disease (CKD). The aim of this study was to investigate relationship between hemoglobin (Hb) concentration, N-terminal proBNP (NT-proBNP) levels and echocardiographic findings in these patients.
Methods: The study included 61 patients with CKD stage IV-V (34 male, mean age 62.6 ± 13.6 years) and 22 age- and sex -matched healthy persons as control group. All participants underwent clinical, laboratory and echocardiographic examination, including Tissue Doppler Imaging and colour M-mode Doppler.
Results: Patients with CKD had lower Hb levels (p<0.001), and higher levels of NT-proBNP (p<0.001) than healthy controls. Patients were divided into two groups according to their mean Hb levels: group A, Hb<10.3 g/dL and group B, Hb≥10.3 g/dL. Patients from group A was significantly older (p<0.001), left ventricular mass index was significantly higher (LVMI, p<0.001), LV diastolic function was worse (septal and lateral E’/A’ ratio: p<0.05 and p<0.01, respectively), and the level NT-proBNP was higher (p<0.001) compared to patients from group B. The natural logarithm of NT-proBNP (lnNT-proBNP) showed highly significant correlation with Hb (p<0.001) and significant correlation with estimated glomerular filtration rate (p=0.035) in CKD patients. Multiple regression analysis revealed Hb levels (p<0.01), cholesterol (p<0.001), LV ejection fraction (p<0.001) and septal E/E’ ratio (p<0.01) as the independent variables predicting as much as 54% variability of lnNTpro-BNP.
Conclusions: The increased NT-proBNP levels in asymptomatic patients with advanced CKD were independently associated with echocardiographic parameters of LV function, but anemia may represent one of the important confounder of the relationship between NT-proBNP and cardiovascular abnormalities.
PMCID: PMC4097409  PMID: 25031507
NT-proBNP; anemia; left ventricular dysfunction; chronic kidney disease
6.  N-terminal fragment of probrain natriuretic peptide is associated with diabetes microvascular complications in type 2 diabetes 
Aim/introduction
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.
Materials and methods
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.
Results
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).
Conclusion
In this hospital-based cohort of type 2 diabetes, the NT-proBNP levels were associated with systemic atherosclerosis and comorbid diabetic microvascular as well as macrovascular complications. It is useful to stratify high-risk diabetic patients by measuring NT-proBNP and to start comprehensive care for preventing the progression of diabetic complications. It is necessary to elucidate the underlying mechanism for the progression of diabetic complications represented by an elevation of NT-proBNP and to demonstrate the ability of NT-proBNP as a predictive global biomarker for diabetic complications in Japanese type 2 diabetic patients.
doi:10.2147/VHRM.S67753
PMCID: PMC4199566  PMID: 25328404
NT-proBNP; diabetic complication; biomarker
7.  Usefulness of natriuretic peptides in primary health care: An exploratory study in elderly patients 
Objective
To explore the negative predictive value (NPV), positive predictive value (PPV), sensitivity, and specificity of natriuretic peptides, cut-off levels, and the impact of gender and age in elderly patients with systolic heart failure (HF).
Design
Cross-sectional exploratory study.
Setting
One primary healthcare centre.
Patients
A total of 109 patients with symptoms of HF were referred for echocardiographic examination with a cardiovascular consultation. Systolic HF was diagnosed (ESC guidelines) in 48 patients (46% men, 54% women, mean age 79 years) while 61 patients (21% men, 79% women, mean age 76 years) had no HF.
Main outcome measures
NPV, PPV, sensitivity, specificity, and cut-off levels.
Results
Including all 109 patients, NPV was 88% for NT-proBNP (200 ng/L) and 87% for BNP (20 pg/ml). PPV was 81% for NT-proBNP (500 ng/L) and 68% for BNP (50 pg/ml). Sensitivity was 96% for NT-proBNP (100 ng/L) and 96% for BNP (10-20 pg/ml). Specificity was 87% for NT-proBNP (500 ng/L) and 71% for BNP (50 pg/ml). Nt-proBNP (β = 0.035; p < 0.001) and BNP (β = 0.030; p < 0.001) were associated with age, but not with gender. In a multivariate analysis age (β = 0.036; p < 0.001) and male gender (β = 0.270; p = 0.014) were associated with NT-proBNP, but only age for BNP (β = 0.030; p < 0.001).
Conclusion
Natriuretic peptides in an elderly population showed high NPVs, but not as high as in younger patients with HF in other studies. Age and male gender were associated with higher levels of NT-proBNP while only age was related to elevated BNP levels.
doi:10.3109/02813430903345074
PMCID: PMC3440611  PMID: 20192890
Echocardiography; elderly; family practice; gender; natriuretic peptides; primary health care; systolic heart failure
8.  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
9.  Natriuretic peptide testing for the evaluation of critically ill patients with shock in the intensive care unit: a prospective cohort study 
Critical Care  2006;10(1):R37.
Introduction
Amino-terminal pro-brain natriuretic peptide (NT-proBNP) is useful in evaluating heart failure, but its role in evaluating patients with shock in the intensive care unit (ICU) is not clear.
Method
Forty-nine consecutive patients in four different ICUs with shock of various types and with an indication for pulmonary artery catheter placement were evaluated. Analyses for NT-proBNP were performed on blood obtained at the time of catheter placement and results were correlated with pulmonary artery catheter findings. Logistic regression identified independent predictors of mortality.
Results
A wide range of NT-proBNP levels were observed (106 to >35,000 pg/ml). There was no difference in median NT-proBNP levels between patients with a cardiac and those with a noncardiac origin to their shock (3,046 pg/ml versus 2,959 pg/ml; P = 0.80), but an NT-proBNP value below 1,200 pg/ml had a negative predictive value of 92% for cardiogenic shock. NT-proBNP levels did not correlate with filling pressures or hemodynamics (findings not significant). NT-proBNP concentrations were higher in patients who died in the ICU (11,859 versus 2,534 pg/ml; P = 0.03), and the mortality rate of patients in the highest log-quartile of NT-proBNP (66.7%) was significantly higher than those in other log-quartiles (P < 0.001); NT-proBNP independently predicted ICU mortality (odds ratio 14.8, 95% confidence interval 1.8–125.2; P = 0.013), and was superior to Acute Physiology and Chronic Health Evaluation II score and brain natriuretic peptide in this regard.
Conclusion
Elevated levels of NT-proBNP do not necessarily correlate with high filling pressures among patients with ICU shock, but marked elevation in NT-proBNP is strongly associated with ICU death. Low NT-proBNP values in patients with ICU shock identifed those at lower risk for death, and may be useful in excluding the need for pulmonary artery catheter placement in such patients.
doi:10.1186/cc4839
PMCID: PMC1550815  PMID: 16507171
10.  Analysis of N-terminal pro-B-type natriuretic peptide and cardiac index in multiple injured patients: a prospective cohort study 
Critical Care  2008;12(5):R118.
Introduction
Increased serum B-type natriuretic peptide (BNP) has been identified for diagnosis and prognosis of impaired cardiac function in patients suffering from congestive heart failure, ischemic heart disease, and sepsis. However, the prognostic value of BNP in multiple injured patients developing multiple organ dysfunction syndrome (MODS) remains undetermined. Therefore, the aims of this study were to assess N-terminal pro-BNP (NT-proBNP) in multiple injured patients and to correlate the results with invasively assessed cardiac output and clinical signs of MODS.
Methods
Twenty-six multiple injured patients presenting a New Injury Severity Score of greater than 16 points were included. The MODS score was calculated on admission as well as 24, 48, and 72 hours after injury. Patients were subdivided into groups: group A showed minor signs of organ dysfunction (MODS score less than or equal to 4 points) and group B suffered from major organ dysfunction (MODS score of greater than 4 points). Venous blood (5 mL) was collected after admission and 6, 12, 24, 48, and 72 hours after injury. NT-proBNP was determined using the Elecsys proBNP® assay. The hemodynamic monitoring of cardiac index (CI) was performed using transpulmonary thermodilution.
Results
Serum NT-proBNP levels were elevated in all 26 patients. At admission, the serum NT-proBNP values were 116 ± 21 pg/mL in group A versus 209 ± 93 pg/mL in group B. NT-proBNP was significantly lower at all subsequent time points in group A in comparison with group B (P < 0.001). In contrast, the CI in group A was significantly higher than in group B at all time points (P < 0.001). Concerning MODS score and CI at 24, 48, and 72 hours after injury, an inverse correlation was found (r = -0.664, P < 0.001). Furthermore, a correlation was found comparing MODS score and serum NT-proBNP levels (r = 0.75, P < 0.0001).
Conclusions
Serum NT-proBNP levels significantly correlate with clinical signs of MODS 24 hours after multiple injury. Furthermore, a distinct correlation of serum NT-proBNP and decreased CI was found. The data of this pilot study may indicate a potential value of NT-proBNP in the diagnosis of post-traumatic cardiac impairment. However, further studies are needed to elucidate this issue.
doi:10.1186/cc7013
PMCID: PMC2592747  PMID: 18789145
11.  Association of cardiac and renal function with extreme N-terminal fragment Pro-B-type natriuretic peptide levels in elderly patients 
Background
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.
Methods
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.
Results
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).
Conclusion
These data suggest that the extreme elevation of NT pro-BNP levels (≥3000 pg/ml) is mainly determined by impaired renal function in elderly patients above 80 years. Extreme NT pro-BNP levels may be useful for assessing the severity of impaired renal function.
doi:10.1186/1471-2261-12-57
PMCID: PMC3422193  PMID: 22834778
NT pro-BNP; Factors; Elderly; Impaired renal function
12.  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 
Objective
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).
Methods
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.
Results
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.
Conclusion
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.
doi:10.2147/CIA.S42700
PMCID: PMC3665499  PMID: 23723693
aged; coronary artery disease; chronic kidney disease; N-terminal pro-brain natriuretic peptide; prognosis
13.  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.
Background
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.
Methods
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.
Results
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.
Conclusions
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.
doi:10.2188/jea.JE20120087
PMCID: PMC3700260  PMID: 23474820
carotenoids; N-terminal pro-brain-type natriuretic peptide; cross-sectional study
14.  Elevated NT-proBNP Levels are Associated with Poor Cognitive Function in Community-Dwelling Older Adults: Results from the Rancho Bernardo Study 
The American journal of medicine  2011;124(7):670.e1-670.e8.
Background
Natriuretic peptides (NP’s) have prognostic value across a wide spectrum of cardiovascular diseases and may predict cognitive dysfunction in patients with cardiovascular disease even in the absence of prior stroke. Little is known about the association of NP’s with cognitive function in community-dwelling adults. We assessed the association between NT-proBNP levels and cognitive function in community-dwelling ambulatory older adults in the Rancho Bernardo Study.
Methods
We studied 950 men and women, aged 60 years and older, who attended a research clinic visit where a medical history and examination were performed, and blood for cardiovascular disease risk factors and NT-proBNP levels were obtained. Three cognitive function tests were administered: Mini Mental State Exam (MMSE), Trail-Making Test B (Trails B), and Category Fluency.
Results
Participants with high NT-proBNP levels (≥450 pg/mL, n=198) were older and had a higher prevalence of coronary heart disease (12% vs. 30%), and stroke (5% vs. 11%) (both p’s≤0.001). In unadjusted analyses, all three cognitive function test scores were significantly associated with NT-proBNP levels (p<0.001). After adjusting for age, sex, education, hypertension, body mass index, exercise, alcohol use, smoking, low density lipoprotein cholesterol, creatinine clearance, and prior cardiovascular disease, elevated NT-proBNP levels remained independently associated with poor cognitive performance on MMSE (odds ratio [95% confidence interval] 2.0 [1.1–3.6], p=0.02) and Trails B (1.7 [1.2–2.7], p=0.01), but not Category Fluency (1.4 [0.9–2.2], p=0.19). Results were unchanged after excluding the 6% of participants with a history of stroke.
Conclusions
NT-proBNP levels were strongly and independently associated with poor cognitive function in community-dwelling older adults.
doi:10.1016/j.amjmed.2011.02.027
PMCID: PMC3173742  PMID: 21683832
natriuretic peptides; cerebrovascular disorders; cardiovascular diseases; community; elderly; cognitive function
15.  N-Terminal Fragment of the Prohormone Brain-Type Natriuretic Peptide (NT-proBNP), Cardiovascular Events, and Mortality in Patients With Stable Coronary Heart Disease 
Context
Identification of individuals at high risk for cardiovascular events is important for the optimal use of primary and secondary prevention measures.
Objective
To determine whether plasma levels of amino terminal fragment of the prohormone brain-type natriuretic peptide (NT-proBNP) predict cardiovascular events or death independent of other available prognostic tests.
Design, Setting, and Participants
Prospective cohort study (2000–2002) of 987 individuals in California with stable coronary heart disease in the Heart and Soul Study, who were followed up for a mean of 3.7 (range, 0.1–5.3) years.
Main Outcome Measures
The association of baseline NT-proBNP levels with death or cardiovascular events (myocardial infarction, stroke, or heart failure). Traditional clinical risk factors, echocardiographic measures, ischemia, other biomarkers, and New York Heart Association classification were adjusted for to determine whether NT-proBNP levels were independent of other prognostic factors. Receiver operating characteristic (ROC) curves were used to assess the incremental prognostic value of adding NT-proBNP level to these other measures.
Results
A total of 256 participants (26.2%) had a cardiovascular event or died. Each increasing quartile of NT-proBNP level (range of quartile 1, 8.06–73.95 pg/mL; quartile 2, 74–174.5 pg/mL; quartile 3, 175.1–459 pg/mL; quartile 4, ≥460 pg/mL) was associated with a greater risk of cardiovascular events or death, ranging from 23 of 247 (annual event rate, 2.6%) in the lowest quartile to 134 of 246 (annual event rate, 19.6%) in the highest quartile (unadjusted hazard ratio [HR] for quartile 4 vs quartile 1, 7.8; 95% confidence interval [CI], 5.0–12.1; P<.001). Each SD increase in log NT-proBNP level (1.3 pg/mL) was associated with a 2.3-fold increased rate of adverse cardiovascular outcomes (unadjusted HR, 2.3; 95% CI, 2.0–2.6; P<.001), and this association persisted after adjustment for all of the other prognostic measures (adjusted HR, 1.7; 95% CI, 1.3–2.2; P<.001). The addition of NT-proBNP level to standard clinical assessment and complete echocardiographic parameters significantly improved the area under the ROC curves for predicting subsequent adverse cardiovascular outcomes (0.80 for clinical risk factors and echocardiographic parameters plus log NT-proBNP vs 0.76 for clinical risk factors and echocardiographic parameters only; P=.006).
Conclusions
Elevated levels of NT-proBNP predict cardiovascular morbidity and mortality, independent of other prognostic markers, and identify at-risk individuals even in the absence of systolic or diastolic dysfunction by echocardiography. Level of NT-proBNP may help guide risk stratification of high-risk individuals, such as those with coronary heart disease.
doi:10.1001/jama.297.2.169
PMCID: PMC2848442  PMID: 17213400
16.  Association between High-Sensitivity C-Reactive Protein and N-Terminal Pro-B-Type Natriuretic Peptide in Patients with Hepatitis C Virus Infection 
Mediators of Inflammation  2012;2012:730923.
Background. Prior study showed HCV-infected patients have increased serum N-Terminal Pro-B-Type Natriuretic Peptide (NT-proBNP) and a possible left ventricular diastolic dysfunction. The objectives of the present paper were to investigate the characteristics of hs-CRP and its correlation with clinical profiles including NT-proBNP and echocardiographic variables in HCV-infected patients. Methods and Results. A total of 106 HCV-infected patients and 106 control healthy individuals were enrolled. The level of serum hs-CRP (median 1.023 mg/L, range 0.03∼5.379 mg/L) was significantly lower in all 106 patients than that in controls (median 3.147 mg/L, range 0.08~7.36 mg/L, P = 0.012). Although hs-CRP did not correlate significantly with NT-proBNP when all patients and controls were included (r = 0.169, P = 0.121), simple regression analysis demonstrated a statistically significant linear correlation between hs-CRP and NT-proBNP in HCV-infected patients group (r = 0.392, P = 0.017). Independent correlates of hs-CRP levels (R2 = 0.13) were older age (β′ = 0.031, P = 0.025) and NT proBNP (β′ = 0.024, P = 0.017). Conclusions. Although the level of serum hs-CRP decreased significantly, there was a significant association between hs-CRP and NT-proBNP in HCV-infected patients.
doi:10.1155/2012/730923
PMCID: PMC3356947  PMID: 22645408
17.  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.
doi:10.3748/wjg.15.5074
PMCID: PMC2768887  PMID: 19860001
NTProBNP; Tumor necrosis factor α; Hepatitis C; Mixed cryoglobulinemia; Heart failure
18.  N-Terminal Pro-B-Type Natriuretic Peptide and Inducible Ischemia in the Heart and Soul Study 
Clinical cardiology  2009;32(8):447-453.
Background
B-type natriuretic peptide (BNP) is predictive of inducible ischemia in patients with coronary heart disease (CHD). Whether N-terminal pro-B-type natriuretic peptide (NT-proBNP) has a comparable strength of association with ischemia is uncertain.
Hypothesis
Resting NT-proBNP levels are associated with inducible ischemia in patients with stable CHD.
Methods
We performed a cross-sectional study of 901 outpatients with stable CHD. NT-proBNP was measured in all patients prior to exercise treadmill testing and stress echocardiography. In addition, plasma BNP was measured in a subset of 355 participants. Logistic regression was used to examine the association of NT-proBNP and BNP quartiles with inducible ischemia.
Results
Inducible ischemia was found in 216 (24%) patients. The proportion with inducible ischemia ranged from 42% (95/225) in the highest quartile of NT-proBNP levels (>410 pg/ml) to 9% (21/226) in the lowest quartile (0–72 pg/ml). The highest quartile had a 7-fold greater odds of inducible ischemia than the lowest quartile (odds ratio [OR]: 7.1, 95% confidence interval [CI]: 4.2–12; P<0.0001). This association remained robust after adjustment for traditional cardiovascular risk factors, left ventricular ejection fraction, and diastolic dysfunction (OR: 3.6, 95% CI: 1.4–9.1; P = 0.009). In the subgroup with measurements of both NT-proBNP and BNP, both natriuretic peptides were predictive of ischemia. The multivariable-adjusted c-statistics for inducible ischemia were 0.71 for NT-proBNP and 0.62 for BNP (entered as continuous variables).
Conclusions
Resting NT-proBNP levels are independently associated with inducible ischemia in outpatients with stable CHD. Baseline elevations of natriuretic peptide may indicate subclinical inducible ischemia in high risk patients with CHD.
doi:10.1002/clc.20569
PMCID: PMC2790280  PMID: 19685518
19.  Serum levels of N–terminal proB–type natriuretic peptide in mechanically ventilated critically ill patients – relation to tidal volume size and development of acute respiratory distress syndrome 
Background
Serum levels of N–terminal proB–type natriuretic peptide (NT–proBNP) are elevated in patients acute respiratory distress syndrome (ARDS). Recent studies showed a lower incidence of acute cor pulmonale in ARDS patients ventilated with lower tidal volumes. Consequently, serum levels of NT–proBNP may be lower in these patients.
We investigated the relation between serum levels of NT–proBNP and tidal volumes in critically ill patients without ARDS at the onset of mechanical ventilation.
Methods
Secondary analysis of a randomized controlled trial of lower versus conventional tidal volumes in patients without ARDS. NT–pro BNP were measured in stored serum samples. Serial serum levels of NT–pro BNP were analyzed controlling for acute kidney injury, cumulative fluid balance and presence of brain injury. The primary outcome was the effect of tidal volume size on serum levels of NT–proBNP. Secondary outcome was the association with development of ARDS.
Results
Samples from 150 patients were analyzed. No relation was found between serum levels of NT–pro BNP and tidal volume size. However, NT-proBNP levels were increasing in patients who developed ARDS. In addition, higher levels were observed in patients with acute kidney injury, and in patients with a more positive cumulative fluid balance.
Conclusion
Serum levels of NT–proBNP are independent of tidal volume size, but are increasing in patients who develop ARDS.
doi:10.1186/1471-2466-13-42
PMCID: PMC3717013  PMID: 23837838
Mechanical ventilation; Acute lung injury; Tidal volume; Ventilator–associated lung injury; NT–proBNP
20.  Cardiopulmonary function in individuals with HIV infection in the antiretroviral therapy era 
AIDS (London, England)  2012;26(6):731-740.
Objective
To determine relationship of echocardiographic measures of pulmonary hypertension to lung function and inflammatory biomarkers in HIV-infected individuals.
Design
Cross-sectional study of 116 HIV-infected outpatients.
Methods
Doppler-echocardiography and pulmonary function testing were performed. Induced sputum and plasma cytokines, sputum cell counts and differentials, markers of peripheral T cell activation, and serum N-terminal pro-brain natriuretic peptide (NT-proBNP) were measured. Univariate and multivariate analyses determined relationship of echocardiographic variables to pulmonary function, inflammation, and NT-proBNP.
Results
Mean estimated pulmonary artery systolic pressure (PASP) was 34.3 mmHg (SD 6.9) and mean tricuspid regurgitant jet velocity (TRV) was 2.5 m/sec (SD 0.32). Eighteen participants (15.5%) had PASP of at least 40 mmHg, and 9 (7.8%) had TRV of at least 3.0 m/sec. Elevated TRV was significantly associated with CD4 cell counts below 200 cells/μl and higher log HIV RNA levels. Forced expiratory volume in one second (FEV1) percent predicted, FEV1/forced vital capacity (FVC), and diffusing capacity for carbon monoxide (DLco) percent predicted were significantly lower in those with elevated PASP or TRV. Sputum interleukin-8, peripheral interleukin-8, peripheral interferon-γ levels, and CD8+ T-cell expression of CD69+ were associated increased with increasing PASP and TRV. Log NT-proBNP was significantly higher with increasing PASP and TRV. Left ventricular function was not associated with PASP or TRV.
Conclusions
Echocardiographic manifestations of pulmonary hypertension are common in HIV and are associated with respiratory symptoms, more advanced HIV disease, airway obstruction, abnormal DLco, and systemic and pulmonary inflammation. Pulmonary hypertension and COPD coexist in HIV and may arise secondary to common inflammatory mechanisms.
doi:10.1097/QAD.0b013e32835099ae
PMCID: PMC3606053  PMID: 22210636
HIV; pulmonary hypertension; emphysema; COPD; inflammation
21.  N-Terminal Pro-B-type Natriuretic Peptide Levels in the Korean General Population 
Korean Circulation Journal  2010;40(12):645-650.
Background and Objectives
B-type natriuretic peptide (BNP) or N-terminal pro-BNP (NT-proBNP) levels may serve as a useful marker of cardiovascular risk for screening of the general population. We evaluated reference levels and distribution of NT-proBNP in the Korean general population based on a large cohort study.
Subjects and Methods
We included 1,518 adult subjects (ages 40-69) of a community-based cohort from the Korea Rural Genomic Cohort (KRGC) Study. Thorough biochemical and clinical data were recorded for all subjects. Levels of NT-proBNP from all participants were determined. In order to determine normal reference levels, subjects with factors known to influence NT-proBNP levels were excluded.
Results
The characteristics of the cohort are described below; subjects were 41.2% male, and the mean age was 54.8±8.4 years. The distribution of risk factors for cardiovascular disease in the cohort included hypertension (25%), left ventricular hypertrophy by electrocardiography (ECG-LVH) (15%), hypercholestolemia (4.5%), smoking (32%), diabetes (10.9%), history of coronary heart disease (4.9%), history of heart failure (0.9%), symptoms of heart failure (6.1%), elevated serum creatinine (≥1.5, 3.7%), and severe obesity (body mass index >30 kg/m2, 4.6%). The levels of NT-proBNP of all subjects are shown below; the mean was 60.1±42.1, and the median was 36.5 pg/mL. In addition, the levels of NT-proBNP of normal subjects (which did not have any risk factors, n=224) are shown below; the mean was 40.8, and the median was 32.1 pg/mL. In normal subjects, the NT-proBNP level was slightly higher in females (25.7±24.8 vs. 46.9±35.4, p<0.001). NT-proBNP level increased with age in both the normal population and the total population. There were no significant differences in NT-proBNP levels in subjects who smoked, or had diabetes mellitus, hypertension or ECG-LVH. However, in subjects with a history of congestive heart failure (CHF) (58.5±103.29 vs. 213.8±258.8, p<0.005), elevated serum creatinine levels (≥1.5 mg/dL, 146.2±98.2 vs. 54.3±38.1, p<0.001), or who were older (≥60, 48.4 vs. 84.2±139.5 pg/mL, p<0.05), the BNP level was higher. In addition, patients with more than 3 risk factors for CHF had higher BNP levels (risk 0: 40.8±34.0, 1-2: 57.4±93.2, ≥3: 85.0±152.9 pg/mL). NT-proBNP levels were also related with age, sex, urine albumin, serum Cr, and high sensitivity C-reactive protein (p<0.05).
Conclusion
We determined the reference value and distribution of NT-proBNP in the Korean adult general population. We also found that adjustments for the independent effects of age, sex and renal function appear necessary when determining cardiac risk based on proBNP levels.
doi:10.4070/kcj.2010.40.12.645
PMCID: PMC3025338  PMID: 21267387
Natriuretic peptides; Cohort studies; Population surveillance; Reference values
22.  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 
PLoS ONE  2014;9(3):e92314.
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.
doi:10.1371/journal.pone.0092314
PMCID: PMC3965412  PMID: 24667631
23.  NT Pro BNP Plasma Level and Atrial Volume Are Linked to the Severity of Liver Cirrhosis 
PLoS ONE  2013;8(8):e68364.
Background and Aims
Plasma levels of NT-pro-BNP, a natriuretic peptide precursor, are raised in the presence of fluid retention of cardiac origin and can be used as markers of cardiac dysfunction. Recent studies showed high levels of NT pro BNP in patients with cirrhosis. We assessed NT pro-BNP and other parameters of cardiac dysfunction in patients with cirrhosis, with or without ascites, in order to determine whether the behaviour of NT pro BNP is linked to the stage of liver disease or to secondary cardiac dysfunction.
Methods
Fifty eight consecutive hospitalized patients mostly with viral or NAFLD-related cirrhosis were studied. All underwent abdominal ultrasound and upper GI endoscopy. Cardiac morpho-functional changes were evaluated by echocardiography and NT-pro-BNP plasma levels determined upon admission. Twenty-eight hypertensive patients, without evidence of liver disease served as controls.
Results
Fifty eight cirrhotic patients (72% men) with a median age of 62 years (11% with mild arterial hypertension and 31% with type 2 diabetes) had a normal renal function (mean creatinine 0.9 mg/dl, range 0.7–1.06). As compared to controls, cirrhotic patients had higher NT pro-BNP plasma levels (365.2±365.2 vs 70.8±70.6 pg/ml; p<0.001). Left atrial volume (LAV) (61.8±26.3 vs 43.5±14.1 ml; p = 0.001), and left ventricular ejection fraction (62.7±6.9 vs. 65.5±4%,; p = 0.05) were also altered in cirrhotic patients that in controls. Patients with F2-F3 oesophageal varices as compared to F0/F1, showed higher e' velocity (0.91±0.23 vs 0.66±0.19 m/s, p<0.001), and accordingly a higher E/A ratio (1.21±0.46 vs 0.89±0.33 m/s., p = 0.006).
Conclusion
NT-pro-BNP plasma levels are increased proportionally to the stage of chronic liver disease. Advanced cirrhosis and high NT-pro-BNP levels are significantly associated to increased LAV and to signs of cardiac diastolic dysfunction. NT pro-BNP levels could hence be an useful prognostic indicators of early decompensation of cirrhosis.
doi:10.1371/journal.pone.0068364
PMCID: PMC3734231  PMID: 23940514
24.  N-terminal pro-B-type Natriuretic Peptide is Associated with Sudden Cardiac Death Risk: the Cardiovascular Health Study 
Background
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.
Objective
To examine the relationship between N-terminal pro-B-type natriuretic peptide (NT-proBNP) and SCD in the Cardiovascular Health Study population.
Methods
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
Results
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).
Conclusion
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.
doi:10.1016/j.hrthm.2010.10.038
PMCID: PMC3826546  PMID: 21044699
Sudden cardiac death; B-type natriuretic peptide; BNP; NT-proBNP
25.  Minimally Elevated Cardiac Troponin T and Elevated N-Terminal Pro-B-Type Natriuretic Peptide Predict Mortality in Older Adults: Results From the Rancho Bernardo Study 
Objectives
This study investigated the prognostic value of detectable cardiac troponin T (TnT) and elevated N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels in a population of community-dwelling older adults.
Background
Minimally elevated levels of TnT, a marker of cardiomyocyte injury, have been found in small subsets of the general population, with uncertain implications. A marker of ventricular stretch, NT-proBNP has clinical utility in many venues, but its long-term prognostic value in apparently healthy older adults and in conjunction with TnT is unknown.
Methods
Participants were 957 older adults from the Rancho Bernardo Study with plasma NT-proBNP and TnT measured at baseline (1997 to 1999) and followed up for mortality through July 2006.
Results
Participants with detectable TnT (≥0.01 ng/ml, n = 39) had an increased risk of all-cause and cardiovascular death (adjusted hazard ratio [HR] by Cox proportional hazards analysis: 2.06; 95% confidence interval [CI]: 1.29 to 3.28, p = 0.003 for all-cause mortality; HR: 2.06, 95% CI: 1.03 to 4.12, p = 0.040 for cardiovascular mortality); elevated NT-proBNP also predicted an increased risk of all-cause and cardiovascular mortality (adjusted HR per unit-log increase in NT-proBNP: 1.85, 95% CI: 1.36 to 2.52, p < 0.001 for all-cause mortality; HR: 2.51, 95% CI: 1.55 to 4.08, p < 0.001 for cardiovascular mortality). Those with both elevated NT-proBNP and detectable TnT had poorer survival (HR for high NT-proBNP and detectable TnT vs. low NT-proBNP and any TnT: 3.20, 95% CI: 1.91 to 5.38, p < 0.001). Exclusion of the 152 participants with heart disease at baseline did not materially change the TnT mortality or NT-proBNP mortality associations.
Conclusions
Apparently healthy adults with detectable TnT or elevated NT-proBNP levels are at increased risk of death. Those with both TnT and NT-proBNP elevations are at even higher risk, and the increased risk persists for years.
doi:10.1016/j.jacc.2008.04.033
PMCID: PMC2613773  PMID: 18672166
aging; cardiovascular diseases; epidemiology; natriuretic peptides; prognosis; risk factors; survival

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