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1.  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
2.  The predictive capacity and additional prognostic power of N-terminal pro-B-type natriuretic peptide in Chinese elderly with chronic heart failure 
Objective
This study was conducted to research the prognostic utility of N-terminal pro-B-type natriuretic peptide (NT-proBNP), compare the utility of the Seattle Heart Failure Score (SHFS) with NT-proBNP, develop a risk-evaluation model based on NT-proBNP, assess the associations of NT-proBNP with patient characteristics, and screen for decisive factors of NT-proBNP in Chinese elderly with chronic heart failure (CHF).
Patients and methods
There were 306 patients (≥60 years) with CHF chosen as study subjects. Each one received an assessment of NT-proBNP on serum. The end point was all-cause mortality during a mean follow-up period of 471 days.
Results
Subjects had a median age of 85 (60–100) years, a median NT-proBNP of 1,743.4 pg/mL, and a median SHFS of 1.87. During the follow-up period, 104 deaths occurred. NT-proBNP was significantly related to mortality (odds ratio 1.603, 95% confidence interval 1.407–1.826; P<0.001) and the significance persisted after full adjustment (odds ratio 1.282, 95% confidence interval 1.103–1.489; P=0.001). Age, New York Heart Association class IV CHF, plasma albumin, and neutrophils/lymphocytes were also independent predictors for mortality (P<0.05 for all). NT-proBNP and the SHFS showed similar predictive capacities (0.736 versus 0.796, P=0.105). The addition of NT-proBNP to the SHFS (0.818 versus 0.796, P=0.168) generated marginal growth in the c-statistic. The model based on NT-proBNP consisting of all selected predictors in this study, including age, New York Heart Association class IV CHF, plasma albumin, neutrophils/lymphocytes, and NT-proBNP, had a moderately higher c-statistic compared with the SHFS (0.846 versus 0.796, P=0.066). NT-proBNP was bound with the SHFS (r=0.500, P<0.001). Characteristics regarding general condition, inflammation, and cardiac and renal function were the decisive factors of NT-proBNP (P<0.05 for all).
Conclusion
As a comprehensive representation of the patient characteristics described earlier, NT-proBNP values provided significant prognostic power similar to the SHFS in Chinese elderly with CHF. A novel model based on NT-proBNP could offer help for risk stratification.
doi:10.2147/CIA.S77417
PMCID: PMC4315566
NT-proBNP; prognosis; chronic heart failure; elderly
3.  Correlation Between Levels of N-terminal Pro-B-Type Natriuretic Peptide and Degrees of Heart Failure 
Background
The N-terminal fragment of pro Brain Natriuretic Peptide (NT-pro BNP) is a neuro-hormone synthesized in the cardiac ventricles in response to increased wall tension. The purpose of this study was to assess the correlation between the NT-pro BNP levels and the New York Heart Association function class (NYHA Fc) of dyspnea and echocardiographic findings for the patients who visited our cardiology departments.
Methods
From October, 2002 to April, 2003, serum NT-pro BNP levels were measured in 348 patients who visited the Samsung Medical Center and the Jong Koo Lee Heart Clinic.
Results
The NT-pro BNP levels were increased with the progression of NYHA Fc of dyspnea (p<0.001 by ANOVA), the increase in the systolic left ventricular internal dimension (p<0.05), and the decrease in the ejection fraction (p<0.01). For the NYHA Fc I patients, the NT-pro BNP levels were positively correlated with age (p<0.001) and left atrial size (p<0.001). For the patients with ischemic heart disease, the NT-pro BNP levels were also positively correlated with the NYHA Fc (p<0.001 by ANOVA). The NT-pro BNP levels were increased with the increase in the systolic (p<0.001) and diastolic pressure (p=0.017), the left ventricular internal dimension as well as the decrease in the ejection fraction (p<0.001). The area under the receiver operating characteristic (ROC) curve for the NT-pro BNP levels was 0.994 (95% confidence interval, 0.979-0.999), and the most reliable cut-off level for the NT-pro BNP was 293.6 pg/mL.
Conclusion
The NT-pro BNP levels were positively correlated with the NYHA Fc of dyspnea and the systolic dysfunction for the patients who visited our cardiology departments. A 300 pg/mL value for the NT-pro BNP cut-off point appears to be a sensitive level to differentiate dyspnea originating from an ailing heart or not for the patients who visited our cardiology departments.
doi:10.3904/kjim.2005.20.1.26
PMCID: PMC3891409  PMID: 15906950
Natriuretic peptides; Heart failure; Myocardial ischemia
4.  N-Terminal Pro-Brain Natriuretic Peptide Is a Useful Prognostic Marker in Patients with Pre-Capillary Pulmonary Hypertension and Renal Insufficiency 
PLoS ONE  2014;9(4):e94263.
N-terminal pro-brain natriuretic peptide (NT-proBNP) is a routinely used prognostic parameter in patients with pre-capillary pulmonary hypertension (PH). As it accumulates in the presence of impaired renal function, the clinical utility of NT-proBNP in PH patients with concomitant renal insufficiency remains unclear. In a retrospective approach, patients with pre-capillary PH (group I or IV) and concomitant renal insufficiency at time of right heart catheterization (glomerular filtration rate (GFR) ≤60 ml/min/1.73 m2) were identified out of all prevalent pre-capillary PH patients treated at a single center. Forty patients with renal insufficiency (25.8%) were identified and matched regarding hemodynamic parameters with a control group of 56 PH patients with normal renal function (GFR >60 ml/min/1.73 m2). Correlations of NT-proBNP levels with hemodynamic and prognostic parameters (time to clinical worsening and overall survival) were assessed. Overall, GFR correlated inversely with NT-proBNP and had the strongest influence on NT-proBNP levels in a stepwise multiple linear regression model including hemodynamic parameters and age (r2 = 0.167). PH patients with renal insufficiency had significant higher levels of NT-proBNP (median: 1935 ng/l vs. 573 ng/l, p = 0.001). Nevertheless, NT-proBNP correlated with invasive hemodynamic parameters in these patients. Using higher cut-off values than in patients with preserved renal function, NT-proBNP levels were significantly associated with time to clinical worsening (>1660 ng/l, p = 0.001) and survival (>2212 ng/l, p = 0.047) in patients with renal insufficiency. Multivariate Cox’s proportional hazards analysis including established prognostic parameters, age and GFR confirmed NT-proBNP as an independent risk factor for clinical worsening in PH patients with renal insufficiency (hazard ratio 4.8, p = 0.007). Thus, in a retrospective analysis we showed that NT-proBNP levels correlated with hemodynamic parameters and outcome regardless of renal function. By using higher cut-off values, NT-proBNP seems to represent a valid clinical marker even in PH patients with renal insufficiency.
doi:10.1371/journal.pone.0094263
PMCID: PMC3994009  PMID: 24751887
5.  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
6.  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
7.  Comparative effects of recombinant human brain natriuretic peptide and dobutamine on acute decompensated heart failure patients with differsent blood BNP levels 
Background
Recombinant human B-type natriuretic peptide (rhBNP) has been indicated for the treatment of acute decompensated heart failure (ADHF). However, the therapeutic efficacy of intravenous rhBNP is not always satisfactory in patients with extremely high blood BNP levels. In this study, we evaluated the effects of rhBNP on patients with different BNP levels.
Methods
One hundred and five patients with ADHF whose left ventricular ejection fraction (LVEF) was <40%, were assigned to a high BNP group (BNP ≤ 3000 pg/mL) or an extra-high BNP group (BNP > 3000 pg/mL) , depending on their admission plasma BNP levels. Each group was then subdivided into rhBNP or dobutamine subgroups according to intravenous administration with either rhBNP or dobutamine for 24-72h. In the high BNP group, 58 patients were randomized to subgroup rhBNP (n = 28) and subgroup dobutamine (n = 30). In the extra-high BNP group, 47 patients were randomized to subgroup rhBNP (n = 24) and subgroup dobutamine (n = 23). The effects of rhBNP and dobutamine on patients in the high and extra-high BNP groups were compared.
Results
In the high BNP group, rhBNP was more efficient than dobutamine at improving NYHA classification (P < 0.05), decreasing plasma BNP levels (P < 0.05), increasing LVEF (P < 0.05), and reducing hospital length of stay (P < 0.05). However, rhBNP displayed no superior therapeutic efficacy to dobutamine in the extra-high BNP group. Adverse cardiovascular events in patients treated with rhBNP were similar to adverse events in patients treated with dobutamine in both the high and extra-high BNP groups.
Conclusions
rhBNP was more efficient than dobutamine at improving heart function in patients with ADHF when plasma BNP was ≤3000 pg/mL. However, rhBNP treatment showed no advantages over dobutamine when plasma BNP reached extremely high levels (>3000 pg/mL).
Trial registration
ClinicalTrials.gov Identifier: NCT01837849.
doi:10.1186/1471-2261-14-31
PMCID: PMC3975880  PMID: 24593826
Acute decompensated heart failure; Recombinant human brain natriuretic peptide; Dobutamine
8.  N-Terminal Pro-B-Type Natriuretic Peptide in Overweight and Obese Patients With and Without Diabetes: An Analysis Based on Body Mass Index and Left Ventricular Geometry 
Korean Circulation Journal  2009;39(12):538-544.
Background and Objectives
Several recent studies have shown that there is an inverse relationship between plasma B-type natriuretic peptide (BNP) and body mass index (BMI) in subjects with and without heart failure. Obesity frequently coexists with diabetes, so it is important to consider the relationship between diabetes and natriuretic peptide levels. We evaluated the influence of diabetes on the correlation of BNP and BMI.
Subjects and Methods
We examined 933 patients with chest pain and/or dyspnea undergoing cardiac catheterization between Feb. 2006 and Nov. 2007 in the Maryknoll cardiac center who had creatinine levels <2.0 mg/dL and normal systolic heart function. BMI was checked, transthoracic echocardiography was performed, and aminoterminal pro-brain natriuretic peptide (NT-proBNP) was sampled at the start of each case.
Results
In 733 non-diabetic patients, mean plasma NT-proBNP levels of non obese individuals (BMI <23 kg/m2), overweight individuals (23≤ BMI <25 kg/m2), and obese individuals (BMI ≥25 kg/m2) showed a significant negative correlation with increasing BMI (856.39±237.3 pg/mL, 601.69±159.6 pg/mL, 289.62±164.9 pg/mL, respectively, p<0.0001). However, in 200 diabetic patients, the correlation between BMI and NT-proBNP was not significant (r=-0.21, p=0.19), and NT-proBNP did not correlate with mitral E/Ea in obese diabetic patients (r=0.14, p=0.56). NT-proBNP was significantly correlated with mitral E/Ea in the non-obese (r=0.24, p=0.008) and non diabetic (r=0.32, p=0.003) groups. Left ventricular (LV) mass index was significantly correlated with NT-proBNP in all BMI groups (r=0.61, p<0.001), and patients with concentric cardiac hypertrophy showed the highest NT-proBNP levels.
Conclusion
The present study demonstrates that obese patients have reduced concentrations of NT-proBNP compared to non obese patients despite having higher LV filling pressures. However, NT-proBNP is not suppressed in obese patients with diabetes. This suggests that factors other than cardiac status affect NT-proBNP concentrations.
doi:10.4070/kcj.2009.39.12.538
PMCID: PMC2801462  PMID: 20049140
B-type natriuretic peptide; Body mass index; Obesity
9.  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
10.  Influence of preoperative serum N-terminal pro-brain type natriuretic peptide on the postoperative outcome and survival rates of coronary artery bypass patients 
Clinics  2010;65(12):1239-1245.
BACKGROUND:
The N-terminal fragment of pro-brain type natriuretic peptide (NT-proBNP) is an established biomarker for cardiac failure.
OBJECTIVE:
To determine the influence of preoperative serum NT-proBNP on postoperative outcome and mid-term survival in patients undergoing coronary artery bypass grafting (CABG).
METHODS:
In 819 patients undergoing isolated CABG surgery preoperative serum NT-proBNP levels were measured. NT-proBNP was correlated with various postoperative outcome parameters and survival rate after a median follow-up time of 18 (0.5–44) months. Risk factors of mortality were identified using χ2, Mann–Whitney test, and Cox regression.
RESULTS:
NT-proBNP levels >430 ng/ml and >502 ng/ml predicted hospital and overall mortality (p<0.05), with an incidence of 1.6% and 4%, respectively. Kaplan–Meier analysis revealed decreased survival rates in patients with NT-proBNP >502 ng/ml (p = 0.001). Age, preoperative serum creatinine, diabetes, chronic obstructive pulmonary disease, low left ventricular ejection fraction and BNP levels >502 ng/ml were isolated as risk factors for overall mortality. Multivariate Cox regression analysis, including the known factors influencing NT-proBNP levels, identified NT-proBNP as an independent risk factor for mortality (OR = 3.079 (CI = 1.149-8.247), p = 0.025). Preoperative NT-proBNP levels >502 ng/ml were associated with increased ventilation time (p = 0.005), longer intensive care unit stay (p = 0.001), higher incidence of postoperative hemofiltration (p = 0.001), use of intra-aortic balloon pump (p<0.001), and postoperative atrial fibrillation (p = 0.031)
CONCLUSION:
Preoperative NT-proBNP levels >502 ng/ml predict mid-term mortality after isolated CABG and are associated with significantly higher hospital mortality and perioperative complications.
doi:10.1590/S1807-59322010001200004
PMCID: PMC3020332  PMID: 21340210
Brain type natriuretic peptide; BNP; NT-proBNP; CABG; Coronary artery disease
11.  Relationship between natriuretic peptides and echocardiography parameters in patients with poorly regulated type 2 diabetes 
This study evaluated the relationship between natriuretic peptide levels and a wide range of echocardiography parameters in a population of thirty-three patients with poorly regulated type 2 diabetes, and no known heart failure. Natriuretic peptides brain natriuretic peptide (BNP) and N-terminal prohormone BNP (NT-proBNP) were measured. Transthoracic echocardiography was performed and cardiac volumes and ejection fraction were measured. Doppler and tissue Doppler were measured and diastolic function was stratified according to recent guidelines. Very few echocardiography parameters were correlated with BNP or NT-proBNP levels. However, left atrial end-systolic volume indexed for body surface area was correlated with natural logarithm (ln) BNP and ln NT-proBNP (r = 0.62 and r = 0.60; P < 0.05). There were significant differences in ln BNP and ln NT-proBNP levels between those with normal and those with abnormal diastolic function (1.4 vs 3.1; P < 0.001 and 3.4 vs 5.8; P < 0.001). This study showed that very few echocardiography parameters were correlated with BNP or NT-proBNP levels in patients with poorly regulated type 2 diabetes, which in part contradicts previous studies in other diabetic populations. The exception was left atrial end-systolic volume that showed a moderate correlation with BNP or NT-proBNP levels. There were significant differences in BNP and NT-proBNP levels between the group with normal left ventricular diastolic function and the group with abnormal diastolic function.
PMCID: PMC2882889  PMID: 20539839
type 2 diabetes; natriuretic peptides; echocardiography
12.  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
13.  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
14.  Log-transformation improves the prognostic value of serial NT-proBNP levels in apparently stable pulmonary arterial hypertension 
Pulmonary Circulation  2011;1(2):244-249.
N-terminal pro B-type natriuretic peptide (NT-proBNP) is a product of cleavage of the cardiac prohormone pro B-type natriuretic peptide into its active form. It has proven to be a useful biomarker in left heart failure. However, studies examining the utility of serial measurements of NT-proBNP in pulmonary arterial hypertension (PAH) patients have shown mixed results. We compared three methods of predicting adverse clinical outcomes in PAH patients: the change in 6 minute walk distance (6MWD), the change in absolute levels of NT-proBNP and the change in log-transformed levels of NT-proBNP. All PAH patients presenting from March-June 2007 were screened. Patients who were clinically unstable, had abnormal renal function or hemoglobin levels or lacked a prior NT-proBNP were excluded. 63 patients were followed up for adverse clinical outcomes (defined as death, transplantation, hospitalisation for right heart failure, or need for increased therapy). Three methods were used to predict adverse events, i.e.: (a) comparing a 6MWD performed in March-June 2007 and a previous 6MWD. A decrease in 6MWD of ≥30m was used to predict clinical deterioration; (b) comparing a NT-proBNP value measured in March-June 2007 and a previous NT-proBNP. An increase in NT-proBNP of ≥250pg/ml was used to predict clinical deterioration (250pg/ml represented approximately 30% change from the baseline median value of NT-proBNP for this cohort); and (c) comparing the loge equivalents of two consecutive NT-proBNP values. We used the formula: loge(current NT-proBNP) - loge(previous NT-proBNP)=x. A value of x≥+0.26 was used to predict adverse events. This is equivalent to a 30% change from baseline, and hence is comparable to the chosen cut-off for absolute levels of NT-proBNP. A loge difference of ≥+0.26 identifies patients at risk of adverse events with a specificity of 98%, a sensitivity of 60%, a positive predictive value of 89%, and a negative predictive value of 90%. A drop in 6MWD of ≥30m has a specificity of 29%, a sensitivity of 73%, a positive predictive value of 24% and a negative predictive value of 24%. It seems possible to risk-stratify apparently stable PAH patients by following the changes in their serial log-transformed NT-proBNP values. In this small pilot study, this method was better than relying on changes in the actual levels of NT-proBNP or changes in 6MWD. This needs to be validated prospectively in a larger cohort.
doi:10.4103/2045-8932.83450
PMCID: PMC3198650  PMID: 22034610
N-terminal pro B-type natriuretic peptide; 6-minute walk distance; biomarker
15.  Relationships of N-terminal pro-B-natriuretic peptide and cardiac troponin T to left ventricular mass and function and mortality in asymptomatic hemodialysis patients 
Background:
Although the cardiac biomarker troponin T (cTnT) is strongly related to mortality in end-stage renal disease, the independent association of N-terminal pro-B-type natriuretic peptide (NT-proBNP) and cTnT in predicting outcomes is unknown.
Objective:
To determine factors associated with NT-proBNP and cTnT, and to determine whether these levels are associated with mortality.
Study Design:
Cohort Study
Settings and Participants:
Asymptomatic hemodialysis patients (n=150) in 4 university-affiliated hemodialysis units.
Exposure and Outcomes:
For cross-sectional analysis, echocardiographic variables as exposures and N-terminal proBNP and cardiac troponin T as outcomes; for longitudinal analysis, association of N-terminal proBNP and cardiac troponin T as exposures to all-cause and cardiovascular disease mortality as outcomes.
Results:
In a multivariate regression analysis, low midwall fractional shortening a measure of poor systolic function was an independent correlate of log NT-proBNP (p<0.01), while left ventricular mass index was an independent correlate of cTnT (p<0.01). Over a median follow-up of 24 months, 46 patients died of which, 26 died due to cardiovascular causes. NT-ProBNP had a strong graded relationship with all-cause (Hazard Ratio (HR) 1.54, 4.78 and 4.03 for increasing quartiles, Chi2 32.2, p<0.001) and cardiovascular mortality (HR 2.99, 10.95, 8.54 Chi2 23.66, p<0.01), while cTnT had a weaker relationship with all-cause (HR 1.57, 2.32, 3.39, Chi2 23.09, p<0.01) and cardiovascular mortality (HR 1, 0.81, 2.12, 2.14, Chi2 15.05, p=0.1). The combination of the two biomarkers did not improve the association with all-cause or cardiovascular mortality compared to NT-proBNP alone. NT-proBNP was a marker of mortality even after adjusting for left ventricular mass index and midwall fractional shortening.
Limitations:
Our cohort was predominantly black and of limited sample size.
Conclusion:
NT-proBNP strongly correlates with left ventricular systolic dysfunction and is more strongly associated with mortality than cTnT in asymptomatic hemodialysis patients.
doi:10.1053/j.ajkd.2007.08.017
PMCID: PMC2408379  PMID: 18037101
NT-proBNP; Troponin T; left ventricular mass; left ventricular function; mortality; hemodialysis
16.  Prognostic utility of B-type natriuretic peptides in patients with heart failure and renal dysfunction 
Clinical Kidney Journal  2012;6(1):55-62.
Background
Renal dysfunction is considered a confounding variable in the interpretation of B-type natriuretic peptides (BNPs) and their amino-terminal fragments (NT-ProBNP) in patients with heart failure (HF). Our aim was to investigate the prognostic utility of BNPs and NT-proBNP in HF outpatients with renal dysfunction, and compare the prognostic significance of the corresponding BNP/NT-ProBNP levels in patients with and without renal dysfunction.
Methods
A total of 2076 patients from 13 HF clinics in the Norwegian Heart Failure Registry were investigated. The BNP/NT-ProBNP levels were categorized centre-wise into four groups using the quartile limits found in patients with preserved renal function. Patients with renal dysfunction, i.e. glomerular filtration rate (GFR) ≤60 mL/min/1.73 m2, were then assigned to BNP groups 1–4 centre-wise according to their level of natriuretic peptides.
Results
Renal dysfunction was present in 37.5% of the patients, of whom the majority (59.1%) had levels of natriuretic peptide in the highest BNP group. Patients with renal dysfunction and BNP levels in the lower three BNP groups had similar 2-year survival as patients without renal dysfunction and comparable BNP levels [crude hazard ratio (HR) 1.25, 95% CI 0.82–1.89, P = 0.302, multiple adjusted HR 0.85, 95% CI 0.54–1.33, P = 0.457]. Beyond 2 years of follow-up, renal dysfunction predicted all-cause mortality irrespective of the level of natriuretic peptides at the start of follow-up.
Conclusion
In HF outpatients, the BNP/NT-ProBNP level predicted 2-year mortality irrespective of renal function and provided important prognostic information on patients with renal dysfunction.
doi:10.1093/ckj/sfs174
PMCID: PMC3888094  PMID: 24422171
B-type natriuretic peptides; heart failure; prognostic marker; renal dysfunction
17.  Relationship Between Obesity and N-Terminal Brain Natriuretic Peptide Level as a Prognostic Value After Acute Myocardial Infarction 
Korean Circulation Journal  2010;40(11):558-564.
Background and Objectives
Recently, the prognostic value of N-terminal brain natriuretic peptide (NT-proBNP) in acute coronary syndrome has been demonstrated in many studies. However, NT-proBNP levels are influenced by various factors such as sex, age, renal function, heart failure severity, and obesity. NT-proBNP concentrations tend to decrease with higher body mass index (BMI). The aim of this study was to examine the influence of obesity on NT-proBNP as a predictive prognostic factor in acute myocardial infarction (AMI) patients.
Subjects and Methods
Using data from the Korea Acute Myocardial Infarction Registry (January 2005 to September 2008), 2,736 AMI patients were included in this study. These patients were divided into men (n=1,972, 70%) and women (n=764, 30%), and were grouped according to their BMIs. Major adverse cardiac events (MACE) during 1 year clinical follow-up were evaluated.
Results
NT-proBNP was significantly higher in lower BMI (p<0.001). Mean NT-proBNP levels of each obesity group were 2,393±4,022 pg/mL in the lean group (n=875), 1,506±3,074 pg/mL in the overweight group (n=724) and 1,100±1,137 pg/mL in the obese group (n=1,137) (p<0.01). NT-proBNP was an independent prognostic factor of AMI in obese patients by multivariative analysis of independent risk factors of MACE (p=0.01).
Conclusion
NT-proBNP is lower in obese AMI patients than in non-obese AMI patients, but NT-proBNP is still of independent prognostic value in obese AMI patients.
doi:10.4070/kcj.2010.40.11.558
PMCID: PMC3008826  PMID: 21217932
Brain natriuretic peptide; Obesity; Myocardial infarction
18.  B-type natriuretic peptides and mortality after stroke 
Neurology  2013;81(23):1976-1985.
Objective:
To measure the association of B-type natriuretic peptide (BNP) and N-terminal fragment of BNP (NT-proBNP) with all-cause mortality after stroke, and to evaluate the additional predictive value of BNP/NT-proBNP over clinical information.
Methods:
Suitable studies for meta-analysis were found by searching MEDLINE and EMBASE databases until October 26, 2012. Weighted mean differences measured effect size; meta-regression and publication bias were assessed. Individual participant data were used to estimate effects by logistic regression and to evaluate BNP/NT-proBNP additional predictive value by area under the receiver operating characteristic curves, and integrated discrimination improvement and categorical net reclassification improvement indexes.
Results:
Literature-based meta-analysis included 3,498 stroke patients from 16 studies and revealed that BNP/NT-proBNP levels were 255.78 pg/mL (95% confidence interval [CI] 105.10–406.47, p = 0.001) higher in patients who died; publication bias entailed the loss of this association. Individual participant data analysis comprised 2,258 stroke patients. After normalization of the data, patients in the highest quartile had double the risk of death after adjustment for clinical variables (NIH Stroke Scale score, age, sex) (odds ratio 2.30, 95% CI 1.32–4.01 for BNP; and odds ratio 2.63, 95% CI 1.75–3.94 for NT-proBNP). Only NT-proBNP showed a slight added value to clinical prognostic variables, increasing discrimination by 0.028 points (integrated discrimination improvement index; p < 0.001) and reclassifying 8.1% of patients into correct risk mortality categories (net reclassification improvement index; p = 0.003). Neither etiology nor time from onset to death affected the association of BNP/NT-proBNP with mortality.
Conclusion:
BNPs are associated with poststroke mortality independent of NIH Stroke Scale score, age, and sex. However, their translation to clinical practice seems difficult because BNP/NT-proBNP add only minor predictive value to clinical information.
doi:10.1212/01.wnl.0000436937.32410.32
PMCID: PMC3854833  PMID: 24186915
19.  Diagnostic accuracy of plasma NT-proBNP levels for excluding cardiac abnormalities in the very elderly 
BMC Geriatrics  2010;10:85.
Background
In the elderly the diagnosis of chronic heart failure is often challenging and the availability of echocardiography can be limited. Plasma levels of NT-proBNP are valuable tools to diagnose patients with heart failure. However, the performance of this biomarker to detect cardiac abnormalities in the very elderly remains unclear. The aims of this study were to investigate the relation between NT-proBNP and cardiac abnormalities and to evaluate the use of NT-proBNP to exclude structural and functional cardiac abnormalities in a community-based sample of "well-functioning" nonagenarians.
Methods
A diagnostic cross-sectional study embedded within the Leiden 85-plus Study in the municipality of Leiden, the Netherlands. Plasma NT-proBNP levels were measured and 2-dimensional echocardiography was performed in a subgroup of 80 well-functioning nonagenarians. Linear regression analysis was used to explore the relation between NT-proBNP and cardiac abnormalities and ROC curve analysis was used to assess the performance of NT-proBNP to exclude cardiac abnormalities. The upper limit of the lowest tertile of NT-proBNP was used as a cut-off value.
Results
NT-proBNP levels were associated with abnormal left ventricular (LV) dimensions, LV systolic and diastolic function, left atrial enlargement and valvular heart disease. LV mass, E/A ratio and degree of aortic regurgitation were identified as independent predictors of NT-proBNP. NT-proBNP levels were higher with greater number of echocardiographic abnormalities (P < 0.001). A cut-off level of 269.5 pg/mL identified patients with abnormal LV dimensions or depressed LV systolic function (sensitivity 85%, negative predictive value (NPV) 77%, area under the curve 0.75 (95% CI 0.64-0.85)). In addition, high NPV were found for LV systolic dysfunction, left atrial enlargement, severe valvular heart disease and pulmonary hypertension. The test performance of NT-proBNP to exclude any echocardiographic abnormality showed a sensitivity of 82% and a NPV of 65%.
Conclusions
In this convenience sample of well-functioning nonagenarians NT-proBNP was related to a wide variety of functional and structural echocardiographic abnormalities. Moreover, NT-proBNP could be used to exclude echocardiographic abnormalities in well-functioning nonagenarians and might be used to indicate who needs to be referred for further cardiovascular examination.
doi:10.1186/1471-2318-10-85
PMCID: PMC2994867  PMID: 21070664
20.  Secretion of Prohormone of B-Type Natriutretic Peptide, proBNP1–108, is Increased in Heart Failure 
JACC. Heart failure  2013;1(3):207-212.
OBJECTIVES
Using a novel, specific assay for proBNP1–108 we tested the hypotheses that proBNP1–108 is secreted by both non-failing and failing human hearts and that proBNP1–108 secretion is increased in failing hearts.
BACKGROUND
The prohormone of B-type natriuretic peptide (proBNP1–108) is a 108-amino acid peptide produced primarily by the heart and cleaved into biologically active BNP1–32 and the biologically inactive NT-proBNP1–76. It is unknown to what extent increased cardiac proBNP1–108 secretion as compared to reduced peripheral processing is responsible for elevated proBNP1–108 levels in patients with heart failure (HF) as compared to subjects without HF.
METHODS
The transcardiac gradient of proBNP1–108 was determined by collecting arterial blood and blood from the coronary sinus (CS). Samples from subjects without overt heart disease (n=9) were collected during cardiac catheterization after coronary artery disease had been excluded. Samples from HF patients (n=21) were collected during implantation of a biventricular pacemaker. ProBNP1–108 was measured with a new assay (BioRad). Values are median (25th/75th percentile).
RESULTS
The gradient of proBNP1–108 across the non-failing hearts was 8 (2/20) ng/L (aorta: 15 (1/25) ng/dL, CS: 24 (8/41) ng/dL; p=0.018). The transcardiac gradient of proBNP1–108 in the failing hearts was 326 (96/482) ng/dL (arterial: 381 (201/586) ng/dL, CS: 709 (408/1087) ng/dL; p<0.001). The transcardiac gradient was greater in failing than non-failing hearts (p=0.001).
CONCLUSION
ProBNP1–108 is secreted by non-failing and failing human hearts, but more so in the latter. It remains to be established where peripheral processing of proBNP1–108 occurs and how this is affected by disease.
doi:10.1016/j.jchf.2013.03.001
PMCID: PMC4120112  PMID: 24621871
proBNP1–108; heart failure; biomarker; natriuretic peptides
21.  Serial Measurements of Serum NT-proBNP as Markers of Left Ventricular Systolic Function and Remodeling in Children with Heart Failure 
American heart journal  2010;160(4):776-783.
Background
Increasing serum levels of N-terminal pro-hormone brain natriuretic peptide (NT-proBNP) are associated with worsening heart failure (HF) in adults. We determined whether changes in NT-proBNP level are associated with changes in symptoms and left ventricular (LV) systolic function and remodeling in children with HF secondary to dilated cardiomyopathy.
Methods
We retrospectively examined associations between serum NT-proBNP levels and NYHA/Ross functional class, LV systolic and diastolic diameter (LVSD-z and LVDD-z), LV ejection fraction (LVEF), and LV shortening fraction (LVSF-z) using generalized linear mixed models. Fluctuation in functional class of subjects was also modeled using logistic regression and receiver operating characteristic (ROC) curves.
Results
In 36 children (14 males), a 10-fold increase in NT-proBNP serum levels was associated (P<0.001) with a 9.8% decrease in LVEF, a 3.25-unit drop in LVSF-z, a 1.53-unit increase in LVDD-z, a 2.64-unit increase in LVSD-z, and an increased odds of being in functional class III/IV (OR 85.5; 95% CI, 10.9 to 671.0). An NT-proBNP level greater than 1000 pg/mL identified children constantly or intermittently in functional class III-IV with 95% sensitivity and 80% specificity. The reliability of a single NT-proBNP value was 0.61, but the means for two and three NT-proBNP values were 0.76 and 0.82, respectively.
Conclusions
In children with HF, NT-proBNP is associated with cardiac symptoms and indices of LV systolic dysfunction and remodeling. NT-proBNP >1000 pg/mL identifies highly symptomatic children. Within subject serial measurements of NT-proBNP are needed for a reliable and accurate determination of disease status and/or course.
doi:10.1016/j.ahj.2010.07.012
PMCID: PMC2964279  PMID: 20934575
22.  Validity of Amino Terminal pro-Brain Natiuretic Peptide in a Medically Complex Elderly Population 
Background
The routine use of natiuretic peptides in severely dyspneic patients has recently been called into question. We hypothesized that the diagnostic utility of Amino Terminal pro Brain Natiuretic Peptide (NT-proBNP) is diminished in a complex elderly population.
Methods
We studied 502 consecutive patients in whom NT-proBNP values were obtained to evaluate severe dyspnea in the emergency department. The diagnostic utility of NT-proBNP for the diagnosis of congestive heart failure (CHF) was assessed utilizing several published guidelines, as well as the manufacturer’s suggested age dependent cut-off points.
Results
The area under the receiver operator curve (AUC) for NT-proBNP was 0.70. Using age-related cut points, the diagnostic accuracy of NT-proBNP for the diagnosis of CHF was below prior reports (70% vs. 83%). Age and estimated creatinine clearance correlated directly with NT-proBNP levels, while hematocrit correlated inversely. Both age > 50 years and to a lesser extent hematocrit < 30% affected the diagnostic accuracy of NT-proBNP, while renal function had no effect. In multivariate analysis, a prior history of CHF was the best predictor of current CHF, odds ratio (OR) = 45; CI: 23-88.
Conclusions
The diagnostic accuracy of NT-proBNP for the evaluation of CHF appears less robust in an elderly population with a high prevalence of prior CHF. Age and hematocrit levels, may adversely affect the diagnostic accuracy off NT-proBNP.
Keywords
Congestive Heart Failure; Natriuretic peptides; Diagnosis; Elderly Patients
doi:10.4021/jocmr606w
PMCID: PMC3194010  PMID: 22121398
23.  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.
Introduction
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.
Methods
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.
Results
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).
Conclusions
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.
doi:10.1186/cc7975
PMCID: PMC2750172  PMID: 19627611
24.  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
25.  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

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