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Background
Natriuretic peptides have expanded the laboratory diagnosis of heart disease. In particular Brain or B-type has been found to be a sensitive measure of congestive heart failure. Specifically, the assays for the protein are:
Accurate in asymptomatic CHF patients
Assessment of ventricular function
Increase with the severity of CHF
Correlate with left ventricular end diastolic pressure
Greater accuracy when compared to echocardiogram ejection fractions
Correlate with pulmonary wedge pressures
OUTLINE
Reference Methods Clinical Utility Interfering Diseases or Substances that Alter Levels Commonly Used Terms Internet Links
REFERENCE METHODS CHARACTERIZATION BNP TRIAGE ASSAY The reference ranges are as follows: 0-80 pg/ml Negative (98% to 99.8% negative predictive value)
80-100 pg/ml Undetermined
100 pg/ml Positive
Elizabeth Sykes, MD, etal.
This study determined whether, for patient monitoring, it is feasible to convert B-type natriuretic peptide (BNP) results obtained using Triage (BNP, Biosite, San Diego, CA), Centaur (BNP, Bayer Diagnostics, Tarrytown, NY), and Elecsys 2010 (N-terminal proBNP; Roche, Indianapolis, IN) assays. Concordance between assays and effects of renal impairment also were assessed. Samples were primarily from emergency center patients.
Biosite testing was performed immediately; Bayer and Roche testing was performed later on plasma stored frozen (–30°C). Logistic regression relationships were as follows: Bayer = 0.57 Biosite + 23.1, n = 121, R2 = 0.85; Roche = 6.09 Biosite – 220.4 + 1,131.6 (if female), n = 131, R2 = 0.57; and Roche = 15.34 Bayer + 2,400.8, n = 150, R2 = 0.23. An increased serum creatinine level (³2 mg/dL [³177 µmol/L]) influenced the Roche results.
We conclude the following from this preliminary study: (1) Results from one method cannot be converted reliably to another using regression relationships. (2) When using manufacturers' cutoff values, concordance between assays was acceptable. (3) Renal impairment affected Roche results.
- Performance characteristics of four automated natriuretic Peptide assays.
Rawlins ML, Owen WE, Roberts WL.
ARUP Institute for Clinical and Experimental Pathology, Salt Lake City.
Am J Clin Pathol. 2005 Mar;123(3):439-45. Abstract quote
Measurement of circulating B-type natriuretic peptide (BNP) and N-terminal proBNP (NT-proBNP) can identify patients with heart failure and guide therapy. The limit of detection, linearity, imprecision, method comparison, analytic concordance, and reference intervals of the Access 2 BNP (Biosite, San Diego, CA), ADVIA Centaur BNP (Bayer Diagnostics, Tarrytown, NY), AxSYM BNP (Abbott Diagnostics, Abbott Park, IL), and E170 NT-proBNP (Roche Diagnostics, Indianapolis, IN) methods were evaluated. The Triage meter BNP assay (Biosite) was the comparison method.
Imprecision testing showed total coefficients of variation of 4.1%, 4.4%, 5.5%, and 0.8% for the Access 2, ADVIA Centaur, AxSYM, and E170, respectively. Relative to the Triage meter, method comparison revealed a slope of 0.96 and r = 0.95, a slope of 0.77 and r = 0.92, a slope of 1.13 and r = 0.94, and a slope of 8.8 and r = 0.80 for the Access 2, ADVIA Centaur, AxSYM, and E170, respectively.
Overall analytic concordance values with the Triage meter were 95.9%, 92.9%, 92.4%, and 84.3% for the Access 2, ADVIA Centaur, AxSYM, and E170, respectively. All automated natriuretic peptide methods showed acceptable analytic performance.PATHOPHYSIOLOGY
Identification and characterization of the major phosphorylation sites of the B-type natriuretic peptide receptor.Potter LR, Hunter T.
Molecular Biology and Virology Laboratory, The Salk Institute for Biological Studies, La Jolla, California 92037, USA.
J Biol Chem 1998 Jun 19;273(25):15533-9 Abstract quote C-type natriuretic peptide (CNP) is a newly discovered factor that stimulates vasorelaxation and inhibits cell proliferation. Natriuretic peptide receptor-B (NPR-B) is the primary signaling molecule for CNP. Recently, the guanylyl cyclase activity of NPR-B was shown to correlate with its phosphorylation state, and it was suggested that receptor dephosphorylation is a mechanism of desensitization.
We now report the identification and characterization of the major NPR-B phosphorylation sites. Mutagenesis and comigration studies using synthetic phosphopeptides were employed to identify five residues (Ser-513, Thr-516, Ser-518, Ser-523, and Ser-526) within the kinase homology domain that are phosphorylated when NPR-B is expressed in human 293 cells. Mutation of any of these residues to alanine reduced the receptor's phosphorylation state and CNP-dependent guanylyl cyclase activity. The reductions were not explained by decreases in receptor protein level as indicated by immunoblot analysis and determinations of cyclase activity in the absence of CNP or in the presence of detergent. Elimination of all of the phosphorylation sites resulted in a completely dephosphorylated receptor whose CNP-dependent cyclase activity was decreased by >90%. However, unlike NPR-A, the dephosphorylated receptor was not completely unresponsive to hormone.
Finally, two additional residues (Gly-521 and Ser-522) were identified that when mutated to alanine reduced the overall phosphorylation state and hormone responsiveness of the receptor without abolishing the phosphorylation of a specific site. These data indicate that phosphorylation of the kinase homology domain is a critical event in the regulation of NPR-B.
Regulation of renal tubular sodium transport by cardiac natriuretic peptides: two decades of research.Beltowski J, W jcicka G.
Department of Pathophysiology, Lublin Medical University, Lublin, Poland.
Med Sci Monit 2002 Feb;8(2):RA13-26 Abstract quote This review presents the current state of our knowledge regarding the regulation of renal tubular sodium transport by natriuretic peptides, with special emphasis on recent findings in this field. Natriuretic peptides constitute a complex system involved in the regulation of sodium balance and blood pressure.
The natriuretic peptide family consists of atrial peptides, such as atrial natriuretic factor (ANF, ANP99-126), long-acting natriuretic peptide (ANP1-30), vessel dilator (ANP31-67) and kaliuretic peptide (ANP79-98), as well as brain or B-type natriuretic peptide (BNP), C-type natriuretic peptide (CNP) and urodilatin. Natriuretic peptides act on target cells through A-type and B-type receptors and stimulate cyclic GMP synthesis. ANF stimulates natriuresis mainly by inhibiting sodium reabsorption in the inner medullary collecting duct. The effect results from coordinate inhibition of apical sodium channels and basolateral Na+, K+-ATPase. Additional effects on sodium transport occur in more proximal nephron segments and on glomerular filtration when hormone concentration is elevated. BNP and urodilatin share the same mechanism of action.
CNP synthetized in several nephron segments acts through specific B-type natriuretic peptide receptors, which are also expressed in renal tubule, but have a different distribution than A-type receptors. ANP1-30, ANP31-67 and ANP79-98 decrease Na+, K+-ATPase activity in tubular cells through a prostaglandin E2-dependent mechanism.
Distinct Roles of Mitogen-activated Protein Kinase Pathways in GATA-4 Transcription Factor-mediated Regulation of B-type Natriuretic Peptide Gene.Kerkela R, Pikkarainen S, Majalahti-Palviainen T, Tokola H, Ruskoaho H.
Department of Pharmacology and Toxicology and Department of Physiology, Biocenter Oulu, P. O. Box 5000, University of Oulu, 90014 Oulu, Finland.
J Biol Chem 2002 Apr 19;277(16):13752-60 Abstract quote The expression of cardiac hormones, atrial natriuretic peptide and B-type natriuretic peptide, is induced by cardiac wall stretch and responds to various hypertrophic agonists such as endothelin-1.
In cardiac myocytes, endothelin-1 induces GATA-4 binding to the B-type natriuretic peptide gene, but the signaling pathways involved in endothelin-1-induced GATA-4 activation are unknown. Mitogen-activated protein kinase pathways are stimulated in response to various extracellular stimuli, and they modulate the function of several transcription activators.
Here we show that inhibition of p38 kinase with SB203580 inhibited endothelin-1-induced GATA-4 binding to B-type natriuretic peptide gene and serine phosphorylation of GATA-4. Inhibition of extracellular signal-regulated protein kinase with MEK1 inhibitor PD98059 reduced basal and p38-induced GATA-4 binding activity, but it had no significant effect on endothelin-1-induced GATA-4 binding activity.
Overexpression of p38 kinase pathway, but not extracellular signal-regulated kinase or c-Jun N-terminal protein kinase, activated GATA-4 binding to B-type natriuretic peptide gene and induced rat B-type natriuretic peptide promoter activity via proximal GATA binding sites. In conclusion, these findings demonstrate that activation of p38 kinase is necessary for hypertrophic agonist-induced GATA-4 binding to B-type natriuretic peptide gene and sufficient for GATA-dependent B-type natriuretic peptide gene expression.
GENERAL
B-type natriuretic peptide (BNP)--validation of an immediate response assay.Vogeser M, Jacob K.
Institute of Clinical Chemistry, Ludwig-Maximilians-Universitat Munich-Grosshadern, Germany.
Clin Lab 2001;47(1-2):29-33 Abstract quote B-type natriuretic peptide, a proteohormone secreted by the left ventricle in response to wall-tension, is a promising laboratory parameter for the detection and follow-up of heart failure.
In this report analytical validation data of a non-isotopic point-of-care testing system for the quantitative determination of BNP (Triage BNP, Biosite, USA) are given. Despite a very short turn-around time of about 10 minutes the assay proved to be reproducible (interassay coefficient of variation (n=10) of 8.4% and 8.0% at concentrations of 19.3 ng/l and 392 ng/l, respectively), linear (r=0.998, from 5 ng/l to 818 ng/l), and rugged with respect to common interferents; compared to the widely used SHIONORIA BNP assay (CIS, France) higher results were found (Triage-BNP = 1.52 x SHIONORIA BNP - 7.0 ng/l; n=70) with a relatively close correlation of the results (r=0.935).
It is concluded that the Triage BNP assay meets the analytical requirements for further clinical validation and may allow a more widespread clinical use of BNP determination in contrast to competing assays with long turn-around times.
CLINICAL UTILITY CHARACTERIZATION ACUTE CORONARY SYNDROME
- B-type natriuretic peptide and extent of lesion on coronary angiography in stable coronary artery disease.
Sahinarslan A, Cengel A, Okyay K, Yazc HU, Elbey S, Cemri M, Ozdemir M, Timurkaynak T.
aDepartment of Cardiology bDepartment of Medical Biochemistry, Gazi University Medical School, Besevler, Ankara, Turkey.
Coron Artery Dis. 2005 Jun;16(4):225-9. Abstract quote
OBJECTIVE: Although it is well established that plasma B-type natriuretic peptide (BNP) levels are higher in patients with acute coronary syndromes, the relationship between plasma BNP level and stable coronary artery disease is not clear. The aim of this study was to examine the relationship between plasma BNP levels and the extent of obstructive lesions on coronary angiography in stable coronary artery patients.
METHODS: Plasma BNP concentrations were measured in 62 patients with a diagnosis of stable angina pectoris who had a left ventricular ejection fraction (LVEF) >/=45% on echocardiographic evaluation. Coronary angiography was performed for all patients, who were than divided into two groups according to the results of the angiography. Group I consisted of the patients who had a lesion leading to an obstruction of the lumen in any coronary artery by less than 50% or those who had normal coronary arteries. All other patients constituted group II.
RESULTS: In group I (n=26), the mean plasma BNP level was 64.8+/-29.5 pg/ml. In group II (n=36), it was 99.7+/-55.4 pg/ml. BNP was significantly higher in group II (P=0.007) than group I. The BNP concentration of the patients with one-vessel disease (n=12), two-vessel disease (n=16), and three-vessel disease (n=8) were 77.9+/-34.9 pg/ml, 109.3+/-67.9 pg/ml, 113.3+/-48.1 pg/ml consecutively. In this respect, the plasma BNP was significantly higher in the groups with more extended vessel disease (P=0.02). When we compared the patients according to involvement of left anterior descending artery (LAD), BNP levels were significantly higher in this group, (116.1+/-55.8 pg/ml versus 64.1+/-30.2 pg/ml; P=0.001).
CONCLUSION: Plasma levels of BNP were higher in patients who have stable coronary artery disease with preserved left ventricular systolic function. The level of increase in plasma BNP concentration was positively correlated with the extent of lesion and LAD involvement on coronary angiography.
The prognostic value of B-type natriuretic peptide in patients with acute coronary syndromes.de Lemos JA, Morrow DA, Bentley JH, Omland T, Sabatine MS, McCabe CH, Hall C, Cannon CP, Braunwald E.
Thrombolysis in Myocardial Infarction Study Group, Boston, USA.
N Engl J Med 2001 Oct 4;345(14):1014-21 Abstract quote BACKGROUND: Brain (B-type) natriuretic peptide is a neurohormone synthesized predominantly in ventricular myocardium. Although the circulating level of this neurohormone has been shown to provide independent prognostic information in patients with transmural myocardial infarction, few data are available for patients with acute coronary syndromes in the absence of ST-segment elevation.
METHODS: We measured B-type natriuretic peptide in plasma specimens obtained a mean (+/-SD) of 40+/-20 hours after the onset of ischemic symptoms in 2525 patients from the Orbofiban in Patients with Unstable Coronary Syndromes-Thrombolysis in Myocardial Infarction 16 study.
RESULTS: The base-line level of B-type natriuretic peptide was correlated with the risk of death, heart failure, and myocardial infarction at 30 days and 10 months. The unadjusted rate of death increased in a stepwise fashion among patients in increasing quartiles of base-line B-type natriuretic peptide levels (P< 0.001). This association remained significant in subgroups of patients who had myocardial infarction with ST-segment elevation (P=0.02), patients who had myocardial infarction without ST-segment elevation (P<0.001), and patients who had unstable angina (P<0.001). After adjustment for independent predictors of the long-term risk of death, the odds ratios for death at 10 months in the second, third, and fourth quartiles of B-type natriuretic peptide were 3.8 (95 percent confidence interval, 1.1 to 13.3), 4.0 (95 percent confidence interval, 1.2 to 13.7), and 5.8 (95 percent confidence interval, 1.7 to 19.7). The level of B-type natriuretic peptide was also associated with the risk of new or recurrent myocardial infarction (P=0.01) and new or worsening heart failure (P<0.001) at 10 months.
CONCLUSIONS: A single measurement of B-type natriuretic peptide, obtained in the first few days after the onset of ischemic symptoms, provides powerful information for use in risk stratification across the spectrum of acute coronary syndromes. This finding suggests that cardiac neurohormonal activation may be a unifying feature among patients at high risk for death after acute coronary syndromes.
Value of plasma B type natriuretic peptide measurement for heart disease screening in a Japanese population.Nakamura M, Endo H, Nasu M, Arakawa N, Segawa T, Hiramori K.
Second Department of Medicine, Iwate Medical University, Morioka, Japan.
Heart 2002 Feb;87(2):131-5 Abstract quote BACKGROUND: Conflict exists regarding the usefulness of measuring plasma B type natriuretic peptide (BNP) concentrations for identifying impaired left ventricular (LV) systolic function during mass screening. Various cardiac abnormalities, regardless of degree of LV dysfunction, are prone to carry a high risk of cardiovascular events.
OBJECTIVE: To examine the validity of plasma BNP measurement for detection of various cardiac abnormalities in a population with a low prevalence of coronary heart disease and LV systolic dysfunction.
DESIGN AND SETTING: Participants in this cross sectional study attended a health screening programme in Iwate, northern Japan. Plasma BNP concentrations were determined in 1098 consecutive subjects (mean age 56 years) by direct radioimmunoassay. All subjects underwent multiphasic health checkups including physical examination, ECG, chest radiography, and transthoracic echocardiography. RESULTS: Conventional diagnostic methods showed 39 subjects to have a wide range of cardiac abnormalities: lone atrial fibrillation or flutter in 11; previous myocardial infarction in seven; valvar heart disease in seven; hypertensive heart disease in six; cardiomyopathy in six; atrial septal defect in one; and cor pulmonale in one. No subjects had a low LV ejection fraction (< 40%). To assess the utility of plasma BNP measurement for identification of such patients, receiver operating characteristic analysis was performed. The optimal threshold for identification was a BNP concentration of 50 pg/ml with sensitivity of 89.7% and specificity of 95.7%. The area under the receiver operating characteristic curve was 0.970. The positive and negative predictive values at the cutoff level were 44.3% and 99.6%, respectively.
CONCLUSION: Measurement of plasma BNP concentration is a very efficient and cost effective mass screening technique for identifying patients with various cardiac abnormalities regardless of aetiology and degree of LV systolic dysfunction that can potentially develop into obvious heart failure and carry a high risk of a cardiovascular event.
B-type natriuretic peptide predicts future cardiac events in patients presenting to the emergency department with dyspnea.Harrison A, Morrison LK, Krishnaswamy P, Kazanegra R, Clopton P, Dao Q, Hlavin P, Maisel AS.
Division of Cardiology and General Internal Medicine, Department of Medicine, Veterans Affairs Medical Center and University of California, San Diego, CA, USA.
Ann Emerg Med 2002 Feb;39(2):131-8 Abstract quote STUDY OBJECTIVE: B-Type natriuretic peptide (BNP) is a neurohormone secreted from the cardiac ventricles in response to volume expansion and pressure overload. We have recently demonstrated that BNP can differentiate congestive heart failure (CHF) from other causes of dyspnea in patients presenting to the emergency department. In this study, we assess whether BNP levels drawn in patients presenting with dyspnea to the ED were a predictor of future cardiac events.
METHODS: In 325 patients presenting with dyspnea to the ED, BNP levels were determined. Patients were then followed up for 6 months to determine the following end points: death (cardiac and noncardiac), hospital admissions (cardiac), and repeat ED visits for CHF. Receiver operating characteristic (ROC) curves, relative risks (RRs), and Kaplan-Meier plots were used to assess the ability of BNP levels to predict future cardiac events.
RESULTS: The area under the ROC curve using BNP to detect a CHF end point-a CHF death, hospital admission, or repeat ED visit-was 0.870 (95% confidence interval [CI] 0.826 to 0.915). A BNP value of 480 pg/mL had a sensitivity of 68%, specificity of 88%, and an accuracy of 85% for predicting a subsequent CHF end point. The area under the ROC curve using BNP to detect death from CHF was 0.881 (95% CI 0.807 to 0.954) and for any cardiac death was 0.877 (95% CI 0.822 to 0.933). BNP was not associated with death from noncardiac causes. Using Kaplan-Meier plots for all CHF events, rising BNP levels were associated with a progressively worse prognosis. Patients with BNP levels more than 480 pg/mL had a 51% 6-month cumulative probability of a CHF event. Alternatively, patients with BNP levels less than 230 pg/mL had an excellent prognosis with only 2.5% incidence of CHF end points. The RR of 6-month CHF death in patients with BNP levels more than 230 pg/mL was 24.1. The RR of 6-month noncardiac death with BNP levels more than 230 pg/mL was 1.1. BNP levels were also predictive of CHF events in subsets of patients with positive CHF histories and ED diagnoses.
CONCLUSION: In this study population, BNP levels measured in patients presenting with dyspnea to the ED are highly predictive of cardiac events over the next 6 months.
Multimarker approach to risk stratification in non-ST elevation acute coronary syndromes: simultaneous assessment of troponin I, C-reactive protein, and B-type natriuretic peptide.Sabatine MS, Morrow DA, de Lemos JA, Gibson CM, Murphy SA, Rifai N, McCabe C, Antman EM, Cannon CP, Braunwald E.
TIMI Study Group, Cardiovascular Division, Brigham and Women's Hospital, Boston, Mass 02115, USA.
Circulation 2002 Apr 16;105(15):1760-3 Abstract quote BACKGROUND: In patients with acute coronary syndromes (ACS), troponin I (TnI), C-reactive protein (CRP), and B-type natriuretic peptide (BNP) each predict adverse cardiac events. Little is known, however, about the utility of these biomarkers in combination.
METHODS AND RESULTS: Baseline measurements of TnI, CRP, and BNP were performed in 450 patients in OPUS-TIMI 16. Elevations in TnI, CRP, and BNP each were independent predictors of the composite of death, myocardial infarction (MI), or congestive heart failure (CHF). When patients were categorized on the basis of the number of elevated biomarkers at presentation, there was a near doubling of the mortality risk for each additional biomarker that was elevated (P=0.01). Similar relationships existed for the endpoints of MI, CHF, and the composite, both at 30 days and through 10 months. In a validation cohort of 1635 patients in TACTICS-TIMI 18, the number of elevated biomarkers remained a significant predictor of the composite endpoint after adjustment for known clinical predictors: patients with one, two, and three elevated biomarkers had a 2.1- (P=0.006), 3.1- (P<0.001), and 3.7- (P=0.001) fold increase in the risk of death, MI, or CHF by 6 months.
CONCLUSIONS: Troponin, CRP, and BNP each provide unique prognostic information in patients with ACS. A simple multimarker strategy that categorizes patients based on the number of elevated biomarkers at presentation allows risk stratification over a broad range of short- and long-term major cardiac events.
CONGESTIVE HEART FAILURE
Utility of B-type natriuretic peptide in the diagnosis of congestive heart failure in an urgent-care setting.Dao Q, Krishnaswamy P, Kazanegra R, Harrison A, Amirnovin R, Lenert L, Clopton P, Alberto J, Hlavin P, Maisel AS.
Department of Medicine, Veteran's Affairs Medical Center, San Diego, California, USA.
J Am Coll Cardiol 2001 Feb;37(2):379-85 Abstract quote OBJECTIVES: The goal of this study was to evaluate the utility of a rapid "bedside" technique for measurement of B-type natriuretic peptide (BNP) in the diagnosis of congestive heart failure (CHF) in an urgent-care setting.
BACKGROUND: B-type natriuretic peptide is a protein secreted from the cardiac ventricles in response to pressure overload. One potential application of measurements of BNP in blood is distinguishing dyspnea due to CHF from other causes.
METHODS: B-type natriuretic peptide concentrations were measured in a convenience sample of 250 predominantly male (94%) patients presenting to urgent-care and emergency departments of an academic Veteran's Affairs hospital with dyspnea. Results were withheld from clinicians. Two cardiologists retrospectively reviewed clinical data (blinded to BNP measurements) and reached a consensus opinion on the cause of the patient's symptoms. This gold standard was used to evaluate the diagnostic performance of the BNP test.
RESULTS: The mean BNP concentration in the blood of patients with CHF (n = 97) was higher than it was in patients without (1,076 +/- 138 pg/ml vs. 38 +/- 4 pg/ml, p < 0.001). At a blood concentration of 80 pg/ml, BNP was an accurate predictor of the presence of CHF (95%); measurements less than this had a high negative predictive value (98%). The overall C-statistic was 0.97. In multivariate analysis, BNP measurements added significant, independent explanatory power to other clinical variables in models predicting which patients had CHF. The availability of BNP measurements could have potentially corrected 29 of the 30 diagnoses missed by urgent-care physicians.
CONCLUSIONS: B-type natriuretic peptide blood concentration measurement appears to be a sensitive and specific test to diagnose CHF in urgent-care settings.
A rapid test for B-type natriuretic peptide correlates with falling wedge pressures in patients treated for decompensated heart failure: a pilot study.Kazanegra R, Cheng V, Garcia A, Krishnaswamy P, Gardetto N, Clopton P, Maisel A.
Division of Cardiology, Department of Medicine, Veteran's Affairs Medical Center, San Diego, California 92161, USA.
J Card Fail 2001 Mar;7(1):21-9 Abstract quote OBJECTIVES: To determine if changes in B-type natriuretic peptide (BNP) levels can accurately reflect acute changes in pulmonary capillary wedge pressure during treatment of decompensated heart failure.
BACKGROUND: Tailored therapy of decompensated congestive heart failure with hemodynamic monitoring is controversial. Other than the expense and complications of Swan-Ganz catheters, its use in titration of drug therapy has no conclusive end point. Because BNP reflects both elevated left ventricular pressure and neurohormonal modulation and has a short half-life, we hypothesized that levels of BNP would decline in association with falling wedge pressures. Final BNP levels would perhaps signify a new set point of neuromodulation.
METHODS AND RESULTS: Twenty patients with decompensated New York Heart Association (NYHA) class III-IV congestive heart failure (CHF) undergoing tailored therapy were studied. BNP levels were drawn every 2 to 4 hours for the first 24 hours (active treatment phase) and then every 4 hours for the next 24 to 48 hours (stabilization period). Hemodynamic data was recorded simultaneously. In 15 patients whose wedge pressure responded to treatment in the first 24 hours, there was a significant drop in BNP levels (55%) versus nonresponders (8%). There was a significant correlation between percent change in wedge pressure from baseline per hour and the percent change of BNP from baseline per hour (r = 0.79, P <.05). When the wedge pressure was kept at a stable, low level during the stabilization phase, BNP levels continued to fall another 37% (937 +/- 140 pg/mL at 24 hours to 605 +/- 128 pg/mL). Patients who died (n = 4) had higher final BNP levels (1,078 +/- 123 pg/mL v 701 +/- 107 pg/mL).
CONCLUSIONS: The data suggest that rapid testing of BNP may be an effective way to improve the in-hospital management of patients admitted with decompensated CHF. Although BNP levels will not obviate the need for invasive hemodynamic monitoring, it may be a useful adjunct in tailoring therapy to these patients.
B-type natriuretic peptide levels: a potential novel "white count" for congestive heart failure.Maisel A.
Division of Cardiology and Department of Medicine, San Diego VA Healthcare System, San Diego, California, USA
J Card Fail 2001 Jun;7(2):183-93 Abstract quote Finding a simple blood test to aid in the diagnosis and treatment of patients with congestive heart failure could have a favorable impact on the costs associated with the disease. B-type natriuretic peptide (BNP) is synthesized in the cardiac ventricles, and its level correlates with left ventricular pressure, amount of dyspnea, and the state of neurohormonal modulation, thus making peptide the first potential "white count" for heart failure.
Data indicate that serial point-of-care testing of BNP should be helpful in patients presenting to urgent care clinics with dyspnea. BNP may also serve as a screen for patients referred for echocardiography. A low BNP level makes left ventricular dysfunction (both systolic and diastolic) highly unlikely. BNP may also provide an effective means of improving in-hospital management of patients admitted with decompensated congestive heart failure. In some cases, BNP level observations may obviate the need for invasive hemodynamic monitoring and, when such monitoring is used, may help tailor treatment of the decompensated patient.
Finally, the role of BNP in the outpatient cardiac or primary care clinic may be one of critical importance in titration of therapies as well as in assessing the state of neurohormonal compensation of the patient.
Utility of a rapid B-natriuretic peptide assay in differentiating congestive heart failure from lung disease in patients presenting with dyspnea.Morrison LK, Harrison A, Krishnaswamy P, Kazanegra R, Clopton P, Maisel A.
Division of Cardiology, Veteran's Affairs Medical Center, San Diego, California 92161, USA.
J Am Coll Cardiol 2002 Jan 16;39(2):202-9 Abstract quote OBJECTIVES: Since B-type natriuretic peptide (BNP) is secreted by the left ventricle (LV) in response to volume elevated LV pressure, we sought to assess whether a rapid assay for BNP levels could differentiate cardiac from pulmonary causes of dyspnea.
BACKGROUND: Differentiating congestive heart failure (CHF) from pulmonary causes of dyspnea is very important for patients presenting to the emergency department (ED) with acute dyspnea.
METHODS: B-natriuretic peptide levels were obtained in 321 patients presenting to the ED with acute dyspnea. Physicians were blinded to BNP levels and asked to give their probability of the patient having CHF and their final diagnosis. Two independent cardiologists were blinded to BNP levels and asked to review the data and evaluate which patients presented with heart failure. Patients with right heart failure from cor pulmonale were classified as having CHF.
RESULTS: Patients with CHF (n = 134) had BNP levels of 758.5 +/- 798 pg/ml, significantly higher than the group of patients with a final diagnosis of pulmonary disease (n = 85) whose BNP was 61 +/- 10 pg/ml. The area under the receiver operating curve, which plots sensitivity versus specificity for BNP levels in separating cardiac from pulmonary disease, was 0.96 (p < 0.001). A breakdown of patients with pulmonary disease revealed: chronic obstructive pulmonary disease (COPD): 54 +/- 71 pg/ml (n = 42); asthma: 27 +/- 40 pg/ml (n = 11); acute bronchitis: 44 +/- 112 pg/ml (n = 14); pneumonia: 55 +/- 76 pg/ml (n = 8); tuberculosis: 93 +/- 54 pg/ml (n = 2); lung cancer: 120 +/- 120 pg/ml (n = 4); and acute pulmonary embolism: 207 +/- 272 pg/ml (n = 3). In patients with a history of lung disease but whose current complaint of dyspnea was seen as due to CHF, BNP levels were 731 +/- 764 pg/ml (n = 54). The group with a history of CHF but with a current COPD diagnosis had a BNP of 47 +/- 23 pg/ml (n = 11).
CONCLUSIONS: Rapid testing of BNP in the ED should help differentiate pulmonary from cardiac etiologies of dyspnea.
Rapid measurement of B-type natriuretic peptide in the emergency diagnosis of heart failure.Maisel AS, Krishnaswamy P, Nowak RM, McCord J, Hollander JE, Duc P, Omland T, Storrow AB, Abraham WT, Wu AH, Clopton P, Steg PG, Westheim A, Knudsen CW, Perez A, Kazanegra R, Herrmann HC, McCullough PA; Breathing Not Properly Multinational Study Investigators.
University of California, San Diego, Veterans Affairs Medical Center, San Diego 92161, USA.
N Engl J Med 2002 Jul 18;347(3):161-7 Abstract quote BACKGROUND: B-type natriuretic peptide is released from the cardiac ventricles in response to increased wall tension.
METHODS: We conducted a prospective study of 1586 patients who came to the emergency department with acute dyspnea and whose B-type natriuretic peptide was measured with a bedside assay. The clinical diagnosis of congestive heart failure was adjudicated by two independent cardiologists, who were blinded to the results of the B-type natriuretic peptide assay.
RESULTS: The final diagnosis was dyspnea due to congestive heart failure in 744 patients (47 percent), dyspnea due to noncardiac causes in 72 patients with a history of left ventricular dysfunction (5 percent), and no finding of congestive heart failure in 770 patients (49 percent). B-type natriuretic peptide levels by themselves were more accurate than any historical or physical findings or laboratory values in identifying congestive heart failure as the cause of dyspnea. The diagnostic accuracy of B-type natriuretic peptide at a cutoff of 100 pg per milliliter was 83.4 percent. The negative predictive value of B-type natriuretic peptide at levels of less than 50 pg per milliliter was 96 percent. In multiple logistic-regression analysis, measurements of B-type natriuretic peptide added significant independent predictive power to other clinical variables in models predicting which patients had congestive heart failure.
CONCLUSIONS: Used in conjunction with other clinical information, rapid measurement of B-type natriuretic peptide is useful in establishing or excluding the diagnosis of congestive heart failure in patients with acute dyspnea.
DIASTOLIC DYSFUNCTION
Utility of B-natriuretic peptide as a rapid, point-of-care test for screening patients undergoing echocardiography to determine left ventricular dysfunction.Maisel AS, Koon J, Krishnaswamy P, Kazenegra R, Clopton P, Gardetto N, Morrisey R, Garcia A, Chiu A, De Maria A.
Division of Cardiology, Veterans Affairs Medical Center and University of California, 3350 La Jolla Village Dr., San Diego, CA 92161, USA.
Am Heart J 2001 Mar;141(3):367-74 Abstract quote BACKGROUND: Although echocardiography is an important tool for making the diagnosis of left ventricular (LV) dysfunction, the cost of this procedure limits its use as a routine screening tool for this purpose. Brain natriuretic peptide (BNP) accurately reflects ventricular pressure, and preliminary studies have found it to be highly sensitive and highly specific in diagnosing congestive heart failure in the emergency department. We hypothesized that BNP might therefore be useful as a screening tool before echocardiography in patients with suspected LV dysfunction.
METHODS: Subjects included patients referred for echocardiography to evaluate the presence or absence of LV dysfunction. Patients with known LV dysfunction were excluded from analysis. BNP was measured by a point-of-care immunoassay (Biosite Diagnostics, San Diego, Calif). The results of BNP levels were blinded from cardiologists making the assessment of LV function. Patients were divided into those with normal ventricular function, abnormal systolic ventricular function, abnormal diastolic function, and evidence of both systolic and diastolic dysfunction.
RESULTS: Two hundred patients in whom LV function was unknown were studied. In the 105 patients (53%) whose ventricular function was subsequently determined to be normal by echocardiography, BNP levels averaged 37 +/- 6 pg/mL. This was significantly less than in those patients with either ultimate diastolic dysfunction (BNP 391 +/- 89 pg/mL (P <.001) or systolic dysfunction (BNP 572 +/- 115 pg/mL (P <.001). A receiver-operator characteristic curve showing the sensitivity and specificity of BNP against the echocardiography diagnosis revealed the area under the curve (accuracy) was 0.95. At a BNP level of 75 pg/mL was 98% specific for detecting the presence or absence of LV dysfunction by echocardiography.
CONCLUSIONS: A simple, rapid test for BNP, which can be performed at the bedside or in the clinic, can reliably predict the presence or absence of LV dysfunction on echocardiogram. The data indicate that BNP may be an excellent screening tool for LV dysfunction and may, in fact, preclude the need for echocardiography in many patients.
Utility of B-natriuretic peptide in detecting diastolic dysfunction: comparison with Doppler velocity recordings.Lubien E, DeMaria A, Krishnaswamy P, Clopton P, Koon J, Kazanegra R, Gardetto N, Wanner E, Maisel AS.
Division of Cardiology, Department of Medicine, Veteran's Affairs Medical Center, and University of California, San Diego, USA.
Circulation 2002 Feb 5;105(5):595-601 Abstract quote BACKGROUND: Although Doppler echocardiography has been used to identify abnormal left ventricular (LV) diastolic filling dynamics, inherent limitations suggest the need for additional measures of diastolic dysfunction. Because data suggest that B-natriuretic peptide (BNP) partially reflects ventricular pressure, we hypothesized that BNP levels could predict diastolic abnormalities in patients with normal systolic function.
METHODS AND RESULTS: We studied 294 patients referred for echocardiography to evaluate ventricular function. Patients with abnormal systolic function were excluded. Cardiologists making the assessment of LV function were blinded to BNP levels. Patients were classified as normal, impaired relaxation, pseudonormal, and restrictivelike filling patterns. Patients diagnosed with evidence of abnormal LV diastolic function (n=119) had a mean BNP concentration of 286 +/- 31 pg/mL; those in the normal LV group (n=175) had a mean BNP concentration of 33 +/- 3 pg/mL. Patients with restrictive like filling patterns on echocardiography had the highest BNP levels (408 +/- 66 pg/mL), and patients with symptoms had higher BNP levels in all diastolic filling patterns. The area under the receiver-operating characteristic curve for BNP to detect any diastolic dysfunction was 0.92 (95% CI, 0.87 to 0.95; P<0.001). A BNP value of 62 pg/mL had a sensitivity of 85%, a specificity of 83%, and an accuracy of 84% for detecting diastolic dysfunction.
CONCLUSIONS: A rapid assay for BNP can reliably detect the presence of diastolic abnormalities on echocardiography. In patients with normal systolic function, elevated BNP levels and diastolic filling abnormalities might help to reinforce the diagnosis diastolic dysfunction.
PREGNANCY
Plasma concentration of atrial natriuretic peptide and brain natriuretic peptide during normal human pregnancy and the postpartum period.Yoshimura T, Yoshimura M, Yasue H, Ito M, Okamura H, Mukoyama M, Nakao K.
Department of Obstetrics and Gynecology, Kumamoto University School of Medicine, Japan.
J Endocrinol 1994 Mar;140(3):393-7 Abstract quote Increases in blood volume are observed during normal gestation and these are reversed shortly after delivery. Although both atrial (A-type) natriuretic peptide (ANP) and brain (B-type) natriuretic peptide (BNP) have been described, the role of these peptides in pregnancy and the postpartum period are unclear.
This study was designed to examine the effects of pregnancy, labour and delivery on plasma levels of ANP and BNP. Plasma levels of ANP and BNP were determined during normal pregnancy, 30 min after separation of the placenta (immediately postpartum) and between 5 and 72 h postpartum (late postpartum; puerperium). Since the assay sensitivity was 20 pg/ml plasma (for both ANP and BNP), values less than this were assigned a value of 20 pg/ml to calculate means. Plasma levels of ANP and BNP were significantly higher at term pregnancy than during the first trimester (ANP increased from 20 +/- 0.2 to 57 +/- 10 pg/ml (S.E.M.), P < 0.001; BNP increased from 25 +/- 2 to 49 +/- 9 pg/ml, P < 0.01). The plasma level of ANP then rose to 157 +/- 38 pg/ml 30 min after separation of the placenta, being significantly (P < 0.01) higher than that seen at term pregnancy.
It declined significantly (P < 0.001) to 32 +/- 3 pg/ml in the late postpartum period. In contrast, the plasma level of BNP 30 min after separation of the placenta was 80 +/- 25 pg/ml, and increased to 116 +/- 17 pg/ml in the late postpartum period, significantly (P < 0.01) higher than the level at term pregnancy.
SCREENING
Plasma natriuretic peptides for community screening for left ventricular hypertrophy and systolic dysfunction: the framingham heart study.Vasan RS, Benjamin EJ, Larson MG, Leip EP, Wang TJ, Wilson PW, Levy D.
Framingham Heart Study, 73 Mt Wayte Ave, Suite 2, Framingham, MA 01702.
JAMA 2002 Sep 11;288(10):1252-9 Abstract quote CONTEXT: Several reports have suggested the usefulness of plasma brain natriuretic peptide (BNP) as a screening test for left ventricular hypertrophy (LVH) and systolic dysfunction (LVSD). Prior studies were limited by small sample sizes and selection bias and none compared the diagnostic performance of these peptides in men and women.
OBJECTIVES: To examine the usefulness of natriuretic peptides for screening for elevated LV mass and LVSD in the community.
DESIGN, SETTING, AND PARTICIPANTS: Community-based prospective cohort study of 3177 participants (1707 women) from the Framingham Study who attended a routine examination in 1995-1998.
MAIN OUTCOME MEASURES: Receiver operating characteristic (ROC) curves, test sensitivity, specificity, positive and negative predictive values, and likelihood ratios for identifying elevated LV mass (sex-specific 90th percentile or higher of LV mass/[height](2)), LVSD (ejection fraction </=50% and/or fractional shortening <29%), and moderate to severe LVSD (ejection fraction </=40% and/or fractional shortening <22%) at different discrimination limits of plasma BNP and N-terminal proatrial natriuretic peptide (NT-ANP), with echocardiography as the criterion standard.
RESULTS: The areas under the ROC curves for elevated LV mass or LVSD were at or below 0.75 for both peptides, were higher for men compared with women, and were similar for BNP and NT-ANP. The diagnostic performance of natriuretic peptides for LVSD improved in women but not in men when select high-risk subgroups were targeted. Discrimination limits based on high specificity (0.95) yielded better positive predictive values and likelihood ratios compared with age- and sex-specific reference limits yet only identified less than one third of participants who had elevated LV mass or LVSD.
CONCLUSION: In our large community-based sample, the performance of BNP and NT-ANP for detection of elevated LV mass and LVSD was suboptimal, suggesting limited usefulness of natriuretic peptides as mass screening tools.
INTERFERING DISEASES OR SUBSTANCES THAT ALTER LEVELS CHARACTERIZATION EXERCISE
Stability of B-type natriuretic peptide levels during exercise in patients with congestive heart failure: implications for outpatient monitoring with B-type natriuretic peptide.McNairy M, Gardetto N, Clopton P, Garcia A, Krishnaswamy P, Kazanegra R, Ziegler M, Maisel AS.
Division of Cardiology and the Department of Medicine, Veteran's Affairs Medical Center and University of California, San Diego, Calif 92161, USA.
Am Heart J 2002 Mar;143(3):406-11 Abstract quote BACKGROUND: B-natriuretic peptide (BNP), a neurohormone secreted from the cardiac ventricles, reflects left ventricular pressure and correlates to disease severity and prognosis. The fact that BNP levels can now be measured by a rapid assay suggests its potential usefulness in the outpatient clinic. However, if patient activity were to markedly alter BNP levels, its use would be less attractive for monitoring patients in the outpatient clinical setting.
METHODS: A total of 30 patients (10 normal, 10 New York Heart Association [NYHA] class I-II, 10 NYHA class III-IV) exercised with an upright bicycle protocol. Exercise was carried out to 75% of maximum heart rate, and venous blood was sampled before, immediately after, and 1 hour after completion of exercise. Plasma levels of BNP, epinephrine, and norepinephrine were measured.
RESULTS: BNP levels at baseline were 29 +/- 11 pg/mL for normal subjects, 126 +/- 26 pg/mL for NYHA I-II subjects, and 1712 +/- 356 pg/mL for NYHA III-IV subjects. The change in BNP levels with exercise was significantly lower than the change in epinephrine and norepinephrine (P <.001). In normal subjects, BNP increased from 29 pg/mL to 44 pg/mL with peak exercise, still within the range of normal (<100 pg/mL). This is compared with larger increases of norepinephrine (716 pg/mL to 1278 pg/mL) and epinephrine (52 pg/mL to 86 pg/mL) with exercise in normal subjects. There were also only small increases in BNP with exercise in patients with congestive heart failure (NYHA I-II, 30%; NYHA III-IV, 18%). For the same groups, epinephrine levels increased by 218% and 312%, respectively, and norepinephrine levels increased by 232% and 163%, respectively. One hour after completion of exercise, there were only minimal changes in BNP levels from baseline state in normal subjects (+0.9%) and patients with NYHA I-II (3.8%). In patients with NYHA III-IV, there was a 15% increase from baseline 1 hour after exercise.
CONCLUSIONS: BNP levels show only minor changes with vigorous exercise, making it unlikely that a normal patient would be classified as having congestive heart failure based on a BNP level obtained after activity. Prior activity should not influence BNP levels in patients with congestive heart failure. Therefore, when a patient presents to clinic with a marked change in their BNP level, it may reflect a real change in their condition.
RENAL DISEASE
Changes in brain natriuretic peptide and atrial natriuretic peptide plasma concentrations during hemodialysis in patients with chronic renal failure.Haug C, Metzele A, Steffgen J, Grunert A.
Institut fur Klinische Chemie, Universitat Ulm, Germany.
Horm Metab Res 1994 May;26(5):246-9 Abstract quote The present study aimed to investigate whether brain natriuretic peptide (BNP), atrial natriuretic peptide (ANP), cortisol and thyroid hormone concentrations change during hemodialysis in patients with chronic renal failure. Blood samples were withdrawn in 30 patients with chronic renal failure before hemodialysis, 2 hours after the beginning and at the end of hemodialysis. ANP and BNP concentrations were determined by radioimmunoassay after Sep Pak C18 extraction.
Cortisol, T3, T4, FT4 and TSH serum concentrations were measured by enzyme immunoassay. BNP and ANP plasma levels were strongly elevated in patients with renal failure (BNP 22.4 fold, ANP 4.7 fold versus controls [n = 20]) and decreased significantly (p < 0.001) during hemodialysis (BNP [pg/ml]: 192.1 +/- 24.9, 178.6 +/- 23.0, 167.2 +/- 21.8; ANP [pg/ml]: 240.2 +/- 28.7, 166.7 +/- 21.3, 133.0 +/- 15.5). BNP plasma concentrations showed a stronger elevation than ANP plasma levels and a less pronounced decrease during hemodialysis (BNP: 13.5 +/- 1.8%, ANP: 40.2 +/- 3.5%, p < 0.001) which might in part be due to the longer half-life of BNP. Cortisol and TSH levels did not change significantly whereas T3, T4 and FT4 levels increased significantly (p < 0.001) during hemodialysis. Since corticosteroids and thyroid hormones stimulate natriuretic peptide release, these data suggest that the dialysis-induced decrease of ANP and BNP plasma concentrations is not augmented by a loss of cortisol or thyroid hormones during hemodialysis.
The present data provide support that BNP and ANP plasma concentrations are sensitive indicators of the extracellular fluid volume status.
Diagnostic potential of cardiac natriuretic peptides in dialysis patients.Mallamaci F, Zoccali C, Tripepi G, Benedetto FA, Parlongo S, Cataliotti A, Cutrupi S, Giacone G, Bellanuova I, Stancanelli B, Malatino LS; CREED Investigstors. The Cardiovascular Risk Extended Evaluation.
CNR Centro Fisiologia Clinica e Divisione di Nefrologia, Ospedali Riuniti, Reggio Calabria, Italy.
Kidney Int 2001 Apr;59(4):1559-66 Abstract quote BACKGROUND: In the general population, the plasma concentrations of atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) are useful to predict left ventricular hypertrophy (LVH) and LV systolic dysfunction. Whether these cardiac hormones have a similar diagnostic potential in dialysis patients is unknown.
METHODS: We studied the diagnostic value of ANP and BNP for alterations in LV mass and function in a cohort of 246 dialysis patients without clinical evidence of heart failure.
RESULTS: Both ANP and BNP were independently related to left ventricular mass (P < 0.0001) as well as to ejection fraction (P < 0.0001). In an analysis based on a prospectively defined threshold (95th percentile of the normal range), BNP had a significantly higher (P < 0.01) sensitivity (88%) than ANP (51%) for the diagnosis of LVH, but the positive predictive value of the two peptides was very similar (92 and 87%, respectively, P = NS). However, the negative predictive value of BNP for excluding LVH was 22% higher than that of ANP (53 vs. 31%, P = 0.05). Both natriuretic peptides had a high sensitivity for the detection of LV dysfunction (87 and 94%), but their positive predictive value was low (25 and 15%). Importantly, both ANP and BNP proved to be very useful for excluding this alteration (negative predictive value 97 and 96%, respectively). An analysis based on the "best cut-offs" of each peptide as identified on the basis of the ROC curves augmented the positive and negative prediction values of BNP for the diagnosis of LVH to 95 and 61%, respectively. This approach also raised the BNP-positive prediction value for the identification of LV dysfunction to 31% but did not modify the diagnostic potential of ANP (either for LVH or for LV dysfunction).
CONCLUSIONS: Measuring the plasma concentration of cardiac natriuretic hormones, particularly BNP, may be useful for the identification of dialysis patients with LVH or for excluding systolic dysfunction.
Circulating natriuretic peptide concentrations in patients with end-stage renal disease: role of brain natriuretic peptide as a biomarker for ventricular remodeling.Cataliotti A, Malatino LS, Jougasaki M, Zoccali C, Castellino P, Giacone G, Bellanuova I, Tripepi R, Seminara G, Parlongo S, Stancanelli B, Bonanno G, Fatuzzo P, Rapisarda F, Belluardo P, Signorelli SS, Heublein DM, Lainchbury JG, Leskinen HK, Bailey KR, Redfield MM, Burnett JC Jr.
Cardiorenal Research Laboratory, Division of Cardiovascular Diseases and Internal Medicine, Mayo Clinic, Rochester, Minn 55905, USA.
Mayo Clin Proc 2001 Nov;76(11):1111-9 Abstract quote OBJECTIVES: To determine levels of natriuretic peptides (NPs) in patients with end-stage renal disease (ESRD) and to examine the relationship of these cardiovascular peptides to left ventricular hypertrophy (LVH) and to cardiac mortality.
PATIENTS AND METHODS: One hundred twelve dialysis patients without clinical evidence of congestive heart failure underwent plasma measurement of NP concentrations and echocardiographic investigation for left ventricular mass index (LVMI).
RESULTS: Plasma atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) concentrations correlated positively with LVMI and inversely with left ventricular ejection fraction, whereas C-type NP and Dendroaspis NP levels did not correlate with LVMI. In dialysis patients with LVH (LVMI >125 g/m2), plasma ANP and BNP concentrations were increased compared with those in dialysis patients without LVH (both P<001). In a subset of 15 dialysis patients without LVH or other concomitant diseases, plasma BNP concentrations were not significantly increased compared with those in 35 controls (mean +/- SD, 20.1+/-13.4 vs 13.5+/-9.6 pg/mL; P=.06), demonstrating that the BNP concentration was not increased by renal dysfunction alone. Furthermore, the BNP level was significantly higher in the 16 patients who died from cardiovascular causes compared with survivors (mean +/- SD, 129+/-13 vs 57+/-7 pg/mL; P<.003) and was significantly associated with greater risk of cardiovascular death in Cox regression analysis (P<.001), as was the ANP level (P=.002).
CONCLUSIONS: Elevation of the plasma BNP concentration is more specifically related to LVH compared with the other NP levels in patients with ESRD independent of congestive heart failure. Thus, BNP serves as an important plasma biomarker for ventricular hypertrophy in dialysis patients with ESRD.
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