B-Type Natriuretic Peptide
Nearly 5 million Americans have heart failure (HF). Making a correct diagnosis early is an important component in the multifaceted approach to detection and/or treatment of this disease. The US Food and Drug Administration recently approved a point-of-care B-type natriuretic peptide assay to be used in the diagnosis of HF. Nesiritide, a synthetic B-type natriuretic peptide, was also approved for use in decompensated HF. B-type natriuretic peptide is released from the cardiac ventricles in response to increased left ventricular volume and/or pressure. This article reviews the nature of this peptide and its potential as a screening tool for HF. It will also present evidence defining the role of B-type natriuretic peptide in the differential diagnosis of dyspnea, prognosis after cardiac events, and in monitoring HF drug therapy.

Nearly 5 million Americans have heart failure (HF). The estimated yearly direct cost of care is up to $38 billion. Making a correct early diagnosis is an important component in a multipronged approach to combating this disease. HF triggers compensatory mechanisms, including the renin-angiotensin-aldosterone mechanism and the sympathetic nervous system. This activation, while initially beneficial, later contributes to the vicious, downward cycle of this disease. Drugs including angiotensin-converting enzyme (ACE) inhibitors, aldosterone antagonists, and β blockers have assisted in slowing or reversing the remodeling process. Another compensatory mechanism activated in the setting of left ventricular dysfunction is the release of the natriuretic peptides. This compensatory response aids the body in maintaining cardiovascular, renal, and endocrine homeostasis. The extent of the activation appears to correlate with the degree of left ventricular dysfunction. Three types of these peptides (A, B, and C) are found in human beings and are produced chiefly by the atrium, ventricles, and endothelium, respectively. The fourth natriuretic peptide type, D-type, is found in the venom of the green mamba (Dendroaspias viridis), and a homologue is found in the plasma and atrial myocardium of normal human beings. The B-type natriuretic peptide (BNP) is the most sensitive marker of left ventricular dysfunction. It is a 32-amino-acid polypetide containing a 17 amino acid ring structure shared by all the natriuretic peptides. Released primarily from the left ventricle in response to high left ventricular pressure and volume overload, BNP is an independent predictor of high left ventricular end-diastolic pressure and volume. It promotes elimination of sodium as well as diuresis. BNP values increase with age and are higher in women. Interpretation of the value of BNP is limited in patients with renal insufficiency/failure. The US Food and Drug Administration recently approved a point-of-care BNP assay to be used in the diagnosis of heart failure. The BNP assay (Biosite, Inc., San Diego, CA) is a rapid immunoassay that requires only a few milliliters of whole blood or plasma.

A simple, rapid, cost-effective test for the accurate diagnosis of HF has been needed for some time. Making an early diagnosis of HF based on symptoms of dyspnea, fatigue, and signs of fluid overload remains a major clinical challenge. Diagnostic accuracy for HF has been reported to be only 74% in the urgent-care setting. Currently, the identification of HF is based on comprehensive history and physical examination combined with diagnostic tests such as the electrocardiogram, chest x-ray, and an assessment of left ventricular function. Lung exam findings can mimic other pulmonary processes, but "classic" rales or S3 on cardiac auscultation increase the probability that ventricular dysfunction is present. The electrocardiogram has no specific HF diagnostic features, although evidence of a prior myocardial infarction, especially if extensive, increases the likelihood of left ventricular systolic dysfunction. Chest x-ray is often insensitive in detecting early HF. An echocardiogram is considered the gold standard in assessing and diagnosing left ventricular dysfunction. However, the limitations of echocardiogram include the cost involved and the difficulty in imaging patients with pulmonary disease and obesity. In addition, 24/7 echocardiograms with experienced, timely interpretation are unavailable in many health-care settings. This problem is especially vexing in emergency department environments. With all the confines of current diagnostic modalities, misdiagnosis or delay in the diagnosis of HF is common.

Natriuretic peptide levels are increased in HF and in the case of A-type natriuretic peptide and BNP, their values generally correlate with hemodynamic parameters such as right atrial pressure, pulmonary capillary wedge pressure, and left ventricular end diastolic pressure. Given that plasma A-type natriuretic peptid and BNP are derived predominantly from the atria and ventricles, respectively, plasma BNP concentration is a more sensitive marker for detecting left ventricular abnormalities. It increases as the left ventricular ejection fraction decreases or in the presence of diastolic dysfunction.

A recent study compared the use of plasma BNP and echocardiograms in detecting the presence or absence of left ventricular dysfunction (Figure 1). Two hundred patients with unknown left ventricular function were referred for echocardiograms to have their left ventricular function evaluated. In addition, BNP levels were drawn. The cardiologists who interpreted the echocardiograms were blinded to the BNP results. Based solely on the echocardiograms, the patients were divided into four groups: normal left ventricular function, abnormal left ventricular systolic function, abnormal left ventricular diastolic function, and both systolic and diastolic left ventricular dysfunction (Figure 2). The results revealed that those with normal left ventricular function had significantly lower plasma BNP levels than those with either systolic or diastolic left ventricular dysfunction. A BNP cutoff level of 75 pg/mL had a 98% negative predictive value. Widespread screening of the general population for HF is limited chiefly by cost and the expected low yield. Whether the BNP assay can be a valuable test in screening high-risk individuals for HF is under continuing investigation.



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Mean and SEM B-type natriuretic peptide (BNP) levels for normal vs. abnormal left ventricular dysfunction. Data from Am Heart J. 2001;141(3):367-374.[4]







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Mean B-type natriuretic peptide (BNP) levels for normal vs. left ventricular dysfunction. BNP values for the different subclasses of left ventricular dysfunction, namely all systolic, diastolic, and all systolic plus diastolic dysfunction. Group systolic plus diastolic dysfunction is a subgroup of all systolic dysfunction. Data are expressed as mean±SEM. Data from Am Heart J. 2001;141(3):367-374.[4]





Extensive data are available supporting BNP's utility as an adjunct in making the diagnosis of HF. Among the most convincing is the Breathing Not Properly study conducted by Maisel et al. The rationale for this study was to determine whether BNP testing could improve the diagnostic accuracy in patients presenting to the emergency department with dyspnea. A series of 1586 patients, who presented to an emergency department with shortness of breath, were evaluated in the usual manner by the emergency department physicians. In addition, a determination of the presence or absence of HF was made. A BNP level was drawn and the physicians were blinded to the results. Later, two cardiologists confirmed the diagnosis of HF based on information that was available to the emergency department physicians (plus the patient's hospital course if they were hospitalized) and all test results, including echocardiogram. The unblinding of the BNP values correlated with the cardiologists' determinations (Figure 3).



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Box plots showing median levels of B-type natriuretic peptid measured in the emergency department in three groups of patients. The Breathing Not Properly Study. Data from N Engl J Med. 2002;347(3):161-167.[2]





BNP's greatest diagnostic importance may be in the setting where the pretest probability of congestive HF being present is in the 50% range. In this setting, a high BNP value would significantly increase the post-test probability of congestive HF being present. Conversely, a low BNP level would significantly decrease the post-test probability of congestive HF. A cutoff value of 100 pg/mL BNP increases the diagnostic accuracy in predicting HF. A lower value virtually eliminates the prospect of the patient having congestive HF. The rapid measurement of BNP in conjunction with clinical assessment is useful in accurately establishing or excluding the diagnosis of congestive HF.

Outpatient management of HF relies on physical exam and subjective assessment usually recorded in the New York Heart Association (NYHA) functional classification scheme. Correlating the plasma BNP level with the NYHA functional class to determine whether plasma BNP level can be an improved biomarker in monitoring patients in the outpatient setting was carried out by Lee et al. They illustrated that the plasma BNP level was superior to the NYHA functional class in objectively monitoring clinical status. A recent study also suggested that BNP could serve as a guide to determine the severity of HF and the efficacy of its treatment. Furthermore, a corresponding change in morbidity and mortality was associated with changes in the BNP level over time.

BNP level and its correlation with systolic dysfunction has been well documented. Diastolic dysfunction is involved in an estimated 40%-50% of patients with HF. It is loosely defined as congestive HF in patients with ejection fractions greater than 50%. The pathophysiology is thought secondary to decreased left ventricular compliance. Although BNP increases in both systolic and diastolic HF, it does not clearly differentiate between the two. In general, the BNP levels associated with systolic dysfunction run higher than that associated with "pure" diastolic dysfunction.

Use of BNP as a diagnostic and prognostic biomarker for ventricular dysfunction has been well documented. Moreover, BNP levels provide prognostic value in the ischemic setting. A recent study by Richards et al. of 666 patients with an acute myocardial infarction showed that high BNP levels after myocardial infarction can independently predict death and HF regardless of their left ventricular function. Furthermore, the raised BNP level with an impaired left ventricular function after myocardial infarction significantly increases the risk of new ischemic events. This study supported prior work that evaluated BNP's role in risk assessment and risk stratification after coronary events.

A new therapeutic option for the treatment of congestive HF is now available. Synthetic BNP (Nesiritide, Scios, Inc., Sunnyvale, CA) is a recombinant human BNP that is given intravenously and is identical in structure to the naturally occurring hormone. It is approved by the US Food and Drug Administration for the treatment of decompensated congestive HF. The actions of Nesiritide include sodium and water excretion, vasodilation including the coronary arteries, and beneficial interactions with the renin-angiotensin-aldosterone mechanism and the sympathetic nervous system. Contraindications to its use include hypersensitivity, cardiogenic shock, and systolic blood pressure <90 mm Hg. In a recent study (Vasodilation in the Management of Acute CHF [VMAC]), Nesiritide was compared with both placebo and nitroglycerin in 489 patients hospitalized with decompensated congestive HF. The study showed that Nesiritide improved hemodynamic function and symptoms more effectively when added to standard therapy compared with placebo or nitroglycerin in the treatment of decompensated HF. Another study of 255 patients admitted with acutely decompensated congestive HF randomized to either Nesiritide or dobutamine showed that those treated with Nesiritide had fewer ventricular arrhythmias than those who received dobutamine.