B-type Natriuretic Peptide (BNP) Assay
Background
B-type natriuretic peptide (BNP) is a cardiac neurohormone secreted from membrane granules in the cardiac ventricles as a response to ventricular volume expansion and pressure overload. 1 The natriuretic peptide system allows the heart to participate in the regulation of vascular tone and extracellular volume status. The natriuretic peptide system and the renin angiotensin system counteract each other in arterial pressure regulation. Levels of atrial natiuretic peptide (ANP) and BNP are elevated in cardiac disease states associated with increased ventricular stretch.
The main circulating and storage form of BNP is 32 amino acid peptide with a ring structure. Physiological actions of BNP are mediated through a guanylate cyclase-linked receptor, natriuretic peptide receptor A (NPR-A). BNP produces arterial and venous vasodilation. Clearance of BNP is promoted by a NPR-C receptor which removes it from the circulation and BNP is also degraded through enzymatic cleavage by neutral endopeptidase. BNP levels are reflective of left ventricular diastolic filling pressures and thus correlate with pulmonary capillary wedge pressure.
BNP is stable in whole blood and a portable, 15 minute assay has been developed for measuring BNP in whole blood samples (Triage BNP Test, Biosite Diagnostics). BNP levels have been shown to be elevated in patients with symptomatic left ventricular dysfunction and correlate with New York Heart Association (NYHA) classific ation and prognosis.
Distinguishing congestive heart failure from other causes of dyspnea is of great importance in patients presenting for medical attention with signs and/or symptoms that may or may not represent heart failure. A number of studies have demonstrated the limited reliability of the physical examination and Chest X-ray in diagnosing heart failure. Even with the best of clinicians, diagnosing heart failure remains a clinical challenge. BNP measurements have now been demonstrated to be a sensitive and specific test to diagnose CHF in the emergency medicine and urgent-care settings. This assay represents the first clinically available blood test to facilitate the diagnosis of heart failure.
Clinical Studies of the BNP Assay
Clinical studies have indicated that the BNP test facilitates the diagnosis of heart failure, beyond existing clinical information. In a study of 250 patients presenting with dyspnea to an Emergency Medical Center, BNP performance was compared to a gold standard of two cardiologists (blinded to BNP levels) reviewing all clinical, radiographic, and echocardiographic data.2 Mean BNP concentration in blood in patients with CHF was 1076 + 138 pg/ml vs. 38 + 4 pg/ml in those without (p < 0.001). In patients with lower extremity edema diagnosed with and without heart failure, BNP levels were 1038 + 163 vs 63 + 16 pg/ml.2 In patients with dyspnea secondary to COPD or heart failure, BNP levels were 86 + 39 with COPD as compared to 1076 + 138 with heart failure.
At a blood concentration of greater than 100 pg/ml, BNP was an accurate predictor of the presence of CHF with a sensitivity of 94%, specificity of 94%, and a 96% negative predictive value. BNP was more accurate in diagnosing CHF than history, symptoms, physical exam findings, CXR, and the ECG. In multivariate analysis, BNP added significant, independent diagnostic power compared to other clinical variables and diagnostic tests. The availability of BNP measurements would have potentially corrected 29 of the 30 diagnoses missed by the physicians evaluating the patient in the emergency medical center.
In a community based study of 1,653 subjects, the BNP assay had a 97% negative predictive value for LV systolic dysfunction.3 In 122 patients suspected of heart failure in a primary care setting who were subsequently referred to a rapid access heart failure clinic, BNP had a sensitivity of 97% and a negative predictive value of 98%.
BNP levels are elevated in both systolic dysfunction and isolated diastolic dysfunction. In a study screening 200 patients scheduled for echocardiography, mean BNP levels were 37 pg/ml in patients where both systolic and diastolic function was normal as compared to 480 pg/ml in patients with abnormal systolic or diastolic function on echocardiography.4 Patients may have a normal left ventricular ejection fraction but still have heart failure due to abnormal diastolic function, elevated ventricular pressures and as a result, elevated BNP levels. BNP levels are higher in older as compared to younger patients and are 5-10 pg/ml higher in women as compared to men.
In the data set submitted to the FDA, BNP concentration were measured in 1286 patients without CHF with mean levels of 22.6 + 27.5 pg/ml.5 A decision threshold set at 100 pg/ml provided a specificity of >98%, i.e. less than 2% expected false positives in individuals without CHF. In 804 patients diagnosed with CHF, mean BNP levels were 525.9 + 451.9 pg/ml. Sensitivity for the assay at this level was 82.4% though most heart failure patients that had BNP levels below the cut point 100 pg/ml had predominately NYHA class I or II functional status. The sensitivity for Class IV heart failure (symptoms at rest) was 96.3%. Mean levels of BNP by NYHA class were Class I 149 pg/ml, Class II 385 pg/ml, Class III 614pg/ml, and Class IV 858 pg/ml. Using the 100 pg/ml cutoff, the negative predictive value of the BNP test was > 98%.
Based on the available information a BNP < 100 pg/ml, allows clinicians to exclude heart failure as a cause of the patients’ symptoms or physical exam signs in most circumstances.
Prognostic Information with BNP
BNP levels have been shown to predict long term mortality in patients with heart failure, independent of other established prognostic variables.6 In a recent study of 72 patients hospitalized with Class III and IV heart failure, BNP levels were obtained on admission and prior to discharge.7 In patients without death or rehospitalization within 30 days, BNP levels rose during hospitalization by 233 pg/ml whereas in those without events BNP levels fell by 215 pg/ml. At a level of 400 pg/ml at time of discharge, BNP was 89% sensitive for events and the negative predictive value was 96%. In another study, 69 patients were randomized to have heart failure therapy guided by standard clinical assessment as compared to guided by BNP levels plus clinical assessment.8 At 6 months, 27% of patients in the BNP group and 53% in the clinical group has an adverse clinical event (p=0.034).
Use of the BNP Assay
The BNP assay is recommended in the following clinical circumstances:
CHF Diagnosis
Patients presenting to the Emergency Medical Center or other acute care setting with signs or symptoms that are suggestive of heart failure, but in whom after a careful history and physical examination the diagnosis is not certain are candidates for the BNP assay. This would include patients presenting with dyspnea, lower extremity edema, or other potential heart failure signs or symptoms. The BNP assay should aid in distinguishing heart failure from other causes of dyspnea such as COPD, asthma, pneumonia, or pulmonary embolization. The BNP assay should also assist in distinguishing heart failure from other causes of edema such as nephrotic syndrome or lower extremity venous insufficiency.
A BNP level of < 100 pg/ml makes it highly unlikely that the patients’ symptoms are resulting from systolic or diastolic dysfunction heart failure. As such, an echocardiogram would be unlikely to provide additional diagnostic information and is not recommended (unless being done to evaluate for cardiac valvular disease or other abnormalities in the absence of heart failure). Myocardial ischemia/infarction and non-cardiac etiologies for the patient symptoms should be considered and appropriate diagnostic testing ordered as clinically indicated.
A BNP level that is elevated helps to confirm a diagnosis of congestive heart failure. Since patients with acute myocardial infarction accompanied by heart failure, would be expected to have elevated BNP levels a positive BNP result should not be viewed as excluding a diagnosis of AMI. In patients with severe right heart failure due to conditions such as pulmonary hypertension or a large pulmonary embolus, BNP levels may be modestly elevated (100 – 200 pg/ml) above the normal range. Levels above 200 pg/ml, however, would almost always indicate left heart failure. In patients with elevated BNP levels above 200 pg/ml, diagnostic testing for pulmonary embolization (CT angiography or ventilation perfusion scanning) would be recommended only when diagnoses of congestive heart failure and pulmonary embolization are being considered.
CHF Management
BNP levels objectively reflect severity of disease in patients with heart failure. BNP levels obtained in patients with established heart failure provides prognostic information and monitoring of levels over time may facilitate titration of heart failure medications. Investigations are currently taking place to further evaluate the clinical utility of BNP testing for these purposes. In patients being treated for heart failure in whom volume status and the degree of compensation are not clear based on history and physical examination, BNP is likely to provide information that has greater clinical utility than Chest X-Ray testing. As BNP levels correlate with pulmonary capillary wedge pressure, the BNP test could be considered in patients where volume status are uncertain and where right heart catheterization or serial echocardiography may otherwise be performed to assess ventricular filling pressures. Heart failure patients with persistently elevated BNP levels would be expected to benefit from increased titration of diuretics and further optimization of ACE inhibitor, beta blocker, and spironolactone dosing. In heart failure patients with persistent or worsening symptoms out of proportion to their BNP levels, alternative causes of symptoms should be considered (i.e. other medical problems such as depression, anemia, or infection).
Caution: The BNP assay, like all laboratory tests, does not provide a definitive diagnosis. The test result should be interpreted by the physician in conjunction with clinical findings and other diagnostic testing.
While a negative BNP assay makes the diagnosis of heart failure unlikely it does not exclude the diagnosis of other potentially serious medical conditions such as unstable angina, acute myocardial infarction, asthma, COPD, or pulmonary embolization. As with the troponin assay, the BNP test result should not be the sole criteria used to determine whether to admit or discharge a patient presenting to the emergency department with dyspnea or other symptoms. Diagnosis, risk assessment, and the decision as to whether inpatient or outpatient management is indicated should be based on the history, physical examination, ECG, and diagnostic tests as indicated.
Assay Characteristics
The Triage BNP Test diagnostic level to exclude heart failure is BNP < 100 pg/ml (negative). A level of > 100 pg/ml is considered positive and indicative of heart failure. An elevated BNP indicates elevated ventricular filling pressure (PCW pressure) as occurs with systolic and diastolic dysfunction heart failure. Elevations can also be seen in acute myocardial infarction severe enough to elevate ventricular pressure. BNP levels are not influenced by hypertension, diabetes, mild renal insufficiency, or COPD. Dialysis patients will have elevated levels reflecting increased ventricular filling pressure. The assay identifies patients with heart failure and correlates with severity of symptoms/NYHA class.
The test measures BNP by immunoassay and utilizes a fluorescence detection system. The assay is linear between 20 and 1300 pg/ml, with a lower limit of detection of 20 pg/ml. Results below and above the detection limits will be reported as < 20 pg/ml and >1300 pg/ml, respectively. Samples >1300 pg/ml cannot be re-assayed after dilution. Collect whole blood in a 4 ml lavender top tube-- a minimum of 2 ml of blood s required. Moderately hemolyzed specimens are acceptable. Samples greater than 4 hours old are not acceptable for testing, based on stability studies. The rapid BNP test will be available only on a STAT basis with a turn-around time of less than 60 minutes. No panic value levels have been set. The cost per reportable for BNP is $26.25 (for comparison, troponin I costs $11.08).
Heart Failure Diagnostic Algorithm
In patients in whom both heart failure and an acute coronary syndrome/myocardial infarction are in the differential diagnosis, serial troponins and ECGs should also be obtained. (see UCLA Chest Pain/Unstable Angina Guidelines). In patients with elevated BNP levels above 200 pg/ml, diagnostic testing for pulmonary embolization (CT angiography or ventilation perfusion scanning) would be recommended only when diagnoses of congestive heart failure and pulmonary embolization are being considered. For CHF management please refer to the UCLA Heart Failure Management Guidelines. The UCLA Cardiology Clinical Guidelines may be found at www.med.ucla.edu/champ.
References
1. Bonow RO. New insights into the cardiac natriuretic peptides. Circulation 1996;93:1946-1950.
2. Dao Q, Krishnaswamy P, Kazanegra R, et al. Utility of B-type natriuretic peptide in the diagnosis of congestive heart failure in an urgent-care setting. J Am Coll Cardiol 2001;37:379-385.
3. McDonagh TA, Robb SD, Murdoch DR, et al. Biochemical detection of left ventricular systolic dysfunction. Lancet 1998;351:13.
4. Maisel AS, Koon J, Krishnaswamy P, et al. Utility of B-natriuretic peptide as a rapid, point-of-care test for screen patients undergoing echocardiography to determine left ventricular dysfunction. Am Heart J, 2001;141:367-374.
5. Triage BNP Test Product Insert. San Diego CA: Biosite Diagnostics Inc. 2000.
6. Tsutamoto T, Wada A, Maeda K, et al. Attenuation of Compensation of Endogenous Cardiac Natriuretic Peptide System in Chronic Heart Failure. Circulation 1997;96:509-516.
7. Cheng V, Kazanagra R, Garcia A, et al. A rapid bedside test for B-type peptide predicts treatment outcomes in patients admitted for decompensated heart failure: a pilot study. J Am Coll Cardiol 2001:37:386-391.
8. Troughton RW, Frampton CM, Yandle TG, et al. Treatment of heart failure guided by plasma amino terminal brain natriuretic peptide (N-BNP) concentrations. Lancet 2000;355:1126-1130.
