Heart failure or congestive heart failure (CHF), when heart failure patients experience a buildup of fluid, is a clinical syndrome characterized by shortness of breath, fatigue and peripheral edema caused by the heart's inability to adequately circulate blood to the body's essential organs. CHF has become so common that it is considered by some to be a new epidemic.1 This dysfunction is associated with coronary artery disease (CAD), chronic hypertension, valvular heart diseases and cardiomyopathies.
The World Health Organization now estimates that 16 million people worldwide are living with some degree of heart failure. Approximately two-thirds of those, according to the National Institutes of Health, will die within five years of their diagnosis. Eighty percent of hospitalized patients age 65 and older are admitted with a diagnosis of CHF, making it the most common diagnosis of hospitalized patients in that age group.2 As a result, more Medicare dollars are spent on heart failure than any other single diagnosis.
In the general population, the prevalence of this disorder is also considerable. In the United States, where heart failure is considered one of the fastest-growing health problems, those 40 and older have a 1-in-5 chance of developing CHF.2 The steadily increasing incidence of this disorder is due, in part, to the increasing age of the population, hypertension and number of patients surviving myocardial infarctions. The incidence of CHF is about 10 per 1,000 population after age 65 years, but 20 per 1,000 for those with hypertension, and about 50 per 1,000 for those with a previous heart attack.2
Diagnosis of CHF is difficult because CHF symptoms are non-specific. Preliminary diagnosis is based strictly on clinical symptoms such as fatigue, shortness of breath (dyspnea), edema-peripheral and pulmonary, tachycardia, rales and heart sounds. These symptoms may be found nonspecifically in individuals who are obese, have chronic obstructive pulmonary disease or pneumonia in the absence of CHF.
Differential diagnosis relies on relatively expensive procedures such as echocardiography and nuclear ventriculography to obtain an objective assessment of the heart's ability to adequately pump blood. In general, a left ventricular ejection fraction (LVEF) of > 40 percent indicates minimum adequate heart function vs. left ventricular systolic dysfunction (LVSD). However, almost half of all CHF patients have adequate LVEF with adequate systolic function but are still in diastolic CHF.3 These patients are diagnosed by exclusion and more accurate methods would clearly aid in their differential diagnosis. The diagnostic accuracy of current procedures for CHF is between 30 percent to 50 percent.
Staging of Heart Failure
As with most pathologies, staging of the severity of heart failure is based primarily on clinical parameters ranging from less to most severe. The major classification system is the New York Heart Association (NYHA). The classification increases in severity from Class I to Class IV. The critical variables for each class are shown in Fig. 1.
Accurate and early diagnosis is important to improve outcomes of CHF patients. The earlier it can be recognized, the greater the options available to the clinician as a mode of treatment.
Early stage CHF can be treated in a prophylactic fashion with drugs commonly used to treat hypertension such as calcium channel blockers, ACE inhibitors, diuretics, beta blockers, vasodilators or inotropes (digoxin) either individually or in combination. As CHF progresses, clinician and patient options become fewer and may require mechanical intervention such as left ventricular assist devices or heart transplant as the only way to sustain life. Early definitive diagnosis is key to reduced morbidity and mortality.
Circulating Marker of CHF
B-type natriuretic peptide (BNP) is one of three natriuretic peptides. Atrial natriuretic peptide (ANP) and BNP originate in the cardiac myocytes, while C-type natriuretic peptide (CNP) originates in the endothelial cells. These peptides are characterized by a common 17 amino acid ring structure with a disulfide bond between two cysteine residues.4 BNP is synthesized within the cardiomyocyte as a preprohormone (preproBNP) of 134 amino acids, from which a prehormone (proBNP) of 108 amino acids and a signal peptide of 26 amino acids are derived. The proBNP precursor protein is then cleaved into a physiologically active 32 amino acid C-terminal peptide (BNP 77-108; BNP-32) and a 76 amino acid N-terminal prohormone fragment (NT-proBNP 1-76). Studies indicate that the proBNP peptide precursor is cleaved either within or on the surface of cardiomyocytes, and that both NT-proBNP (1-76) and physiologically active C-terminal BNP-32 molecule (77-108) are released into the bloodstream.4,5 Figs. 2 and 3 show the parent and cleavage products and final structural form of the mature BNP peptide.4,5
The function of natriuretic peptides is to regulate blood pressure, electrolyte balance and fluid volume. BNP is produced primarily by the ventricle in response to pressure and stretch and functions to counteract the vasoconstrictive effects of the renin-angiotensin aldosterone system (RAAS) on increasing blood pressure and retaining salt and water. 4,5
The homeostatic feedback pathways that regulate fluid, salt and blood pressure via RAAS, the sympathetic nervous system, neuroendocrine and natriuretic peptides are shown in Fig. 4. The physiologically active ANP, BNP and CNP molecules are removed from circulation by binding to one of three natriuretic peptide clearance receptors (NPR-A, NPR-B, NPR-C) and enzymatic degradation via endopeptidase. NPR-C, which is present in the renal tubular cells and vascular cells, clears circulating peptides. NT-proBNP and BNP are also cleared by the kidneys; however, NT-proBNP is cleared only by this pathway. BNP has a biological half-life of approximately 20 minutes. It has been speculated that NT-proBNP probably has a biological half-life between one to two hours, although no definitive data has been published to date.4,5 Because of this short half-life and its rapid clearance from circulation, BNP measurements correlate well with ventricular functional status.
Commercial Assays for BNP and NT-proBNP
Within the past 15 years, numerous retrospective and prospective clinical studies have demonstrated that BNP can be used for a wide range of clinical applications related to heart failure, including diagnosis, monitoring and prognosis.6 While the original work was performed by investigators with "home brew" research assays, the introduction of the first commercial assay for BNP in 1993 by Shionogi & Co. Ltd. ( Osaka, Japan) allowed for the first routine use of this hormone. Publications using the ShionoRIAT BNP radioimmunoassay form the backbone of data that has helped define the clinical utilities of BNP.
A survey of literature in the National Library of Medicine PUBMED.database revealed that approximately 95 percent of investigators have used BNP in obtaining their findings (1470 citations for BNP vs. 77 citations for NT-proBNP). Of the BNP publications, the majority of these studies have used the ShionoRIA BNP assay. This assay uses two monoclonal antibodies: BC-203, directed against the carboxy terminus of BNP, and KYhBNP-II, which is directed against the ring structure of BNP. The radioimmunoassay requires an overnight incubation.
In March 2001, Biosite® Inc. (San Diego, CA) received FDA approval to market their point-of-care Biosite Triage® BNP test. This system employs a single-use cartridge to measure each sample specimen and utilizes two antibodies, one of which is fluorescently tagged. The assay requires 15 minutes of reaction time. According to the manufacturer, the total imprecision (CV) is 10 percent to 16 percent. Its intended uses are as an aid in the diagnosis and assessment of severity of CHF. It may also be used in risk stratification of patients with acute coronary syndromes.
In clinical studies on patients with and without CHF, at a cut-off of 100 pg/mL, the Biosite Triage BNP Test was 98 percent specific in differentiating CHF from non-CHF. BNP was shown to have a high negative predictive value in ruling out CHF. Additionally, the level of BNP correlated with the severity of disease as assessed by the NYHA CHF classification.7
In November 2002, Roche Diagnostics (Indianapolis, IN) received FDA clearance to market the Elecsys® proBNP assay. The assay uses two polyclonal antibodies, one of which is labeled with ruthenium complex and measures the inactive cleavage product of BNP, NT-proBNP. The electrochemiluminescent test is performed on the automated Elecsys immunoassay analyzer and requires 18 minutes to first result. Two cut-offs are used, one at 125 pg/mL for patients < 75 years old and a second cut-off at 450 pg/mL for patients > 75 years of age. Using these cut points, the specificity for CHF vs. non-CHF was 89 percent. Total precision ranged from 3.6-5.8 percent.8
In February 2003, Bayer HealthCare LLC, Diagnostics Division (Tarrytown, NY) released the ADVIA Centaur® BNP Assay for ex-U.S. distribution on the ADVIA Centaur Chemiluminescent System.9 The assay uses the same antibodies as the original ShionoRIA BNP manual assay with one antibody coupled to acridinium ester (KYh-BNPII) and one antibody coupled to paramagnetic latex particles (BC-203). The use of an F(ab')2 fragment for the tracer antibody reduces the possibility of HAMA effects. The assay was calibrated based on clinical trials to be harmonized with the Triage BNP test decision threshold of 100 pg/mL. At this cut-off, the ADVIA Centaur BNP assay has > 96 percent specificity in distinguishing CHF from non-CHF populations. Total precision ranges from 2.3 percent to 4.7 percent. Time to first result is 18 minutes and throughput is 218 tests per hour.
Clinical Applications of BNP
BNP levels have been shown to correlate to hemodynamic parameters associated with cardiac function and may serve as a surrogate for a number of cumbersome and expensive testing procedures, including echocardiography for determination of LVEF, pulmonary capillary wedge pressure (PCWP), and cardiac imaging. Representative studies provide data for indications for use that include diagnostic, prognostic, screening and therapeutic applications.
Circulating levels of BNP are known to increase with age and vary between men and women. In the absence of heart failure, women possess higher BNP levels than men of the same age group. A diagnostic cut-off of 100 pg/mL is most often used to differentiate heart failure patients from non-heart failure patients, as studies using this cut-off have demonstrated >95 percent specificity for such differentiation.10
Correlation with NYHA Classifications
In a study by Maisel et al of 1,586 patients (mean age 64 years) presenting to an emergency department with acute dyspnea (shortness of breath), BNP levels utilizing the Biosite Triage assay were shown to directly correlate with the New York Heart Association (NYHA) classifications for heart disease.10 Class I patients had a mean BNP level of 150 pg/mL; Class II, 250; Class III, 550; and Class IV, 900. The final diagnosis was dyspnea due to CHF in 744 patients (47 percent, mean BNP 675 pg/mL), dyspnea due to noncardiac causes in 72 patients with a history of left ventricular dysfunction (5 percent, mean BNP 346 pg/mL) and no finding of congestive heart failure in 770 patients (49 percent, mean BNP 110 pg/mL) (Fig. 5). BNP levels by themselves were more accurate than any historical or physical findings or laboratory values in identifying CHF as the cause of dyspnea.
The results of this study demonstrate an increase in BNP levels proportional to increasing NHYA class and are consistent with other multicenter trials using either Biosite Triage,7 Bayer ADVIA Centaur9 or Roche Elecsys NT-pro BNP8. A comparison of the ratios of BNP values between NYHA classes shows similar proportionality among the three assays with the exception of Class III and IV, where NT-pro BNP shows minimal change between these two classes. This is most likely due to the increased half-life of NT-pro BNP (one to two hours) compared to BNP (20 minutes) and possibly reflects a loss of quantitative correlation with NYHA classification at higher concentrations due to the decreased rate of clearance of NT-pro BNP from the circulation.
Correlation with Left Ventricular Systolic Dysfunction (LVSD)
In a study by McDonagh et al, BNP levels were shown to be useful in the detection of asymptomatic LVSD.11 LVSD was defined as a LVEF <30 percent as measured by echocardiography. In this study of 1,653 asymptomatic individuals, mean BNP levels were significantly higher in the group with LVSD than in patients with LVEF of >30 percent. The negative predictive value was 97.5 percent, suggesting that BNP may serve as the first line test in ruling out CHF prior to selecting patients who would require additional work-up, including echocardiography.
Other studies have shown similar findings where there is an inverse correlation of BNP and LVEF ranging from 811 pg/mL at < 30 percent to 60 pg/mL when the LVEF was >50 percent.12 It has been estimated that the use of BNP could reduce the cost of LVSD detected by 26 percent to 49 percent, depending on whether the group being screened is either a high or low risk group.13
Smith et al studied BNP levels in a slightly older group (age 76 ± 4 years) of patients from general practice.14 In this unselected group of 155 elderly patients, BNP levels were shown to be as effective as echocardiography in a community screening program for LVSD. Using a cut-off of 55 pg/mL, BNP had a negative predictive value of 99 percent in ruling out CHF.
In a study of 200 patients in whom LV function was initially unknown, BNP levels reflected LVSD as determined by LVEF.15 In 105 patients determined to have a normal echocardiogram, BNP levels averaged 37 pg/mL. In contrast, in patients with either systolic or diastolic dysfunction, BNP levels were significantly higher-572 and 391 pg/mL, respectively. The authors concluded that BNP levels can accurately predict LV status based on echocardiogram and that BNP is an excellent tool for screening of LVSD.
Prediction of Adverse Outcomes in Acute and Chronic Heart Disease
To determine the prognostic value of BNP in acute coronary syndrome, DeLemos et al. studied 2,525 patients presenting with a broad range of ischemic symptoms, including myocardial infarction and prolonged chest pain.16 A single measurement of BNP obtained in the first few days (40 ± 20 hours) after the onset of symptoms correlated with the long-term risk of death and non-fatal cardiac events, including a second MI or the need for catheterization or bypass surgery (cut point > 80 pg/mL). At 30 days and 10 months, the odds ratio of an adverse outcome ranged from 3.8 to 5.8 fold and was proportional to the concentration of BNP.
Given the high incidence of death in patients with CHF and the efficacy of implantable cardioverter-defibrillators, an appropriate tool for prediction of sudden death is desirable. Berger et al studied 452 patients with LVEF < 35 percent and without mechanical assist devices or heart transplantation.17 By univariate analysis they determined that the level of BNP was the most significant predictor of death superceding ANP and NT-proBNP concentrations as well as systolic blood pressure and NYHA class. Further, in multivariate analysis, BNP stood alone as the only independent predictor of sudden death in this population.
In a second study, Koglin et al studied 78 CHF patients in a multivariable prognostic model to monitor the clinical course and outcomes for 398 days.18 Parameters assessed included BNP and variables used to develop the heart failure survival score (HFSS), which include LVEF, ischemic cardiomyopathy, resting heart rate, mean blood pressure and intraventricular conduction volume. Changes in BNP level were significantly related to changes in physical activity and prediction of survival status and was as powerful as the HFSS. The authors conclude that BNP alone may provide a more cost-effective screening tool that helps reduce the need and frequency for more expensive cardiac testing.
Selection and Monitoring of Therapy
Because BNP is produced in response to cardiac overload resulting in intracardiac pressure and stretch, it stands to reason that CHF therapy aimed at stabilizing or improving cardiac output and reducing hemodynamic stress would result in reduction of endogenous BNP levels. Pharmacologic treatment usually requires combination drug therapy (polypharmacy); positive or negative responses are monitored based on clinical acumen and empirical judgment. Estimation of improvement or adverse response to treatment are assessed by clinical changes in edema, jugular venous distension, ability to exercise, blood pressure and X-ray appearances. Studies of individual agents and combination therapy comparing clinical judgement vs. BNP levels have demonstrated that selection and titration of therapy based solely on monitoring changes in BNP results in improvements in morbidity and prolonged survival.
Stanek et al studied the effect of the addition of the beta blocker-atenolol added to a background therapy of digitalis and enalapril (ACE inhibitor) in 100 patients with LVEF of <25 percent.19 BNP was measured before initiation of therapy and followed for up to four years. Stepwise multiple regression of 10 variables, including BNP, LVEF, symptom class, treatment allocation (atenolol vs. placebo) and NT-proBNP, found that BNP was the strongest single predictive marker of survival followed by LVEF, NT-proBNP and treatment allocation. The authors concluded that measurement of BNP levels is important for monitoring therapeutic responses of patients receiving combined therapy with angiotensin converting enzyme inhibitors and beta blockers.
In a study to evaluate a new type of CHF therapy (angiotensin receptor blockers), 4,284 patients with LVEF of <40 percent were randomized to either valsartan or placebo in addition to combined therapy with ACE inhibitor and/or a beta blocker.20 BNP was measured at baseline four, 12 and 24 months after randomization. Results showed that by 24 months, BNP was elevated by 13 percent in the placebo group but reduced by 12 percent in the valsartan group. Since the baseline measurements in both groups were identical (178,181 pg/ml), this represents an overall difference of 24 percent between the placebo and valsartan groups. The reduction in BNP level correlated well with clinical efficacy, as valsartan reduced morbidity and mortality by 13.2 percent and reduced the risk of hospitalization for CHF by 27.5 percent.20
Richards et al studied the ability of BNP to predict outcome in 415 patients with ischemic ventricular dysfunction randomized to receive either placebo or carvedilol (beta blocker).21 Baseline BNP levels above the median were associated with increased mortality rates and heart failure. In patients with baseline BNP levels above the median, the use of carvedilol reduced the mortality rate by 8 percent and the heart failure rate by 13 percent. Overall, the use of carvedilol in patients with higher pretreatment levels of BNP reduced the incidence of mortality and heart failure. Thus, BNP may be used as a selection criteria in determining those patients who will benefit most from certain treatment regimens.
A recent report demonstrates the efficacy of BNP measurements in monitoring response to exogenous BNP infusions.22 Recombinant BNP, chemically known as nesiritide (Natrecor®, Scios Inc., Sunnyvale, CA), has been approved as a pharmaceutical for acute treatment of Class IV decompensated heart failure and has been shown, short term, to lower filling pressures and improve symptoms of dyspnea in these patients.23 The approved treatment regimen is a single injection followed by short-term infusion (24-48 hours) in patients with acute decompensated heart failure.
Results of this study demonstrated that following a baseline measurement prior to initiating therapy, BNP levels returned to about twice pretreatment levels during the infusion phase and infused BNP was totally cleared from the system by two hours after the conclusion of drug administration. Interestingly, following cessation of BNP infusion, there was a steady decrease in endogenous BNP levels by about 20 percent of pretreatment level that persisted up to 24 hours post cessation of infusion. The authors conclude that therapeutic BNP treatment actually resets the neurohormonal axis and temporarily improves ventricular wall tension. Because of the short half-life of BNP, short-term changes in ventricular status are capable of being monitored.22
The European Society of Cardiology has approved the use of BNP measurements as an aid in the screening and diagnosis of heart failure.24 Given the growing body of literature and the availability of routine, reproducible assays, it is expected that leading cardiology associations in the United States will soon follow suit.
Many patients with CHF remain unidentified or misdiagnosed and may, therefore, not receive appropriate therapy in a timely fashion. As with most chronic diseases, identification and intervention at an early stage leads to prolonged survival and an overall improvement in the quality of life. However, as with most other clinical laboratory tests, BNP should not be used alone but in conjunction with physical exam, patient history and other noninvasive and invasive laboratory procedures. When used in this context, BNP measurements add significant value in aiding clinicians in the differential diagnosis of CHF and the selection and monitoring of therapy.
Dr. Bluestein is the principal staff scientist/technical manager for the ADVIA Centaur® BNP project, Bayer Healthcare LLC, Diagnostics Division, Lab Testing Segment R&D, Tarrytown, NY. Dr. Despres is a senior staff scientist/project manager; Dr. Belenky is a senior scientist for the ADVIA Centaur® BNP project; Dr. Ghani is manager of Clinical Trials; and Dr. Armstrong is director of Disease Focus Research and Development, Bayer Healthcare LLC.
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