Until recently, no simple blood test could detect heart failure or monitor its progression or guide its treatment. With the increasing availability of assays for the measurement of brain natriuretic peptide (BNP), a cardiac hormone, this test may have a role in detecting, monitoring, and perhaps preventing chronic heart failure.

Pathophysiology

The heart secretes natriuretic peptides as a homeostatic signal to maintain stable blood pressure and plasma volume and to prevent excess salt and water retention. Atrial natriuretic peptide (ANP) initially was identified in the atrial myocardium of rats.¹ BNP subsequently was isolated in porcine brains.² Natriuretic peptides have several actions: (1) down-regulating the sympathetic nervous system and the renin-angiotensin-aldosterone system, (2) facilitating natriuresis and diuresis through the afferent and efferent hemodynamic mechanisms of the kidney and distal tubules, (3) decreasing peripheral vascular resistance, and (4) increasing smooth muscle relaxation. Natriuretic peptides also may inhibit cardiac growth and hypertrophy, counteracting the mitogenesis that causes ventricular remodeling.^3–5

BNP primarily is secreted by the ventricles in the heart as a response to left ventricular stretching or wall tension.⁶ It may be a backup hormone that is activated only after a prolonged period of volume overload.⁷ Cardiac myocytes secrete a BNP precursor that is synthesized into proBNP, which consists of 108 amino acids. After it is secreted into the ventricles, proBNP is cleaved into the biologically active C-terminal portion and the biologically inactive N-terminal (NT-proBNP) portion.

Influences on BNP Levels

Many medications used to treat heart failure (e.g., diuretics such as spironolactone [Aldactone], angiotensin-converting enzyme inhibitors, angiotensin-II receptor blockers) reduce natriuretic peptide concentrations.^8–13 Therefore, many patients with chronic stable heart failure will have BNP levels in the normal diagnostic range (i.e., BNP level less than 100 pg per mL [100 ng per L]). However, digoxin and some beta blockers appear to increase natriuretic peptide concentrations.^14–16 Exercise causes a short-term increase in BNP levels,¹⁷ although only small changes (i.e., increase of 0.9 percent in patients without heart failure, 3.8 percent in patients with New York Heart Association [NYHA] class I or II heart failure, and 15 percent in patients with NYHA class III to IV heart failure) are detectable one hour after exercise.¹⁸ No circadian variation has been reported when BNP is measured every three hours for 24 hours,¹⁹ and there is less hourly variation with BNP than with ANP.²⁰

BNP to Diagnose Heart Failure

There is no agreed-upon first-line test for the diagnosis of heart failure and no simple method of measuring the adequacy of cardiac output in relation to normal levels of activity. Heart failure usually is diagnosed in persons with known heart disease who present with nonspecific symptoms (e.g., breathlessness, ankle swelling) and signs (e.g., basal lung crackles). To confirm clinically suspected heart failure, physicians rely on surrogate measures of cardiac function such as left ventricular ejection fraction. However, it is clear that a large proportion of patients with heart failure, particularly older patients and women, have preserved systolic function (i.e., diastolic heart failure). The best way to diagnose and treat these patients is unclear. BNP increases when cardiac myocytes are strained; therefore, BNP is an effective method for detecting heart failure with or without systolic dysfunction.

Elevated BNP levels also have been associated with renal failure (because of reduced clearance),²¹ pulmonary embolism, pulmonary hypertension,^22,23 and chronic hypoxia.

A systematic review included 20 studies evaluating BNP testing in the diagnosis of heart failure.²⁴ The eight studies that measured BNP against a reference standard of reduced left ventricular ejection fraction (i.e., 40 percent or lower or the equivalent) had a pooled diagnostic odds ratio of 12 (95% confidence interval [CI], 8 to 16).²⁴ This result is consistent with a moderately accurate diagnostic test. The seven studies that measured BNP against clinical criteria (i.e., a consensus view using all other clinical information and often using a panel of two or three cardiologists) had a pooled diagnostic odds ratio of 31 (95% CI, 27 to 35).²⁴ The two studies that measured BNP against echocardiographic criteria for systolic and diastolic heart failure had a pooled diagnostic odds ratio of 38 (95% CI, 6 to 237).²⁴ Therefore, the review showed a greater agreement with a heart failure measure that included diastolic heart failure than one that included systolic heart failure alone (assuming there were no other differences between the studies).²⁴

Results from significant studies of the diagnostic accuracy of BNP and NT-proBNP measurements are shown in Table 1.^25–29 The largest of these studies enrolled 1,586 patients presenting with dyspnea to seven emergency departments.²⁵ Using a cutoff BNP level of 50 pg per mL (50 ng per L), the positive likelihood ratio was 2.6 (95% CI, 2.3 to 2.8), and the negative likelihood ratio was 0.05 (95% CI, 0.03 to 0.07). This indicates that a low BNP value is highly effective at ruling out heart failure, whereas a value more than 50 pg per mL is only a fair indicator of disease.

The number of studies conducted in the primary care setting is approximately equal to the number set in hospitals, and little difference in diagnostic odds ratio has been shown between the two settings. Although the sensitivity and specificity of BNP testing in primary care and hospital settings are similar, interpretation of the test varies between asymptomatic and symptomatic patients and between primary and acute care settings (Table 2^25,27,29).

The optimal cutoff value for a heart failure diagnosis and whether reference levels should vary with age and sex remain unclear. There is a trade-off, because lowering the cutoff decreases the false-negative rate (i.e., increased sensitivity and fewer missed diagnoses) but increases the false-positive rate (i.e., decreased specificity and more incorrect diagnoses). In addition, the average levels of BNP and NT-proBNP are greater in women than in men and increase with age.^19,30 However, these higher levels in women may reflect an increasing prevalence of undetected and possibly asymptomatic cardiac dysfunction in this group.

A trial that included patients presenting with dyspnea to a Swiss emergency department assessed health outcomes and cost of treatment associated with BNP-assisted diagnoses.³¹ The trial showed that, compared with no BNP test, the test reduced the median length of hospitalization (eight versus 11 days) and the mean total cost of treatment ($5,410 versus $7,264).³¹ These results are attributable to the test’s ability to rule out heart failure, allowing the physician to initiate treatment for an alternative diagnosis such as chronic obstructive pulmonary disease or pneumonia. According to an updated guideline from the American College of Cardiology (ACC) and the American Heart Association (AHA), BNP measurements can be useful in patients presenting in the urgent care setting when the clinical diagnosis of heart failure is uncertain.³²

Determining Prognoses

Nineteen studies showed that elevated BNP levels in patients with heart failure are associated with an increased risk of death or cardiovascular events.³³ Pooled results from five studies showed that a BNP increase of 100 pg per mL caused a 35 percent increase in risk of death.³³ BNP was the only statistically significant independent predictor of mortality in nine studies, indicating that BNP tests potentially are more useful than traditional predictors of mortality (e.g., age, ischemic etiology, left ventricular ejection fraction, NYHA classification, serum creatinine levels).³³

Screening and Prevention

Because BNP tests can predict death and cardiovascular events in patients without a previous heart disease diagnosis, they are being studied as a possible tool for heart failure screening. Although BNP tests may help detect patients at high risk of overt heart failure and may prevent its progression, randomized controlled trials are needed to determine who should be tested and whether or not treating asymptomatic patients is beneficial.

Several studies (some of which excluded persons previously diagnosed with heart failure) have measured the prognostic value of BNP in asymptomatic populations. In the two largest studies, the relative risk of death during the four to five years of follow-up approximately doubled in patients with a BNP value higher than relatively low cutoff levels (17.9 to 23.3 pg per mL [17.9 to 23.3 ng per L]).^34,35

Monitoring Patients with Heart Failure

BNP measurement is a potential tool for monitoring treatment response in patients with heart failure because of the test’s ability to diagnose heart failure, predict prognosis, and correlate with more invasive clinical measures (e.g., pulmonary capillary wedge pressure).³⁶ Prognostic studies have shown that BNP levels measured after treatment took effect were more predictive of the risk of death or further cardiovascular events than those initiated at first presentation.^37,38

Ideally, randomized trials would offer definitive evidence; however, only two small trials (including 69 and 21 patients) have evaluated BNP-guided treatment.^39,40 The first trial showed a nearly twofold decrease in cardiovascular events,³⁹ and the second trial showed a decrease in BNP levels with BNP-guided treatment.⁴⁰ However, according to the ACC/AHA guideline on the management of heart failure, the value of serial BNP measurements in guiding therapy for patients with heart failure is not well established.³² Larger randomized controlled trials are needed before routine BNP monitoring of heart failure can be recommended.