Version May 2024
INTRODUCTION — The natriuretic peptide system impacts salt and water handling and pressure regulation and may influence myocardial structure and function.
B-type natriuretic peptide (BNP) is a natriuretic hormone initially identified in the brain but released primarily from the heart, particularly the ventricles. Cleavage of the prohormone pro-BNP produces biologically active 32 amino acid BNP as well as biologically inert 76 amino acid N-terminal pro-BNP (NT-proBNP).
Atrial natriuretic peptide (ANP) is a hormone that is released from myocardial cells in the atria and, in some cases, the ventricles in response to volume expansion and possibly increased wall stress [1]. ANP circulates primarily as a 28 amino acid polypeptide, consisting of amino acids 99 to 126 from the C-terminal end of its prohormone, pro-ANP.
The release of both ANP and BNP is increased in heart failure (HF), as ventricular cells are recruited to secrete both ANP and BNP in response to the high ventricular filling pressures [2]. The plasma concentrations of both hormones are increased in patients with asymptomatic and symptomatic left ventricular dysfunction, permitting their use in diagnosis (figure 1).
Natriuretic peptide levels are elevated in some patients with coronary heart disease, valvular heart disease, constrictive pericarditis, pulmonary hypertension, and sepsis (table 1). The diagnostic and prognostic value of measuring plasma BNP and NT-proBNP in asymptomatic individuals and patients with such non-HF conditions is discussed here. While the discussion here will focus on patients without overt HF, BNP or NT-proBNP elevations in some of these settings may be a sign of undiagnosed HF.
The diagnostic and prognostic value of measuring plasma BNP, NT-proBNP, and midregional pro-ANP in patients with HF are discussed separately. (See "Natriuretic peptide measurement in heart failure".)
ASSAY INTERPRETATION — A number of variables affect plasma B-type natriuretic peptide (BNP) and N-terminal pro-BNP levels, including the assay used, age (higher normal values with age), sex (higher values in women), body mass index (lower levels with higher body mass index), and genetic factors. In addition, there is intraindividual and analytic assay variation. These issues are discussed in greater detail separately. (See "Natriuretic peptide measurement in heart failure", section on 'Assay interpretation' and "Natriuretic peptide measurement in heart failure", section on 'Age, sex, and body mass'.)
CONDITIONS
Renal failure — Plasma B-type natriuretic peptide (BNP) and N-terminal pro-BNP (NT-proBNP) concentrations are elevated in patients with renal failure. In patients with chronic kidney disease, decreased estimated glomerular filtration rate is associated with increased plasma BNP and even greater elevation in NT-proBNP concentrations. This issue is discussed in detail separately. (See "Natriuretic peptide measurement in heart failure", section on 'Renal failure'.)
Predictor of cardiovascular events
Population-based studies — Plasma BNP and the N-terminal fragment of pro-atrial natriuretic peptide (NT-proANP) levels are predictors of the development of HF, as well as other cardiovascular events, in asymptomatic patients without HF. This was demonstrated in a prospective evaluation of 3346 participants (mean age 59 years) in the Framingham Heart Study [3]. At five years, 119 patients died (3.6 percent) and 79 had a first cardiovascular event (myocardial infarction [MI], coronary insufficiency, death from coronary heart disease, HF, or stroke; 2.4 percent). Baseline plasma BNP and NT-proANP levels above the 80th percentile were both associated with a significant increase in the subsequent development of HF (adjusted hazard ratio [HR] 3.07 and 5.02), as well as less marked increases in all-cause mortality, atrial fibrillation, and stroke or transient ischemic attack.
The ability of NT-proBNP to predict cardiovascular events was evaluated in a population-based study of 626 older adults [4]. Individuals with NT-proBNP levels above the 80th percentile (more than 655 pg/mL) had, at five-year follow-up, a significant increase in mortality compared with those with lower values (adjusted HR for mortality 1.96 overall and 1.82 after adjustment for left ventricular dysfunction, and an absolute unadjusted increase in mortality of 24.5 percent). Among the 537 participants with no prior history of cardiovascular disease, those with NT-proBNP above the 80th percentile had a significantly higher risk of a first major cardiovascular event (adjusted HR 3.24).
Prognosis in ACS — Elevations in plasma BNP or NT-proBNP are associated with increased mortality in patients with an acute coronary syndrome (ACS). The prognostic value of plasma BNP and NT-proBNP in this setting is discussed in detail separately. (See "Risk factors for adverse outcomes after non-ST elevation acute coronary syndromes", section on 'BNP and NT-proBNP'.)
Prognosis in stable angina — Plasma BNP concentrations have prognostic value in patients with stable angina [5,6]. The magnitude of this effect was illustrated in a review of 1085 such patients who had plasma BNP measured at baseline and were then prospectively followed for a mean of 2.5 years [6]. There was a stepwise decrease in event-free survival across quartiles of plasma BNP. After adjustment for confounders including left ventricular ejection fraction (LVEF), patients in the highest quartile (plasma BNP >100 pg/mL) had a significant 6.1-fold increase in risk compared with those in the lowest quartile (plasma BNP <12 pg/mL); the HR was 4.4 for plasma BNP values >100 pg/mL.
Plasma NT-proBNP appears to have equivalent predictive value in these patients [5]. The predictive value of NT-proBNP in patients with stable angina was evaluated in a report of 1034 patients who were referred for coronary angiography and then followed for nine years [7]. At follow-up, 288 patients (28 percent) had died. The patients who died had significantly higher NT-proBNP values at presentation (386 versus 120 pg/mL). Patients with NT-proBNP values in the highest quartile were older, had a lower LVEF, and were more likely to have diabetes and a prior MI. In a multivariable model, these patients had an HR for death of 2.4 compared with those in the lowest quartile.
Similar findings were noted in a review of 1059 patients with chronic stable angina [8]. At a median of 3.6 years, the five-year mortality progressively increased from 4.7 percent in patients in the lowest quartile of NT-proBNP to 7.8 percent, 11.4 percent, and 32.7 percent in the second, third, and highest quintiles, respectively (adjusted HR 6.0, 95% CI 1.6-23 for the highest compared with lowest quintile). A similar prognostic value was noted for cardiovascular mortality (table 2). However, as in the previous study, patients in the highest NT-proBNP quartile had other major comorbidities including highest rates of diabetes, atrial fibrillation, and New York Heart Association class III or IV (18.5 versus 0.8 percent in the lowest quartile).
Further studies are required to determine if measurement of BNP or NT-proBNP has clinical utility in the management of patients with stable angina.
Postoperative complications — Pre- and postoperative elevations in plasma BNP are associated with an increased risk of adverse cardiovascular events at 30 days. In a 2009 meta-analysis that included seven studies of 2841 patients who had a serum BNP measurement before noncardiac surgery, there was a statistically significant association between a preoperative elevation in serum BNP and the cardiovascular outcomes of death, cardiac death, and nonfatal MI at 30 days (adjusted odds ratio [OR] 19.3) [9]. A 2011 meta-analysis that evaluated postoperative mortality at six months or later came to a similar conclusion [10].
The relationship between pre- and postoperative natriuretic peptide levels and cardiovascular outcomes was evaluated in a meta-analysis of 18 studies (n = 2179) in which natriuretic peptide was sampled preoperatively and within seven days after surgery [11]. An elevated preoperative natriuretic peptide level (>92 ng/L for BNP or >300 ng/L for NT-proBNP) predicted the primary composite outcome of death or nonfatal MI at 30 days (OR 3.4) and at ≥180 days (OR 2.6). The addition of postoperative natriuretic peptide to a risk-prediction model containing preoperative natriuretic peptide improved risk classification at 30 and ≥180 days. Elevated postoperative natriuretic peptide was the strongest independent predictor of the primary outcome at both time points. While it appears that natriuretic peptide measured either before or shortly after surgery has prognostic information, the implications of this finding are uncertain.
Valvular heart disease — The potential prognostic value of natriuretic peptide measurement in patients with valvular heart disease is discussed separately. (See "Clinical manifestations and diagnosis of low gradient severe aortic stenosis" and "Chronic primary mitral regurgitation: General management", section on 'Natriuretic peptide levels'.)
Constrictive pericarditis — Hemodynamic assessment is often required to distinguish constrictive pericarditis from restrictive cardiomyopathy. However, wall stretch is increased in the latter but minimized in the former by the thickened pericardium. This difference suggests that measurement of plasma BNP might have value in distinguishing between these two disorders.
This hypothesis was evaluated in a report of six patients with constrictive pericarditis and five with restrictive cardiomyopathy in which plasma BNP was markedly elevated in patients with restrictive cardiomyopathy but just above normal in those with constrictive pericarditis (825 versus 128 pg/mL) [12]. These intriguing observations need to be confirmed in a larger number of patients to determine the accuracy of BNP testing in this setting. (See "Differentiating constrictive pericarditis and restrictive cardiomyopathy", section on 'Plasma BNP'.)
Pulmonary hypertension — Plasma BNP concentrations are elevated in patients with primary or secondary pulmonary hypertension. In such patients, they correlate positively with right atrial pressure, mean pulmonary artery pressure, pulmonary vascular resistance, and right ventricular mass, and inversely with cardiac index [13,14]. Using elevated plasma BNP to determine the cause of dyspnea in patients with pulmonary hypertension may be misleading since lung disease is responsible for the dyspnea unless the patient has secondary pulmonary hypertension due to left heart disease. (See "Treatment and prognosis of pulmonary arterial hypertension in adults (group 1)".)
Sepsis — The data supporting the diagnostic accuracy of natriuretic peptides are largely derived from emergency department patients. The role of BNP and NT-proBNP in other settings, in particular the intensive care unit (ICU), is less well established.
An observational series from a single center suggests that in an ICU setting, patients with a diagnosis of sepsis are as likely to have elevated BNP and NT-proBNP levels as patients with decompensated HF [15]. Among 249 consecutive patients, 24 were diagnosed with sepsis and 51 with decompensated HF. The following findings were noted:
●BNP and NT-proBNP levels were similar in both groups (572 versus 581 ng/L and 6526 versus 4300 ng/L for sepsis and HF patients, respectively).
●Patients with decompensated HF had a significantly higher mean pulmonary artery capillary wedge pressure (22 versus 16 mmHg) and a lower mean cardiac index (2.2 versus 4.6 L/min per m2).
Thus, in a heterogeneous population of critically ill patients, levels of natriuretic peptides were similar in patients with sepsis and those with decompensated HF.
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Perioperative cardiovascular evaluation and management" and "Society guideline links: Cardiac valve disease".)
SUMMARY
●Plasma B-type natriuretic peptide (BNP) and N-terminal pro-BNP levels (NT-proBNP) are elevated in patients with heart failure (HF) as well as in some patients without overt HF with a variety of conditions including renal failure, coronary heart disease, valvular heart disease, restrictive cardiomyopathy, pulmonary hypertension, and sepsis (table 1). (See 'Introduction' above.)
●Elevated BNP or NT-proBNP levels predict an increased risk of cardiovascular events in various patient populations, including those with and without prior symptomatic cardiovascular disease. (See 'Predictor of cardiovascular events' above.)
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