B-type natriuretic peptide and N-terminal pro-B-type natriuretic peptide – Diagnostic role in stable coronary artery disease

Abstract

B-type natriuretic peptide (BNP) and its N-terminal fragment (NT-proBNP) are released from ventricular cardiomyocytes in response to an increase in ventricular wall stress and to myocardial ischemia. Both BNP and NT-proBNP have proven to be reliable diagnostic and prognostic biomarkers in patients with heart failure. Recently, the diagnostic roles of BNP and NT-proBNP in patients with coronary artery disease (CAD) have been investigated. For patients with acute coronary syndromes, data have been derived from a great number of studies, whereas in patients with stable CAD, only a limited amount of recent data is available; although limited, these data show that elevations in BNP and NT-proBNP levels are associated with the extent of CAD, thus providing prognostic information for an unfavourable clinical outcome. However, clinical and therapeutic implications are indistinct and need to be elucidated in further studies.

In recent years, biomarkers have emerged as important tools for diagnosis, risk stratification and therapeutic decision making in cardiovascular diseases. In particular, cardiac troponins have become the cornerstone for diagnostic workup of patients with acute coronary syndromes. Currently, several promising new biomarkers are under scientific investigation. However, most of these new biomarkers are not yet suitable for clinical application, with the exception of B-type natriuretic peptide (BNP) and its N-terminal fragment (NT-proBNP). Both markers have proven their diagnostic usefulness in a great number of studies and, thus, have progressed from the laboratory bench to clinical application. The present reports aims to summarize existing data concerning BNP and NT-proBNP measurements in patients with coronary artery disease (CAD), and their clinical implications.

PHYSIOLOGY

BNP, which is also called brain-type natriuretic peptide, was first described in 1988 after isolation from porcine brain. However, it was soon found to originate mainly from the heart as a cardiac hormone.

BNP belongs to the natriuretic peptide family together with other structurally similar peptides, namely, atrial natriuretic peptide, C-type natriuretic peptide and urodilatin. The natriuretic peptides have a common, characteristic, biochemical structure that consists of a ring of 17 amino acids and a disulfide bridge between two cysteine molecules. The major source of BNP synthesis and secretion is the ventricular myocardium. Whereas atrial natriuretic peptide is stored in granules and can be outpoured immediately after stimulation, only small amounts of BNP are stored in granules, and rapid gene expression with de novo synthesis of the peptide is the underlying mechanism for the regulation of BNP secretion. BNP is synthesized as a 108 amino acid prohormone (proBNP). Upon release into circulation, proBNP is cleaved into equal proportions, that is, into the biologically active 32 amino acid BNP, which is the C-terminal fragment, and into the biologically inactive 76 amino acid N-terminal fragment (NT-proBNP).

Both molecules are constantly released and can be detected in the blood. The main stimulus for increased BNP and NT-proBNP synthesis and secretion is myocardial wall stress. Furthermore, factors such as myocardial ischemia, as well as endocrine and paracrine modulation by other neuro-hormones and cytokines, respectively, are also of importance.

In systemic circulation, BNP mediates a variety of biological effects by interacting with natriuretic peptide receptor type A, which leads to intracellular cyclic GMP production. The physiological effects of BNP are manifold and comprise natriuresis/ diuresis, peripheral vasodilation and inhibition of the renin-angiotensin-aldosterone system and sympathetic nervous system. BNP is cleared from the plasma by binding to natriuretic peptide receptor type C and through proteolysis by neutral endopeptidases. In contrast, NT-proBNP is mainly cleared by renal excretion. However, recent studies suggest that there may also be other important clearing mechanisms for NT-proBNP. The half-life of BNP is 20 min, whereas NT-proBNP has a half-life of 120 min; this difference explains why NT-proBNP serum levels are approximately six times higher than BNP levels, even though both molecules are released in equimolar proportions (Figure 1) (1).

Figure 1).

Schematic illustration of B-type natriuretic peptide (BNP) and N-terminal pro-BNP (NT-proBNP) synthesis, release and receptor interaction. BNP is synthesized as a prohormone in cardiomycytes. Upon release into circulation, the prohormone is cleaved into BNP and its N-terminal fragment (NT-proBNP) in equimolar proportions. The interaction of BNP and natriuretic peptide receptor type A (NPR-A) mediates biological effects via an intracellular cyclic GMP (cGMP) increase. NEP Neutral endopeptidase. Reproduced with permission from reference 17

CLINICAL APPLICATIONS

The diagnostic value of BNP and NT-proBNP has primarily been investigated in patients with heart failure. In a large number of studies, it has consistently been found that BNP and NT-proBNP levels are elevated in patients with heart failure; moreover, the levels of BNP and NT-proBNP have been found to be related to disease severity, as indicated by functional class (New York Heart Association class), left ventricular systolic ejection fraction and left ventricular diastolic function (1). Independent of their diagnostic value, several large-scale studies have convincingly demonstrated that high BNP and NT-proBNP levels provide strong prognostic information for an unfavourable outcome (eg, death, cardiovascular death, readmission to hospital or cardiac events) in patients with heart failure or asymptomatic left ventricular dysfunction (2). In multivariable models, BNP and NT-proBNP were shown to be superior to other prognostic parameters and, in some studies, even to be the only independent prognostic factors. Head-to-head studies comparing the diagnostic performance of BNP and NT-proBNP testing have been performed in patients with heart failure and patients with asymptomatic left ventricular dysfunction. These studies showed that both markers performed equally well, with almost identical areas under the receiver operating characteristics curves (3). Thus, it can be concluded from these studies that there is no meaningful difference between the markers in terms of risk stratification in clinical routine.

CAD

Originally, BNP and NT-proBNP were considered to be biomarkers of heart failure. More recently, however, there is a growing body of data on the relevance of both markers in CAD. It is widely believed that the underlying pathophysiological process for an increase in BNP and NT-proBNP levels is left ventricular systolic or diastolic dysfunction due to myocardial ischemia leading to increased wall stress. Nevertheless, data derived from experimental studies suggest that there is a direct release of BNP and NT-proBNP from cardiomyocytes in response to myocardial ischemia, independent of ventricular wall stress (4,5). In agreement with these experimental findings, it has been shown that BNP levels increase even after temporary myocardial ischemia induced by balloon inflation during coronary interventions (6).

Subsequently, several large-scale clinical trials (Orbofiban in Patients with Unstable coronary Syndromes-Thrombolysis In Myocardial Infarction [OPUS-TIMI] 16, Treat angina with Aggrastat and determine Cost of Therapy with Invasive or Conservative Strategy [TACTICS]-TIMI 18, Fragmin and fast Revascularisation during InStability in Coronary artery disease [FRISC] II, Global Utilization of Strategies To open Occluded arteries [GUSTO] IV, and Platelet Receptor inhibition in Ischemic Syndrome Management [PRISM]) (7,8) have evaluated the prognostic value of BNP and NT-proBNP in patients presenting with non-ST elevation acute coronary syndromes. In all of the studies, elevated levels of BNP and NT-proBNP were consistently found. Furthermore, both markers were highly predictive of an adverse outcome, independently of other bio-markers (especially troponins and C-reactive protein).

STABLE CAD

Whereas the roles of BNP and NT-proBNP in acute coronary syndromes have been investigated in many independent studies, only few data exist on the diagnostic and prognostic roles of BNP and NT-proBNP in patients with stable CAD.

In a study (9) including 355 outpatients with stable CAD, the relationship of BNP measured before exercise testing (stress echocardiography) to inducible myocardial ischemia was evaluated. Of these 355 participants, 113 had inducible myocardial ischemia. Compared with participants in the lowest BNP quartile (0 pg/mL to 16.4 pg/mL), those in the highest BNP quartile (105 pg/mL or greater) had double the risk of inducible ischemia (adjusted RR=2.0, 95% CI 1.2 to 2.6; P=0.008). The relationship between elevated BNP levels and inducible ischemia was especially evident in the 206 participants who had a history of myocardial infarction (adjusted RR=2.6, 95% CI 1.5 to 3.7; P=0.002) and was absent in those without a history of myocardial infarction (adjusted RR=1.0, 95% CI 0.3 to 2.2; P=0.9). This association between BNP levels and inducible ischemia remained strong after adjustment for measures of systolic and diastolic dysfunction (9) (Figure 2). Similar to this study, the diagnostic value of NT-proBNP was investigated in a prospective study of 94 patients with stable angina pectoris (10). All patients underwent exercise testing, myocardial scintigraphy and coronary angiography. Using single-photon emission computed tomography, NT-proBNP levels were found to be elevated in patients with inducible myocardial ischemia versus those without (396±80 pg/mL versus 160±101 pg/mL; P<0.01), and this was closely linked to the extent of CAD (no CAD: 148±29 pg/mL; one- or two-vessel disease: 269±50 pg/mL; three-vessel disease 624±186 pg/mL; P<0.01) (Figure 3). In a multivariate analysis, NT-proBNP was an independent predictor of CAD. The area under the receiver operating characteristics curve was 0.72 for NT-proBNP to predict CAD. Therefore, combining NT-proBNP assessment with conventional exercise testing, the predictive value to detect CAD can be improved. NT-proBNP was also measured before and 15 min after maximal exercise, and no increase in NT-proBNP was observed (10). Similar results with increased NT-proBNP levels were associated with the extent of inducible ischemia, and no significant rise in NT-proBNP levels after exercise testing were reported by Sabatine et al (11). In contrast, a rise in BNP levels immediately after exercise has been consistently found in several studies (11,12).

Figure 2).

Frequencies of inducible ischemia in relation to quartiles of B-type natriuretic peptide (BNP). Adapted with permission from reference 9

Figure 3).

N-terminal pro-B-type natriuretic peptide (NT-proBNP) in relation to exercise test (ET), presence of coronary artery disease (CAD), thallium scintigraphy (Tl) and a combination of positive Tl and the presence of CAD. Reproduced with permission from reference 10

In several independent studies with follow-up periods ranging from two to nine years, the prognostic information provided by BNP and NT-proBNP determination has been evaluated. In these studies, BNP and NT-proBNP levels were consistently found to be predictive of long-term mortality and adverse cardiovascular events (13–16). However, no cut-off values are clearly defined and therapeutic consequences remain open.

CONCLUSIONS

BNP and NT-proBNP have emerged as powerful biomarkers in various cardiovascular diseases. Both markers were originally introduced as biomarkers for heart failure. However, there is a growing body of recent evidence suggesting diagnostic and prognostic roles for BNP and NT-proBNP in patients with CAD, either acute coronary syndromes or stable chronic CAD. However, the clinical and therapeutic consequences derived from elevated BNP and NT-proBNP levels are not yet elucidated and require further investigations.