REVIEW URRENT C OPINION

Brain natriuretic peptide: a biomarker for all cardiac disease? Gnanadevan Mahadavan, Thanh H. Nguyen, and John D. Horowitz

Purpose of review To evaluate new development in the utility of brain natriuretic peptide and N-Terminal brain natriuretic peptide (BNP/NT-Pro-BNP) in the management of various cardiovascular diseases. The determination of plasma BNP levels has an established role in the discrimination of pulmonary oedema from other causes of acute dyspnoea, and there is increasing evidence of the utility of BNP/NT-Pro-BNP assay both as a prognostic tool in chronic heart failure and as a means of guiding therapy in heart failure patients aged below 70 years. Recent findings Findings have substantially extended the clinical utility of BNP/NT-Pro-BNP assay. In heart failure with preserved left ventricular ejection fraction, BNP elevation may also facilitate diagnosis, although its precise utility is uncertain. In the acute catecholamine-induced myocardial inflammatory condition of Tako-Tsubo cardiomyopathy (TTC), BNP/NT-Pro-BNP elevations are marked and persist for at least 3 months, despite the absence of pulmonary oedema. In TTC, BNP/NT-Pro-BNP therefore serves as an ancillary diagnostic measure as well as a marker of recovery. Among other conditions in which BNP assay may provide prognostic information are atrial fibrillation (in which the extent of elevation predicts thromboembolic risk) and pulmonary hypertension. Summary BNP/NT-Pro-BNP assay has widespread utility as an adjunct to cardiovascular disease diagnosis and management. Keywords brain natriuretic peptide, heart failure, novel uses

INTRODUCTION Brain natriuretic peptide (BNP; also known as B-type natriuretic peptide) and N-Terminal brain natriuretic peptide (NT-Pro-BNP) are released into plasma via cleavage of Pro-BNP under conditions of myocardial stretch and/or inflammation. Although most commercial ‘BNP’ assays cross-react significantly with inactive peptides, including Pro-BNP, measurement of BNP/NT-Pro-BNP levels in plasma has been widespread use in clinical practice. The novel utilities of determination of plasma concentrations of BNP/NT-Pro-BNP are discussed in the current review.

PATHOPHYSIOLOGY OF BRAIN NATRIURETIC PEPTIDE BNP is a vasodilator natriuretic peptide largely, but not entirely, secreted from ventricular myocardium. www.co-cardiology.com

Pathways for synthesis and release of BNP are summarized in Fig. 1. BNP is formed within ventricular myocardium by progressive cleavage of a larger precursor peptide, prepro-BNP1-134 to Pro-BNP1-108. The critical step is the cleavage of the Pro-BNP1-108 molecule into an active moiety, BNP1-32, and a larger inactive moiety, N-terminalproBNP1-76 (NT-ProBNP) by two prohormone convertases called corin and furin.

The Queen Elizabeth Hospital, Department of Cardiology, Basil Hetzel Institute, The University of Adelaide, Australia Correspondence to Professor John D. Horowitz, MBBS, B.Med.Sci (Hons), PhD, FRACP, Cardiology Unit, The Queen Elizabeth Hospital, 28 Woodville Road, Woodville South, SA 5011, Australia. Tel: +61 08 8222 6725; fax: +61 08 8222 6422; e-mail: [email protected] edu.au Curr Opin Cardiol 2014, 29:160–166 DOI:10.1097/HCO.0000000000000036 Volume 29  Number 2  March 2014

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Brain natriuretic peptide Mahadavan et al.

KEY POINTS  BNP and NT-Pro-BNP guided therapy in heart failure has potential mortality benefit.  BNP may have a role in the therapeutics of HFpEF.  BNP and HT-Pro-BNP may help predict recovery in TTC.  NT-Pro-BNP may help predict atrial fibrillation in cryptogenic stroke.

Although BNP has a half-life of 20 min and is quickly cleared, NT-Pro-BNP has a longer half-life of 1–2 h, which results in higher circulating levels and less fluctuation in levels [1]. BNP binds to the membrane-bound NPR-A (natriuretic peptide A receptor) mediating natriuresis, vasodilatation, renin inhibition, antimitogenesis, anti-ischaemic effects and positive lusitropism via cGMP signalling [2]. BNP is degraded by the ectoenzyme neutral endopeptidase, and cleared by NPR-C receptor, mainly via the kidneys. Unlike atrial natriuretic peptide (ANP), BNP is synthesized and secreted in bursts rather than stored in granules [3] under conditions of pressure and volume overload, reflecting both systolic and diastolic function. Although ventricular distension is

the classical stimulus, BNP release also may occur with ischaemia, inflammation, redox stress and the local effects of catecholamines, angiotensin II and endothelin-1 [4–6]. In normal controls, there is a reasonable correlation between BNP and NT-Pro-BNP levels. In congestive heart failure (CHF), the NT-Pro-BNP plasma level is 2–10 times higher than the BNP concentration [7]. Despite high plasma levels of ‘BNP’ as determined by standard assay methodologies, CHF is in reality associated with potential BNP insufficiency that results from depletion of the authentic bioactive BNP1-32 [8,9]. This apparent paradox can be explained by the fact that the standard commercial BNP immunoassays (widely used in clinical settings) recognize both inactive and active BNP-like peptides (Figure). In addition, abnormal Pro-BNP processing into the active form may contribute to the BNP deficiency [10]. Furthermore, CHF patients also may manifest a state of BNP resistance at the level of signal transduction post NPR-A binding [11].

‘CLASSICAL’ INDICATIONS FOR BRAIN NATRIURETIC PEPTIDE AND N-TERMINAL BRAIN NATRIURETIC PEPTIDE MONITORING The clinical utility of assay of BNP and NT-Pro-BNP has evolved from a purely diagnostic and triage tool

Mechanical: Ventricular distension (myocyte stretch) Non–mechanical: Ischaemia, Inflammation, Redox stress Catecholamines (a/b), Angiotensin II, Endothelin–1

Pre–proBNP 1–134 Myocardium ProBNP 1–176

26AA signal sequence

Corin/furin cGMP

NT–proBNP 1–176

BNP1–132

t1/2 = 1–2 hr

t1/2 = 18 min

Blood

ProBNP3–108

ProBNP3–108

ProBNP3–76

Natriuresis Positive lusitropy Vasodilatation ↓RAAS

ProBNP3–32

FIGURE 1. Schematic: Pathways for brain natriuretic peptide secretion and degradation. BNP, brain natriuretic peptide; RAAS, renin angiotensin aldosterone system. 0268-4705 ß 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins

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Heart failure Table 1. ‘Classical’ uses of brain natriuretic peptide and N-Terminal brain natriuretic peptide Acute pulmonary oedema

Breathing not properly study Multinational study 2002 (BNP) [12] REDHOT study 2006 (BNP) [13,14]

Heart failure hospitalization (Predicting rehospitalization and mortality)

Verdiani et al. (BNP) [15] Berger et al. (BNP) [16] Logeart et al. (BNP) [17] Hartmann et al. (COPERNICUS trial) NT-Pro-BNP [18]

CHF

Meta-analysis by Li et al. [19 ] of 11 randomized controlled trials including PRIMA (2010) [20], PROTECT (2011) [21], STARBRITE (2011) [22]

(Guided Therapy with BNP/NT-Pro-BNP)

UPSTEP (2011) [23]

&

BNP, brain natriuretic peptide; CHF, chronic heart failure; COPERNICUS, carvedilol prospective randomized cumulative survival; NT-Pro-BNP, N-Terminal brain natriuretic peptide; PRIMA, can Pro-brain-natriuretic peptide guided therapy of chronic heart failure improve heart failure morbidity and mortality? study; PROTECT, Pro-BNP outpatient tailored chronic heart failure; REDHOT, Rapid Emergency Department Heart Failure Outpatient Trial; STARBRITE, strategies for tailoring advanced heart failure regimens in the outpatient setting: brain natriuretic peptide versus the clinical congestion score trial; UPSTEP, use of peptides in tailoring heart failure project.

in acute heart failure, to include a risk stratification tool in those with left ventricular systolic dysfunction, and finally to an adjunctive method to tailor therapy in CHF, as summarized in Table 1 [13–18,19 ,20–23]. A landmark assessment of 1586 patients, the Breathing Not Properly Multinational Study [12], demonstrated that BNP levels below 50 pg/ml had a high negative predictive value of 96% for a ‘clinical consensus’-based diagnosis of acute pulmonary oedema. Values more than 100 pg/ml diagnosed acute pulmonary oedema with an accuracy of 83%. This study effectively demonstrated that adding BNP assay to clinical judgement would raise the accuracy of the diagnosis of acute heart failure from 74 to 81%. NT-Pro-BNP has also been shown to have an extremely strong negative predictive value (97%) for acute heart failure in the emergency setting in 345 patients, and also increased the accuracy of a clinical diagnosis of acute heart failure [24]. Preliminary results of the Rapid Emergency Department Heart Failure Outpatient Trial (REDHOT) study [13] indicated that the extent of BNP elevation significantly reflected the severity of CHF, in contrast to physicians’ perceived severity. In a secondary analysis of the REDHOT trial comparing the implications of ‘grey zone’ (100–500 pg/ml) with those of marked (>500 pg/ml) elevation of BNP levels, it was demonstrated that marked BNP elevation defined a poor prognosis subgroup irrespective of functional class status [14]. The next stage was the utilization of high admission BNP levels in predicting in-hospital [25] and post-discharge mortality in heart failure patients [16]. High predischarge BNP level was shown in a multivariate analysis to predict re-admissions and mortality [17]. &

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As regards NT-Pro-BN, there is a similar body of evidence in predicting symptoms of heart failure and mortality risk in those with chronic left ventricular dysfunction, as shown by Richards et al. [26]. In the Carvedilol Prospective Randomized Cumulative Survival study, NT-Pro-BNP established itself as a predictor of all-cause mortality and hospitalizations for heart failure in 1011 participants [18]. It has recently been suggested that BNP and NTPro-BNP levels can be utilized to guide heart failure therapy. In a recent meta-analysis of 11 randomized controlled trials of 2414 patients using BNP and NTPro-BNP to guide heart failure therapy, there was a reduction in all cause mortality [relative risk, 0.83; 95% confidence interval (CI), 0.69–0.99; P ¼ 0.035] as compared with clinically driven therapy (Fig. 1). BNP-guided therapy has also been shown to reduce heart failure hospitalizations in patients below 70 years of age. It is thought that older patients may have more comorbid diseases, including hypertension, chronic kidney disease, diabetes mellitus and dysrhythmias, which reduces their tolerance and their responsiveness to treatment [19 ]. There are also a number of novel indications for BNP/NT-Pro-BNP monitoring, which constitutes the main purpose of this review, as summarized in Table 2 [27 ,28–41,42 ,43 ,44,45]. Of the various novel indications, we will concentrate on four of the better-established ones. &

&&

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HEART FAILURE AND PRESERVED EJECTION FRACTION Heart failure and preserved ejection fraction (HFpEF) manifests itself mainly by exertional dyspnoea as its predominant symptom. BNP and NT-Pro-BNP have been included in the algorithm Volume 29  Number 2  March 2014

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Brain natriuretic peptide Mahadavan et al. Table 2. Novel applications for brain naturetic peptide and N-Terminal brain natriuretic peptide monitoring Condition

Recent publications

HFpEF Diagnosis

Lagoeiro 2013 [48 ]

Prognosis

van Veldhuisen et al. [27 ], Anand et al. [28]

&&

&&

TTC

Nef et al. [29], Grabowski et al. [30], Madhavan et al. [31], Morel et al. [32], Ahmed et al. [33], Nguyen et al. [34]

PAH Diagnosis

Williams et al. [35]

Prognosis

Fritz et al. [36]

Hypertrophic cardiomyopathy

Geske et al. [37]

Aortic stenosis

Katz et al. [38], Ros¸ca et al. [39], Cimadevilla et al. [40], Ben-Dor et al. [41]

Atrial fibrillation

RE-LY (substudy) [42 ] &&

Predicting thromboembolic risk

ARISTOTLE (substudy) [66 ]

Predicting AF in cryptogenic stroke

Rodrı´guez-Ya´n ˜ez et al. [43 ]

&&

&&

DOXURUBICIN-induced cardiotoxicity

Roziakova et al. [44], Cil et al. [45]

AF, atrial fibrillation; HFpEF, heart failure and preserved ejection fraction; PAH, pulmonary arterial hypertension; TTC, Tako-Tsubo cardiomyopathy; RE-LY, Randomized Evaluation of Long-term Anticoagulation Therapy.

for diagnosing HFpEF in the European Society of Cardiology consensus statement [46]. Plasma BNP and N-Terminal BNP have been shown to correlate closely with left ventricular end-diastolic pressure, and are consistently elevated at rest in patients with left ventricle (LV) systolic dysfunction [47]. Although resting plasma BNP is frequently also elevated in patients with HFpEF, although with different cut offs, this is less consistent, and generally with little additive value than the standard echo criteria in diagnosing HFpEF as shown by Lagoeiro et al. [48 ]. Anjan et al. [49 ] found normal BNP levels were present in 29% of symptomatic outpatients with HFpEF who had elevated pulmonary capillary wedge pressures, and, although BNP is useful as a prognostic marker in HFpEF, a normal BNP does not exclude the outpatient diagnosis of HFpEF. Whether this is because left ventricular end diastolic pressure is less consistently raised at rest in such patients or whether it is because many patients labelled as having HFpEF do not in fact have heart failure, as discussed above, is uncertain. Dahlstrom et al. [50] have shown that asymptomatic patients with only mild abnormalities of relaxation (reversal of the E/A ratio) have relatively normal concentrations of natriuretic peptides, whereas patients with a ‘pseudo normal’ or restrictive transmitral filling pattern show more consistent elevations in BNP at rest. In healthy individuals, plasma BNP rises very little with exercise, but in &&

&&

systolic heart failure patients the rise is marked. BNP is also known to rise markedly during episodes of cardiac ischaemia [51]. However, to date no studies have assessed the utility of plasma BNP during exercise for diagnosing patients with HFpEF. The acute rise in BNP may enhance the diagnostic utility of plasma BNP in diagnosing HFpEF at the early stages prior to hospitalization as well as improving its prognostic capabilities. Plasma BNP has also been shown to be an important prognostic marker in patients with HFpEF in terms of predicting mortality [52 ]. van Veldhuisen et al. [27 ] established that the BNP levels for patients with HFpEF were lower for patients with reduced ejection fractions, but for a given BNP level the risk of hospitalization and all-cause mortality is similar in both groups. BNP also appeared to be a better predictor of outcome than the left ventricular ejection fraction. In a posthoc analysis of the I-PRESERVE trial, there was evidence that treatment with Irbesartan prior to BNP elevation above the median levels established in the entire cohort resulted in beneficial effect on the primary outcome [hazard ratio (HR), 0.74; 95% CI, 0.60–90; P ¼ 0.003], all-cause mortality (HR, 0.75; 95% CI, 0.56–0.99; P ¼ 0.046) and heart failure composite outcome (HR, 0.57; 95% CI, 0.41–0.80; P ¼ 0.001) [28]. Furthermore, BNP may well play a role in the pathophysiology and therapeutics of HFpEF. This

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Heart failure

has been the basis for a phase two study to try and increase the level of BNP with an angiotensin receptor neprilysin inhibitor in patients with HFpEF. This showed significant reductions in left atrial volumes at 36 weeks and a reduction in NT-Pro-BNP [53 ]. &&

TAKO-TSUBO CARDIOMYOPATHY Tako-tsubo cardiomyopathy (TTC) is a disorder characterized by acute development of segmental (usually periapical) left ventricular systolic dysfunction. The differential diagnosis of TTC includes both myocardial ischaemia and infarction, and traditionally TTC has become, to a large extent, a diagnosis of exclusion. Even though there is no agreement to date as to the appropriate acute management of TTC, earlier diagnosis would at least enable clinicians to avoid unnecessary investigations or treatments (e.g. fibrinolytic therapy) and the risks that might attend them. Furthermore, greater diagnostic precision would facilitate prospective study of the disorder, including, ultimately, the evaluation of potential therapeutic interventions. Patients with TTC not infrequently have low cardiac output status at initial presentation [54], but definite pulmonary oedema is very rare [55]. Nevertheless, a number of investigations have reported that, at the time of diagnosis, plasma levels of BNP [30–32,56,57] and/or NT-Pro-BNP [29,34] are markedly elevated. It has been widely assumed, on the basis of reasonable associative and clinical chemical evidence, that hypersecretion of catecholamines plays a part in the initiation of TTC [32,38,41]. Furthermore, a number of current investigations from both biopsy studies and cardiac magnetic resonance imaging have suggested that TTC is associated with intramyocardial inflammation activation [54,57– 63]. Both activation of inflammatory processes and extensive release of catecholamines could precipitate formation of BNP. More interestingly, a recent study by Chan et al. [64] has documented that BNP in turn, induces release of catecholamines from the heart and from synaptic endings, leading to a potential ‘vicious cycle’. Our data suggested that TTC is associated with substantial increases in both BNP and NT-Pro-BNP levels, which remain elevated at least 3 months after acute attack [34]. Furthermore, the extent of NT-Pro-BNP elevation appears to reflect a predictable response to catecholamine stimulus and correlates directly with the initial degree of left ventricular wall motion anomaly. Finally, the extent of elevation of NT-Pro-BNP levels may assist in the precatheterization differentiation of TTC from other 164

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acute coronary syndromes in aging females. The potential clinical utility of BNP/NT-Pro-BNP assay in TTC lies predominantly in approximately 60% of patients who do not present as ‘S-T elevation myocardial infarction’, and therefore do not undergo emergency cardiac catheterization. The combination of antecedent stressor exposure, female sex, and BNP at least 6000 pg/ml in troponin-positive patients with diffuse T-wave changes on ECG gives approximately a 90% probability of diagnosis of TTC prior to echocardiography.

ATRIAL FIBRILLATION It was shown in 2009 in a community-based population that elevated NT-Pro-BNP levels correlated with the presence of atrial fibrillation irrespective of echocardiographic parameters [65]. In the last year, there have been a number of publications that have taken this further. The Randomized Evaluation of Long-term Anticoagulation Therapy trial had initially described the importance of the level of NT-Pro-BNP in patients with atrial fibrillation, with higher levels correlating with the risk of thromboembolic events and cardiovascular mortality. The addition of NT-Pro-BNP to the CHADS2 and CHA2DS2-VASc scores significantly improved the discriminatory performance for both outcomes [42 ]. This was verified in the Apixaban for the Prevention of Stroke and other thromboembolic events in subjects with Atrial Fibrillation (ARISTOTLE) cohort, with rising NT-Pro-BNP levels having a strong association with ischaemic strokes [66 ]. However, the role of BNP in cryptogenic stroke may well prove to be the most interesting, as in a recent publication NT-Pro-BNP levels above 360 pg/ml were associated with a five-fold increase in the possibility of detecting atrial fibrillation during follow up, and may therefore influence the decision to anticoagulate for secondary prevention [43 ]. &&

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PULMONARY ARTERIAL HYPERTENSION Pulmonary arterial hypertension (PAH) is a progressive vasculopathy characterized by extensive remodelling of the pulmonary circulation that results in narrowing of the arterial lumen and impaired flowmediated vasodilation. Plasma BNP and NT-Pro-BNP are not specific for the right or LV. However, in patients in whom left heart disease has been excluded who are at risk for PAH, the elevated levels have been predictive of right heart strain. Therefore, NT-Pro-BNP may prove useful as a screening test for PAH in systemic Volume 29  Number 2  March 2014

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Brain natriuretic peptide Mahadavan et al.

sclerosis, in which PAH is prevalent and responsive to therapy. At an NT-Pro-BNP level of 395 pg/ml, the sensitivity and specificity for predicting the presence of systemic sclerosis associated pulmonary hypertension (SSc-PAH) were 56 and 95%, respectively, in a study of 109 patients of whom 68 had evidence of PAH on a right heart study. In the same study, for every order of magnitude increase in NT-Pro-BNP level in patients with PAH, the risk of death increased four-fold (P ¼ 0.002 for baseline level and P ¼ 0.006 for follow-up level) [35]. There has been a recent study in which the baseline level of BNP in a cohort with PAH was predictive of 2-year mortality. A repeat level at 12 weeks after treatment with ambrisentan did not provide additional prognostic information beyond that obtained by the initial value [36]. There is also evidence for the involvement of BNP in the pathophysiology of PAH and it remains possible that BNP may eventually prove therapeutically useful in this condition. As early as 1997, BNP was shown to have antiproliferative and antihypertrophic properties in pulmonary artery smooth muscle cells, and increased generation of intracellular cyclic GMP [67]. The therapeutic implications of this have not been fully explored to date.

CONCLUSION Over the last few years published findings have helped establish the versatility of BNP and NTPro-BNP as a diagnostic and prognostic tool in various forms of heart failure. Its role has also extended to help guide therapy in CHF, predict recovery in TTC, possibly play a role in the therapeutics of HFpEF and predict stroke risk in atrial fibrillation. Acknowledgements The study was supported in part by a research grant from the National Heart and Medical Research Council of Australia. Conflicts of interest J.H. is a co-inventor of a patent related to the treatment of Tako-Tsubo cardiomyopathy. There are no other conflicts of interest.

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Volume 29  Number 2  March 2014

Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.

Brain natriuretic peptide: a biomarker for all cardiac disease?

To evaluate new development in the utility of brain natriuretic peptide and N-Terminal brain natriuretic peptide (BNP/NT-Pro-BNP) in the management of...
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