Heart failure CLINICAL USEFULNESS OF B-TYPE NATRIURETIC PEPTIDE MEASUREMENT: PRESENT AND FUTURE PERSPECTIVES

Heart failure CLINICAL USEFULNESS OF B-TYPE NATRIURETIC PEPTIDE MEASUREMENT: PRESENT AND FUTURE PERSPECTIVES Take the online multiple hoie questions assoiated with this artile (see page 1488) EFFECTS Correspondene to: Professor Paulo M Bettenourt, Unidade Cuidados Intermédios Mediina, Hospital S Joaõ, Alameda Hernani Monteiro, 4200 Porto, Portugal; pbettfer@ esoteria.pt T Paulo M Bettenourt Heart 2005; 91:1489 1494. doi: 10.1136/hrt.2005.063784 he identifiation of natriureti peptides led to an explosion of basi and linial investigations to larify their physiology, pathophysiologi role in heart failure, and linial usefulness. The knowledge base and emerging information on B-type natriureti peptide (BNP) is plentiful but the onsensus on its appliation is still sparse. The natriureti peptide family omprises atrial natriureti peptide (ANP), BNP, C-type natriureti peptide (CNP), and D-type natriureti peptide. ANP and BNP are synthesised in the heart, CNP is produed mainly in vessels, and D-type natriureti peptide has been isolated in plasma and atrial myoardium. The preursor prohormone of eah natriureti peptide is enoded by a separate gene. BNP is a 108 amino aid pro-hormone that, after leavage by the proteolyti enzyme furin, is separated into a 32 amino aid arboxi-terminal biologially ative portion (BNP) and a 76 amino aid amino terminal part without biologial ativity (NT-proBNP) (fig 1). At present, there are four BNP assays ommerially available for routine linial pratie. BNP an be assayed by a rapid fluoresene immunoassay (Biosite Diagnosti), an enzyme immunoassay (Abbott Laboratories), or a hemiluminesent immunoassay (Bayer Healthare), and NT-proBNP an be measured by an eletrohemiluminesent assay (Rohe Diagnostis). ANP and BNP exert their effets through interation with speifi high affinity reeptors on the target ells. Three effetive reeptors have been identified at target sites and kidneys. These reeptors, loated on ell membranes, although not refleting their affinity for the different peptides, are termed: natriureti reeptor type A, natriureti reeptor type B, and type C a learane reeptor. Most ardiovasular and renal effets of ANP and BNP result from yli guanylmonophosphate formation whih ats as a seond messenger responsible for the ellular physiologial responses to natriureti peptide stimulation. Natriureti peptides are leared from plasma by binding to natriureti peptide reeptors and through proteolysis by peptidases. NT-proBNP has a longer half life than BNP (118 v 18 minutes). Renal exretion is urrently regarded as the main learane mehanism of NT-proBNP. Relative onentrations of NT-proBNP and BNP may shift when healthy individuals are ompared to heart failure patients. The signifiane of this shifting is not well understood, but hanges in BNP prodution and shift in the degradation and half life aused by reeptor regulation may be the aetiology of this observation. OF NATRIURETIC PEPTIDES Natriureti peptides play a key role in the homeostasis of pressure and volume. Inreased seretion of natriureti peptides redues blood pressure and plasma volume through oordinate ations in the brain, adrenal gland, kidney, and vasulature. ANP and BNP produe a dose dependent derease in blood pressure, in part from diret vasodilatation and in part from a redution in ardia preload aused by inreased venous apaitane and shifting of intravasular volume into the extravasular ompartment due to inreased permeability of the vasular endothelium and inreased hydrauli pressure in the apillary bed. Suppression of the renin angiotensin aldosterone system, diuresis and natriuresis are also mehanisms related to the derease in preload. ANP and BNP lead to a redution of sympatheti tone through suppression of entral sympatheti outflow, dampening of baroreeptors, and suppression of ateholamines from autonomi nerve endings. Anti-mitogeni ation of both ANP and BNP has been doumented in the ardiovasular and other systems. Renal ations of ANP and BNP lead to natriuresis and diuresis through diret tubular ations and haemodynami modulation. An inrease in glomerular pressure leads to an inrease in glomerular filtration (through dilatation of the afferent renal arterioles and onstrition of the efferent arterioles) and the relaxation of mesangial ells inreases the surfae area for filtration. ANP and BNP inhibit angiotensin II stimulated sodium and water transport in proximal onvoluted tubules, inhibit water transport in 1489

Figure 1 Synthesis and seretion of B-type natriureti peptide (BNP). 1490 olleting duts by antagonising vasopressin, and blok sodium reabsorption in the inner medullary. 1 PATHOPHYSIOLOGY The ativation of the ardia natriureti peptides is a hallmark of heart failure. The inrease in BNP in heart failure is seondary to inreased synthesis and release, triggered by wall streth, ventriular dilation and/or inreased pressure, as well as from other loal and irulating humoral fators. In hroni heart failure a differential ativation of BNP has been desribed. In an animal model of early left ventriular dysfuntion, BNP mrna and tissue BNP are notably inreased in the left atrium but remain low in ventriular myoardium, despite an inrease in irulating BNP. In severe heart failure, ventriular mrna and tissue BNP are also notably inreased. This ventriular BNP prodution ontributed signifiantly to a further inrease in irulating BNP. Thus, in ontrast to physiologi onditions of early heart failure, severe heart failure is haraterised by the ativation of ventriular BNP prodution. This ventriular reruitment of the BNP gene represents a reativation of the fetal genes programme. Although the plasma onentrations of BNP are signifiantly inreased in heart failure, they are Table 1 B-type natriureti peptide (BNP) measurement: onfounders Inrease BNP Inreasing age Female sex Pulmonary disease Systemi hypertension Hyperthyroidism Cushing syndrome Gluoortioids use Conn s syndrome Hepati irrhosis with asites Renal failure Paraneoplasti syndrome Subarahnoid haemorrhage ACE, angiotensin onverting enzyme. Derease BNP Obesity Cardioative drugs: ACE inhibitors Spironolatone b Blokers (long term) Diuretis insuffiient to produe the biologial effets of natriureti peptides, suggesting that severe heart failure is a state of relative defiieny of natriureti peptides. 2 BIOLOGIC DETERMINANTS OF BNP MEASUREMENTS Blood onentrations of BNP and NT-proBNP inrease with age, presumably as a result of left ventriular (LV) stiffness and progressive deterioration of renal funtion. Uniformly aross ommunity ohorts women have higher BNP values than men of the same age strata. Patients with severe lung disease, hypertension, and diabetes may have higher BNP and NT-proBNP onentrations than age mathed ontrols. Patients with impairment of renal funtion (glomerular filtration rate (GFR), 60 ml/min) also have higher BNP onentrations than age mathed ontrols. The observation of lower onentrations of BNP in obese people remains unexplained (table 1). Drugs used in heart failure treatment an modify irulating onentrations of BNP. Diuretis and vasodilators derease BNP onentrations rapidly (together with falling intraardia filling pressures); angiotensin onverting enzyme (ACE) inhibitors, angiotensin II reeptor antagonists, and spironolatone also lead to dereases in BNP onentrations. The effets of b blokers on BNP are more omplex. On the one hand, beause adrenergi stimulation inhibits the release of BNP, initiation of b blokers will slightly inrease natriureti peptide onentrations. On the other hand, long term onentrations of BNP fall beause of improvement in neurohumoral ambient, haemodynami variables and left ventriular funtion. BNP TESTING IN CLINICAL PRACTICE The role of BNP testing is learly defined for diagnosing patients with suspeted heart failure (outpatients with new symptoms and patients with aute dyspnoea) and for assessing the prognosis of heart failure patients. Other promising, although not yet defined, potential uses in routine pratie inlude identifiation of high risk groups for heart

Figure 2 Performane of B-type natriureti peptide in the identifiation of left ventriular systoli dysfuntion and heart failure. failure, dynami risk stratifiation, and monitoring of heart failure treatment (figs 2 and 3). DIAGNOSIS Many years have passed sine it was first suggested that natriureti peptides might aid in the diagnosis, predition of prognosis, and linial management of heart failure. Over the years, these onepts have been refined in several ways. The fat that natriureti peptide plasma onentrations are signifiantly inreased in patients with high left ventriular wall tension led to many studies evaluating the possible role of ANP, NT-proANP, BNP and more reently NT-proBNP as a diagnosti test for heart failure and ventriular dysfuntion. In the vast majority of these studies BNP and NT-proBNP proved to be the most aurate natriureti peptides in the identifiation of partiipants with left ventriular systoli dysfuntion (LVSD) or heart failure. Many single entre ommunity based epidemiologial and hospital ohort studies have now reported on the effiay of BNP and NTproBNP in the diagnosis of heart failure and LVSD. COMMUNITY SCREENING It is aknowledged that asymptomati LVSD is a treatable preursor of heart failure. This reognition generated enthusiasm for developing tools for LVSD sreening. In the ommunity approximately 75% of systoli dysfuntion patients are linially undeteted. Sreening for LVSD is, however, hallenging as it is present in only 1 2% of the entire population. Until now more than five ommunity based studies have been reported. The overall auray (analysed by the area under the ROC urve (AUC)) of BNP and NT-proBNP in the identifiation of partiipants with LVSD has varied between the suboptimal value of 0.56 and the linially relevant value of 0.88. In all of these studies the negative preditive value of BNP and NT-proBNP has been very high (between 93% and 98%), supporting the value of the test in ruling out LVSD. The preditive value of a positive test that is, a BNP or NT-proBNP above the best ut off value of eah study has been onsistently modest (between 15 30%). This means that most partiipants with high BNP or NT-proBNP onentrations would be falsely diagnosed as having LVSD. For example, in the Olmsted County ohort, with a low prevalene of LVSD (1.1%), 24% of the population would require an ehoardiogram based on raised BNP onentrations and the vast majority of these ehoardiograms (96%) would reveal an ejetion fration. 40%. In the North Glasgow ohort (with a prevalene of LVSD of 3.2%) the probability of LVSD was 16% for partiipants with high BNP values. These results show that the performane of BNP and NT-proBNP for the detetion of LVSD in the ommunity is fair, mainly beause of the low speifiity even at ut points yielding very high negative preditive values, ompromising any potential usefulness of the test as a sreening proedure. Therefore, BNP testing is not appropriate for sreening for LVSD in the general population. Other areas where BNP may have a diagnosti role inlude the identifiation of groups at low and high risk of LVSD and the detetion of individuals with a range of sublinial ardiovasular disorders with funtional or strutural ardia abnormalities. The definition of the high risk LVSD group is probably the ause of the onfliting results reported. Using BNP as a sreening test for men and women older than 60 years with previous hypertension and known ardiovasular disease, the potential linial value is limited, as illustrated by an AUC of 0.65 for men and 0.86 for women. Sub-analysis from the North Glasgow ohort identified a group of high risk individuals based on symptoms, ECG findings, and blood pressure. Using this high risk approah, the addition of BNP testing in the linial assessment programme would redue the number of ehoardiograms needed to identify one partiipant with systoli dysfuntion from 17 to 12. The ost effetiveness of this kind of approah has not been evaluated. 3 4 The idea of sreening for ardia funtional and/or strutural abnormalities (stage B heart failure aording to the Amerian College of Cardiology/Amerian Heart Assoiation) looks muh more interesting and intimately related to the pathophysiology of natriureti peptides. Data from an Asian population showed that when sreening for this purpose, BNP had an overall auray of 0.97. The negative preditive value was 99% and the positive preditive value was 44%. Using this broader onept of ardia abnormalities, BNP sreening appears to have a more pertinent role than when used for targeting LVSD. There are also data to suggest that high risk individuals with high BNP onentrations are at risk of developing ardia strutural and funtional impairment that is, BNP testing ould be used to identify people who will progress from stage A to stage B heart failure. The value of BNP for sreening high risk groups is not lear. Definition of high risk groups, the target ardia abnormalities, as well as ost benefit analysis are neessary before it beomes routine pratie. BNP IN THE DIAGNOSIS OF HEART FAILURE IN SYMPTOMATIC PATIENTS Symptoms and signs suggestive of heart failure are unspeifi and have a low sensitivity to heart failure diagnosis. In primary are more than 70% of patients with suspeted heart failure have other disorders aounting for symptoms. Assigning the ause of dyspnoea and exerise intolerane in patients who may have ardia and non-ardia disease is a ommon linial dilemma. We now have a body of evidene that BNP and NT-proBNP an assist liniians in the 1491

Figure 3 Use of B-type natriureti peptide in linial pratie. 1492 diagnosis of heart failure in the ambulatory as well as in the emergeny setting. Potential overall auray of BNP in the diagnosis of heart failure in primary are measured by the AUC has been uniformly high aross studies. In a landmark study, the Hillingdon heart failure study, of patients with suspeted new heart failure, the AUC for BNP was 0.96, with a positive preditive value of 70% and a negative preditive value of 98% at the ut off value of 76 pg/ml. 5 Other trials showed more modest preditive values of a positive result of BNP or NTproBNP. The very important lesson from these studies is that low BNP or NT-proBNP onentrations during the initial approah to patients with suspeted heart failure an onfidently exlude heart failure diagnosis. A positive result should lead to investigations in order to detet ardia funtional and strutural abnormalities or other onditions assoiated with raised BNP onentrations (mild to severe hroni obstrutive pulmonary disease, renal failure, myoardial ishaemia, atrial fibrillation). Other groups evaluated the inrement in auray that NTproBNP an give to liniians in the diagnosis of heart failure. It has been shown that general pratitioner awareness of NTproBNP onentrations greatly improves diagnosti auray ompared to review of linial reords by a ardiologist. These results learly define a role for NT-proBNP in assisting the diagnosis of heart failure. Conern over the false negative that is, heart failure patients with low NT-proBNP onentrations has been addressed. Heart failure patients with low BNPs are mainly patients with borderline LVSD or are on ardioative drugs known to lower BNP onentrations. These observations on the linial value of BNP and NTproBNP in the validation of heart failure linial diagnosis have been mostly based on best ut off points derived from the ROC urves obtained by eah study data. In linial pratie physiians rely on normal and abnormal values of a speifi test. Using this approah in a subgroup from a multientred analysis of epidemiologial studies of partiipants with breathlessness, 90% of partiipants had a plausible ardiovasular ause for high NT-proBNP onentrations, and 4% had renal failure as possible ause of high NT-proBNP. The rule out value of BNP in the ambulatory setting of patients with suspeted new heart failure is well established. In patients with a positive test that is, high BNP onentrations a full investigation should be undertaken beause ardiovasular, moderate to severe respiratory, or relevant renal abnormalities are very likely to be present. BNP is not a stand alone test it is of greatest value when it omplements linial judgment along with other available tests. ACUTE SETTING Patients presenting with aute dyspnoea frequently pose a hallenge to liniians, the ause being unertain in up to a third of patients attending emergeny departments beause of shortness of breath. Table 2 Diagnosis of aute heart failure based on a sore inluding NT-proBNP, pulmonary x ray, age, and linial parameters: aute heart failure sore (Pride) Preditor Elevated NT-proBNP 4 Interstitial oedema on hest x ray 2 Orthopnoea 2 Absene of fever 2 Current loop diureti use 1 Age.75 years 1 Rales on lung examination 1 Absene of ough 1 Points A sore of.7 has a high preditive auray for the diagnosis of aute heart failure.

Preliminary observations suggested that BNP onentrations were higher in patients with dyspnoea aused by heart failure than in dyspnoea resulting from pulmonary disease. More reently, multientre studies onfirmed these observations and provided evidene that determining BNP and NTproBNP onentrations an help liniians in the differential diagnosis of aute dyspnoea. 6 The rule-out value of BNP and NT-proBNP in this setting is well doumented. Patients with BNP onentrations, 100 pg/ml or NT-proBNP onentrations, 300 pg/ml are very unlikely to have heart failure (negative preditive value 99%). Patients with BNP onentrations. 500 pg/ml or NT-proBNP onentrations. 450 pg/ml (, 50 years of age), 900 pg/ml (50 75 years), and 1800 pg/ml (. 75 years) have a very high probability of having heart failure as the ause of their aute dyspnoea (the linial judgment must also onsider other diagnoses, namely aute oronary syndrome and pulmonary embolism). Patients with BNP onentrations between 100 500 pg/ml or NT-proBNP onentrations between 300 pg/ml and 450, 900, and 1500 pg/ml, respetively, aording to age, have several other diagnosti possibilities that need to be onsidered. Aross the trials, in the aute setting BNP proved superior to linial judgment, but the best performane has been ahieved by ombining BNP results with linial judgment. A sore using linial parameters together with NT-proBNP has been developed and tested in an independent population, and has proven to have a very high preditive value for the diagnosis of aute heart failure (table 2). Diagnosti algorithms inorporating BNP determination have been developed in order to alert liniians to the potential usefulness of BNP measurement and also to all attention to alternatives. BNP testing improves the ability to diagnose and exlude heart failure in patients with aute dyspnoea. Combination of a strategy based on BNP determination and linial assessment is the ideal approah to optimise early diagnosis and intervention. 7 8 Deision ut-points for heart failure diagnosis, based on onsensus between expert opinions and manufaturers, are summarised in table 3. Cut-points are not yet learly defined and more work is required to optimise them. Loal entres should be audited before deiding on ut-points in their own populations, in onsultation with the loal biohemial laboratory. Assays harateristis must also be onsidered. BNP FOR ESTIMATING HEART FAILURE PROGNOSIS BNP is a powerful prognosis index in the heart failure setting. Higher onentrations of BNP are assoiated with inreased ardiovasular and all ause mortality, independently of age, Table 3 Proposed ut-off for ruling in and ruling out heart failure Heart failure in ambulatory setting New York Heart Assoiation (NYHA) lass, and ejetion fration. The prognosti usefulness of BNP is well doumented in the whole spetrum of heart failure severity and is observed regardless of heart failure treatment. Raised onentrations of BNP are also independently assoiated with sudden ardia death. BNP is higher in patients with more severe symptoms and those with more severe ardia impairment. However, the linial impat of BNP determination as a prognosti index is still ontroversial. Risk stratifiation based on BNP has been suggested mainly in the seletion of patients needing ardia transplantation and in the identifiation of patients at low risk of adverse events suitable for onservative approahes. DYNAMIC RISK STRATIFICATION There is inreased enthusiasm in the utility of serial BNP measurement for risk stratifiation. Data from outpatients show that serial determination of BNP an improve the prognosti determination in heart failure patients. The identifiation of patients at high risk of adverse outomes is suggested as a way for more aggressive intervention and lose follow up, but linial evidene supporting this suggestion is still laking. In deompensated heart failure serial determinations of BNP have been shown to be assoiated with outomes in observational studies. Patients not ahieving signifiant dereases in NT-proBNP onentrations (30% dereases) have a very high inidene (80%) of hospital readmission or death in a six month period. These observations led to the onsideration that BNP may be used to help liniians arrive at the disharge deision. A randomised ontrolled trial of Aute dyspnoea Rule-out heart failure NT-proBNP,125 pg/ml,75 years NT-proBNP,300 pg/ml,450 pg/ml >75 years BNP,70 pg/ml BNP,100 pg/ml GFR,60 ml/min BNP 200 pg/ml Rule-in heart failure NT-proBNP BNP BNP, B-type natriureti peptide; GFR, glomerular filtration rate. Clinial usefulness of BNP measurement: key points B-type natriureti peptide (BNP) an be measured in serum and plasma as a biologially ative portion BNP and as an amino terminal portion NT-proBNP Ventriular wall streth is the major determinant of inreased BNP onentrations in heart failure patients BNP has a very high negative preditive value for the identifiation of persons with left ventriular systoli dysfuntion and heart failure The prognosti power of BNP is well established in heart failure patients; serial determination of BNP an improve prognosti information in ompensated and deompensated heart failure patients Treatment titration aimed at lowering BNP is promising and will probably modify the therapeuti approah to heart failure patients in the near future Age.75: NT-proBNP.1800 pg/ml Age 50 75: NT-proBNP.900 pg/ml Age,50: NT-proBNP.450 pg/ml.500 pg/ml 1493

1494 treatment modifiation and disharge time aording to hange in BNP from admission to the point where linial ompensation is thought to have been ahieved is neessary to onfirm this suggestion. 9 BNP FOR TITRATING HEART FAILURE TREATMENT BNP testing an help physiians to make linial deisions in heart failure patients, although muh work is neessary in this emerging field before it an be used in linial pratie. BNP onentrations are known to fall with treatment for heart failure. The onept is that the deision to titrate heart failure treatment or to use more aggressive strategies might be based not only on state of the art knowledge but also on BNP onentrations. Beause BNP dereases in patients improving linially, treatment of heart failure patients with vasodilators titrated to derease BNP to normal ranges is feasible. There is some evidene for the possible benefit of an NT-proBNP guided treatment approah. 10 A pilot randomised study found fewer total ardiovasular events in the group randomised to NT-proBNP guided treatment ompared to a similar group of patients whose treatment was guided by ommonly used linial variables. Larger studies are now underway in order to answer important questions related to this issue. Can BNP be used as an instrument to individualise treatment in heart failure? What is the best BNP target onentration? However, there are still onerns on the role of BNP in treatment monitoring. BNP rises as renal funtion delines, so redution of BNP based on diuretis may result in worsening renal funtion and subsequent inreases in BNP onentrations. In addition, the knowledge of biologial variability of BNP in heart failure patients is needed for liniians to be able to interpret BNP hanges over time. FUTURE OF BNP TESTING IN HEART FAILURE Several fields are urrently under investigation: ost effetive strategies for seleting persons at high risk of LVSD for further ardia investigations; and diagnosis of diastoli heart failure (there may be a potential for BNP testing as suggested by preliminary results). Work in progress in dynami risk stratifiation based on serial BNP will larify its value in the identifiation of patients at high risk warranting aggressive treatment, and of patients without signifiant neurohumoral ativation with good prognosis. The more exiting perspetive of BNP testing is undoubtedly in monitoring treatments in heart failure patients. Studies designed to test if intensifiation of treatment guided by BNP determination improves outomes ompared to state of art therapy are ongoing and will hopefully give important insights into the individualised management of heart failure. In ompliane with EBAC/EACCME guidelines, all authors partiipating in Eduation in Heart have dislosed potential onflits of interest that might ause a bias in the artile REFERENCES 1 de Lemos JA, MGuire DK, Drazner MH. B-type natriureti peptide in ardiovasular disease. Lanet 2003;362:316 22. Review with emphasis on the linial aspets, physiology, and pathophysiology of natriureti peptides. 2 Chen HH, Burnett JC. Natriureti peptides in the pathophysiology of ongestive heart failure. Curr Cardiol Rep 2000;2:198 205. Exellent review on the pathophysiologi role of natriureti peptides on heart failure progression. 3 MDonagh TA, Robb SD, Murdoh DR, et al. Biohemial detetion of leftventriular systoli dysfuntion. Lanet 1998;351:9 13. First epidemiologial study demonstrating the very high negative preditive value of BNP in the identifiation of people with left ventriular systoli dysfuntion. 4 Vasan RS, Benjamin EJ, Larson MG, et al. 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