Natriuretic Peptidesin the Diagnosis andManagement of AcuteHeart Failure

Asim A. Mohammed, MD, James L. Januzzi, Jr, MD*

KEYWORDS� Natriuretic peptides � Heart failure � Age� Chronic kidney disease � Multi-marking panels

Heart failure (HF) is oneof themajor health problemsin modern medicine. It is the most common cause ofhospitalization in people older than 65 years.Despite advances in pharmacotherapy for treatingHF, the incidence and the morbidity and mortalityassociated with HF continue to rise. This rise in inci-dence is in part because of the aging of the popula-tion and age-related prevalence of risk factors suchas hypertension, and the improved survival ofpatients who have acute coronary syndromes,a group at especially high risk for developing HF.A recent study, which showed that in the last 25years, the incidence of HF has tripled,1 confirmedthe magnitude of economic burden faced by themodern health system.

Traditionally, HF diagnosis has been challengingbecause of a broad differential diagnosis; thisleads to high mortality, morbidity, and hospitaliza-tion rates in this patient population. Fortunately,since the discovery of atrial natriuretic factor,which draws attention to the endocrine functionof the heart,2 there has been remarkable advance-ment in the understanding of natriuretic peptides(NPs) and the potential role they may play in eval-uating, prognosticating, and managing HF.

The NP assays commonly used clinically areB-type NP (BNP) and its amino-terminal cleavageequivalent (NT-proBNP); both are used worldwidefor diagnosing and managing HF cost-effectively.

Dr. Mohammed is supported by the Dennis and Marilynsupported in part by the Balson Fund for CardiovascularHarvard Medical School, Boston, MA, USA* Corresponding author. Division of Cardiology, DepartHarvard Medical School, 32 Fruit Street, Yawkey 5984, BE-mail address: jjanuzzi@partners.org (J.L. Januzzi Jr.).

Heart Failure Clin 5 (2009) 489–500doi:10.1016/j.hfc.2009.04.0071551-7136/09/$ – see front matter ª 2009 Elsevier Inc. All

NATRIURETIC PEPTIDE BIOLOGY

After BNP gene transcription and translationoccurs, a 108-amino acid intracellular precursormolecule, pro-BNP108 is produced within the myo-cyte; this precursor subsequently is cleaved byfurin- or coriin-like endoprotease to produce the76-amino acid NT-proBNP and the biologicallyactive C-terminal fragment BNP. The BNP geneis located on the chromosome 1. The nuclear tran-scription factor, GATA 4, is responsible for regu-lating the BNP gene transcription. The BNP geneis expressed in the atria and ventricles. Thesynthesis and release of BNP and NT-proBNPare caused by changes in the wall strain of cardio-myocyte in all chambers of heart. Aside from thewall tension, however, other triggers for NPrelease exist, including hormones such as norepi-nephrine, proinflamatory cytokines, glucocorti-coids, and myocardial ischemia.

After release, NT-proBNP circulates with variousdegrees of glycosylation. With respect to BNP, thesecreted 3- amino acid protein, BNP1–32, isdegraded rapidly to BNP3-32 by neutral endopepti-dases, and BNP6–32 by meprin-A. Lastly, a signifi-cant amount of biologically inactive pro-BNP108

also is released, which is cross-identifiedby commercial assays for detection of BNP andNT-proBNP.

Barry Fellowship in Cardiology, while Dr. Januzzi isResearch.

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From the HF perspective, NPs may be viewedloosely as the body’s response to the volume over-load, neurohormonal derangement, and activationof the renin–angiotensin system. The principalactions of BNP are natriuresis, reduction in periph-eral vascular resistance, hypotension, and diuresis.These effects are mediated by binding to NP recep-tors (NPRs), which are expressed in the cardiovas-cular system, lungs, kidneys, skin, platelets, andcentral nervous system. There are three types ofNPRs: NPR-A, NPR-B, and NPR-C. The NPR-Aand NPR-B receptors are distributed widely in themyocardium and blood vessels, while the NPR-Cis a clearance receptor. The activation of NPR-Areceptor activates guanylyl cyclase, leading torise in cyclic guanylyl monophosphate, leading tothe mentioned actions of BNP.

Half-Life and Clearance

The half-life of BNP is estimated as 21 minutes, andthe half-life of NT-proBNP is estimated as 70minutes. BNP is degraded after it binds to NPR-Cby endopeptidases and other enzymes. BNP alsois cleared passively by the kidneys. On the otherhand, NT-proBNP is cleared passively by organswith high blood flows. This is responsible for itslonger half-life.

ANALYTICAL CONSIDERATIONS

Assays for measuring BNP and NT-proBNP arewidely available, and the choice of which assayclinicians should use depends partially onanalyzers installed in their hospitals, as both NPsprovide valuable information.

Preanalytical Factors

Blood collection in plastic tubes is essential forBNP, while either glass or plastic tubes areadequate for NT-proBNP. NT-proBNP is a rela-tively stable molecule that is not affected bytemperature changes, making it a more conve-nient molecule to work with, whereas with BNP,rapidity of testing is very important, as it isunstable at room temperature.

Analytical Factors

Previously, methods to measure BNP and NT-proBNP were cumbersome radioimmunoassays,which have been replaced by point-of-care(POC) and automated solutions. Choosing POC,as opposed to automated testing mandates care-ful consideration, as both options have theirstrengths and weaknesses. The main advantageof POC testing is the proximity to the patient butat the cost of lower accuracy when compared

with automated assays, which are considerablymore accurate, less expensive, and allow forhigh-volume throughput, but take longer toprovide the result. POC options for BNP and NT-proBNP are available, as are automated solutions.Automated versions of the NT-proBNP assay mayprovide superior harmony with their POC counter-parts, compared with corresponding BNPmethods.

Postanalytical Factors

It is critical to understand the importance of certainpostanalytical factors such as age, gender, andethnicity, to optimally appreciate the results ofNP testing. Galasko and colleagues3 identifiedthat older age and female gender were associatedwith higher concentrations of NT-proBNP inapparently healthy subjects. The latter findingwas investigated more comprehensively in theDallas Heart Study,4 where Chang and colleaguesdemonstrated that the higher levels of NPs inwomen were associated inversely with androgenichormones, suggesting that in fact the observationis framed better, as men have lower levels of NPsbecause of the effects of androgenic hormones.

It has been reported that African Americans mayhave higher NP levels compared with non-AfricanAmericans, although these differences may notbe significant when taking into consideration otherrelevant covariants, such as age, body mass index(BMI), and renal function. Notably, although thesefindings are apparent in healthy subjects, amongthose who have acute dyspnea with or withoutHF, the effects of age are manageable, and sexand race do not affect the diagnostic value ofBNP or NT-proBNP.

Important variables to consider when interpret-ing BNP and NT-proBNP are renal function andBMI. Given that both peptides are low-molecularweight proteins, both BNP and NT-proBNPdepend partially on renal function for their clear-ance, but the relationship is more complex thansimple renal clearance. Patients who have chronickidney disease (CKD) almost universally haveelevated BNP or NT-proBNP values. These areprognostic across the spectrum of presentationsfrom asymptomatic to acute dyspnea, suggestingthat rather than being considered false positives,values of NPs in CKD are true elevations, reflectingthe parallel increase in heart disease occurringwith CKD.

The curious inverse association between BMIand NP values has been studied. It has beenshown unequivocally that NP levels are lower inoverweight and obese patients, in spite of theirhaving higher left ventricular (LV) mass and higher

Natriuretic Peptides 491

intracardiac pressures when compared withsubjects who have normal BMI. Although themechanism remains unclear, several studieshave reported an inverse association betweenNPs and BMI,5–7 presumably on the basis ofdecreased release.

Biological Variability

Biologic variability refers to the daily or weeklyalterations in NP concentrations in the absenceof obvious clinical changes. It reflects the temporalchanges in BNP or NT-proBNP production byeach patient, and most probably is caused byshifts in cardiac filling pressures and hemody-namics. Although biological variability when ex-pressed as a percentage of baseline value maybe very high in healthy subjects, this is in thecontext of low absolute values of the NPs, where100% changes in value may be meaningless. Inthe setting of HF, however, Schou and colleagues8

demonstrated a biological variability of 23% forNT-proBNP and 43% for BNP in a population ofwell-controlled HF. Hence, in the context ofmeasuring NP levels in a patient who has priorHF, it is of particular importance to have a baselineor dry NP level, which is defined as NP measuredwhen the patient is most stable. Any change morethan approximately 25% for NT-proBNP and 40%for BNP should be regarded as a significantchange.9,10

Fig.1. Receiver operating characteristic curve for various cutNT-proBNP. Both peptides are highly sensitive and specific founder the ROC (receiver operated curve). (Adapted from Mament of B-type natriuretic peptide in the emergency diagnopermission; and Januzzi JL, Camargo CA, Anwaruddin S, etthe emergency department (PRIDE) study. Am J Cardiol 200

NATRIURETIC PEPTIDE IN ACUTE HEART FAILURE

As noted, acute HF is often a difficult diagnosis toestablish in the emergency department (ED),mainly because of the various conditions thatmay present with dyspnea. Also, HF may presentwith nonspecific symptoms such as fatigue anddizziness, making it a challenging diagnosis tosecure. Hence, delays in HF diagnosis are notuncommon, which result not only in increasedmorbidity and mortality, but also increased costof health care. Thoughtful application of NP testinghas been shown to be helpful in this setting, and assuch NP testing is incorporated into existing clin-ical guidelines for the diagnostic evaluation ofHF.11–13

Role of Natriuretic Peptides in Diagnosisand Exclusion of Heart Failure

The Breathing Not Properly Multinational Study,14

a landmark study of NP testing, highlighted thevalue of BNP testing in patients presenting to theED with acute dyspnea. In this multicenter trialinvolving 1586 dyspneic patients, Maisel andcolleagues14 showed that a BNP concentrationgreater than 100 pg/mL had 83% accuracy forthe clinical diagnosis of HF (Fig. 1), superior toexisting The National Health and Nutrition Exami-nation Survey criteria (67% accuracy) and the Fra-mingham criteria (73% accuracy). Results of BNPtesting were better than clinical judgment alone,

off levels of (A) B-type natriuretic peptide (BNP) and (B)r the diagnosing acute HF, with a highly significant areaisel AS, Krishnswamy P, Nowak RM, et al. Rapid measure-sis of heart failure. N Engl J Med 2002;347(3):165; withal. The N-terminal Pro-BNP investigation of dyspnea in5;95(8):951; with permission.)

Table1Differential diagnosis for increased and decreasednatriuretic peptides levels

Increased natriuretic peptides

Physiologic

Age

Female gender

Cardiovascular disease

Heart failure

Ischemia

Arrhythmia

Valvular heart disease

Hypertension with left ventricularhypertrophy

Asymptomatic left ventricular dysfunction

Noncardiac causes

Pulmonary embolism

Cor pulmonale

Sepsis

Pulmonary hypertension

Hyperthyroidism

Kidney failure

Tumors

Intracerebral hemorrhage

Advanced liver disease

Excessive cortisol levels

Decreased natriuretic peptides

Obesity

Cardiac medicine

Angiotensin-converting enzyme inhibitors

Angiotensin II receptor blockers

Diuretics

Spironolactone

Beta-blockera

Nonpharmacological factors

Exercise

Cardiac resynchronization therapy

LV assist devices

a Beta-blockers may raise natriuretic peptide levelsinitially.

Mohammed & Januzzi492

but more importantly, the additive value of BNPplus clinical judgment was superior to either alone.

Although a BNP less than 100 pg/mL hada reasonable negative predictive value (NPV) of88%, the value of BNP to confidently excludeacute HF (ie, a NPV greater than 95%) was consid-erably lower, at 30 pg/mL. Indeed, Cowie andcolleagues15 showed that a cut-off value of22 pg/mL for BNP could rule out the diagnosis ofHF with high NPV of 98%. The positive predictivevalue (PPV) of BNP for HF at 100 pg/mL was79%. This relatively less robust PPV is expected,as several other conditions can cause a BNP inthis range, even in the absence of HF (Table 1).Nonetheless, BNP testing in the Breathing NotProperly Multinational Study was valuable acrossa range of patients, including those who hadprior HF14 and CKD;16 BNP was more importantthan chest radiography for diagnosing HF.14

Bayes-Genis and colleagues17 suggested theimportance of NT-proBNP for diagnosing acuteHF and proposed values to rule in and rule outthis diagnosis. Later, data from Christchurch,New Zealand,18 showed that the NT-proBNPlevels were elevated greatly in acute HF and itsutility was comparable to BNP for this indication.Likewise, Mueller and colleagues19 evaluatedboth NPs in 251 dyspneic patients and found nodifference between them for diagnostic evaluation.Most definitive data supporting NT-proBNPtesting came from the ProBNP Investigation ofDyspnea in the Emergency Department (PRIDE)study,20 a prospective study of 599 acutelydyspneic patients, of whom 209 had HF. ThePRIDE study confirmed the value of NT-proBNPin the acute HF setting by demonstrating signifi-cant increases in NT-proBNP among those whohad acute HF compared to those without (4435pg/mL versus 131 pg/mL). Also, an NT-proBNPconcentration greater than 900 pg/mL had a PPVof 76% for diagnosing acute HF, similar to the find-ings for a BNP greater than 100 pg/mL in theBreathing Not Properly Multinational Study. Inthe PRIDE study, NT-proBNP levels correlatedwith the severity of HF symptoms, and multi-variable analysis showed that an elevation ofNT-proBNP level was the strongest predictor ofHF in acutely dyspneic patients in the ED. Further-more, the PRIDE study also showed that, similar toBNP, the NT-proBNP was superior to clinical judg-ment for diagnosing HF in this setting, and NT-proBNP plus clinical judgment were superior toeither alone (Fig. 2).

NPs received further support from the Brain Natri-uretic Peptide for Acute Shortness of Breath Evalu-ation (BASEL)21 and Improved Management ofPatients with Congestive Heart Failure (IMPROVE

CHF)22 studies, which were randomized, prospec-tive decision-making trials. In the BASEL study, Mu-eller and colleagues21 showed that the use of BNPlevels significantly reduced the need for hospitaladmission (75% versus 85%) or to intensive care(15% versus 24%). Time to discharge also wasreduced in the BNP group compared with thecontrol group (8 days versus 11 days), without thetrade-off of increased rehospitalization, resulting in

Fig. 2. Receiver operating characteristic curve compar-ison of results from NT-proBNP testing relative to clinicaljudgment. (Adapted from Januzzi JL, Camargo CA,Anwaruddin S, et al. The N-terminal Pro-BNP investiga-tion of dyspnea in the emergency department (PRIDE)study. Am J Cardiol 2005;95(8):952; with permission.)

Natriuretic Peptides 493

a significant cost reduction of 26%. Similarly, theIMPROVE CHF study22 validated this point for NT-proBNP. In this randomized, controlled, blinded,prospective multicenter study, 500 patients pre-senting with shortness of breath to an ED wererandomized to management strategy either guidedby NT-proBNP results or standard clinical care. NT-proBNP guidance resulted in reduced duration ofED visits by 21% (6.3 to 5.6 hours; P 5 .031), reho-spitalization over 60 days by 35% (51 to 33 days;P 5. 046), and direct medical costs of all ED visits,hospitalizations, and subsequent outpatientservices over 60 days from enrollment ($6129 to$5180 perpatient; P5 .023). These results were pre-dicted by a decision-analytic framework analysisdata obtained in the PRIDE study.23

The reductions in clinician indecision, commonin dyspneic patients most likely explain the cost-effectiveness resulting from the use of NPs. Clini-cian indecision also is associated with moreresource utilization, longer lengths of stay andworse outcomes. Routine earlier measurementsof NPs have been related with better outcomesby reducing the clinician indecision about thecorrect diagnosis. This, along with more secureand early treatment, probably is linked to thesedifferences in outcome.

Cut Points

NPs are continuously distributed variables, withsome degree of overlap between patients withand without HF. The degree of this overlap is notfixed, with influence by numerous variables in theabsence of HF, including normative processessuch as age, but also relevant structural heartdisease including abnormalities in heart rhythm,ischemic heart disease, valvular disease, andpulmonary hypertension. Accordingly, it should

not be surprising that a single cut point for eitherpeptide is less helpful than considering themarkers as continuous variables, where higherconcentrations are more likely to be associatedwith HF and the converse.

For both BNP and NT-proBNP to exclude acuteHF in symptomatic patients, very low values arenecessary. For BNP, the value is approximately20 to 30 pg/mL,15 while for NT-proBNP, a cut pointthat has a NPV of 98% to 99% is 300 pg/mL.20

Values above these levels, whether or not theyare below the rule in cut point, may be associatedwith HF.

To identify acute HF, it has been argued that anadvantage of BNP is the use of a single cut point of100 pg/mL across all patient types. This overlysimplistic approach ignores the foregoing discus-sion about the inability of this cut point to ruleout HF, and the fact that several conditions,including advanced age, may lead to a BNPgreater than 100 pg/mL in the absence of HF.Indeed, there is no manifest advantage of BNPover NT-proBNP when using a single cut point.The PRIDE investigators found that an NT-proBNPgreater than 900 pg/mL provides an equal diag-nostic value as a BNP greater than100 pg/mL;20

yet superior diagnostic accuracy could be had bysimply adjusting for age, a significant confounderwhen interpreting both BNP and NT-proBNP.Accordingly, an age-stratified approach of 450/900/1800 pg/mL for ages less than 50/50 to 75/greater than 75 years was found to be superiorto a single cut point.24 Age-appropriate cut pointsfor BNP are not known.

Gray Zone

When evaluating cut points of NPs in the diagnosisof HF, an intermediate or gray zone must beappreciated. For BNP, these values are between100 pg/mL and 500 pg/mL, while for NT-proBNP,the value is between 300 pg/mL and the age-adjusted cut point (450 pg/mL, 900 pg/mL and1800 pg/mL).25,26

Gray zone values of NPs are found in mild HFwith normal systolic function, from other cardiacdisorders such as myocardial ischemia or atrialfibrillation (AF), or from pulmonary embolism andinfections. According to a subanalysis of the Inter-national Collaborative of NT-proBNP (ICON) study,clinical parameters including the absence ofcough, a prior history of HF, presence of parox-ysmal nocturnal dyspnea, jugular venous disten-tion, and use of loop diuretics on presentationpredict a diagnosis of HF.26 Hence the clinicaljudgment assumes extra importance when theNP levels are in the gray zone.

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ELEVATED NATRIURETIC PEPTIDE LEVELSWITHOUT HEART FAILUREChronic Kidney Disease

It has been reported that 33% to 56% of patientswith HF have CKD, while conversely, patientswith CKD have relevant structural heart diseasethat is equivalent to the loss of renal function. Asnoted previously, both NPs are cleared partiallyby the kidneys. Hence, patients who have CKDare expected to have elevated levels of BNP orNT-proBNP. Although this finding originally wasconsidered a false positive, it now is known thatelevated NPs in patients who have CKD predictstructural heart disease and poor outcome.27

When used for diagnosing HF in patients whohave CKD, BNP and NT-proBNP appear to beaffected equally by loss of renal function. Bothmarkers retain utility for diagnosing HF if adjustedfor renal function. Subanalyses from the BreathingNot Properly Multicenter Study and the PRIDEstudy demonstrated that the accuracy of bothNPs is impaired only modestly in patients whohave renal dysfunction when compared withpatients who have normal renal function withslightly higher cut points (200 pg/mL for BNP and1200 pg/mL for NT-proBNP).14,16,20 Using theage-adjusted cut points recommended by theICON study, there was no need for changingthe cut points to diagnose HF in patients whohad CKD.24

Chronic Heart Failure

Among patients who have prior HF, elevation ofNPs is anticipated, as they are sensitive measuresof HF presence and severity, and these elevationsare correlated directly with outcomes. Whena dyspneic patient who has prior HF is evaluatedwith BNP and NT-proBNP, however, it may bechallenging to differentiate acute or chronic HFfrom other causes of dyspnea. In this situation, itis important to compare the NP level with previousavailable NP values, or ideally with the dry NPvalue. As described previously, with the knowl-edge that the biological variation in stable chronicHF is 25%, a change in NP of greater than 25% issupportive of acute destabilization.

Coronary Artery Disease

Expression of the cardiac BNP gene is increased inmyocardial ischemia, resulting in elevation of BNPand NT-proBNP. It is uncertain how ischemia trig-gers BNP release, but it may be related in part toischemia-mediated wall stress or tissue-levelhypoxia. Indeed, based on basic and clinical obser-vations, such tissue-level hypoxia/ischemia has

been noted as an independent trigger for BNPrelease.28–30 NPs may not be diagnostic of acutecoronary syndrome, but are excellent predictorsof mortality and morbidity in this condition.

Atrial Fibrillation

Both BNP and NT-proBNP levels are elevated inpatients who have acute and chronic AF. NT-proBNP levels are higher in HF patients whohave AF than in HF patients with sinus rhythmand have an independent prognostic value despitethe presence of AF. Moreover, NP levels decreaseafter restoration of sinus rhythm by cardioversion.Furthermore, the NP levels also have been shownto predict the recurrence of AF following cardio-version and predict development of AF followingpacemaker placement for sick sinus syndromeand postcardiac surgery.

Valvular Heart Disease

Diseases of cardiac valves may cause chronicpressure and volume overload, which leads toincrease in myocardial wall stress; hence, thereis increased secretion of NPs, even in the absenceof HF. Among patients who have aortic stenosis,NP levels correlate directly with the mean trans-aortic valve pressure gradient, LV wall stress,and symptom status and inversely with valvearea. Furthermore, NP levels have been shown tobe predictive of the development of symptoms inasymptomatic patients with aortic stenosis andwith outcomes after valve replacement surgery.Similar data exist for aortic regurgitation.

With respect to the mitral valve, BNP and NT-proBNP rise in parallel with the severity of regurgi-tation, even in the absence of symptoms andpredict clinical outcomes. Similarly, amongpatients who have mitral stenosis, it has beenreported that NP levels rise in proportion to theseverity of the stenosis, which runs counter tothe concept that they are LV markers. Lastly,right-sided valvular heart disease also may leadto elevations of BNP or NT-proBNP, but suchelevations are typically lower than those associ-ated with left-sided lesions; nonetheless, right-sided valvular heart disease should be consideredwhen interpreting concentrations of thesemarkers.

Pulmonary Diseases

Both BNP and NT-proBNP have been shown to beof value in sorting out the cause of dyspnea amongpatients who have both chronic obstructive airwaydisease and concomitant HF, and they may beable to identify a significant percentage of patientswith chronic lung disease who have unexpected or

Natriuretic Peptides 495

masked HF. Having said this, NPs have beenshown to be elevated in non-HF disorders thatcause chronic right ventricular (RV) dysfunction,such as primary pulmonary hypertension, chronicobstructive pulmonary disease, thromboembolicpulmonary hypertension, and left-to-right cardiacshunts. In patients who have chronic pulmonaryhypertension, an increase in NPs not only corre-lates with the degree of RV dysfunction but alsowith the risk for mortality.

With respect to pulmonary thromboembolism,a low NP level is useful for ruling out an adverseoutcome, and elevated NP levels in patients whohave acute pulmonary embolism suggest RVdysfunction and warrant further evaluation. Apersistent elevation of NT-proBNP levels within24 hours after an acute pulmonary embolismsuggests severe right ventricular dysfunction andhence a poor prognosis, which warrants aggres-sive management. Based on this correlation,investigators have incorporated NT-proBNP ina risk stratification algorithm for patients whohave acute pulmonary embolism.31

Critical Illness

Sepsis, major trauma, complicated major surgery,or other critical illness can impair cardiac functiondirectly, leading to poor outcomes. Elevations ofBNP and NT-proBNP levels occur in these settingsand are directly predictive of adverse outcomesincluding death, independent of HF, LV mass, orintracardiac filling pressures, possibly reflectingmyocardial depression from direct toxic effect ofinflammatory mediators. Both BNP and NT-proBNP are independent predictors of outcomein unselected patients who are critically ill.

LOW NATRIURETIC PEPTIDE LEVELSIN HEART FAILURENonsystolic Heart Failure

HF with preserved systolic function affects up to50% of patients who have HF and is an importantconsideration when applying NP testing. Maiseland O’Donoghue and their colleagues32,33 demon-strated that the presence of nonsystolic HF isassociated with lower values for BNP and NT-proBNP, respectively, than those in patients whohave systolic HF. This may lead, in patients whohave nonsystolic HF, to an NP value below therule in threshold, but rarely does it lead to a resultbelow the rule out cut-point of 30 pg/mL and 300pg/mL for BNP and NT-proBNP, respectively.

Body Mass Index

Levels of both NPs are significantly lower in over-weight and obese patients in a manner parallel toBMI, and independent of the elevated filling pres-sures in these patients. The effects of BMI-medi-ated NP suppression include a change in optimalcut points for BNP, but not NT-proBNP. Theauthors of the Breathing Not Properly MultinationalStudy proposed a cut point of BNP 54 pg/mL inobese patients to improve sensitivity in this popu-lation. Although the level of NT-proBNP is alsolower in obese patients, a subanalysis of theICON study demonstrated no need for cut pointadjustment for BMI when using the age-adjustedcut points, and NT-proBNP retained its prognosticramification across all weight categories.

NATRIURETIC PEPTIDES IN THEMANAGEMENTOFACUTE HEART FAILURE

A prerequisite for adequate management of HF isthe correct and timely recognition of its presenceand severity. As already discussed, NPs are notonly important in evaluating patients for acutedyspnea in the ED but also, their use for managingacute HF in the ED is associated with less resourceutilization, shorter hospitalization stay, and signifi-cant reduction in rehospitalization.

The standard approach for managing patientswho have acutely decompensated HF is basedon clinical assessment (including history, physicalexamination, vital signs, daily weights, and urinaryoutput) and simple laboratory evaluations,including assessment of renal function. Theseapproaches, however, have relatively poor sensi-tivity and specificity in decompensated HFpatients, leading to high short-, medium-, andlong-term mortality and readmission rates. Usingsimple parameters such as renal function, bloodpressure, and some other variables, patients whohave HF can be stratified as low-risk and high-risk. These parameters are less helpful, however,in treating and monitoring patients. In this regard,there is increasing interest in the use of NPs tomonitor adequacy of therapy for acute HF, frompresentation to outpatient follow-up.

It is accepted that NP levels at presentation offersignificant prognostic information. A follow-upmeasure after treatment may be of even morevalue, however. More favorable outcomes areobserved in patients who have considerablereductions in NP concentration during acute HFtherapy, which argues for an association betweenadequacy of therapy for HF and NP values. Fall inthe NP level after treatment for HF reflects reduc-tion of the acutely raised filling pressures

Mohammed & Januzzi496

in patients who have acutely destabilized HF.Kazanegra and colleagues34 first showed thatamong patients who responded to HF treatment,BNP levels fell in parallel with pulmonary capillarywedge pressure. Knebel and colleagues35 alsoshowed similar reductions in NT-proBNP, witha drop in pulmonary capillary wedge pressurefollowing treatment. In contrast, those patientswho did not have a significant improvement infilling pressures or hemodynamics did not havea significant decline in NT-proBNP values. Cioffiand colleagues36 showed that the lack of responseof NPs after treatment was not necessarily alwaysassociated with a fall in filling pressures, but wasassociated with reduction in adverse outcome.

The clinical significance of the response of NT-proBNP to therapeutic intervention in terms of clin-ical events has been assessed. Among 100patients presenting with acute dyspnea, Bayes-Genis and colleagues17 showed that the transho-spital (day 1 to day 7) change in levels ofNT-proBNP was 15% or less in patients whodeveloped complications, when compared withpatients who survived, who usually showeda 50% or greater fall in NT-proBNP levels fromday 1 to day 7. In this study, the percentage reduc-tion in NT-proBNP during admission for acute HFhad an area under the receiver operating charac-teristic curve of 0.78 (P 5 .002), better than thepresenting NT-proBNP concentration. Di Sommaand colleagues37 also showed a reduction of58% in NT-proBNP concentrations over a 7-dayperiod following successful treatment for acutelydestabilized HF. Logeart and colleagues38 showedthat high predischarge BNP levels were a strong,

independent predictor of death or readmission,stronger than the commonly used clinical andechocardiographic parameters, following anepisode of decompensated HF. These investiga-tors also showed that patients who achieveda predischarge BNP level under 350 pg/mL hadthe most favorable longer-term outcomes.

Bettencourt and colleagues39 demonstrated theimportance of the transhospital gradient of NT-proBNP concentrations for predicting outcomes.Even though an NT-proBNP greater than 6779pg/mL at presentation predicted a trend towardshazard for readmission or death, the post-treat-ment NT-proBNP value greater 4137 pg/mL wasa more powerful predictor of hazard and a 8%increase in the odds for death or readmissionover 6 months per 1000 pg/mL of NT-proBNPover this threshold (P<.0001). Furthermore,patients who had exhibited a greater than 30%drop in their NT-proBNP concentrations had supe-rior outcomes compared with patients who hadless than 30% decline, and dramatically betterthan those who actually had a rise in their NT-proBNP despite being considered ready fordischarge from the hospital. This latter group hada very poor event-free survival after discharge(Fig. 3). These data support the monitoring of thedischarge NP levels to determine the adequacyof the HF therapy and to predict hazard.

In light of these findings, a possible algorithm forBNP or NT-proBNP based management of in-patients who have acute decompensated HF isto obtain a baseline measurement for diagnosis,triage, and in-hospital prognostication, then treatthe patient using the usual guidelines for HF.

Fig. 3. Association between in-hospital change in NT-proBNPconcentrations and subsequentoutcomes among patients treatedfor acute heart failure. Amongthose with inadequate fall (orrise) in NT-proBNP concentrations,a significant risk for death or reho-spitalization is noted. (From Bet-tencourt P, Azevedo A, Pimenta J,et al. N-terminal-pro-brain natri-uretic peptide predicts outcomeafter hospital discharge in heartfailure patients. Circulation2004;110:2172; with permission.)

Natriuretic Peptides 497

When the patient is viewed to be recompensatedsuccessfully on clinical grounds, obtain a BNP orNT-proBNP to evaluate for successful resolution(Fig. 4). Current data suggest that a fall of at least30% during inpatient hospitalization would bedesirable for either peptide, with absolute targetvalues of less than 350 pg/mL for BNP and lessthan 4000 pg/mL for NT-proBNP.

FUTURE APPLICATIONS: MULTIMARKER PANELS

Now that it is established that BNP and NT-proBNP are powerful prognostic markers whenused in isolation, there is considerable interest inthe use of other biomarkers that complement riskstratification together with BNP or NT-proBNP,and which offer other targets for therapeuticintervention.

Natriuretic Peptides and Renal Function

The Acute Decompensated Heart Failure NationalRegistry investigators demonstrated the impor-tance of abnormal renal function for predictingdeath after an acute HF presentation,40 but thisanalysis lacked NPs. As demonstrated by vanKimmenade and colleagues,27,41 abnormalities inrenal function are independently predictive ofadverse outcome in patients who have acutedecompensated HF, but only in those who presentwith very high NT-proBNP concentrations. Indeed,a proposal to redefine the concept of cardio–renalsyndrome (previously defined as a change in serumcreatinine greater than or equal to 0.3 mg/dL duringacute HF treatment) was suggested by these inves-tigators, who found that such a change in serum

Measure NT-proBNP/B

Management per s

(history, physical examination, daily weights, flu

Improved c

Fall of >30%

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levels met

Fall of ≤ 30%

target le

not m

(Target levels: NT-proBNP<400

Re-measure NT-

Discharge

Standard follow up

Discha

Intensive fo

Fig. 4. A suggested algorithm for natriuretic peptide-baselized heart failure.

creatinine was of prognostic importance only inthe context of a markedly elevated NT-proBNP.Furthermore, they showed that combining the twovariables (ie, elevated NT-proBNP and a glomerularfiltration rate (GFR) less than 60 mL/min/1.73 m2)was superior for identifying patients with HF athighest risk for short-term death than either vari-able alone. In addition, they showed that HFsubjects who had moderate or severe renaldysfunction but lower NT-proBNP concentrationshad 60-day outcomes comparable to those withoutrenal dysfunction.

Natriuretic Peptides and Troponins

Troponins frequently are elevated in HF withoutmanifest myocardial ischemia. Despite the unclearnature of their mechanism of release, multiplestudies have demonstrated a prognostic role fortroponins in HF. As demonstrated by Sakhuja andcolleagues,42 the combined predictive value of anNP with a troponin in 209 patients who presentedto the ED with acute HF was superior to eithermarker alone (see article by Latini in this issue).

Natriuretic Peptides and Anemia

Anemia is common in patients who have HF, and ithas been related with poor outcomes in the acuteHF setting. In addition, the deleterious effects ofanemia on myocardial function may lead toelevated NP levels, even in the absence of HF.The ICON study24 showed the serum hemoglobinlevel to be a significant independent predictor ofshort-term adverse outcome in acute HF. Baggishand colleagues43 studied the combined predictive

NP at presentation

tandard of care

id restriction, medications, standard labs)

linically

and/or

vels

et

0pg/mL; BNP <350pg/mL)

Rise of ≥ 30% in

NT-proBNP or BNP

value

proBNP/BNP

rge

llow up

Delay discharge

Intensify treatment

d management of the inpatient with acutely destabi-

Mohammed & Januzzi498

power of hemoglobin as a function of NT-proBNPconcentration in 690 patients who presented to anED with acute HF, demonstrating higher 60-daymortality rates in anemic patients who had highNT-proBNP (23.5%) when compared to anemicpatients with low NT-proBNP (9.2%) and nonane-mic patients who had high NT-proBNP (13.9%).The investigators concluded that the combinationof hemoglobin and NT-proBNP (greater than5180 pg/mL) measurements provides powerfuladditive information and is superior to the use ofeither in isolation.

Fig. 5. Rates of mortality at 1 year among patientswith dyspnea as a function of multimarker score.(From Rehman SU, Martinez-Rumayor A, Mueller T,et al. Independent and incremental prognostic valueof multimarker testing in acute dyspnea: resultsfrom the ProBNP Investigation of Dyspnea in theEmergency Department (PRIDE) study. Clin ChimActa 2008;392:43; with permission.)

Natriuretic Peptides and Other Biomarkers

Apart from markers discussed previously, thereare other markers that potentially can be usedfor risk stratification in acute HF. These includeC-reactive protein (CRP), galectin-3 (a markerproduced by activated cardiac macrophages),and ST2 (an interleukin receptor family member,produced by myocytes in response to stretch).

CRP was examined in the PRIDE study byRehman and colleagues,44 who demonstratedthe importance of inflammation together with my-ocyte stretch (as reflected in NT-proBNP concen-trations). In their analysis, hs (high sensitivity) CRPwas independently and additively prognostic toNT-proBNP. This suggests that inflammation playsa pivotal role in the response to acute HF, and maybe causative in negative remodeling after such anevent. Indeed, the results from measuring markersof myocardial fibrosis, galectin-3 and ST2, supportthis concept.

Galectin-3, in combination with NT-proBNP hasbeen shown to be a strong predictor of short-termmortality in acute HF.45 An even more powerfulpredictor of death in acute HF is the marker ST2,a protein secreted by stretched cardiac myocytesand fibroblasts. ST2 has been examined in thePRIDE study46 and in a larger pooled analysis.47

In both, ST2 was a powerful prognostic marker,additive to NT-proBNP or BNP, and the combina-tion provided superior risk stratification (see arti-cles by Lee and de Lemos l in this issue).

Ultimately, a multimarker strategy such as thatproposed by Rehman and colleagues48 (Fig. 5)may provide such utility. Critical to this approach,however, is the recognition that expanded use ofbiomarkers for evaluating and managing acuteHF will depend on the following four factors: (1)That the markers used provide independent (ratherthan redundant) physiologic information; (2) Thatthe markers used provide independent prognosticvalue; (3) That the individual markers present a targetfor clinical decision making; and (4) That the markersused are robust, widely available, and cost-effective.

SUMMARY

HF is a growing problem for the modern health-care system, and the use of NP testing in patientswho have known or suspected HF is useful indiagnosis and risk stratification. Such testing isbeing expanded to assess the efficacy of treat-ment of patients who have acute HF, and ulti-mately to the postdischarge care of suchpatients. The first steps into the biological era ofHF care have been taken in acute HF. This erawill expand, including biomarkers as an importantcomponent of the entire spectrum of manage-ment, from diagnosis through to chronictreatment.

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