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Natriuretic Peptide Testing in Heart Failure Han-Na Kim and James L. Januzzi, Jr Circulation 2011;123;2015-2019 DOI: 10.1161/CIRCULATIONAHA.110.979500 Circulation is published by the American Heart Association. 7272 Greenville Avenue, Dallas, TX 72514 Copyright © 2011 American Heart Association. All rights reserved. Print ISSN: 0009-7322. Online ISSN: 1524-4539 The online version of this article, along with updated information and services, is located on the World Wide Web at: http://circ.ahajournals.org/cgi/content/full/123/18/2015 Subscriptions: Information about subscribing to Circulation is online at http://circ.ahajournals.org/subscriptions/ Permissions: Permissions & Rights Desk, Lippincott Williams & Wilkins, a division of Wolters Kluwer Health, 351 West Camden Street, Baltimore, MD 21202-2436. Phone: 410-528-4050. Fax: 410-528-8550. E-mail: [email protected] Reprints: Information about reprints can be found online at http://www.lww.com/reprints Downloaded from circ.ahajournals.org by on May 30, 2011 CLINICIAN UPDATE Natriuretic Peptide Testing in Heart Failure Han-Na Kim, MD, MPH; James L. Januzzi, Jr, MD C ase presentation 1: A 78-year-old woman with a history of morbid obesity, coronary artery disease, chronic obstructive pulmonary disease, and chronic kidney disease (serum creatinine 2.0 mg/dL) presented to the emergency department with worsening dyspnea. Her ECG shows no acute ischemic changes; her chest radiograph reveals chronic emphysematous changes with mild bilateral infiltrates. Her lung examination is notable for diffuse wheezing, and she has chronic lower extremity edema. Her aminoterminal pro-B-type natriuretic peptide (NT-proBNP) level is 5500 pg/mL (upper limit of normal is ⬍1800 pg/mL for age ⬎75 years). Does this patient have acutely decompensated heart failure (ADHF)? Overview: Natriuretic Peptides in Acute Dyspnea Many patients presenting with acute dyspnea (including those with ADHF) have multiple coexisting medical disorders that may complicate their diagnosis and management. Diagnostic uncertainty in the setting of acute dyspnea is associated with longer hospital length of stay, more diffuse diagnostic and therapeutic efforts, increased healthcare costs, and higher likelihood for repeat heart failure (HF) hospitalization or death.1 The addition of testing for brain natriuretic peptide (BNP) or NT-proBNP to standard clinical assessment has been shown to be valuable for an accurate and efficient diagnosis and prognostication of HF, and the use of BNP or NT-proBNP may be associated with improved clinical outcomes.2– 4 Pathophysiology of Natriuretic Peptides in Heart Failure Circulating levels of BNP/NT-proBNP are normally very low in healthy individuals. In response to increased myocardial wall stress due to volume- or pressure-overload states (such as in HF), the BNP gene is activated in cardiomyocytes. This results in the production of an intracellular precursor propeptide (proBNP108); further processing of this propeptide results in release of the biologically inert aminoterminal fragment (NT-proBNP) and the biologically active BNP (Figure 1). In addition, a significant portion of BNP or NT-proBNP detected by current assays includes uncleaved proBNP108, whereas BNP concentrations also include the detection of various subfragments that arise from the degradation of the intact BNP hormone. The bio- logical activity of BNP includes stimulation of natriuresis and vasorelaxation; inhibition of renin, aldosterone, and sympathetic nervous activity; inhibition of fibrosis; and improvement in myocardial relaxation. Although released in a 1:1 ratio, the measured NT-proBNP level is higher than that of BNP, in part because NT-proBNP is passively cleared from the circulation more slowly (half-life of 120 versus 20 minutes). Unlike BNP, NT-proBNP is not cleared by natriuretic peptide (NP) receptors or neutral endopeptidases. Rather, NT-proBNP is cleared by various organs, including the skeletal tissue, liver, and kidneys.5 A common misconception is that NT-proBNP is more dependent on renal function for clearance than is BNP; both are equally cleared by the kidneys.6 Diagnostic Applications of Brain Natriuretic Peptide or Amino-Terminal Pro-B-Type Natriuretic Peptide in Acutely Decompensated Heart Failure Brain natriuretic peptide and NT-proBNP levels are increased in HF, and correlate well with ventricular wall stress and severity of HF.2,7 The Breathing Not From the Cardiology Division, Massachusetts General Hospital, Boston MA. Correspondence to James L. Januzzi, Jr, MD, FACC, Cardiology Division, Massachusetts General Hospital, Yawkey 5984, 55 Fruit St, Boston, MA 02114. E-mail [email protected] (Circulation. 2011;123:2015-2019.) © 2011 American Heart Association, Inc. Circulation is available at http://circ.ahajournals.org DOI: 10.1161/CIRCULATIONAHA.110.979500 Downloaded from circ.ahajournals.org by on May 30, 2011 2015 2016 Circulation May 10, 2011 Figure 1. Biology of the natriuretic peptide system. BNP indicates brain natriuretic peptide; NT-proBNP, amino-terminal pro-B-type natriuretic peptide; and DPP-IV, dipeptidyl peptidase-4. Properly Multinational Study2 and the Pro-BNP Investigation of Dyspnea in the Emergency Department7 showed that NP levels were more accurate for diagnosis or exclusion of ADHF than clinical judgment, particularly in the context of diagnostic uncertainty.8 When added to comprehensive clinical assessment, BNP and NT-proBNP are both incrementally useful for diagnosis of ADHF, and both are endorsed in current practice guidelines for HF evaluation (particularly when diagnostic indecision is present).9 Interpretation and Differential Diagnosis of Elevated Natriuretic Peptide Levels Elevated concentrations of BNP or NT-proBNP are powerfully associated with the presence of HF; however, there is no value for either that is 100% diagnostic for HF. Both BNP and NT-proBNP may be elevated in a number of other disease states, and patient factors may influence results. Among HF syndromes, systolic dysfunction and HF with preserved ejection fraction may cause elevated BNP or NT-proBNP, although HF with preserved ejection fraction may be associated with lower values of both peptides than HF due to systolic dysfunction.10 In addition, other relevant cardiac diagnoses, including right ventricular failure (due to primary cardiac pathology or secondary to pulmonary embolism or pulmonary hypertension),11 valvular heart disease,12 and arrhythmias such as atrial fibrillation13 may cause elevation of BNP or NT-proBNP. In addition to cardiovascular variables that influence NP concentrations, advancing age and renal dysfunction may lead to higher values without overt HF, whereas obesity may result in unexpectedly lower BNP or NT-proBNP concentrations, even in those with HF.14,15 Overall, the recommended approaches for use of BNP or NT-proBNP for the exclusion and identification of ADHF work well. To troubleshoot complex situations such as renal disease,16,17 adjustment in cutoff points may help (Table). Another important situation is the patient with a gray zone BNP or NT-proBNP value. Approximately 20% of patients with acute dyspnea have BNP or NT-proBNP levels that are above the cutoff point to exclude HF but too low to definitively identify it. Knowledge of the differential diagnosis of non-HF elevation of NP, as well as interpretation of the BNP or NT-proBNP value in the context of a clinical assessment, is essential20; gray Downloaded from circ.ahajournals.org by on May 30, 2011 Kim and Januzzi Table. HF Natriuretic Peptide Testing 2017 Suggested Cut Points for BNP and NT-proBNP Use in Several Situations Cutoff Value, pg/mL Sensitivity, % Specificity, % PPV, % NPV, % Reference To exclude ADHF BNP NT-proBNP ⬍30–50 97 62 71 96 2 ⬍300 99 68 62 99 7 To identify ADHF Single cutoff point strategy BNP ⬍100 90 76 79 89 2 NT-proBNP ⬍900 90 85 76 94 7 18 Multiple cutpoint strategy ⬍100 to exclude; 90 73 75 90 100–400: gray zone * * * * ⬎400 to rule in 63 91 86 74 ⬍450 for age ⬍50 y 90 84 88 66 19 ⬍200 88 63 83 72 17 (1) ⬍1200, all ages 89 72 74 94 16 170 for BMI ⬍25 kg/m2 90 77 78 90 15 110 for BMI 25–35 kg/m2 90 77 77 90 54 for BMI ⱖ35 kg/m2 91 70 70 91 ⬍900, no adjustment for BMI 87 76 79 90 Age-stratified cut points, no adjustment for BMI 86 90 85 95 BNP, gray zone approach NT-proBNP, age-stratified approach ⬍900 for age 50–75 y ⬍1800 for age ⬎75 y Special situations Renal dysfunction (GFR ⬍60 mL 䡠 min 䡠 1.73 m⫺2) BNP NT-proBNP or (2) age-stratified approach, above Obesity BNP NT-proBNP 14 PPV indicates positive predictive value; NPV, negative predictive value; ADHF, acutely decompensated heart failure; BNP, brain natriuretic peptide; NT-proBNP, amino-terminal pro-B-type natriuretic peptide; GFR, glomerular filtration rate; and BMI, body mass index. * indicates not applicable. zone values are not without prognostic meaning, however, and should be approached with caution.20 In our patient, if the initial BNP concentration had been 90 pg/mL (upper limit of normal is ⬍200 pg/mL for renal dysfunction), or if her NT-proBNP had been 450 pg/mL, in an elderly female with renal dysfunction, ADHF would be less likely as the primary cause of her symptoms. However, we should keep in mind that HF with preserved ejection fraction might be present, or values might have been low because of her morbid obesity. On the other hand, her NT-proBNP of 5500 pg/mL is most consistent with ADHF, irrespective of age or renal function. As be- fore, interpretation of the NP result in the clinical context is very important. Natriuretic Peptides and Prognosis in Heart Failure Across all stages of HF, elevated BNP or NT-proBNP concentrations are at least comparable prognostic predictors of mortality and cardiovascular events relative to traditional predictors of outcome in this setting,21 with increasing NP concentrations predicting worse prognosis in a linear fashion. This prognostic value may be used to stratify patients at the highest risk of adverse outcomes (Figure 2).22 In ADHF, an initial value of BNP or NT-proBNP is prognostically useful; however, a follow-up measurement after therapy provides incremental prognostic value. Observational studies suggest that when BNP/NT-proBNP concentrations decrease by 30% or more in this setting, a better prognosis is expected than when values fail to decrease or actually increase.23 However, prospective randomized studies definitively supporting in-hospital monitoring are not yet available. Future Directions: Natriuretic Peptides for Guided Management of Chronic Heart Failure Case Presentation 2: The 78-year-old woman discussed in case 1 is found to Downloaded from circ.ahajournals.org by on May 30, 2011 2018 Circulation May 10, 2011 Figure 2. Age-adjusted Kaplan-Meier survival curve of mortality at 1 year associated with an elevated amino-terminal pro-B-type natriuretic peptide (NT-proBNP) concentration at emergency department presentation with dyspnea in those with acutely decompensated heart failure. Reproduced from Januzzi et al22 with permission of the publisher. Copyright © 2006, American Medical Association. have an ejection fraction of 35% and is treated with a loop diuretic, as well as with maximum-dose angiotensinconverting enzyme inhibition and carvedilol. She is discharged home and seen in her cardiologist’s office for follow-up, where she feels physically as she did at her baseline examination, with only mild dyspnea on maximal exertion. Her NT-proBNP level is 2150 pg/mL; on recheck 3 months later, it is 4800 pg/mL, but she remains unchanged clinically. What is the meaning of this finding, and how might the clinician respond? Elevated BNP (above approximately 125 pg/mL) or NT-proBNP (above approximately 1000 pg/mL) values are prognostically meaningful in chronic HF, and a rising pattern is predictive of impending adverse outcome, irrespective of other subjective and objective prognostic metrics. Furthermore, therapies that are favorable for chronic HF (such as -blockers, vasodilators, or aldosterone blockers) tend to lower concentrations of BNP or NT-proBNP. Thus, there is increasing interest in guiding HF therapy with BNP or NT-proBNP, with the goal of lowering concentrations of these markers (and maintaining their suppression) as part of the therapeutic approach in HF. Although evidence is increasing that NP-guided outpatient management of HF may improve clinical outcomes,4 more information is needed before adoption of such an approach, which is currently being tested in clinical trials.24 Nonetheless, an HF patient on an ostensibly stable medication program with a rising NP concentration is at high risk for adverse outcome and should be scrutinized closely for opportunities to optimize management. Follow-Up of Cases 1 and 2 The optimal treatment strategy for our 78-year-old patient in case 1 would be to ascertain the cause of ADHF, while simultaneously administering decongestive therapy with intravenous loop diuresis. In the meantime, optimization of her HF medical regimen, including uptitration of the angiotensin-converting enzyme inhibitor dose and a review of and potential increase in the dose of her -blocker (when safely able to do so) would be indicated; the addition of an aldosterone blocker is recommended if persistent New York Heart Association functional class III or IV symptoms are present. Follow-up NP measurement at the time of discharge would be useful to ensure adequacy of therapy, while serving to facilitate a smooth transition to outpatient management. In case 2, an increasing NP concentration in a seemingly unchanged outpatient with chronic HF should prompt assessment and reaction. Among the causes of a rising BNP or NT-proBNP in a seemingly stable outpatient are noncompliance with medication, an inadequate medication program, dietary indiscretions, coronary ischemia, atrial arrhythmia, and progressive decline in cardiovascular function. In this context, whether or not the patient appears to be on a maximal treatment program, reassessment of the patient is indicated. This includes possible investigation for causes of a rising NP value, as well as simultaneous uptitration of medications when possible; consideration for eligibility for therapies such as cardiac resynchronization therapy or implantable-cardioverter defibrillator implantation is also reasonable. Acknowledgments The authors would like to thank Drs Paul Clopton, Lori Daniels, and Alan Maisel for their assistance. Disclosures Dr Januzzi has received significant grant support from Roche Diagnostics, Siemens, and Critical Diagnostics. Dr Kim reports no conflicts. References 1. 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KEY WORDS: heart failure 䡲 natriuretic peptides 䡲 case management 䡲 biomarkers 䡲 prognosis Downloaded from circ.ahajournals.org by on May 30, 2011