Natriuretic Peptide Testing in Heart Failure

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 amino-terminal 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 biological 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.

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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.

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 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 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 before, 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

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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.

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 have an ejection fraction of 35% and is treated with a loop diuretic, as well as with maximum-dose angiotensin-converting 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 β-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 β-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.

Disclosures

Dr Januzzi has received significant grant support from Roche Diagnostics, Siemens, and Critical Diagnostics. Dr Kim reports no conflicts.