Understanding the natriuretic peptides.

Three types of natriuretic peptides have been identified in the human body: A, or atrial type (ANP), identified in the late 1980s; B, or brain type (BNP), identified in 1988; and C type (CNP), identified in 1990. These three hormones have a common structure, as shown in Figure 1. ANP and BNP, when released from the atria and the ventricles of the heart, are known to have vasodilatory effects and promote urinary sodium loss (natriuresis) as well as urinary water loss (diuresis). CNP is released from the endothelium, and as far as is known today, this molecule has no systemic effects.

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As with many hormones in the body, both ANP and BNP are initially synthesized as prohormones. In response to atrial and ventricular wall stretch, such as that seen in congestive heart failure as a result of pressure and/or volume overload, the prohormone is cleaved to generate the active hormone (e.g., BNP) and an N-terminal biologically inactive fragment (i.e., NTproBNP). Both are then released into the blood stream in a 1:1 ratio (see Figure 2).

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Although the plasma levels of all four molecules (ANP, NTproANP, BNP, and NTproBNP) reflect volume status and myocardial pressure, only BNP and NTproBNP are used diagnostically. This is most likely due to the fact that ANP has a very short in vivo half-life of two to five minutes and is present in plasma at low concentrations; for this reason, the rest of this article will focus on BNP and NTproBNP. The in vivo half-life of BNP is 20 minutes, while that of NTproBNP is 60 to 120 minutes; there is also a significant difference in the in vitro stability of both molecules: four to eight hours at room temperature versus 48 hours, respectively. Thus, although the two molecules are released from the heart in a 1:1 fashion, the circulating concentrations start to diverge very quickly, resulting in higher plasma concentrations of NTproBNP compared to BNP.

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What is congestive heart failure?

Heart failure is a condition that occurs when the heart cannot deliver a sufficient oxygenated blood supply to the rest of the body to meet its demands. Congestive heart failure (CHF) is a common form of heart failure that results in excessive fluid retention and often leads to congested lungs and swelling of the lower extremities. Patients suffering from CHF typically present to the emergency department with dyspnea (shortness of breath) and may also have evidence of edema. These symptoms can mimic a number of other conditions, such as asthma, an acute coronary syndrome, chronic obstructive pulmonary disease, or a pulmonary embolism. The treatments that should be initiated vary dramatically for these different conditions; thus, diagnostic tools, such as the natriuretic peptide assays, that can help distinguish between these conditions are very important.

Clinical utility of BNP and NTproBNP

The FDA has cleared both BNP and NTproBNP assays for use as aids in the diagnosis and assessment of the severity of heart failure and for risk stratification of patients with acute coronary syndrome. The situation with the two natriuretic peptides is very similar to the situation with Troponin I and Troponin T: Both molecules, in most cases, provide the same kind of information, although the circulating levels are different. The FDA-cleared cutoffs for these assays are 100 pg/mL for BNP; for NTproBNP, a dual, age-related cutoff of 125 pg/mL for patients less than 75 years and 450 pg/mL for patients 75 years and older is used. These cutoffs are for use in ruling out a diagnosis of CHF. What does this mean? If a patient has a level below the cutoff for the respective assay being used, there is a fairly high confidence level that the symptoms the patient has are due to something other than CHF. It should be noted, however, that both false-positive and false-negative values can be obtained with either assay.

The levels of both BNP and NTproBNP are known to be affected by age, gender (women have higher levels than men), and renal function. The reasons why levels are affected by age and gender differences are not well understood but may be related to estrogen effects, the normal age-related decline in renal function, and possible increased prevalence of unrecognized left-ventricular dysfunction in the elderly. NTproBNP appears to be more sensitive to New York Heart Association (NYHA) Class I and II disease (less symptomatic than classes III and IV) than BNP, although false-negative results can be obtained with both assays in these patients. BNP levels may be depressed in obese patients, as receptors for BNP are found on the surface of adipocytes. A number of other conditions (see Table 1) can also result in increased levels of BNP and NTproBNP in the blood stream. The elevations in levels seen in these additional disease states are the reason that the current cutoffs are rule-out cutoffs only.

Future uses of the natriuretic peptide assays

Recently, algorithms that incorporate additional cutoffs have been proposed for both assays. These algorithms may be useful for establishing a "rule-in" diagnosis of CHF for the patient presenting to the emergency department (Figure 3) with acute shortness of breath. To date, these algorithms have only been tested in limited populations and have not been cleared by the FDA, but the data are promising that a diagnostic cutoff in addition to the rule-out cutoff may be possible.

Many physicians would like to use the natriuretic peptide assays for monitoring their CHF patients. When a CHF patient presents to the emergency department with shortness of breath, one of the first treatment steps is to remove the excess fluid in the body and get the patient back to as "dry" a state as possible. A BNP or NTproBNP value in this "dry" state could then be used to monitor the patient in the future; significant increases in the level over time would suggest that the patient is starting to retain fluids again and requires more aggressive monitoring.

Table 1. (2) Conditions that cause elevated natriuretic peptide levels.

Disease                           NP concentration

Cardiac diseases
 - Heart failure                  Greatly increased
 - AMI (first two to five days)   Greatly increased
 - Hypertension with LVH          Increased
Pulmonary diseases
 - Acute dyspnea                  Increased
 - Pulmonary embolism             Increased
 - Obstructive pulmonary disease  Increased
Hyperthyroidism                   Increased
Hypothyroidism                    Decreased
Diabetes                          Normal or Increased
Liver cirrhosis with ascites      Increased
Renal failure (acute or chronic)  Increased

Table 2. Manufacturers of BNP or NTproBNP.

Available BNP assays
Abbott
Bayer
Beckman Coulter
Biosite

Available NTproBNP assays
Dade Behring
Roche

NTproBNP assays under development
DPC
Inverness
Ortho-Clinical Diagnostics

Figure 3. Proposed algorithms for natriuretic assay interpretation for
patients with shortness of breath.

Proposed algorithm for BNP (3)
  BNP <100 pg/mL     CHF very unlikely
  BNP 100-400 pg/mL  Indeterminate "gray zone"
  BNP >400 pg/mL     CHF likely
Proposed algorithm for NTproBNP (4)
  NTproBNP <300 pg/mL acute CHF unlikely regardless of age; or
  Use the age-related cutoffs of <125 pg/mL for age <75 and <450 pg/mL
    for age [greater than or equal to]75
CHF likely if:
  Age <50       NTproBNP >450 pg/mL
  Age 50 to 75  NTproBNP >900 pg/mL
  Age >75       NTproBNP >1800 pg/mL
NTproBNP >10,000 pg/mL, CHF very likely, regardless of age

References

1. Adapted from Mair J, Friedl W, Thomas S, Puschedorf B. Natriuretic peptides in assessment of left-ventricular dysfunction. Scand J Clin Lab Invest. 1999;59(suppl 230):132-142.

2. Adapted from Clerico A, Emdin M. Diagnostic accuracy and prognostic relevance of the measurement of cardiac natriuretic peptides: a review. Clin Chem. 2004;50:33-50.

3. Adapted from Maisel AS. Acute Emergency Department management of heart failure. Heart Fail Rev. 2003;8:339-344.

4. Adapted from Baggish AL, Cameron R, Anwaruddin S, et al. A clinical and biochemical critical pathway for the evaluation of patients with suspected acute congestive heart failure: the ProBNP investigation of dyspnea in the emergency department (PRIDE) algorithm. Crit Pathways in Cardiol. 2004;3:171-176.

By Mary Lou Gantzer, PhD

Mary Lou Gantzer, PhD, is vice president of clinical & scientific affairs in Newark, DE, for Dade Behring Inc.