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Articles |
1
Laboratory of Cardiovascular Endocrinology, Consiglio Nazionale delle Ricerche Institute of Clinical Physiology, University of Pisa, 56100 Pisa, Italy.
a Address correspondence to this author at: Laboratory of Cardiovascular Endocrinology, Cell Biology, and Molecular Genetics, Consiglio Nazionale delle Ricerche, Institute of Clinical Physiology, via Savi 8, 56100 Pisa, Italy. Fax 39-050-553461; e-mail clerico{at}nsifc.ifc.pi.cnr.it
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Abstract |
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 Top Abstract Introductionmeasurement of anp, bnp,...measurement of cnhs and...anp and bnp methodsassays for the n-terminal...comparison of clinical relevance...the need for a...References |
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Approach: Here we review recent studies concerning the competitive (such as RIA, enzyme immunoassay, or luminescence immunoassay) and noncompetitive immunoassays (such as two-site IRMA, ELISA, or immunoluminometric assay) for the different cardiac natriuretic peptides to compare the analytical characteristics and clinical relevance of assays for the different CNHs and the different assay formats.
Content: Developing sensitive, precise, and accurate immunoassays
for cardiac natriuretic peptides has been difficult because of their
low concentrations (on average, 
3–6 pmol/L) in healthy subjects and
because of their structural, metabolic, and physiological
characteristics. Competitive assays have historically suffered from
lack of sensitivity and specificity for the biologically active
peptides. These usually require tedious extraction procedures prior to
analysis. Recently, immunometric assays have been developed that have
improved sensitivity and specificity; it appears these will be the
methods of choice.
Summary: To date, there is no consensus on the best assay procedure of cardiac natriuretic peptides. To facilitate widespread propagation of determination of these hormones in routine clinical practice, it will be necessary to study the new generation of noncompetitive immunometric methods that are less time-consuming and more sensitive and specific. Although several studies suggest that BNP exhibits better clinical utility than the other CNHs, more studies examining multiple CNHs in the same cohorts of patients will be necessary.
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Introduction |
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TopAbstractIntroductionmeasurement of anp, bnp,...measurement of cnhs and...anp and bnp methodsassays for the n-terminal...comparison of clinical relevance...the need for a...References |
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Several studies suggest the importance of measuring the circulating concentrations of CNHs in the classification and/or prediction of mortality/survival rates in patients with heart failure (1)(2)(3)(4). In particular, a CNH assay might reduce the need for more expensive and invasive cardiac investigations in patients with cardiac disease (1)(2)(3)(4)(5). Because of the clinical relevance of CNH measurement, several different procedures have been proposed (3)(4). However, as yet the best procedure (gold standard) has not been ascertained, because CNH determination by competitive immunoassay methods is affected by several analytical problems (3)(4).
After we summarize the technical characteristics and potential clinical indications of various immunoassay methods for CNHs, their analytical performance and clinical relevance will be discussed and compared. Suggestions will be made for their use in clinical practice and for development of a new generation of CNH immunoassays.
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measurement of anp, bnp, and related peptides: which peptide should be measured? |
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TopAbstractIntroductionmeasurement of anp, bnp,...measurement of cnhs and...anp and bnp methodsassays for the n-terminal...comparison of clinical relevance...the need for a...References |
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) (3)(4). Even if the N-terminal
proANP1–98 is biologically inactive, several
studies (8)(9)(10)(11) have indicated that some peptides, produced
in vivo by the degradation of this peptide, are biologically active.
These peptides have been named the long-acting natriuretic
peptide (i.e., N-terminal
proANP1–30); the vessel dilator
peptide (i.e., proANP31–67); and the
kaliuretic peptide (i.e., proANP79–98). However,
these N-terminal proANP hormones exhibit (at least in part) different
biological properties as well as different mechanisms of action
(i.e., binding to different receptors) with respect to the
ANP/BNP system (11)(12). Like ANP, BNP
is also produced in the prohormone form
(proBNP1–108), which before the
secretion by cardiomyocytes is split into the inactive
N-terminal fragment proBNP1–76 and the
biologically active hormone BNP (i.e., COOH-terminal proBNP
77–108)
(3)(4)(12).
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measurement of cnhs and related peptides by immunoassay methods |
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TopAbstractIntroductionmeasurement of anp, bnp,...measurement of cnhs and...anp and bnp methodsassays for the n-terminal...comparison of clinical relevance...the need for a...References |
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anp and bnp methods |
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TopAbstractIntroductionmeasurement of anp, bnp,...measurement of cnhs and...anp and bnp methodsassays for the n-terminal...comparison of clinical relevance...the need for a...References |
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) (3)(4). For these
reasons, preliminary extraction and/or chromatographic purification of
large volumes (>1 mL) of plasma (or tissue extract) is required for
eliminating these interferences, thus increasing accuracy (i.e.,
specificity) and sensitivity of the determination of competitive
immunoassay methods (such as RIA or EIA) (4). Noncompetitive immunometric assays for the measurement of ANP and BNP have been developed recently to overcome the problems encountered with competitive assays (3)(4). The methods of this second generation are generally "two-site" (sandwich) immunometric assays, using two specific monoclonal antibodies or antisera prepared against two sterically remote epitopes of the ANP (14)(15)(16)(17) or BNP (18)(19)(20) peptide chain.
As reviewed recently (3)(4), noncompetitive immunoassay methods have several advantages over competitive assays. Noncompetitive assays are generally 5–20 times more precise and sensitive than their respective competitive assays and are not significantly affected by nonspecific or specific interference. Therefore, noncompetitive immunoassays methods for ANP and BNP do not usually require preliminary extraction and purification of the sample and also use a lower plasma volume (generally, 0.05–0.3 mL) than competitive assays (4). Furthermore, noncompetitive immunometric assays generally have a larger working range than that of competitive assays (4). These facts suggest that noncompetitive immunoassays for ANP and BNP may be more suitable for clinical routine than competitive assays (4).
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assays for the n-terminal proANP and proBNP |
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TopAbstractIntroductionmeasurement of anp, bnp,...measurement of cnhs and...anp and bnp methodsassays for the n-terminal...comparison of clinical relevance...the need for a...References |
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). However, immunoassays for N-terminal peptide fragments of proANP
and pro BNP may also be affected by several analytical problems, mainly
concerning the assay specificity.
The intact N-terminal proANP1–98 is a long
peptide; this implies that each anti-N-terminal proANP antibody
recognizes only one epitope of the peptide. Consequently, because
low-molecular mass fragments of N-terminal
proANP1–98 are present within the circulation,
different competitive immunoassays, using different antibodies, may
give different results (3)(4), as seen in Table 1
.
EIA methods that use antisera specific for different epitopes of
N-terminal proANP1–98 peptide chain usually show
cross-reactions close to 100% with the intact
proANP1–98 peptide (3)(4). Even if
the values found with these EIAs are highly correlated when compared
(r = 0.917; n = 115; P <0.0001),
however, these methods show significantly different clinical results
and reference values (Table 1
).
These data agree closely with the results of other studies (21)(22)(23), indicating that RIAs for the assay, respectively, of the long-acting natriuretic peptide, the vessel dilator peptide, and the kaliuretic peptide actually also recognize the whole N-terminal proANP1–98.
It is theoretically conceivable that a two-site noncompetitive immunometric assay, using two different monoclonal antibodies specific for two sterically remote epitopes of intact N-terminal proANP1–98, would be more suitable than a competitive method to measure the intact N-terminal proANP1–98, with only minor interference from its degradative fragments, as demonstrated recently for an IRMA method (24).
In conclusion, competitive and noncompetitive immunoassay methods for the N-terminal proANP1–98 may measure, at least in part, different substances, which probably have different biological activities and metabolic pathways and thus different clinical relevance (8)(9)(10)(11).
Noncompetitive assays for the determination of the N-terminal proBNP
peptide, which use antisera or antibodies specific for different
epitopes of the peptide chain, could also have different results, as
demonstrated by the comparison of two EIA methods (Table 1
). Recently,
two noncompetitive immunoluminometric assays for N-terminal
BNP1–76 have also been described
(25)(26). These immunoluminometric assay methods
are highly sensitive (2–3 pmol/L) (25)(26) and
specific for the intact peptide chain N-terminal
BNP1–76 (25); furthermore, they could
be easily modified for use in a fully automated system (25).
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comparison of clinical relevance of immunoassay methods for cnhs |
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TopAbstractIntroductionmeasurement of anp, bnp,...measurement of cnhs and...anp and bnp methodsassays for the n-terminal...comparison of clinical relevance...the need for a...References |
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Studies comparing the clinical usefulness of different CNH assays in patients with different degrees of heart failure have produced conflicting results. In some studies, the assay for N-terminal proANP1–98 peptides was shown to be equally or even more clinically useful than other CNH assays (27)(28)(29), whereas in others (30)(31)(33)(34)(35)(36) BNP was found to be the best marker of myocardial involvement.
Although these conflicting results could be partly explained by a heterogeneous nature of groups studied, the different specificities of methods used to measure the CNHs could also play an important role. Unfortunately, a comparison of analytical and clinical performances of these assays is difficult because the analytical characteristics of methods used are not always specified in clinical studies.
The ANP assay could be more useful than that of other CNHs in some
pathophysiological conditions. ANP is produced predominantly in atrial
cardiomyocytes and can be promptly released from these cells after an
acute stimulation (atrial stretch and overload) (7).
Furthermore, ANP has a shorter plasma half-life (3–5 min) than BNP
and especially intact N-terminal proANP1–98
(3)(4). For these reasons, ANP should be a good
marker of acute overload and/or rapid cardiovascular hemodynamic
changes. Indeed, circulating concentrations of ANP decrease more after
hemodialysis than those of BNP in patients with chronic renal failure
(3)(4), whereas changes in plasma concentrations
of intact N-terminal proANP1–98 are less
pronounced (Fig. 1
). However, other causes should be also taken into account to
explain the greater variations of ANP and BNP during hemodialysis
compared with intact N-terminal proANP1–98, such
as the lower molecular weight of ANP and BNP than that of intact
N-terminal proANP1–98, allowing a better
crossing through the hemodialysis membrane filter. Furthermore, ANP
increases more than N-terminal proANP1–98 during
rapid ventricular pacing (37).
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The assays of long-acting natriuretic peptide, vessel dilator peptide, and kaliuretic peptide, released simultaneously with ANP, should be also considered to be a marker of atrial stretch and overload.
Less information is available on the clinical relevance of the measurement of N-terminal BNP1–76 compared with other CNH-related peptides (12)(25)(26); however, at present, this assay may have the same clinical indications as the intact N-terminal proANP1–98 assay.
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the need for a new generation of immunoassay methods |
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TopAbstractIntroductionmeasurement of anp, bnp,...measurement of cnhs and...anp and bnp methodsassays for the n-terminal...comparison of clinical relevance...the need for a...References |
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2.5 million patients suffer from heart failure
(38). Several recent studies have underlined the clinical
importance to routinely assay CNHs for classification, follow-up,
and/or in prediction of mortality/survival rates of all patients with
heart failure (1)(2)(3)(4)(5)(27)(28)(29)(30)(31)(32)(33)(34)(35)(36).
This implies that reliable assays for CNHs must be available for all
clinical laboratories; unfortunately, we are far from this goal. As
reviewed previously in detail (4), developing a reliable
assay for CNHs presents nearly insurmountable analytical problems. CNHs
are a complex family of related peptides with both similar peptide
chains and degradation pathways. Moreover, CNHs have greatly differing
plasma concentrations (Table 1
) and half- lives and may also
undergo minor modifications in plasma, such as oxidation. For these
reasons, several peptides may simultaneously interfere in an
immunoassay, giving falsely high values. On the other hand, an assay
that is very specific for a particular peptide may lead to
underestimation, because peptide alteration may occur in the
circulation, during specimen collection, or during storage.
Indeed, several methods for CNH assays have been described, but all
have some problems concerning lack of sensitivity, precision, and/or
accuracy (specificity). Furthermore, these methods, even when measuring
similar or identical peptides, show different clinical results and
reference values (Table 1
) so that each laboratory has to determine its
own reference interval.
CNHs and related peptides are generally measured with competitive immunoassay methods that use radioactive labels (i.e., RIA). The main advantage of RIAs compared with other immunoassays is the lower cost (4). The substitution of a RIA with a commercial noncompetitive immunoassay method may increase the cost for materials from two- to threefold (or more) in a laboratory, which has the opportunity to completely (or partially) set up an RIA without using expensive commercial products (i.e., the possibility of preparing specific antibodies and radioactive tracers directly) (4). However, radioactive tracers are less stable and safe than nonradioactive labels and can only be used in a few clinical laboratories.
Noncompetitive immunometric assays (such as some IRMAs) for CNHs generally have a better degree of sensitivity, precision, and specificity than the respective competitive immunoassays (such as RIA or EIA) (3)(4). Therefore, this second generation of immunoassay methods should be preferred in all laboratories interested in pathophysiological and clinical research on CNHs, requiring a maximum sensitivity, precision, and accuracy. However, these methods are still time-consuming (an assay typically requires from 12 to 36 h) and cannot be used in a fully automated analytical system.
Because at present there is no a general consensus on the best method for CNH assay, at the present time each laboratory must choose the methods and the peptides (hormones) to assay that meet its own clinical requirements as well as to other issues, such as stability (of both analytes and materials), ease of measurement, and costs.
In our opinion, to allow a more widespread propagation of CNH assay in all clinical laboratories and routine clinical practice it is necessary to set up a new generation of noncompetitive immunometric assays that are more sensitive, precise, and easy to perform, do not use radioactive labels, and can be directly used in fully automated analytical systems. Indeed, some recently developed immunoluminometric assay methods for N-terminal proBNP1–76 show some of above-cited analytical characteristics (including their possible use in a fully automated system); therefore, they should be taken as a starting point for the development of a new generation of CNH immunoassays (25)(26). More recently, a rapid, fully automated method for BNP assay, which could be used for point-of-care testing of patients with congestive heart failure, has also been described (39).
Three main problems must be resolved to allow widespread propagation of CNH assay in clinical practice, including their use in emergency and primary care, as suggested by several authors (1)(2)(3)(4)(31):
(a) An increase in analytical sensitivity should be achieved. This improvement should allow the determination of all the normal range of CNHs with an acceptable CV (<15%); this goal is particularly pressing for the BNP assay (4)(19)(20). As demonstrated recently for other hormone immunoassays (for example, for thyroid-stimulating hormone assay), an increase in the analytical sensitivity also produces an increase in functional (clinical) sensitivity (40).
(b) An increase in analytical specificity (accuracy) is also necessary, in particular for the assay of proANP1–98- and proBNP1–76-related peptides and hormones.
(c) An increase in practicability is also necessary. We think that it will not be possible to spread the routine measurement of CNHs in clinical practice, including in emergency and primary care, without a new generation of immunoassay methods that permit the determination of CNHs in a few hours (or even minutes).
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Footnotes |
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References |
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TopAbstractIntroductionmeasurement of anp, bnp,...measurement of cnhs and...anp and bnp methodsassays for the n-terminal...comparison of clinical relevance...the need for a...References |
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