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Articles

Plasma Brain Natriuretic Peptide as an Indicator of Left Ventricular Systolic Function and Long-term Survival After Acute Myocardial Infarction

Comparison With Plasma Atrial Natriuretic Peptide and N-Terminal Proatrial Natriuretic Peptide

Torbjørn Omland, MD; Asbjørn Aakvaag, MD, PhD; Vernon V. S. Bonarjee, MD; Kenneth Caidahl, MD, PhD; Rolv Terje Lie, PhD; Dennis W. T. Nilsen, MD, PhD; Johan A. Sundsfjord, MD, PhD; Kenneth Dickstein, MD, PhD

From the Department of Clinical Biology, Division of Endocrinology, University of Bergen (Norway) Medical School (T.O., A.A.); Cardiology Division, Department of Medicine, Central Hospital in Rogaland, Stavanger, Norway (V.V.S.B., D.W.T.N., K.D.); Department of Clinical Physiology, Sahlgrenska University Hospital, University of Gothenburg, Sweden (K.C.); Section for Medical Statistics and Informatics, University of Bergen, Norway (R.T.L.); and Institute of Medical Biology, University of Tromsø, Norway (J.A.S.).

Correspondence to Torbjørn Omland, MD, Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, 75 Francis St, Boston, MA 02115.

	Abstract

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Background Elevated plasma levels of atrial natriuretic peptide (ANP) and the N-terminal fragment of the ANP prohormone (N-ANP) are associated with decreased left ventricular function and decreased long-term survival after acute myocardial infarction (AMI). Previous data suggest that plasma brain natriuretic peptide (BNP) may increase proportionally more than plasma ANP after AMI and in chronic heart failure. The diagnostic and prognostic value of plasma BNP as an indicator of left ventricular dysfunction and long-term survival after AMI, relative to that of ANP and N-ANP, remain to be established.

Methods and Results Venous blood samples for analysis of ANP, N-ANP, and BNP were obtained on day 3 after symptom onset from 131 patients with documented AMI. Left ventricular ejection fraction was determined by echocardiography in a subsample of 79 patients. Twenty-eight cardiovascular and 3 noncardiovascular deaths occurred during the follow-up period (median, 1293 days). All three peptides proved to be powerful predictors of cardiovascular mortality by univariate Cox proportional hazards regression analyses (ANP: P<.0001; N-ANP: P=.0002; BNP: P<.0001). In a multivariate model, plasma BNP (P=.021) but not ANP (P=.638) or N-ANP (P=.782) provided additional prognostic information beyond left ventricular ejection fraction. Logistic regression analysis showed that ANP (P=.003) and N-ANP (P=.027) but not BNP (P=.14) were significantly associated with a left ventricular ejection fraction 45%.

Conclusions These results suggest that plasma BNP determination provides important, independent prognostic information after AMI. Although plasma ANP appears to be a better predictor of left ventricular dysfunction, plasma BNP may have greater potential to complement standard prognostic indicators used in risk stratification after AMI because of its strong, independent association with long-term survival, enhanced in vitro stability, and simplicity of analysis.

Key Words: prognosis • atrial natriuretic factor • peptides • myocardial infarction • heart failure

	Introduction

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The cardiac natriuretic peptide system is activated after AMI.^{1 2 3 4 5 6} Elevated circulating levels of ANP and N-ANP in the subacute phase have been shown to predict adverse outcome in patients with AMI.^{7 8 9 10 11} The relationship between these natriuretic peptides and survival is believed to be based mainly on their reflection of increased LV filling pressure secondary to LV dysfunction.¹² Recent data suggest that circulating concentrations of the predominantly ventricular-derived BNP may increase proportionally more than circulating ANP concentrations after AMI^{3 4} and in chronic heart failure.^{13 14} However, to the best of our knowledge, no study has previously compared the diagnostic value of BNP, ANP, and N-ANP as indicators of LV dysfunction after AMI. Although some preliminary data indicate that plasma BNP is related to survival,¹⁵ the relative long-term prognostic value of BNP, ANP, and N-ANP in patients with AMI also remains to be established. In this report, we present data from a cohort of 131 patients with documented AMI and a median follow-up time of 1293 days, and we compare the merit of these three members of the cardiac natriuretic peptide family as indicators of LV dysfunction, defined as LV ejection fraction 45%, and long-term survival after AMI.

	Methods

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Study Design and Patient Population
All of the 131 patients included in the present study participated in the randomized, placebo-controlled, double-blind Cooperative New Scandinavian Enalapril Survival Study. This multicenter trial addressed the effect on mortality of enalapril treatment initiated early after symptom debut in patients with AMI. The patients were not selected according to clinical or objective signs of LV dysfunction, and the trial encompassed subjects with LV function that ranged from normal to severely depressed. The CONSENSUS II trial inclusion and exclusion criteria, as well as the results of the main study, have been described in detail previously.¹⁶

Patients included in the present substudy all were recruited from a single center, the Central Hospital in Rogaland, Stavanger, Norway, during the period from September 1990 to March 1991. Venous blood samples for neurohormonal measurements were obtained on day 3 after the onset of symptoms. Only patients with documented AMI were included in the present substudy, ie, patients included in CONSENSUS II without evidence of myocardial necrosis were excluded from the analysis. In a subsample of patients, echocardiographic examinations that permitted quantification of LV end-systolic and end-diastolic volumes were performed between day 2 and day 5. Demographic and clinical characteristics of the complete patient sample and of the subgroup with echocardiographic recordings are listed in Table 1.

View this table: [in this window] [in a new window]   Table 1. Characteristics of the Complete Patient Sample and the Subgroup With Echocardiographic Recordings

Clinical examinations were performed regularly during hospitalization, and the highest Killip class¹⁷ was registered. Patients in a Killip class II were categorized in the heart failure group and those in Killip class I were classified in the non–heart failure group. During the period from June 1994 to August 1994, all surviving patients were interviewed. Deaths were classified as cardiovascular or noncardiovascular according to the diagnosis stated on the patient's death certificate. The date of death was registered and duration of follow-up calculated.

Blood Sampling Procedures and Hormonal Assays
Blood samples were drawn by venipuncture after at least 30 minutes' supine rest, immediately placed on ice, and centrifuged within 30 minutes. Plasma was aspirated and transferred into plastic test tubes that were stored at -70°C until analysis. Samples of plasma from each patient were distributed into four separate, parallel test tubes to permit analysis of various neurohormones at different times without repeated thawing and refreezing. Determination of plasma ANP and N-ANP concentrations was performed during and shortly after the termination of the CONSENSUS II study according to a prespecified protocol. Determination of plasma BNP levels was performed with use of plasma that had previously been thawed and refrozen once.

As described previously,¹⁸ plasma ANP was measured by radioimmunoassay after extraction on a C18 octadecyl silica microcolumn with kits from Amersham International. Plasma N-ANP levels were determined by direct radioimmunoassay without prior extraction of peptide.¹⁹ Performance characteristics of these methods in our laboratory have been described previously.^{18 19} Plasma BNP concentrations were determined by use of a specific immunoradiometric assay (Shionoria BNP kit) manufactured by Shionogi & Co, Ltd.²⁰ The assay uses two monoclonal antibodies, which recognize the carboxyterminal sequence and the ring structure of human BNP, respectively.²¹ In accordance with the recommendations of the manufacturer, unextracted plasma was used in the analysis. The sensitivity of the assay (minimal detectable quantity) was found to be 0.8 pmol/L. The within-assay coefficient of variation was 5.6% in the concentration range 0.9 to 14.4 pmol/L, 5.3% in the concentration range 14.5 to 28.8 pmol/L, and 5.3% in the concentration range >28.9 pmol/L. Correlation with samples measured by a conventional radioimmunoassay after prior extraction²² was close (r=.91). According to the manufacturer, the cross-reactivity with ANP is <0.001%.

Echocardiographic Examination
Echocardiography was performed with a Vingmed CFM 750 (Vingmed Sound, Horten, Norway) machine between day 2 and day 5 (median, day 3) after AMI in a subsample of 79 patients in accordance with the recommendations of the American Society of Echocardiography.²³ Two-dimensional apical two- and four-chamber views were used for volume measurements, from which the ejection fraction was derived. The detailed methodology and the variation of measurements have been reported previously.²⁴

Statistical Analysis
Because of a skewed distribution of data, hormone plasma levels were logarithmically transformed for statistical analysis. However, data are presented as nontransformed mean±SEM. The ability of the variables to predict the presence of LV dysfunction, defined as LV ejection fraction 45%, was assessed by logistic regression analysis. The prognostic value of the variables was tested in a Cox proportional hazards regression analysis.²⁵ Patients who were dying of a noncardiovascular cause were censored at the time of death. Kaplan-Meier estimates of the survival functions were plotted for patients with high and low plasma BNP, with the 75th percentile value used as the cut-off point.²⁶ Comparison between groups was based on the log-rank test. Linear regression analysis was used to assess the relation between continuous variables.

	Results

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No patient was lost to follow-up. During follow-up, 28 patients (21.4%) died of a cardiovascular cause, whereas 3 patients (2.3%) died of a noncardiovascular cause. During the primary hospitalization, 38 patients (29%) demonstrated clinical signs of heart failure. The majority of these patients (n=30) were classified as Killip class II; the remaining patients were classified as Killip class III (n=5) or IV (n=3). Systolic LV function varied considerably in the patient sample. In the subsample of patients for whom echocardiographic recordings were available, LV ejection fraction averaged 47.3±1.2% (range, 14.5% to 71.0%). Twenty-seven patients (34%) had LV ejection fraction 45%. Serum creatinine on admission to hospital averaged 92.0±2.5 µmol/L, whereas peak creatine kinase–MB levels averaged 148.5±11.3 IU/L. Plasma ANP on day 3 after symptom onset averaged 36.7±2.3 pmol/L, plasma N-ANP 1617±135 pmol/L, and plasma BNP 33.1±3.8 pmol/L. There were no significant between-group differences in plasma ANP, N-ANP, or BNP concentrations when patients were subdivided according to treatment with enalapril or placebo.

Plasma levels of ANP and N-ANP correlated closely (r=.80; P<.001), whereas the correlations between circulating BNP and ANP (r=.51; P<.001) and BNP and N-ANP (r=.61; P<.001) were less strong. All three peptides correlated significantly with patient age and with serum creatinine levels at the time of admission (Table 2). These relationships were most pronounced for N-ANP and least pronounced for BNP. None of the peptides correlated significantly with peak creatine kinase–MB fraction values.

View this table: [in this window] [in a new window]   Table 2. Correlation Between Cardiac Natriuretic Peptides, Renal Function, and Patient Age

All three peptides were significantly elevated in patients with signs of clinical heart failure during the primary hospitalization (ANP: 55.3±5.6 versus 29.1±1.7 pmol/L, P<.001; N-ANP: 2638±406 versus 1199±53 pmol/L, P=.001; BNP: 62.2±10.7 versus 21.2±1.9 pmol/L, P=.001). Plasma ANP and N-ANP but not BNP levels were also significantly increased in patients with LV ejection fraction 45% (ANP: 46.6±5.2 versus 29.5±2.8 pmol/L, P=.002; N-ANP: 1764±227 versus 1327±154 pmol/L, P=.022; BNP: 38.0±8.2 versus 21.5±3.3 pmol/L, P=.17). LV ejection fraction and plasma concentrations of ANP (r=-.48; P<.001), N-ANP (r=-.40; P<.001), and BNP (r=-.31; P=.006) correlated inversely. When the dichotomous variable LV dysfunction (defined as LV ejection fraction 45%) versus no LV dysfunction was used as the dependent variable, univariate logistic regression analyses showed that ANP (P=.003) and N-ANP (P=.027) but not BNP (P=.14) were significantly associated with LV dysfunction.

The Kaplan-Meier survival curves for patients subdivided into two groups according to the 75th percentile concentration of BNP in plasma are depicted in the Figure. Univariate Cox proportional hazards regression analyses showed that BNP, ANP, and N-ANP were all significant predictors of long-term prognosis, both in the complete sample and in the subsample that encompassed patients with echocardiographic recordings (Table 3). By multivariate analysis of the complete sample of patients (LV ejection fraction not considered as a covariate), only plasma BNP (P=.0006) provided additional prognostic information beyond in-hospital clinical heart failure (Table 3). Furthermore, in the subsample with echocardiographic recordings, plasma BNP was the only variable that significantly provided additional prognostic information (P=.021) beyond LV ejection fraction (Table 3). In other words, adding BNP to LV ejection fraction increased the total predictive value of the multivariate model. These results were consistent regardless of the use of forward or backward stepwise procedures in the Cox proportional hazards regression analyses.

View larger version (14K): [in this window] [in a new window]   Figure 1. Kaplan-Meier survival curves for patients with AMI subdivided into two groups according to the 75th percentile concentration of BNP in plasma (33.3 pmol/L).

View this table: [in this window] [in a new window]   Table 3. Cox Regression Analyses of Association Between Background Variables and Survival Time

Comparison with the cohort of 6090 patients included in the CONSENSUS II trial shows that the current subsamples of patients had a slightly higher mean age (neurohormonal subsample versus echocardiographic subsample versus main trial: 68, 67, and 66 years old, respectively), a slightly higher proportion of male patients (75%, 73%, and 73%), and a somewhat lower proportion of Q-wave infarctions (51%, 58%, and 59%) but a higher proportion of anterior wall infarctions (51%, 52%, and 47%). By day 180 (the end of the main trial), 11.5% of the patients in the current sample and 10.6% of the patients in the main trial had died.¹⁶

	Discussion

Top Abstract Introduction Methods Results Discussion References

 
The present study demonstrates that circulating BNP in the subacute phase of AMI is a powerful, independent predictor of adverse outcome. Although plasma ANP and N-ANP also are predictive of mortality, neither seems to provide prognostic information beyond LV ejection fraction. Comparison of their relative prognostic merit in univariate and multivariate Cox proportional hazards regression models indicates that plasma BNP determination may be the single most powerful prognostic indicator of these three natriuretic peptides. The results of the linear regression analysis and the logistic regression analysis suggest that plasma ANP and N-ANP are better predictors of LV dysfunction than plasma BNP. Therefore, plasma BNP may be less suitable as an indicator of depressed LV ejection fraction after AMI than ANP and N-ANP. This apparent dissociation between diagnostic and prognostic accuracy challenges the concept that the prognostic value of the natriuretic peptides is based merely on their ability to reflect global LV systolic function.

Diagnostic Value of Natriuretic Peptides
The plasma concentration of BNP in healthy individuals has been reported to be lower than that of ANP.^{13 27} Conversely, after AMI and in chronic heart failure, the plasma BNP/ANP ratio is reversed, which suggests that BNP may be more closely related to LV dysfunction than ANP. Although one small study,²⁷ which encompassed 16 patients, reported closer correlation between LV ejection fraction and BNP than between LV ejection fraction and ANP after AMI, most studies have found comparable correlations between ANP, BNP, and hemodynamic indexes, both after AMI⁴ and in patients with chronic heart disease.^{21 28 29 30} In the present study, we found a somewhat weaker relationship between LV ejection fraction and plasma BNP than between LV ejection fraction and plasma ANP (and plasma N-ANP).

Early treatment with ACE inhibitors in patients with clinical evidence of heart failure³¹ or decreased LV ejection fraction³² after AMI is associated with pronounced reduction in long-term mortality and morbidity, whereas the effect in more unselected patient groups is modest or nonexistent.^{16 33 34} These findings have resulted in increasing interest in simple and inexpensive methods to identify asymptomatic patients who may benefit from such therapy.^{35 36} In an earlier study of 58 patients with AMI,³⁷ the diagnostic accuracy of plasma BNP was found to be superior to that of plasma ANP in the identification of patients with LV dysfunction. This observation is somewhat in contrast with the present finding of a weak relationship between circulating BNP and LV ejection fraction, which suggests a limit to the usefulness of plasma BNP determination in the early identification of patients with reduced LV ejection fraction after AMI. Larger studies in an unselected patient population with AMI are required to clarify the role of cardiac natriuretic peptide determination in the diagnosis of LV dysfunction.

Long-term Prognostic Value of Natriuretic Peptides
LV systolic function is a major prognostic indicator after AMI.^{38 39} Recently, the association between elevated plasma levels of atrial-derived natriuretic peptides and reduced long-term survival after AMI has been demonstrated convincingly.^{9 10 11} The present results partly confirm and partly challenge as well as extend our understanding regarding the prognostic value of circulating cardiac natriuretic peptides after AMI. In contrast to the present results, the neurohormonal substudy of the SAVE trial reported that N-ANP provides superior prognostic information to ANP.⁹ This finding was interpreted as being due to the prolonged plasma half-life of N-ANP, which makes it a better integrator of atrial peptide secretion than ANP. In contrast to the SAVE results, the present data suggest that the predictive ability of ANP is slightly better than that of N-ANP, although the difference is not very marked. The discrepancy between the SAVE results and the present data may be due to a weak relationship between N-ANP and survival in the present data set, or conversely, to a relatively weak association between ANP and survival in the SAVE neurohormonal substudy. Taking into account the large sample size of the neurohormonal substudy of the SAVE trial, the prognostic power of ANP may seem surprisingly small in comparison with results obtained in other studies.^{11 40 41} When treated as a continuous variable in a multivariate model, ANP failed to be a significant, independent predictor of cardiovascular mortality in the SAVE substudy.¹⁰ Pertinent to this issue, direct comparison of the relationship between plasma peptide concentrations and invasive indexes previously has shown comparable correlations to atrial pressures for ANP and N-ANP.⁴²

The present data suggest that plasma BNP but not ANP or N-ANP provides prognostic information in addition to that provided by LV ejection fraction. This finding also diverges somewhat from the results of the SAVE study, in which N-ANP was found to supply significant prognostic information independently of LV ejection fraction.⁹ This discrepancy may be due to differences in patient selection and sample size. However, the SAVE analysis may have underestimated the prognostic power of LV ejection fraction because only patients within a rather narrow range of LV ejection fraction values were included, whereas the present study includes patients with a wide range of LV systolic function.

Why Is BNP a Stronger Prognostic Indicator Than ANP and N-ANP?
Various mechanisms may contribute to the different prognostic merits of circulating ANP, N-ANP, and BNP after AMI. First, the site of synthesis and release may differ for ANP and BNP. Northern blot hybridization analysis and selective catheterization studies both suggest that circulating BNP is derived predominantly from ventricular tissue and that ANP is derived predominantly from atrial tissue in subjects without cardiac disease.^{13 21 43} In patients with LV dysfunction, circulating ANP probably is derived from ventricular tissue as well.^{13 21 43} Interestingly, recent data suggest that the secretion of BNP but not ANP is significantly greater from the infarcted region than from the noninfarcted region of the left ventricle.⁴⁴ Consequently, in contrast to ANP (and N-ANP), plasma BNP secretion may more accurately reflect regional wall stress in the infarcted region of the ventricle. Increased regional wall stress is believed to be associated with adverse ventricular remodeling and a poor prognosis after AMI.⁴⁵ A potential association between plasma BNP levels and LV remodeling thus may contribute to the independent prognostic value of plasma BNP.

Second, differences in synthesis and secretion patterns potentially may influence the relative predictive value of the natriuretic peptides. Although both ANP and BNP appear to be released in response to pressure and volume overload, recent studies⁴⁶ have shown that atrial stretch induces a rapid increase in gene expression of BNP but not ANP. Whereas acute regulation of BNP synthesis seems to occur at the level of gene expression, regulation of ANP release may instead occur at the level of hormone secretion. The clinical relevance of these observations remains unresolved.

Third, differences in the metabolic clearance of the natriuretic peptides theoretically may also affect their predictive value after AMI. The pathways of metabolic clearance of ANP have been studied extensively,^{47 48 49} whereas the clearance mechanisms of BNP and N-ANP are less well characterized.^{14 50 51} Both neutral endopeptidase– and clearance receptor–mediated metabolism of ANP have been demonstrated.^{47 48 49} Total metabolic clearance rates of ANP are unaltered in experimental heart failure, which suggests that decreased clearance does not contribute to increased ANP levels in heart failure.⁴⁹ For BNP, neutral endopeptidase–mediated degradation appears to be the predominant metabolic pathway.^{14 50} The in vitro binding capacity of clearance receptors is much lower for BNP than for ANP.¹⁴ This observation may account for the considerably shorter in vivo plasma half-life of ANP (slow component, 13.3 minutes) than of BNP (20.7 minutes).¹⁴ The in vivo plasma half-life of N-ANP has been estimated to be even longer (54.8 minutes), with the mechanism of clearance believed to be renal elimination.⁵¹

The impact of differences in metabolic clearance on the relative prognostic value of the natriuretic peptides is difficult to assess. However, as demonstrated by the present data, the correlation between plasma concentrations of the natriuretic peptides and serum creatinine was stronger for N-ANP than for ANP and BNP. As renal function failed to predict prognosis in this patient sample, it is possible that the minor influence of renal function on circulating concentrations of BNP may have contributed to the stronger relationship between BNP and prognosis. In contrast, plasma N-ANP seems to be significantly affected by variations in renal function, which possibly reduces its prognostic value.

Limitations
In the present study, blood samples were obtained at a single standardized time point, ie, in the morning on the third day of hospitalization. Because of the differences in release and metabolic clearance patterns of the natriuretic peptides, the timing of blood sampling is a crucial issue that may have affected the results of the study. Whether the relative prognostic value of the natriuretic peptides would have differed from the present results had another day of blood collection been selected remains speculative. Until larger studies have been conducted that compare the prognostic value of the natriuretic peptides in blood samples collected at multiple time points in the acute and subacute phase, our data should not be extrapolated to other time points of blood collection. However, the choice of day 3 was based on the following rationale. First, we wanted to choose a time point, based on available data in the literature, that would provide optimal reproducibility. In agreement with the observed differences in synthesis, secretion, and metabolic clearance of the natriuretic peptides, previous studies have shown that their plasma concentration profiles differ in the acute phase. A peak in plasma ANP levels occurs at the time of admission to the hospital.¹ In contrast, a peak in plasma BNP concentrations has been reported to occur 16 hours after admission.⁴ Despite these differences during the first 24 hours after symptom onset, plasma concentration patterns appear to be comparable from day 2. For both ANP and BNP, the early decline is followed by a second increase on day 2 or day 3, with peak levels occurring on day 3 or day 4.^{1 4} The magnitude and duration of the second peak is augmented in patients with LV dysfunction and clinical heart failure.^{1 4} Except for a less pronounced early decrease, the pattern for N-ANP is similar.^{6 52} By day 3, concentrations of all three peptides seem to be in a relatively steady state, and we believe that day 3 plasma levels are not likely to differ markedly from those of days 4 or 5. Second, we wanted to choose a time point that would distinguish between patients with and without LV dysfunction. Whereas the rapid fluctuations in peptide levels during the first 24 hours were likely to obscure any relationship to LV function, persistently increased circulating natriuretic peptide levels on day 3 are believed to reflect LV dysfunction.^{1 4} Third, from a practical point of view, we wanted to perform the blood sampling when patients were still in our coronary care unit or in the adjacent subacute cardiology ward. From day 4 after AMI, a substantial proportion of patients in our hospital are transferred to other wards, which increases the probability of failure to obtain complete neurohormonal and echocardiographic data.

An important issue is to what extent the current sample reflects the patients included in the CONSENSUS II trial and the general population of patients with AMI. More than 60% of eligible patients were included in the CONSENSUS II trial,¹⁶ and an even higher inclusion rate was obtained at our center, the single largest center that participated in the main trial. The demographic and clinical characteristics of patients were comparable for patients in the main study and in the present subsample. Moreover, except for the exclusion of hypotensive patients, a group that encompassed a number of patients with large Q-wave infarctions, we believe that the present study subjects in the whole are representative of the general AMI population in Scandinavia.

The number of patients with echocardiographic registrations was relatively modest. Due to the substantial prognostic power of plasma BNP and LV ejection fraction, these variables proved to be significant and independent predictors of mortality by multivariate analysis. However, we cannot rule out that other variables of the ones examined would have provided additional prognostic information in a larger patient sample.

The BNP samples previously had undergone a single thawing/refreezing cycle. It is possible, albeit not probable, that this influenced the results of the present analysis. Recent data have shown impressive in vitro stability of BNP, even at room temperature.⁵³ It seems unlikely, therefore, that thawing of plasma to 0°C for a brief period would result in significant degradation of this peptide. Of note, the SAVE study N-ANP data were based on samples that had undergone a similar thawing/refreezing procedure.⁹

Clinical Implications and Conclusions
The clinical implications of the demonstration of statistically significant associations between a laboratory test and prognosis depend not only on the strength of the association but also on practical aspects of the assay, such as the stability of the substance to be measured and the applicability and versatility of the biochemical analysis in question. Thus, the in vitro instability and the rather time-consuming and cumbersome radioimmunoassay commonly used to measure plasma ANP concentrations may limit its applicability in clinical practice. Recent data demonstrate impressive in vitro stability of both N-ANP and BNP.^{53 54} Furthermore, an immunoradiometric assay, which permits analysis of unextracted plasma and reduces the duration of the analytic procedure to less than 24 hours, has been developed recently.^{20 21} The strong, independent association with survival, minor influence of confounding factors, in vitro stability, and simplicity of the analysis all make plasma BNP measurement an attractive candidate to complement already-established prognostic indicators used in risk stratification after AMI. The relatively poor relation to LV systolic function suggests, however, that its potential as a marker of LV dysfunction in the early phase after AMI is limited.

	Selected Abbreviations and Acronyms

 

AMI = acute myocardial infarction ANP = atrial natriuretic peptide BNP = brain natriuretic peptide CONSENSUS II = Cooperative New Scandinavian Enalapril Survival Study LV = left ventricular N-ANP = the N-terminal fragment of the atrial natriuretic peptide prohormone SAVE = Survival and Ventricular Enlargement trial

	Acknowledgments

 
This study was supported in part by grants from the University of Bergen, the Central Hospital in Rogaland, and Merck Research Laboratories (Norwegian subsidiary), Drammen, Norway.

Received October 30, 1995; revision received December 18, 1995; accepted December 21, 1995.

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