Risk assessment in patients with unstable angina/non-ST-elevation myocardial infarction and normal N-terminal pro-brain natriuretic peptide levels by N-terminal pro-atrial natriuretic peptide

Rudolf Jarai1,2, Nelly Iordanova1, Robert Jarai3, Annamaria Raffetseder4, Wolfgang Woloszczuk4, Mariann Gyöngyösi2, Georg Geyer4, Johann Wojta2 and Kurt Huber1,2,*

1Third Department of Medicine (Cardiology and Emergency Medicine), Wilhelminen Hospital Vienna, Montleartstrasse 37, A-1171 Vienna, Austria
2Department of Cardiology, University of Vienna, Vienna, Austria
3Department of Psychology, University of Pecs, Pecs, Hungary
4Ludwig-Boltzmann Institute of Experimental Endocrinology, Vienna, Austria

Received 21 November 2003; revised 15 September 2004; accepted 5 October 2004; online publish-ahead-of-print 20 December 2004.

* Corresponding author. Tel: +43 1 49150 2301; fax: +43 1 49150 2309. E-mail address: kurt.huber{at}univie.ac.at


    Abstract
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 Conclusions
 Acknowledgements
 References
 
Aims To compare the accuracy of the N-terminal fragment of its pro-hormone (Nt-proBNP) and N-terminal pro-atrial natriuretic peptide (Nt-proANP) in the prediction of the 2 year mortality and to investigate whether additional measurement of Nt-proANP to troponin I (TnI) could improve risk assessment in the subgroups of patients with unstable coronary artery disease (UCAD) and normal Nt-proBNP.

Methods and results Plasma levels of the TnI, Nt-proANP, and Nt-proBNP were determined in 120 consecutive patients with UCAD without ST-segment elevations and normal left ventricular function. In multivariable logistic regression analysis, TnI and Nt-proBNP were independent predictors of mortality (P=0.01 and P=0.02, respectively). However, in the group of patients with normal Nt-proBNP levels, only Nt-proANP and TnI were independently associated with mortality (P=0.007 and P=0.03, respectively). Accordingly, patients with elevated Nt-proANP levels in this group of patients had significantly higher mortality rate than patients with normal Nt-proANP levels (P=0.003).

Conclusion Our results suggest that determination of Nt-proANP might improve risk assessment in patients with UCAD, especially when Nt-proBNP is in the normal range.

Key Words: Atrial natriuretic peptide • Brain natriuretic peptide • Troponin I • Acute coronary syndromes • Risk prediction


    Introduction
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 Conclusions
 Acknowledgements
 References
 
Elevation of plasma levels of brain natriuretic peptide (BNP) and the N-terminal fragment of its pro-hormone (Nt-proBNP) is associated with increased mortality in patients with congestive heart failure, left ventricular systolic dysfunction, after acute myocardial infarction (AMI),18 and in patients with unstable coronary artery disease (UCAD).9 Nt-proBNP exhibits an exponential relationship with mortality in UCAD. Accordingly, highest mortality rate has been observed in the small group of patients within the highest Nt-proBNP quartile. In contrast, lower Nt-proBNP levels possess limited prognostic value. Positive troponin I or T (TnI; TnT) levels in patients with UCAD have been shown to be strong predictors of mortality irrespective of Nt-proBNP levels.10,11 The combination of both BNP/Nt-proBNP and TnI significantly improved risk assessment in patients with UCAD.1012

Plasma levels of atrial natriuretic peptide (ANP) and N-terminal pro-atrial natriuretic peptide (Nt-proANP) levels are also elevated in congestive heart failure and after AMI.1316 Recently, it has also been shown that Nt-proANP is a strong predictor of mortality in patients with UCAD independent of TnT and other risk factors of coronary artery disease.17 ANP and BNP exhibit similar hormonal effects,18 and the secretion of both peptides is stimulated by myocardial stretch and ischaemia.1921 However at the level of gene expression, ANP and BNP are regulated differentially.19,2224 Accordingly, elevations of Nt-proANP and Nt-proBNP in UCAD might reflect distinct pathological processes in accordance with myocardial ischaemia. Therefore, simultaneous determination of these peptides might improve the risk assessment of patients with UCAD.

The aim of the present study was to compare the accuracy of Nt-proBNP and Nt-proANP in the prediction of the 2-year mortality and to investigate whether additional measurement of Nt-proANP to TnI could improve risk assessment in the subgroup of patients with UCAD and normal Nt-proBNP.


    Patients and methods
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 Conclusions
 Acknowledgements
 References
 
Patients
One hundred and fifty-two consecutive patients, who were admitted to our chest pain unit with normal left ventricular function as determined by echocardiography at presentation (ejection fraction ≥52%), were included in the study. We included men and women older than 20 years with typical angina within the last 24 h with signs of myocardial ischaemia in the 12 lead ECG: patients with either ST-depression of 0.1 mV in two continuous leads, T-wave inversion or both with concomitantly elevated TnI (≥0.15 ng/mL) levels were diagnosed as non-ST-elevation myocardial infarction (NSTEMI), whereas patients without TnI elevations were diagnosed as unstable angina (UA). Exclusion criteria were signs of acute ST-elevation myocardial infarction, reduced global ventricular function or signs of heart failure at admission, pacemaker ECGs, suspected myocarditis or pericarditis, as well as disorders known to influence plasma Nt-proBNP and Nt-proANP levels (e.g. renal and hepatic disorders).

The endpoint of the study was cardiovascular death within 2 years. Follow-up information of the patients was collected at 24 months after inclusion in the study.

Blood sampling and analyses
Venous blood samples were obtained immediately at presentation of the patients at the chest pain unit. In case of normal troponin levels on admission, a second blood sample was obtained after 4–6 h. Cardiac TnI levels were analysed by use of the OPUS plus Immunoassay System (Behrings Diagnostic Inc., Vienna, Austria) and accepted as pathological if the first or the second determination exhibited a concentration of ≥0.15 ng/mL.

Cardiac natriuretic peptides were measured in plasma samples by immunoassays (Biomedica, Vienna, Austria). Nt-proANP was measured by a non-competitive sandwich-type immunoassay with a detection limit of 50 pmol/L and normal plasma level lower than 1.9 nmol/L. Nt-proBNP 8–29 was measured by a competitive enzyme immunoassay using a sheep antibody specific for proBNP 8–29 and the synthetic peptide as a standard. Detection limit of this assay is 5 pmol/L.

Statistics
The Mann–Whitney U test was performed to compare plasma levels of Nt-proBNP, Nt-proANP, and TnI between patients with or without clinical events during the follow-up period. Spearman rank correlation was performed to detect linear correlation between the respective biomarkers. The predictive capacity of TnI, Nt-proBNP, and Nt-proANP was assessed by receiver-operating characteristic (ROC) curves, and the comparison of the predictive values of these markers was achieved by pair-wise comparison of the area under the ROC-curves according to Hanley and McNeil.38 Stepwise multivariable logistic regression analysis with backward selection method was used to estimate possible associations between Nt-proBNP, Nt-proANP, and TnI levels and mortality after 2 years. The logistic model included age, diabetes mellitus, hypertension, hypercholesterolaemia, previous myocardial infarction, smoking, familial history of coronary artery disease, and creatinine kinase MB levels. Using Box–Tidwell transformation, we proved the linear relationship between the logit of the endpoint and the explanatory variables. Variables with significance levels of P>0.1 were excluded from the multivariable model. Prognostic significance of TnI, Nt-proBNP, and Nt-proANP were tested as continuous as well as dichotomized variables in two independent logistic regression models. For cut-off values we used the upper limit of normal range for all three markers: 0.33 nmol/L for Nt-proBNP, 1.94 nmol/L for Nt-proANP (according to the product instruction manual of Nt-proANP and Nt-proBNP) and 0.15 ng/mL for TnI. To test whether the logistic regression models provide reliable data at a sample size of 120 patients, we performed power analysis according to Tosteson et al.25 The analyses showed that each of the models exhibited a power of >80%. According to statistical guidelines,26 these results confirmed the reliability of our tests. In the group of patients with normal Nt-proBNP, mortality rates of patients with or without elevated Nt-proANP levels were compared using the {chi}2 test. All significance tests were two-sided and statistical significance was considered present if P<0.05. To avoid inflation of type I error by multiple testing, Bonferroni adjustments were performed. All statistical analyses were assessed using the Software Package for Social Sciences for Windows (SPSS for Windows, SPSS Inc., IL, USA).


    Results
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 Conclusions
 Acknowledgements
 References
 
One hundred and twenty patients had echocardiography, TnI, Nt-proBNP, and Nt-proANP values available at admission and 2-year outcome. The baseline characteristics of our study population, including left ventricular ejection fraction at admission, are depicted in Table 1. Patients who died during the follow-up were significantly older, hypercholesterolaemic, and showed significantly higher TnI, Nt-proANP, and Nt-proBNP levels, respectively. Thirty-six percent of the patients had NSTEMI and 64% had UA. Fifty percent of patients had elevated Nt-proANP levels and 24% of the patients had elevated Nt-proBNP levels at admission.


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Table 1 Patient demographics
 
Bivariate correlations
In the whole study population, Nt-proANP and Nt-proBNP levels correlated significantly (r=0.63; P<0.0001). The correlation was very strong in the group of patients with elevated Nt-proBNP (r=0.74; P<0.0001) but weak and not significant below this cut-off point (r=0.16; P=0.06). TnI concentrations showed no significant correlation with Nt-proANP or Nt-proBNP levels (r=0.03; P=0.679 and r=0.10; P=0.246), respectively.

ROC-analysis
ROC-curves of TnI, Nt-proBNP, and Nt-proANP and the respective area under the ROC-curves for discriminating patients who died, from those who survived the study period are depicted in Figure 1. The areas under the ROC-curves indicated good predictive performance of all markers. There were no significant differences among the area under the ROC-curves. ROC analysis in the group of patients with low Nt-proBNP levels (>0.33 nmol/L) revealed that whereas TnI and Nt-proANP had significant predictive values in detecting patients who died during the follow-up period, Nt-proBNP possessed no predictive capacity (Figure 2).



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Figure 1 ROC-curves of TnI, Nt-proBNP, and Nt-proANP for predicting mortality after 2 years. SE, standard error; Asympt.Sig., asymptotic significance.

 


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Figure 2 ROC-curves of TnI, Nt-proBNP, and Nt-proANP for predicting mortality after 2 years in the group of patients with normal Nt-proBNP levels. SE, standard error; Asymp.Sig., asymptotic significance.

 
Stepwise multivariable logistic regression analysis
Logistic regression analysis, adjusted for age, diabetes mellitus, hypertension, hypercholesterolaemia, previous myocardial infarction, smoking, familial history of coronary artery disease, and creatinine kinase MB levels, revealed an independent association of TnI and Nt-proBNP levels with 2 years mortality and no independent prognostic significance of Nt-proANP levels (Table 1). Similar results were obtained after dichotomization of TnI, Nt-proBNP, and Nt-proANP levels (data not shown).

In the group of patients with normal Nt-proBNP levels, however, only TnI and Nt-proANP levels were significantly associated with mortality, whereas Nt-proBNP provided no significant prognostic information (Table 2) beyond that of TnI or Nt-proANP.


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Table 2 Multivariate logistic regression analysis
 
Accordingly, elevated levels of Nt-proANP, in the presence of Nt-proBNP levels within the normal range, were associated with a significantly higher mortality rate compared with patients with normal Nt-proANP and Nt-proBNP levels (Figure 3).



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Figure 3 Mortality rate according to Nt-proANP levels in the group of patients with normal Nt-proBNP.

 

    Discussion
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 Conclusions
 Acknowledgements
 References
 
To our knowledge, this is the first prospective study investigating the prognostic significance of Nt-proANP in addition to Nt-proBNP in patients with UCAD with preserved left ventricular function. Our results suggest that Nt-proBNP levels are the strongest predictor for 2-year mortality in these patients and that the measurement of Nt-proANP might provide additional important prognostic information beyond that of TnI when Nt-proBNP levels are within the normal range.

Our results are in accordance with results of recent reports, which confirm the long-term prognostic significance of the B-type natriuretic peptide family in UCAD.3,27,28 From these studies it also became clear that this strong prognostic significance is independent of other known risk factors for coronary artery disease in patients with or without clinical signs of heart failure or left ventricular dysfunction, as well as in patients with different index diagnoses (STEMI, NSTEMI, UA).28 Simultaneous determination of BNP and other coronary risk factors, like C-reactive protein and troponins, has been shown to significantly improve risk assessment of patients with UCAD.12 Furthermore, we could show that a risk score, which includes clinical as well as biochemical variables, extended by Nt-proBNP levels performs significantly better in predicting outcome after an acute ischaemic event.29

The prognostic significance of the ANP family in UCAD has been less extensively investigated in the past although studies have shown that elevated ANP and/or Nt-proANP levels have strong prognostic significance in patients with UCAD independent of age, diabetes mellitus, history of AMI, ST-changes, congestive heart failure, troponin I or T, creatinine, and treatment assignment,9,17 respectively. It is also known that ANP/Nt-proANP secretion is induced by myocardial ischaemia and hypoxia. However, it could also be shown that when both ANP and BNP were included in the multivariable regression analysis, only BNP/Nt-proBNP remains an independent predictor of outcome after AMI.7 In accordance with these results, Nt-proANP had no independent relationship with mortality when Nt-proBNP was included in the multivariable analysis of our study.

On the other hand, the strong predictive power of Nt-proBNP was apparent only among patients with highest Nt-proBNP levels; lower values of Nt-proBNP had no prognostic significance. These results are in agreement with recently published data showing that BNP and/or Nt-proBNP elevations are exponentially associated with mortality, exhibiting highest rate of death among the highest BNP and/or Nt-proBNP levels.10,11 Moreover, similar to our results, it could be shown that mortality increases significantly only above the 80th percentile of the BNP levels.10

Interestingly, in the group of patients with normal Nt-proBNP levels, Nt-proANP had important prognostic significance independent of TnI levels and might therefore help to improve risk stratification of these patients.

The different relationships of Nt-proANP and Nt-proBNP to long-term mortality, seen in the present study, might be explained by the fact that despite similar receptor affinity and hormonal effects, the functional roles of these peptides are substantially different in physiological as well as pathophysiological conditions.3032 Moreover, we found no significant correlation between Nt-proANP and Nt-proBNP when the levels of the latter were within the normal range, which suggests, and is in agreement with other studies, that the secretion of these peptides is regulated differentially by myocardial ischaemia.24,3337

Unfortunately, based on our study, we cannot explain why patients with elevated natriuretic peptide levels have quite a high incidence of death in the subsequent 2 years, despite well preserved ventricular function and reperfusion therapy. However, our findings are in agreement with results of clinical trials and studies with a larger sample size. In the global utilization of strategies to open occluded arteries IV (GUSTO IV) trial, more than 50% of all deaths occurred above the 80th Nt-proBNP percentile. The fast assessment in thoracic pain (FAST) study revealed an almost 70% mortality rate of patients with NSTEMI and 40% mortality rate among those with UA with Nt-proBNP levels above the 75th percentile. In our study, 60% of patients died with Nt-proBNP levels above the 75th percentile. In the fragmin and fast revascularization during instability in coronary artery disease (FRISC II) trial, association of Nt-proBNP elevations to mortality was not influenced by the presence or absence of reduced left ventricular function and Nt-proBNP was a strong predictor of outcome in the group of patients undergoing revascularization within 7 days after the index event as well as among those patients randomized to conservative management.

According to the results of the present study and recent investigations, it could be assumed that a risk score, consisting of clinical variables such as age, sex, risk factors and ECG-changes as well as biochemical markers of myocardial necrosis and ischaemia, inflammatory processes, renal, and ventricular function, would optimize estimation of patients' risk and our management of UCAD as well.

The main limitation of this report is the relatively small number of patients included. According to the power analysis of our logistic regression model and to the fact that distribution of Nt-proANP and Nt-proBNP levels and their associations with long-term mortality are similar to studies with larger sample size, we believe, that our results might provide important additional information.


    Conclusions
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 Conclusions
 Acknowledgements
 References
 
In conclusion, the present study suggests that elevated plasma levels of Nt-proANP and Nt-proBNP are related to different pathological processes, which might influence the clinical outcome at different clinical stages of acute coronary syndromes. For a better accuracy of risk prediction in patients with UCAD, determination of Nt-proANP seems to be of special interest when Nt-proBNP is within the normal range.


    Acknowledgements
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 Conclusions
 Acknowledgements
 References
 
The Association for the Promotion of Research in Arteriosclerosis, Thrombosis and Vascular Biology supported this work. R.J. was a recipient of a scholarship from the Austrian Cardiology Society. The excellent analytical work of Mrs A. Raffetseder is gratefully acknowledged.


    References
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 Conclusions
 Acknowledgements
 References
 

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