Analysis of N-terminal-pro-brain natriuretic peptide and C-reactive protein for risk stratification in stable and unstable coronary artery disease: results from the AtheroGene study

Renate Schnabel1,*, Hans J. Rupprecht1, Karl J. Lackner3, Edith Lubos1, Christoph Bickel4, Jürgen Meyer1, Thomas Münzel1, François Cambien2, Laurence Tiret2 and Stefan Blankenberg1,2 for the AtheroGene Investigators

1Department of Medicine II, Johannes Gutenberg-University Mainz, Langenbeckstr. 1, 55131 Mainz, Germany
2INSERM U525, Faculté de Médecine Pitié-Salpêtrière, Paris, France
3Department of Clinical Chemistry, Johannes Gutenberg-University Mainz, Germany
4Innere Abteilung Bundeswehrzentralkrankenhaus, Koblenz, Germany

Received 17 January 2004; revised 27 August 2004; accepted 8 September 2004; online publish-ahead-of-print 30 November 2004.

* Corresponding author. Tel: +49 6131 175169; fax: +49 6131 175691. E-mail address: schnabelr{at}web.de

See page 207 for the editorial comment on this article (doi:10.1093/eurheartj/ehi078)


    Abstract
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Acknowledgements
 References
 
Aims N-terminal-pro-brain natriuretic peptide (Nt-proBNP) is a reliable risk predictor in acute coronary artery disease (CAD). Little is known about patients with stable angina pectoris (SAP). We aimed to investigate the prognostic impact of Nt-proBNP in a population with CAD especially focussing on patients with SAP.

Methods and results We obtained baseline samples from a prospective cohort of 904 consecutive patients with CAD. Cardiovascular events were registered during follow-up (median 2 years; maximum 3.7 years). Baseline Nt-proBNP was significantly higher among individuals with cardiovascular events compared with those without (711.5 vs. 238.8 pg/mL; P<0.0001). A similar association was found if the analysis was performed in patients who presented with stable angina (330 vs. 166.5 pg/mL; P=0.006) or acute coronary syndrome (990.9 vs. 527.7 pg/mL; P=0.03). In the SAP group, patients within the top quartile (>487.9 pg/mL) had a 3.7-fold (95% CI 1.2–9.1; P=0.01) increase in cardiovascular risk. After adjustment for most potential confounders including left ventricular ejection fraction, Nt-proBNP remained predictive for patients with serum concentrations in the upper quartile in comparison with patients in the lowest quartile (hazard ratio highest vs. lowest quartile: 4.0; P=0.03) (n=417).

Conclusion Baseline concentration of Nt-proBNP is independently related to future cardiovascular events in patients with stable angina.

Key Words: Nt-proBNP • hs-CRP • Stable angina pectoris • Coronary artery disease • Risk stratification • Multi-marker strategy


    Introduction
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Acknowledgements
 References
 
Circulating biomarkers deriving from different origins have brought substantial progress in the understanding of pathophysiology and clinical decision-making over the wide spectrum of coronary artery disease (CAD).13 Recent studies elaborated the prognostic value of serum hormones like brain natriuretic peptide (BNP) predominantly released from ventricular myocardium as a response to ventricular dilatation and pressure overload in patients with heart failure and acute coronary syndrome (ACS).4,5 N-terminal-pro-brain natriuretic peptide (Nt-proBNP), a more stable fragment of the BNP precursor, has been identified as a risk predictor after myocardial infarction.6 In addition, atherosclerosis shows features of an inflammatory process.7,8 Among inflammatory markers, high-sensitivity C-reactive protein (hs-CRP) has consistently been proved to be a risk predictor of cardiovascular events in various clinical settings.911 With respect to BNP, most studies evaluated patients in the acute state of disease, whereas data are lacking concerning the impact of BNP or Nt-proBNP in patients with stable angina pectoris (SAP).12

The present study was planned to examine: (i) the prognostic implications of cardiac hormonal activation revealed by plasma levels of Nt-proBNP; and (ii) the inflammatory response as reflected by hs-CRP in a prospective patient population over the whole spectrum of CAD with special emphasis on the group of stable angina patients. In addition, the predictive value of Nt-proBNP in the subgroup of patients with left ventricular ejection fraction (LVEF) within normal range should be evaluated. Combined analysis of risk prediction was carried out to evaluate a multi-marker strategy in the individualization of risk stratification.


    Methods
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Acknowledgements
 References
 
Study population
Between June 1999 and July 2001, 904 patients who underwent coronary angiography at the Department of Medicine II of the Johannes Gutenberg-University Mainz or the Bundeswehrzentralkrankenhaus Koblenz, with at least one stenosis >30% diagnosed in a major coronary artery, were enrolled in a cardiovascular registry (AtheroGene study). The patient population comprised outpatients and patients referred from other hospitals for the evaluation of coronary artery status. A detailed study description has been outlined elsewhere.13,14 Briefly, exclusion criteria of the AtheroGene study were evidence of haemodynamically significant valvular heart disease, surgery, or trauma within the prior month, known cardiomyopathy, known malignant disease, febrile conditions, or oral anticoagulant therapy within the prior 4 weeks. Unstable angina (n=417) was classified by Braunwald classification (class B or C), 92 patients had acute myocardial infarction (ST-segment elevation in at least two corresponding leads plus troponin elevation). LVEF was determined by LV-angiography and off-line analysis according to the area–length method.

Patients were followed up during a median (25th/75th interquartile range) of 2.0 (1.4/2.9) years with a maximum of 3.7 years. Follow-up information was obtained about death from cardiovascular causes (n=39), and non-fatal myocardial infarction (n=28), both accounting for future cardiovascular events in the following, and death from causes not related to heart disease (n=13). Information about the cause of death or clinical events was obtained from hospital or general practitioner charts. Study participants had German nationality. The study was approved by the ethics committee of the University of Mainz. Participation was voluntary and each study subject gave written informed consent.

Laboratory methods
Blood was drawn from all study subjects under standardized conditions before coronary angiography was performed. Samples were stored at –80°C until analysis. Serum Nt-proBNP was determined using an electrochemiluminescence sandwich immunoassay (ECLIA, Roche Diagnostics, Mannheim, Germany) on an Elecsys System 2010. Intra- and interassay precision for the luminescence sandwich immunoassay was 0.8–3.0% and 2.2–5.8%, respectively. The linear range of detection of this assay was 5–35 000 pg/mL, cross-reactivity with BNP, atrial natriuretic peptide was <0.001%. The conversion factor into pmol/L is 0.118. CRP was determined by a highly sensitive, latex particle-enhanced immunoassay (detection range of 0–20 mg/L, Roche Diagnostics, Mannheim, Germany). Serum lipid levels were measured immediately.

Statistical considerations
Mean levels and proportions of baseline cardiovascular risk factors were calculated for study participants who developed subsequent cardiovascular events. Comparing the event group with individuals with event-free survival, log-rank test was used for categorical variables and a Cox univariate model for testing continuous variables. Nt-proBNP and hs-CRP were log-transformed to reduce the effect of extreme values. The cumulative event plots by Nt-proBNP and hs-CRP quartiles were estimated by the Kaplan–Meier method and compared using the log-rank test. In all survival analyses, the endpoint was death from cardiovascular causes and non-fatal myocardial infarction. Patients who died from other causes were censored at the time of death. Hazard ratios for future coronary events according to quartiles of Nt-proBNP and hs-CRP were estimated by Cox regression models adjusting for potential confounders. Quartile ranges determined within the subgroups were applied. We stepwise-adjusted for age and sex (Model 1), further for classical risk factors and clinical features like body mass index (BMI), history of hypertension, diabetes, smoking status, high density lipoprotein, statin and beta-blocker therapy, extent of vessel disease, ACS (Model 2), and the inflammatory marker hs-CRP or Nt-proBNP, respectively (Model 3). The final adjustment additionally included LVEF (Model 4).

We further evaluated the combined role of Nt-proBNP and hs-CRP on cardiovascular risk and therefore tested for interaction followed by a dichotomized analysis of both variables by using the highest quartile as cut-off point. Hazard ratios and their 95% confidence intervals (CI) are reported. P-values are two-sided, P<0.05 was considered to be significant. All calculations were carried out using SPSS, version 11.5.


    Results
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 Acknowledgements
 References
 
The mean age of the entire study population was 60.7±9.9 years; 77% were male patients. No significant correlation between Nt-proBNP serum levels and future non-fatal stroke was seen.

Table 1 presents baseline characteristics in the overall study population of patients with cardiovascular events and those who remained free of reported events. Of the classical risk factors, only patients presenting with diabetes had a higher prevalence of future cardiovascular events. As expected, patients suffering from future cardiovascular events had higher baseline concentrations of hs-CRP and lower HDL-cholesterol levels.


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Table 1 Baseline characteristic of the study population
 
Nt-proBNP serum concentration distribution among the study participants was slightly skewed; ranging from 10.93 to 16 550 pg/mL with a median of 252 pg/mL and an interquartile interval from 101.8 to 727.8 pg/mL. Baseline Nt-proBNP was significantly higher among individuals with cardiovascular events compared with those without (711.5 vs. 238.8 pg/mL; P<0.0001). A similar association was found if the analysis was divided into patients who presented with stable angina (330 vs. 166.5 pg/mL; P=0.006) or ACS (990.9 vs. 527.7 pg/mL; P=0.03). Whereas Nt-proBNP was a strong predictor of future cardiovascular death (1395.0 vs. 238.8 pg/mL; P<0.0001), it only showed a non-significant trend towards higher levels in those subjects suffering from future non-fatal myocardial infarction (280.6 vs. 238.8 pg/mL; P=0.06).

As outlined in Table 2, concentration of Nt-proBNP was related to older age and female gender and, as expected, the clinical features of ACS and ejection fraction. A history of myocardial infarction affected the Nt-proBNP baseline concentration to a lesser extent.


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Table 2 Predictors of Nt-proBNP and hs-CRP
 
Figure 1 provides Kaplan–Meier curves for event-free survival according to quartiles of Nt-proBNP and hs-CRP serum concentration within the subgroups. The unadjusted cardiovascular event rate was highest for individuals within the upper Nt-proBNP quartile [Plog rank Q (quartile)4 vs. Q1–3 0.001] in the SAP group. Here the event rate of the individuals in the upper quartile of Nt-proBNP (11.2%) was 3.2-fold higher than the event rate within the lower three quartiles (3.5%). The threshold effect observed in the SAP population was also present in the subgroup of patients presenting with ACS (Plog rank Q4 vs. Q1–3 0.019). In contrast to Nt-proBNP, the cardiovascular risk increased in a stepwise fashion across increasing quartiles of baseline hs-CRP activity in both forms of CAD manifestation.



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Figure 1 Kaplan–Meier survival curves of future cardiovascular events according to quartiles of Nt-proBNP and hs-CRP divided into the subgroups of patients presenting with SAP and ACS.

 
To assess whether the effect of baseline Nt-proBNP on risk was independent of most potential confounders, four Cox predictive models were applied. Tables 3 and 4 present the hazard ratio for cardiovascular events associated with increasing quartiles of Nt-proBNP.


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Table 3 Hazard ratios according to quartiles of baseline Nt-proBNP in patients with stable angina
 

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Table 4 Hazard ratios according to quartiles of baseline Nt-proBNP in patients with ACS
 
In the SAP group, patients within the highest quartile of Nt-proBNP had the highest probability of cardiovascular risk (3.7-fold risk increase, 95% CI 1.2–9.1; P=0.01). This association was slightly attenuated after controlling for various confounders but remained independently significant (Table 3). In the final adjustment, which included left ventricular ejection fraction (LVEF), Nt-proBNP still tended to be associated with an increased cardiovascular risk even if a conventional level of statistical significance was not achieved in the trend statistic. LVEF correlated negatively with Nt-proBNP baseline levels in the overall study population (r=–0.47; P=0.01) and the subgroup with stable angina (r=–0.44; P=0.01) (data not shown). Nt-proBNP serum levels in the upper quartile remained significantly predictive for future cardiovascular events even in the subgroup of patients with preserved LVEF (>40%) (P<0.0001). Risk factor adjustment (equivalent to Model 2) applied to hs-CRP quartiles resulted in a 2.4-fold (95% CI: 1.1–4.6; P=0.027) increase in risk for future cardiovascular events for patients in the upper quartile compared with the lowest.

If introduced into the Cox predictive model as log-transformed variables, Nt-proBNP revealed a 2.62-fold (95% CI: 1.32–5.21; P=0.006) risk increase after full adjustment including hs-CRP, whereas the inflammatory marker lost independent risk prediction after final adjustment (P=0.063).

When analysis was focussed on patients with ACS only individuals in the upper quartile revealed a trend towards increased risk of future cardiovascular events. The relatively weak association might be explained by the small number of cases in the ACS subgroup. Risk factor adjustment (similar to Model 2) for hs-CRP quartiles meant a 2.6-fold (95% CI: 1.0–6.3; P=0.046) risk of future cardiovascular events for subjects in the fourth quartile of the ACS-group compared with the first quartile.

If hs-CRP and/or Nt-proBNP were introduced as log-transformed variables into the Cox predictive model Nt-proBNP revealed a 1.48-fold (95% CI: 1.02–2.14; P=0.04) risk increase after full adjustment including hs-CRP, hs-CRP showed a 2.15-fold (95% CI: 1.17–3.95; P=0.014) increased risk.

We further explored to what extent the inflammatory predictor hs-CRP might add to the predictive value of Nt-proBNP in patients presenting with SAP (Figure 2). The test for interaction was negative and we assumed an additive effect for both biomarkers. Elevation of Nt-proBNP or hs-CRP (both >75th percentile) without elevation of the respective biomarker was slightly related to increased cardiovascular risk, not reaching statistical significance. However, individuals with combined elevation of both biomarkers were at the highest risk of future cardiovascular events. These individuals revealed a hazard ratio of 4.0 (95% CI: 1.8–9.2; P=0.001) (Figure 2) for patients in the SAP group.



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Figure 2 Hazard ratios for future cardiovascular events according to baseline levels of Nt-proBNP and hs-CRP in combined analysis. The relative risk and 95% CI for the patients presenting with SAP is provided. The slightly decreased number of patients is caused by missing hs-CRP data.

 
However, if formal model comparison is performed for a model including only Nt-proBNP compared with models with both markers (Nt-proBNP and hs-CRP), no increase in C-statistics could be observed. In addition, the overall magnitude of risk prediction of combined markers is similar to that obtained by Nt-proBNP single marker determination.


    Discussion
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Acknowledgements
 References
 
In this prospective study of patients with CAD, Nt-proBNP was significantly associated with future cardiovascular events in patients with SAP. Nt-proBNP was an independent risk predictor even in patients without impaired ejection fraction.

BNP is established as a marker of myocardial strain,15 and thus provides information of cardiac function and supports the clinical diagnosis of heart failure.12,16,17 Released under myocardial stress it represents the extent of myocardial damage and indicates myocardial dysfunction independent of left ventricular systolic function.18,19 Therefore, the potential clinical use of BNP should also be considered in a setting of ACS. In this context, BNP has emerged as a valid risk predictor.4,20,21 In our study population we measured the more stable fragment Nt-proBNP of the BNP precursor. It is assumed to have a longer half-life of ~60–120 min, which has still to be established in humans.2224

For the first time, we are now able to extend the knowledge of Nt-proBNP as a robust and independent risk predictor towards lower risk groups, patients with stable coronary disease and without impaired ejection fraction.

Nt-proBNP, which is closely related to left ventricular systolic function,25 was sensitive enough to detect patients with increased risk even in the subgroup without impaired ejection fraction (>40%) and expected lower risk of adverse events. The extent of disturbed diastolic function was not further investigated and might in part explain the risk increase in some subjects of this population. On the other hand, ongoing myocardial damage and repetitive micro-ischaemia, which leads to an elevation of hs-CRP, might be related to the elevation of Nt-proBNP and indicate continuous myocardial stress resulting in increased risk of future cardiovascular events.2 It has been shown that elevated BNP is independently associated with inducible ischaemia among patients with stable CAD and in patients with acute cardiac ischaemia in the absence of overt heart failure.26,27 However, various confounding effects of Nt-proBNP should be considered. As previously demonstrated,28 gender seems to have an important impact on Nt-proBNP-levels, which has not been explained physiologically. Furthermore, our study confirmed that renal function and age, as well as beta-blocker therapy (data not shown), may alter Nt-proBNP levels and must be considered in the determination of cut-off values.2932 Using routine measurements in standardized, commercially available assays it may in the near future, be feasible to get fast, automated, and increasingly reliable results at any hospital.29,33

The current data discuss the hypothesis that in the evaluation of individual risk, various circulating biomarkers deriving from different origins may support risk stratification most accurately. Atherosclerosis is partly an inflammatory process, to which we contributed by measuring a representative marker of inflammation. Our data add to the discussion of the value of hs-CRP as a predictive marker in patients with ACS and stable angina. Adjustment for various confounders showed that hs-CRP may be a weaker predictor than interleukin-18, myeloperoxidase, or soluble CD40 ligand in this specific clinical setting. After full adjustment the association between hs-CRP and outcome only reached borderline significance in contrast to the other biomarkers mentioned.3437 The potential use for hs-CRP in various clinical settings has recently been carefully discussed.9,11,3840

Our data do not support the hypothesis that the additional assessment of hs-CRP leads to better risk stratification compared with Nt-proBNP alone. However, this result needs to be confirmed in larger studies.

Some limitations of this study, in addition to those discussed above, merit consideration. The serum markers were measured at admission; we did not examine changes over time or their potential change due to various medications. However, variation of serum markers under therapy and the time course of disease may dilute predictive power. For CRP, stability of serum levels could be shown over a long period.41 In contrast, Nt-proBNP levels depend on cardiac stress under specific circumstances and may change over time. Yet we tried to generate a comprehensive view of the present cardiovascular state and succeeded in assessing future events. The emerging hypothesis of whether or not models including both hs-CRP and Nt-proBNP lead to better risk prediction than NT-proBNP alone cannot be conclusively interpreted by our data but needs further evaluation in large scale prospective studies. In addition, investigation has to be undertaken to find the most powerful marker of the extent of inflammation as hs-CRP might not be the most sensitive. In conclusion, this prospective study of Nt-proBNP serum levels substantially contributed to cardiovascular risk assessment in patients with CAD, especially those with stable angina and without left ventricular systolic function impairment.


    Acknowledgements
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Acknowledgements
 References
 
The test assays for Nt-proBNP and hs-CRP were kindly provided by Roche Diagnostics, Mannheim, Germany. We are indebted to Margot Neuser for her excellent graphical work. The work was supported by a grant of the ‘Stiftung Rheinland-Pfalz für Innovation’, Ministry for Science and Education (AZ 15202-386261/545), Mainz, Germany.


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 Discussion
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