High levels of N-terminal pro B-type natriuretic peptide are associated with ST resolution failure after reperfusion for acute myocardial infarction
1From the Service de Cardiologie, CHU Bocage, Dijon, 2IFR santé STIC, Université de Bourgogne, 3Service de Cardiologie, Clinique de Fontaine, Fontaine les Dijon, 4Service de Cardiologie, Centre Hospitalier, Semur en Auxois, 5Service de Cardiologie, Centre Hospitalier, Beaune, 6Service de Cardiologie, Centre Hospitalier, Châtillon sur Seine, and 7Laboratoire de Biochimie, CHU Bocage, Dijon, France
Address correspondence to Dr Y. Cottin, Service de Cardiologie, CHU Dijon, Bd de Lattre de Tassigny, 21034 Dijon Cedex, France. email: yves.cottin{at}chu-dijon.fr
Received 26 September 2006 and in revised form 29 December 2006
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Background: B-type natriuretic peptide and the N-terminal fragment of its prohormone, N-terminal pro-brain natriuretic peptide (Nt-proBNP), provide valuable prognostic information on short- and long-term mortality in patients with acute coronary syndrome
Aim: To investigate the association between plasma NT-proBNP levels and ST-segment resolution (STR) after reperfusion in patients with ST-segment elevation myocardial infarction (STEMI).
Methods: Consecutive patients from the French regional RICO survey with STEMI who were treated by primary PCI or lysis <12 h were included. Blood sample was taken on admission to measure plasma NT-proBNP. Maximal ST segment elevation was measured on the single worst ECG lead before and 90 min after reperfusion. Patients were categorized as STR(–) (<50% STR) or STR(+) (
50% STR).
Results: Of the 486 patients included, 133 (27%) were STR(–). STR(–) patients had similar cardiovascular risk factors but higher in-hospital mortality (5% vs. 1%, p = 0.03) than STR(+) patients. The STR(–) group had higher median (IQR) levels of Nt-proBNP: 938 (211–3272) vs. 533 (169–1471) pg/ml, p = 0.003. On multivariate analysis, the highest quartile of Nt-ProBNP, Q waves and lysis were independent risk factors for incomplete STR.
Discussion: Our data show a strong association between high levels of Nt-proBNP at admission and incomplete STR, suggesting that Nt-proBNP may be useful for early risk stratification in reperfusion therapy after acute myocardial infarction.
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Reperfusion therapy has significantly improved survival after acute ST elevation myocardial infarction (STEMI), but its efficacy is difficult to evaluate. The evolution of ST-segment elevation after reperfusion therapy correlates with clinical outcomes and recovery of left ventricular function, and can easily be monitored using a 12-lead electrocardiogram (ECG) before and after reperfusion (by either lysis or percutaneous coronary intervention, PCI).1,2 Moreover, B-type natriuretic peptide and the N-terminal fragment of its prohormone, N-terminal pro-brain natriuretic peptide (Nt-proBNP), provide valuable prognostic information on short- and long-term mortality in patients with acute coronary syndrome.3–6 Recent studies suggest that levels of natriuretic peptide or its prohormone could reflect the severity of coronary artery disease and the extent of myocardium at risk, and predict angiographic success after reperfusion in patients with STEMI.7–11 The aim of the present study was to assess the relationship between Nt-proBNP levels on admission and ST-segment resolution (STR) in patients with acute STEMI.
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Patients
From 1 January 2001, RICO (a French regional survey for acute myocardial infarction) has prospectively collected in-hospital data for all patients hospitalized for acute myocardial infarction (AMI) in all public centres or privately funded hospitals of one eastern region of France. All consecutive patients admitted between 1 January 2001 and 31 March 2005 with AMI (<12 h after symptom onset), diagnosed according to European Society of Cardiology and American College of Cardiology criteria,12 and referred for primary PCI or thrombolysis, were included in this study. Our study complied with the Declaration of Helsinki, was approved by the ethics committee of university hospital of Dijon, and every patient gave written consent before participation.
Electrocardiographic analysis
The 12-lead ECGs were obtained immediately before and 90 min after either the start of thrombolysis or recanalization of the infarct-related artery by PCI. Maximal ST-segment elevation, measured 20 ms after the J-point, was that in the single lead showing maximum deviation.1,2 Patients with complete ST segment resolution, defined by 50% resolution (50% STR) were compared with patients without ST-segment resolution (<50% STR). ECG were analysed in a blinded fashion by two expert cardiologists. Classification was identical for the two experts in 80% of the patients. Discrepancies were resolved by consensus, or by repeat analysis for the remaining 20% patients.
Data collection
Demographic data, cardiovascular risk factors and history, haemodynamic parameters (heart rate, systolic and diastolic blood pressures), and presence of a Q wave on admission ECG were collected. Heart failure was defined as Killip class >1 on admission. Obesity was defined as body mass index (BMI) (weight/height kg/m2) 30. Left ventricular ejection fraction (LVEF) was measured by echocardiography at 3 ± 1 days after admission, using the Simpson method, and dichotomized at 40% for more clinical relevance. The LVEF value at 40% was chosen because of its strong association with outcome after MI in major clinical trials.13,14 In-hospital adverse events—death, ventricular arrhythmia (ventricular tachycardia, VT or fibrillation, VF), recurrent MI or cardiogenic shock—were recorded. Cardiogenic shock was defined as systolic blood pressure <90 mmHg, persisting for >1 h despite fluid challenge, associated with clinical signs of hypoperfusion.15 Recurrent MI was diagnosed by ECG modifications and increased serum troponin. Reperfusion therapy (lysis or primary PCI), glycoprotein IIb/IIIa receptor inhibitor, and treatments administered <48 h after hospitalization were also recorded. Endpoints were defined as in-hospital cardiac events (death, recurrent MI or cardiogenic shock).
Laboratory analysis
Blood samples for Nt-proBNP level assessment were collected in EDTA containing tubes on admission and stored at –20°C before analysis (<3 days). Plasma Nt-proBNP was determined by ELISA using Elecsys Nt-proBNP sandwich immunoassay on Elecsys 2010 (Roche Diagnostics). The inter- and intra-assay coefficients of variation were both <3.1%. The sensitivity of the assay was 5 pg/ml. Cross-reactivity with other natriuretic peptides (BNP), atrial natriuretic peptide (ANP) and C-type natriuretic peptide (CNP) was <0.01%. Baseline serum creatinine clearance was estimated by the Cockcroft-Gault formula.16 Blood samples were also taken to determine admission blood glucose. Blood samples for CK assessment were taken every 8 h during the first 3 days after admission. The peak values of CK during the hospital stay were analysed.
Statistical analysis
Continuous data were expressed as medians (IQR), dichotomous data as percentages. Comparisons between the two STR groups were performed either with unpaired Student's t test, or with non-parametric Mann-Whitney U-test as appropriate. Categorical data (gender, hypertension, diabetes, obesity, smoking, prior MI, heart failure, Q wave, LVEF<40%, reperfusion therapy, treatments and angiographic data) were analysed using the 
2 test. Correlation coefficients (r) were determined by Spearman correlation analysis, to assess the associations between STR and admission variables. Multivariate logistic regression analysis was used to analyse the relationships between STR and associated variables. Nt-proBNP concentrations were categorized into quartiles and the highest quartile of pro-peptide was compared to the remaining patients. The highest quartile of Nt-proBNP (>213 pg/ml) is associated with increased mortality after ACS.17,18 The variables introduced into the model were those associated with incomplete STR at p < 0.2 by univariate analysis: highest quartile of Nt-proBNP level, anterior wall location, LVEF <40%, Q wave, heart rate, and lysis (vs. PCI).19 Statistical analyses used NCSS software, version 2000 (Statistical Systems). A p value <0.05 was considered statistically significant, and two-sided tests were used.
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Of 486 enrolled patients, 353 (73%) had complete ST segment resolution STR(+) and 133 (27%) had incomplete ST-segment resolution STR(–). No difference was observed in the baseline characteristics for the two groups (Table 1). The proportion of patients with altered left ventricular ejection fraction (
40%) were higher in the STR(–) than the STR(+) group (26 vs. 14%, p < 0.003). The proportion of patients treated by primary PCI or by glycoprotein IIb/IIIa receptor blocker was higher in the STR(+) than in the STR(–) group (43 vs. 23%, p < 0.001 and 40 vs. 29%, p = 0.023, respectively). Otherwise, they were similar for acute medications, except for ACE inhibitors (STR(+) 78% vs. STR(–) 62%, p < 0.001). No difference was observed between the two groups with respect to angiographic data. The STR(–) group had a higher median (IQR) level of Nt-proBNP at admission: 938 (211–3272) vs. 533 (169–1471) pg/ml, p = 0.003. In-hospital mortality and occurrence of cardiogenic shock were both higher in the STR(–) group (7/133 (5.3%) vs. 5/353 (1.4%), p = 0.035 and 27/133 (20.3%) vs. 40/353 (11.3%), p = 0.016, respectively) (Figure 1). In contrast, the rate of recurrent MI was similar in the two groups: 20/133 (15.0%) vs. 40/353 (11.3%), p = 0.341 (Figure 1). Plasma Nt-proBNP and heart rate were negatively associated with STR; no correlation was observed with other admission variables (Table 2). On multivariate analysis, the highest quartile of Nt-ProBNP (OR 1.87 (95%CI 1.08–3.21), p = 0.024), Q waves (OR 1.67(95%CI 1.03–2.70), p = 0.036) and lysis (OR 3.17 (95%CI 1.86–5.39), p < 0.001) were independent factors for incomplete STR (Table 3). Heart rate and anterior wall location were not significant predictors of STR after adjustment for covariates.
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In our unselected consecutive patients with STEMI treated by fibrinolytic therapy or primary PCI, admission Nt-proBNP plasma levels were higher in the STR(–) group than in the STR(+) group, and Nt-proBNP levels on admission were independently associated with ST segment resolution, even after adjustment for potential confounders.
Several human studies have consistently observed that levels of BNP or Nt-proBNP measured 2–5 days after presentation of AMI are associated with short- and long-term risk of cardiac death.4,9,10,20,21 In the COMA trial, STEMI patients with patent arteries had lower levels of BNP than those with occluded arteries.22 The prognostic value of BNP levels depends on whether samples were taken early or in the sub-acute phase.18,23
In the present study, Nt-proBNP was determined before any revascularization. Mega et al. showed that an elevated BNP level before lysis was associated with lower likelihood of successful epicardial reperfusion.24 After primary PCI, BNP levels at admission are a powerful, independent predictor of short-term death and angiographic success.8 We have demonstrated the possibility of early risk stratification based on a biological marker, in the setting of acute reperfusion therapy, and regardless of the type of reperfusion. Our findings suggest that an Nt-proBNP-guided approach may well be useful for identifying patients with high risk for failure of reperfusion therapy. Patients with elevated Nt-proBNP may be particularly appropriate candidates for novel agents that may improve reperfusion efficacy.
ST-segment resolution reflects epicardial reperfusion, and studies based on both contrast echocardiography and angiographic ‘blush’ scores, showed that among patients with normal epicardial blood flow, persistent ST elevation usually indicates tissue damage and impaired microvascular perfusion.25,26 The relationship we observed between STR and Nt-proBNP level on admission may be explained by several mechanisms. A meta-analysis showed that the prognostic value of natriuretic peptide levels in non-STEMI is similar whether blood is obtained at the time of first patient contact or in the following hours. Moreover, early recanalization is crucial to limit left ventricular remodelling, and the neurohormonal response is independently associated with mortality in patients with left ventricular dysfunction.27 Nt-proBNP is a more sensitive predictor of outcome than left ventricular ejection fraction.28 Studies of experimental infarction in rats have shown rapid induction of ventricular BNP gene expression and BNP production not only in the infarct region and the peri-infarct region, but also in the surrounding non-ischaemic myocardium.29 These changes in gene expression were seen as early as 4 h post infarction and peaked 1 day following infarction. In isolated rat ventricular myocytes, hypoxia induces BNP expression. Infusing BNP into isolated perfused rat hearts prior to and during left main coronary artery occlusion, resulted in reduced infarct size in a concentration-dependent fashion.
Conclusions
Our data suggest a strong association between high admission plasma NT-proBNP and incomplete STR in patients after reperfusion, and highlight the potential relevance of Nt-proBNP for early risk stratification in the setting of reperfusion therapy after acute myocardial infarction.
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This work was supported by the Association de Cardiologie de Bourgogne, The University Hospital, Dijon, France and by grants from Union Régionale des Caisses d’Assurance Maladie de Bourgogne (URCAM), and Agence Régionale de l’Hospitalisation (ARH) de Bourgogne.
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