SEARCH

SEARCH BY CITATION

Abstract

  1. Top of page
  2. Abstract
  3. Methods
  4. Results
  5. Discussion
  6. Limitations
  7. Conclusions
  8. References

J Clin Hypertens (Greenwich). ©2010 Wiley Periodicals, Inc.

The aim of this research was to describe N-terminal part of the prohormone B-type natriuretic peptide (NT-proBNP) levels over time in patients with acute coronary syndrome (ACS) before and after percutaneous coronary intervention (PCI). NT-proBNP, troponin I (Tn-I), creatine kinase (CK), CK MB isoenzyme (CKMB), fibrinogen, D-dimers, and C-reactive protein (CRP) were measured in 300 consecutive patients with ACS before undergoing successful reperfusion with PCI in the first 48 hours, 2 days after, and at the end of the 1st, 3rd, 6th, 12th, 18th, and 24th month. The concentration of NT-proBNP was cross-correlated with the levels of NT-proBNP in 300 patients without ACS and was significantly increased before and after PCI and at the end of the 3rd month, contrasting with the fast conversion to normal levels of Tn-I, CK, CKMB, fibrinogen, D-dimers, and CRP. In patients with ACS undergoing successful PCI, NT-proBNP shows slow kinetics, especially in patients with an increased thrombolysis in myocardial infarction risk score, hypertension, and diabetes. Nevertheless, cardiac neurohormonal activation may be a unifying feature among patients at high risk for cardiovascular events after ACS and PCI. J Clin Hypertens (Greenwich). 2010;12:861–868.

Brain (B-type) natriuretic peptide (BNP) is a peptide hormone released primarily from the cardiac ventricles in response to myocyte stretch. It is synthesized as an inactive prohormone that is split into the active hormone BNP and the inactive N-terminal fragment (NT-proBNP). BNP has a number of systemic effects, including vasodilation, increases in urinary volume and sodium output, and inhibition of the sympathetic nervous system and the renin-angiotensin-aldosterone system.1,2 Elevated BNP and NT-proBNP levels may not only reflect increased left ventricular wall stress but may also result directly from cardiac ischemia.3 The prognostic importance of BNP and NT-proBNP has been extensively studied in patients with heart failure as well as in patients with acute coronary syndrome (ACS), and both markers have been shown to be strong predictors of morbidity and mortality.4–6 Data from the Framingham Heart Study identified BNP as a strong predictor of morbidity and mortality in the general population even when BNP levels were below the threshold of 100 pg/mL, which is normally used to identify patients with heart failure.7 BNP has been shown to provide valuable prognostic information in patients with ACS.6,8,9 However, the prognostic importance of natriuretic peptides in patients with acute coronary artery disease (CAD) and percutaneous coronary intervention (PCI) is unclear. Biochemical markers, including troponin I (Tn-I),10 high-sensitivity C-reactive protein (CRP), and NT-proBNP, have become available for the additional evaluation of risk stratification in ACS patients. An association between the level of these biomarkers and the risk of future cardiovascular events has been discussed in patients with ACS.11–13 Therefore, we undertook the present study to evaluate the effect of the level of NT-proBNP on 24-month follow-up and studied the prognostic implications of elevations especially in Tn-I, NT-proBNP, and CRP across the spectrum of ACS. A combined prediction for analysis of cardiac events was also carried out to evaluate a multi-marker strategy for the individualization of risk stratification.

Methods

  1. Top of page
  2. Abstract
  3. Methods
  4. Results
  5. Discussion
  6. Limitations
  7. Conclusions
  8. References

Patients

We studied 300 patients admitted to the cardiology department with a diagnosis of ACS for their angina pain and 300 patients without ACS (controls). One hundred patients had ST-segment elevation ACS (STEACS), 40 had thrombolytic treatment and subsequent PCI, and 200 had non–ST-segment elevation ACS (NSTEACS) or unstable angina (UA).The baseline characteristics of the patients are shown in Table I.

Table I.   Baseline Characteristics (N=300)
CharacteristicTotal
Age, y60±5
Male sex, %188 (62.6)
Hypertension, No. (%)163 (54.33)
Diabetes, No. (%)98 (32.66)
Dyslipidemia, No. (%)168 (56)
Smoking, No. (%)205 (68.3)
Family history of coronary heart disease, No. (%)87 (29)

The eligible patients were 30 years and older (300 patients: 188 men, 98 diabetics, mean age 60±5 years) with ≥1 episode of typical angina pain lasting >5 minutes and at least one of the following signs of ischemia: electrocardiographic findings suggestive of ischemic change (elevated or depressed ST-segment or T-wave inversion), or positive Tn-I test. In all patients, we studied realization echocardiography measurement on left ventricular function before and after PCI. According to medical history, the majority of patients with hypertension had received angiotensin-converting enzyme (ACE) inhibitors or angiotensin II receptor blockers (valsartan) before hospitalization. Moreover, the majority of patients with diabetes received thiazolidinediones (either rosiglitazone or pioglitazone) or insulin and a few were taking combined sulfonylurea and metformin therapy. No patient was treated with aspirin or clopidogrel before hospitalization. Finally, only a few patients with dyslipidemia had been treated with simvastatin.

Biochemical Analysis

In all patients, plasma samples for the determination of cardiac markers were collected at baseline (before undergoing successful reperfusion with PCI), 48 hours, and at the 1st, 3rd, 6th, 12th, 18th, and 24th month. Tn-I and NT-proBNP were quantified by use of a 1-step enzyme immunoassay based on electrochemiluminescence technology (Elecsys 2010; Roche Diagnostics, Laval, QC, Canada).14 CRP was determined with the Hitachi 717 system (Roche Diagnostics, Nutley, NJ).15 All samples were stored at −80°C before analysis, and the biomarker measurements were performed in samples that underwent only a single thaw cycle. Creatine kinase (CK), CK MB isoenzyme (CKMB), fibrinogen, and D-dimers were also measured. All biochemical markers were correlated with NT-proBNP, risk factors for cardiac events, thrombolysis in myocardial infarction (TIMI) risk score, and stents placed.

In this study, we evaluated the NT-proBNP plasma concentrations in patients with ACS before and 24 months after PCI was performed and the correlation of the results to major CAD risk factors. In addition, the concentration of NT-proBNP was cross-correlated with the levels of NT-proBNP in 300 patients without ACS (controls).

Percutaneous Coronary Intervention

Forty-eight hours at the latest after the ACS, patients were transferred to the catheterization laboratory and underwent successful PCI. Since it is often difficult to achieve an adequate pretreatment goal with clopidogrel in clinical practice, more rapid achievement of platelet P2Y12 inhibition may improve patient outcomes. All patients received 300 mg to 600 mg of clopidogrel and 325 mg of aspirin at admission and were transferred to the catheterization laboratory after 48 hours (at the latest) while receiving intravenous glycoprotein IIb/IIIa inhibitors and unfractionated heparin. Patients were then transferred to the intensive care unit where they remained hemodynamically stable for 24 hours, while receiving, among other medications according to American College of Cardiology/American Heart Association/European Society of Cardiology guidelines, glycoprotein IIb/IIa inhibitors. Medication after PCI included aspirin 100 mg, clopidogrel 75 mg, β-blockers, statins, and ACE inhibitors on a daily base.

Follow-Up

The patients were followed for 2 years regarding occurrence of death and major cardiac events (MACEs). By definition, MACE is a composite of clinical events and usually includes end points reflecting safety and effectiveness, especially STEACS, NSTEACS, and UA.

Statistical Analysis

We examined the association between baseline levels of NT-proBNP at the beginning of hospitalization and in the 1st, 3rd, 6th, 12th, 18th, and 24th month and correlated them with Tn-I, CK, CKMB, fibrinogen, D-dimers, CRP, TIMI risk score, CAD risk factors, and stents placed.

Data were expressed as mean (±standard error of the mean). Comparisons between the two groups with the unpaired or paired t test as suited and analysis of variance for continuous variables and chi-square test for categoric variables were performed. Correlation between the NT-proBNP levels and biochemical markers was assessed by linear regression analysis. Multivariate analysis was performed using tiered Cox proportional hazards models incorporating factors with predictive significance on univariate analysis. Cox regression analysis was used to determine the prognostic value of NT-proBNP and risk factors for cardiac events. For each risk factor, a hazard ratio (HR) with 95% confidence interval (CI) was calculated. Sensitivity, specificity, positive predictive value, negative predictive value, and overall accuracy of all the biochemical cardiac markers for detection of cardiovascular events were assessed and compared with the McNemar test. All analyses were performed with the SPSS v14.0 for Windows application (SPSS Inc, Chicago, IL). Differences were considered significant at P<.05.

Results

  1. Top of page
  2. Abstract
  3. Methods
  4. Results
  5. Discussion
  6. Limitations
  7. Conclusions
  8. References

The mean follow-up period was 24 months. NT-proBNP was measured in all patients before undergoing successful reperfusion with PCI in the first 48 hours, 2 days later, and at the end of the 1st, 3rd, 6th, 12th, 18th, and 24th month. The left ventricular functions in all patients were normal. The concentration of NT-proBNP was cross-correlated with the levels of NT-proBNP in 300 patients without ACS (controls) and was significantly increased before PCI (P<.05) (Figure 1). Two days after PCI, NT-proBNP concentration remained high (P<.05) and then decreased gradually, but was still high in the 1st (P<.05) and 3rd (P<.05) month, reaching normal levels in about 6 months (P>.05) (Figure 1).

image

Figure 1.  The concentration of N-terminal prohormone B-type natriuretic peptide (NT-proBNP) was cross-correlated with the levels of NT-proBNP in 300 patients with and without acute coronary syndrome (ACS). It remained high 2 days after percutaneous coronary intervention and then decreased gradually, but was still high in the 1st and 3rd month, reaching normal levels in about 6 months.

Download figure to PowerPoint

Tn-I, CK, CKMB, fibrinogen, D-dimers, and CRP values were measured at the same time. Levels of NT-proBNP were independently correlated with TIMI risk score, Tn-I, CK, CKMB, fibrinogen, D-dimers, CRP, and stents placed. Plasma levels of Tn-I, CK, CKMB, fibrinogen, and CRP were normal at the end of the 1st month (P<.05) (Figure 2 and Figure 3). However, we noticed that patients with increased TIMI risk score (P<.05) (Figure 4), especially diabetic patients (P<.05) (Figure 5) and those in whom drug-eluding stents were placed (Figure 4) had significantly increased plasma levels of NT-proBNP at the beginning of hospitalization. During the 24 months of follow-up, 2 patients had sudden deaths and 10 had MACEs; restenosis was mainly observed in them and faced with success.

image

Figure 2.  Plasma levels of creatine kinase (creatine phosphokinase [CPK]), fibrinogen, and D-dimers were normal at the end of the 1st month.

Download figure to PowerPoint

image

Figure 3.  Plasma levels of troponin I (Tn [I]), creatine kinase MB isoenzyme (CKMB), and C-reactive protein (CRP) were normal at the end of the 1st month.

Download figure to PowerPoint

image

Figure 4.  Levels of N-terminal prohormone B-type natriuretic peptide (NT-proBNP) were independently correlated with thrombolysis in myocardial infarction (TIMI) risk score and with stents placed. Patients with increased TIMI risk score and in those with drug-eluding stents (DES) had significantly increased plasma levels of NT-proBNP at the beginning of hospitalization. BMS indicates bare metal stents.

Download figure to PowerPoint

image

Figure 5.  A statistically significant difference in mean N-terminal prohormone B-type natriuretic peptide (NT-proBNP) levels has been observed between diabetic patients and smokers.

Download figure to PowerPoint

No statistically significant difference in mean NT-proBNP levels has been observed in patients with or without any CAD risk factor (P>.05) except diabetics (HR, 1.14; P=.006), hypertensives (HR, 1.16; P=.005), smokers (HR, 1.17; P=.003), and those with dyslipidemia (HR, 2.42; P=.048) (Figure 5 and Figure 6), who had a statistically significant difference at the 1st, 3rd, and 6th month. Finally, the main characteristics of results of NT-proBNP levels are demonstrated in Figure 7.

image

Figure 6.  A statistically significant difference in mean N-terminal prohormone B-type natriuretic peptide (NT-proBNP) levels has been observed between hypertensive and dyslipidemic patients.

Download figure to PowerPoint

image

Figure 7.  Main results of N-terminal prohormone B-type natriuretic peptide (NT-proBNP) levels in this study.

Download figure to PowerPoint

Sensitivity, specificity, positive predictive values, negative predictive values, and overall accuracy at admission for NT-proBNP, Tn-I, CK-MB, CK, CPR, D-dimers, and fibrinogen are depicted in Table II. At 24-month follow-up, sensitivity, specificity, positive and negative predictive values, and overall accuracy of NT-proBNP increased at values of 92.3%, 93.5%, 37.5% and 99.6%, and 93.4%, respectively (Figure 8), in contrast with all others blood markers.

Table II.   Diagnostic Accuracy of Admission Values for Acute Coronary Syndromes
 Sensitivity, %Specificity, %PPV, %NPV, %Accuracy, %P Value
  1. Abbreviations: CK, creatine kinase; CKMB, creatine kinase MB isoenzyme; CRP, C-reactive protein; NPV, negative predictive value; NT-proBNP, N-terminal prohormone B-type natriuretic peptide; PPV, positive predictive value; Tn-I, troponin I.

NT-proBNP809037.598.190<.0001
Tn-I85.793.5809698.6<.0001
CRP6687.82397.986.7<.0001
CKMB839254.596.695.8<.0001
CK6382.7209784<.001
D-dimers4070.5994.168.4<.001
Fibrinogen37.565.7793.563.8<.001
image

Figure 8.  The sensitivity, specificity, and overall accuracy of N-terminal prohormone B-type natriuretic peptide (NT-proBNP) at admission and during 24-month follow-up.

Download figure to PowerPoint

Discussion

  1. Top of page
  2. Abstract
  3. Methods
  4. Results
  5. Discussion
  6. Limitations
  7. Conclusions
  8. References

We studied the prognostic value of cardiac markers for adverse outcomes in patients with ACS. However, because ACS is a heterogenous group, both clinically and pathophysiologically, prognostic significance of cardiac biomarkers has not been well evaluated in patients with ACS. We found that NT-pro BNP levels predicted a wide range of cardiovascular outcomes and provided information that was incremental to that obtained from established risk factors.

CRP was found to significantly correlate with the extent and severity of CAD.16 It is therefore possible that an elevated level of CRP reflects a more diffuse process of coronary atherosclerosis, with a higher plaque burden and increased vascular inflammation and a higher prevalence of myocardial damage. Thus, in our study, higher levels of CRP had a predictive role for the occurrence of cardiac events in patients with ACS, especially in diabetics, in accordance with previous findings,17 which revealed that elevation in CRP levels seems to correlate with in-hospital and short-term prognosis. Together with CRP, we also identified that patients with adverse events had a higher tendency for diabetes, as reported by other studies.18–20 These trial findings have provided evidence of increased CRP levels in relation to the insulin resistance syndrome, suggesting that chronic subclinical inflammation may be part of the metabolic syndrome. Moreover, some studies have reported that elevated CRP levels in patients with CAD are associated with a profound impairment of systemic endothelial vascular reactivity,21 endothelial dysfunction,22,23 and atherogenesis.24

NT-proBNP is a circulating cardiac hormone that is mainly released from the ventricle in response to increased stretch or wall tension.25,26 Therefore, NT-proBNP has been widely used as a simple and useful marker for left ventricular overload, such as left ventricular dysfunction or hypertrophy, and for prognosis in patients with chronic heart failure. NT-proBNP has been shown to provide significant prognostic information across the spectrum of ACS.27 One study with 122 patients who predominantly had STEMI suggested that NT-proBNP may provide prognostic information superior to that obtained from BNP.28 In one small-scale, cross-sectional study, BNP levels were higher in patients with UA than in those with stable angina.26 In another pilot study, BNP levels were predictive of short-term survival after adjustment for conventional contemporary risk markers, including Tn-I.10 In patients with ACS undergoing successful PCI in our investigation, NT-proBNP displayed slow kinetics post-PCI returning to normal values at about 6 months. This is in marked contrast with the fast conversion to normal levels of Tn-I, CK, CKMB, fibrinogen, D-dimers, and CRP. Nevertheless, patients with increased TIMI risk score, especially diabetics and those in whom drug-eluting stents were placed, had significantly increased plasma levels of NT-proBNP at the beginning of hospitalization, whereas 12 major cardiac events were observed during the 24-month follow-up period. No statistically significant difference in mean NT-proBNP levels were observed between patients with or without any CAD risk factor except for diabetics, hypertensives, smokers, and patients with dyslipidemia who had a statistically significant difference at the 1st, 3rd, and 6th months. The majority of the patients with hypertension at admission had increased mean baseline systolic and diastolic blood pressure (150/100 mm Hg). After PCI and for 24 months, the mean blood pressure was then below 130/80 mm Hg. This was likely the result of aggressive treatment following the procedure and patient compliance to pharmacologic treatment. Using NT-proBNP in this study, we were accordingly able to identify a high-risk group of patients with hypertension and electrocardiographic left ventricular hypertrophy, which seem to be strong prognostic risk markers for cardiovascular events. NT-proBNP is useful as a biomarker in point-of-care diagnosis of ACS and for evaluating effectiveness of treatment. In contrast, CRP values may be useful in patients suspected to have cardiovascular disease or to guide the intensity of therapy in patients with diabetes and the metabolic syndrome. However, CRP values do not provide direction as to how the therapy should be targeted.

Although there are conflicting data, it seems likely that plasma NT-proBNP levels may prove useful in screening for left ventricular abnormalities in diabetic and hypertensive patients, in predicting the presence of silent myocardial ischemia, in providing a prognostic index in diabetic and hypertensive patients following acute myocardial infraction, and in predicting cardiovascular outcome in diabetic and hypertensive patients. In our study, it seems that NT-proBNP does provide clinically useful information regarding prognosis in patients with hypertension. NT-proBNP may also find a place in monitoring the effectiveness of antihypertensive therapy in improving cardiac structure and function and in reducing the risk of complications from hypertension.

Serial measurements of NT-proBNP in patients with ACS may be used for dynamic risk assessment and may be helpful for rapidly identifying patients who are suitable for early discharge or need more intensive therapy, including intervention, although the data at present are contraindicating.29,30 According to the guidelines, ACSs include UA pectoris, non-STEMI (non-STEMI), and STEMI.31–33 In patients with acute STEMI, both BNP and to a greater proportion NT-proBNP increased rapidly and peaked at 12 to 24 hours after the onset of chest pain, decreased slightly thereafter, but remained increased for up to 12 weeks.34 It was shown that patients with larger infarcts and lower ejection fractions presented a biphasic increase in BNP with a second peak on day 5 after admission, while patients with smaller infarcts had a monophasic increase.35

The value of natriuretic peptide measurement for risk stratification after ACS has been reported in several large trials. Patients with UA or non-STEMI showed the highest mortality in the highest NT-proBNP quartile or tertile, and NT-proBNP was an independent predictor or one of the most important predictors of death during long-term follow-up (between 1 year and 40 months) in the Fast Assessment in Thoracic Pain (FAST),36 the Assessment of Safety and Efficacy of a New Thrombolytic (ASSENT),37 the Global Utilization of Strategies To Open Occluded Arteries-IV (GUSTO-IV),38 and the Framingham and Fast Revascularization During Instability in Coronary Artery Disease (FRISC II),39 trials. A significant difference in NT-proBNP quartile-dependent mortality risk has already been seen within 2 days of the GUSTO-IV trial.38 At 1 year, an exponential increase in mortality was found in the spectrum of NT-proBNP (Roche) levels of the GUSTO-IV trial, with mortalities of 0.4% in the lowest decile (−98 ng/L) and 27.1% in the highest decile (>4634 ng/L).38 [Correction added after online publication 16-Jul-2010: The reference citation has been changed.] No significant difference in the prognostic value of BNP or NT-proBNP was found in either short- (OR, 4.31; 95% CI, 3.77–4.94) or long-term (OR, 3.38; 95% CI, 2.44–4.68) mortality, without any significant influence of whether the sample collection occurred on admission or within several hours (OR, 4.42; 95% CI, 3.83–5.10) or days after admission (OR, 3.51; 95% CI, 2.64–4.67).40 Furthermore, the prognostic value of natriuretic peptide determination was similar in STEMI and non-STEMI patients, with increasing mortality rates across NT-proBNP quartiles.6,41

Acute ischemia elicits increased NT-proBNP levels. In our study population, NT-proBNP levels and risk factors present statistically significant cross-correlation, especially in diabetics, hypertensives, smokers, and in those with hypercholesterolemia. The present study also demonstrates that plasma NT-proBNP measured in patients with ACS before and after PCI when compared with CK, CKMB, CRP, Tn-I, D-dimers, and fibrinogen, NT-proBNP was more sensitive for the diagnosis, with a similar high negative predictive value. More important, when measured in association with these biochemical markers on admission and after long-term follow-up, NT-proBNP levels added significantly to their diagnostic performance, increasing the sensitivity and negative predictive value to 92.3% and 99.6%, respectively. Future prospective studies are necessary for the recognition of patients at high risk for cardiac events. Measurement of NT-proBNP on admission improves the early risk stratification of patients with ACS, suggesting the need for development of targeted therapeutic strategies.

Limitations

  1. Top of page
  2. Abstract
  3. Methods
  4. Results
  5. Discussion
  6. Limitations
  7. Conclusions
  8. References

A limitation of this and all similar studies is the fact that circulating concentrations of the natriuretic peptides before the ischemic event are unknown. Accordingly, we cannot rule out the possibility that preexistent ventricular dysfunction, hypertrophy, or renal impairment, and not the ischemic injury per se, are the cause of NT-proBNP elevation and the relation to outcome. By adjusting for history of prior ACS, congestive heart failure, and hypertension, as well as for ejection fraction and serum creatinine, we attempted to minimize this effect.

Conclusions

  1. Top of page
  2. Abstract
  3. Methods
  4. Results
  5. Discussion
  6. Limitations
  7. Conclusions
  8. References

Elevated levels of CRP, Tn-I, CK, CKMB, fibrinogen, D-dimers, TIMI risk score, and NT-proBNP on admission would appear to have an independent prognostic value and the combination of multiple cardiac markers might have an incremental value in the risk stratification of patients with ACS. We demonstrate that neurohumoral activation, as evidenced by NT-proBNP elevation, is an independent and powerful determinant of the short-term cardiac risk in patients with ACS. Serial measurements of NT-proBNP in patients with ACS may be used for monitoring the clinical course of the patients. If future prospective studies confirm that those patients are indeed at very low risk for cardiovascular events during short-term follow-up, serial NT-proBNP levels may be helpful for rapidly identifying patients suitable for early discharge.

References

  1. Top of page
  2. Abstract
  3. Methods
  4. Results
  5. Discussion
  6. Limitations
  7. Conclusions
  8. References
  • 1
    Levin ER, Gardner DG, Samson WK. Natriuretic peptides. N Engl J Med. 1998;339:321328.
  • 2
    Hall C. Essential biochemistry and physiology of (NT-pro)BNP. Eur J Heart Fail. 2004;6:257260.
  • 3
    Goetze JP, Christoffersen C, Perko M, et al. Increased cardiac BNP expression associated with myocardial ischemia. FASEB J. 2003;17:11051107.
  • 4
    Tsutamoto T, Wada A, Maeda K, et al. Attenuation of compensation of endogenous cardiac natriuretic peptide system in chronic heart failure: prognostic role of plasma brain natriuretic peptide concentration in patients with chronic symptomatic left ventricular dysfunction. Circulation. 1997;96:509516.
  • 5
    Omland T, Persson A, Ng L, et al. N-terminal pro-B-type natriuretic peptide and long-term mortality in acute coronary syndromes. Circulation. 2002;106:29132918.
  • 6
    De Lemos JA, Morrow DA, Bentley JH, et al. The prognostic value of B-type natriuretic peptide in patients with acute coronary syndromes. N Engl J Med. 2001;345:10141021.
  • 7
    Wang TJ, Larson MG, Levy D, et al. Plasma natriuretic peptide levels and the risk of cardiovascular events and death. N Engl J Med. 2004;350:655663.
  • 8
    Omland T, Aakvaag A, Bonarjee VV, et al. Plasma brain natriuretic peptide as an indicator of left ventricular systolic function and long-term survival after acute myocardial infarction. Circulation. 1996;93:19631969.
  • 9
    Arakawa N, Nakamura M, Aoki H, et al. Plasma brain natriuretic peptide predicts survival after acute myocardial infarction. J Am Coll Cardiol. 1996;27:16561661.
  • 10
    Omland T, De Lemos JA, Morrow DA, et al. Prognostic value of N-terminal pro-atrial and pro-brain natriuretic peptide in patients with acute coronary syndromes. Am J Cardiol. 2002;89:463465.
  • 11
    Sabatine MS, Morrow DA, De Lemos JA, et al. Multimarker approach to risk stratification in non-ST elevation acute coronary syndromes: simultaneous assessment of troponin I, C-reactive protein, and B-type natriuretic peptide. Circulation. 2002;105:17601763.
  • 12
    Mega JL, Morrow DA, De Lemos JA, et al. B-type natriuretic peptide at presentation and prognosis in patients with ST-segment elevation myocardial infarction: an ENTIRE-TIMI-23 substudy. J Am Coll Cardiol. 2004;44:335339.
  • 13
    Schnabel R, Rupprecht HJ, Lackner KJ, et al. 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. Eur Heart J. 2005;26:241249.
  • 14
    Muller-Bardorff M, Hallermayer K, Schroder A, et al. Improved troponin T ELISA specific for cardiac troponin T isoform: assay development and analytical and clinical validation. Clin Chem. 1997;43:458466.
  • 15
    Cotton F, Thiry P, Hsain AB, et al. Analyzer transfer of a broad range high-sensitivity C-reactive protein immunoassay. Clin Lab. 2001;47:405409.
  • 16
    Lagrand WK, Visser CA, Hermens WT, et al. C-reactive protein as a cardiovascular risk factor: more than an epiphenomenon? Circulation. 1999;100:96102.
  • 17
    Morrow DA, Rifai N, Antman EM, et al. C-reactive protein is a potent predictor of mortality independently of and in combination with troponin T in acute coronary syndromes: a TIMI 11A substudy (Thrombolysis in Myocardial Infarction). J Am Coll Cardiol. 1998;31:14601465.
  • 18
    Festa A, D’Agostino R Jr, Howard G, et al. Chronic subclinical inflammation as part of the insulin resistance syndrome: the Insulin Resistance Atherosclerosis Study (IRAS). Circulation. 2000;102:4247.
  • 19
    Kondo N, Nomura M, Nakaya Y, et al. Association of inflammatory marker and highly sensitive C-reactive protein with aerobic exercise capacity, maximum oxygen uptake and insulin resistance in healthy middle-aged volunteers. Circ J. 2005;69:452457.
  • 20
    Nakanishi N, Shiraishi T, Wada M. C-reactive protein concentration is more strongly related to metabolic syndrome in women than in men: the Minoh Study. Circ J. 2005;69:386391.
  • 21
    Pasceri V, Willerson JT, Yeh ET. Direct proinflammatory effect of C-reactive protein on human endothelial cells. Circulation. 2000;102:21652168.
  • 22
    Fichtlscherer S, Rosenberger G, Walter DH, et al. Elevated C-reactive protein levels and impaired endothelial vasoreactivity in patients with coronary artery disease. Circulation. 2000;102:10001006.
  • 23
    Arroyo-Espliguero R, Avanzas P, Cosin-Sales J, et al. C-reactive protein elevation and disease activity in patients with coronary artery disease. Eur Heart J. 2004;25:401408.
  • 24
    Wiese S, Breyer T, Dragu A, et al. Gene expression of brain natriuretic peptide in isolated atrial and ventricular human myocardium: influence of angiotensin II and diastolic fiber length. Circulation. 2000;102:30743079.
  • 25
    Yasue H, Yoshimura M, Sumida H, et al. Localization and mechanism of secretion of B-type natriuretic peptide in comparison with those of A-type natriuretic peptide in normal subjects and patients with heart failure. Circulation. 1994;90:195203.
  • 26
    Talwar S, Squire IB, Downie PF, et al. Plasma N terminal pro-brain natriuretic peptide and cardiotrophin 1 are raised in unstable angina. Heart. 2000;84:421424.
  • 27
    Horio T, Shimada K, Kohno M, et al. Serial changes in atrial and brain natriuretic peptides in patients with acute myocardial infarction treated with early coronary angioplasty. Am Heart J. 1993;126:293299.
  • 28
    Richards AM, Nicholls MG, Yandle TG, et al. Plasma N-terminal pro-brain natriuretic peptide and adrenomedullin: new neurohormonal predictors of left ventricular function and prognosis after myocardial infarction. Circulation. 1998;97:19211929.
  • 29
    Richards AM, Nicholls MG, Yandle TG, et al. Neuroendocrine prediction of left ventricular function and heart failure after acute myocardial infarction: the Christchurch Cardioendocrine Research Group. Heart. 1999;81:114120.
  • 30
    Morrow DA, De Lemos JA, Sabatine MS, et al. Evaluation of B-type natriuretic peptide for risk assessment in unstable angina/non-ST-elevation myocardial infarction: B-type natriuretic peptide and prognosis in TACTICS-TIM1 18. J m Coll Cardiol. 2002;41:12641272.
  • 31
    Jernberg T, Lindahl B, Siegbahn A, et al. N-terminal pro-brain natriuretic peptide in relation to inflammation, myocardial necrosis, and the effect of an invasive strategy in unstable coronary artery disease. J Am Coll Cardiol. 2003;42:19091916.
  • 32
    Alpert JS, Thygesen K, Antman E, et al. Myocardial infarction redefined–a consensus document of the Joint European Society of Cardiology/American College of Cardiology Committee for the redefinition of myocardial infarction. J Am Coll Cardiol. 2000;36:959969.
  • 33
    Braunwald E, Antman EM, Beasley JW, et al. ACC/AHA 2002 guidelines update for the management of patients with unstable angina and non-ST-segment elevation myocardial infarction. J Am Coll Cardiol. 2002;40:13661374.
  • 34
    Gill D, Seidler T, Troughton RW, et al. Vigorous response in plasma N-terminal pro-brain natriuretic peptide (NT-BNP) to acute myocardial infarction. Clin Sci (Lond). 2004;106:135139.
  • 35
    Morita E, Yasue H, Yoshimura M, et al. Increased plasma levels of brain natriuretic peptide in patients with acute myocardial infarction. Circulation. 1993;88:8291.
  • 36
    Jernberg T, Stridsberg M, Venge P, et al. N-terminal pro brain natriuretic peptide on admission for early risk stratification of patients with chest pain and no ST-segment elevation. J Am Coll Cardiol. 2002;40:437445.
  • 37
    Bjorklund E, Jernberg T, Johanson P, et al. Admission NT-proBNP and its interaction with admission troponin T and ST-segment resolution for early risk stratification in ST-elevation myocardial infarction. Heart. 2006;92(6):735740.
  • 38
    James SK, Lindahl B, Siegbahn A, et al. N-terminal pro-brain natriuretic peptide and other risk markers for the separate prediction of mortality and subsequent myocardial infarction in patients with unstable coronary artery disease: a Global Utilization of Strategies To Open occluded arteries (GUSTO) IV substudy. Circulation. 2003;108:275281.
  • 39
    FRISC-2 investigators. Invasive compared with non-invasive treatment in unstable coronary-artery disease: FRISC II prospective randomised multicentre study. Lancet. 1999;354:708715.
  • 40
    Galvani M, Ferrini D, Ottani F. Natriuretic peptides for risk stratification of patients with acute coronary syndromes. Eur J Heart Fail. 2004;6:327333.
  • 41
    Galvani M, Ottani F, Oltrona L, et al. N-terminal pro-brain natriuretic peptide on admission has prognostic value across the whole spectrum of acute coronary syndromes. Circulation. 2004;110:128134.