Journal of the American College of Cardiology 2006 by the American College of Cardiology Foundation Published by Elsevier Inc.

Vol. 47, No. 3, 2006 ISSN 0735-1097/06/$32.00 doi:10.1016/j.jacc.2005.09.039

B-Type Natriuretic Peptide and the Risk of Cardiovascular Events and Death in Patients With Stable Angina
Results From the AtheroGene Study
Renate Schnabel, MD,* Edith Lubos, MD,* Hans J. Rupprecht, MD,* Christine Espinola-Klein, MD,* Christoph Bickel, MD, Karl J. Lackner, MD, Franois Cambien, MD, Laurence Tiret, PHD, Thomas Mnzel, MD, FAHA,* Stefan Blankenberg, MD* Mainz and Koblenz, Germany; and Paris, France
The aim of this study was to assess the predictive value of the cardiac hormone B-type natriuretic peptide (BNP) for long-term outcome in a large cohort of stable angina patients. BACKGROUND Recent data suggest a role of BNP in stable ischemic heart disease beyond its known value in heart failure and acute coronary syndromes. METHODS In 1,085 patients with coronary artery disease (CAD) baseline levels of BNP were prospectively associated with cardiovascular (CV) events during a mean follow-up of 2.5 years. RESULTS BNP concentrations were signicantly elevated in patients with future CV events (median [25th/75th interquartile range] 119.2 [43.6/300.4] pg/ml vs. 36.2 [11.3/94.6] pg/ml; p 0.001). Kaplan-Meier survival analysis showed a stepwise decrease in event-free survival across quartiles of BNP baseline concentration (plog rank 0.001). Patients in the highest quartile revealed a 6.1-fold increased risk (p 0.001) compared to patients in the lowest quartile after adjustment for potential confounders. For a cut-off value of 100 pg/ml, an independently increased risk of adverse outcome (hazard ratio [HR] 4.4; p 0.001) could be demonstrated. One standard deviation (SD) decrease in ejection fraction implied the most prominent increase in risk of future CV events (HR 1.69; p 0.001) followed by one SD increase in BNP (HR 1.53; p 0.001). The highest prognostic accuracy could be demonstrated for BNP (area under the curve 0.671). CONCLUSIONS The data of this large group of CAD patients provide independent evidence that BNP is a strong predictor of cardiovascular risk in patients with stable angina independent of left ventricular systolic performance and known risk factors. (J Am Coll Cardiol 2006;47: 552 8) 2006 by the American College of Cardiology Foundation OBJECTIVES

The degree of cardiac neurohormonal activation as indicated by B-type natriuretic peptide (BNP) has been extensively investigated in cardiac disease, primarily in mechanistic disorders of cardiac function. As a hormone indicator of myocardial stretch (1) BNP is an excellent marker of heart failure and has already entered international guidelines. Its reliable characteristics as a biomarker have spurred further investigations in other cardiovascular disease entities. Indeed, there is an increasing body of evidence for the concept that BNP might be an indicator of hypoxia and ischemia itself which may result in myocyte stress under ischemic conditions despite constancy in measurable hemodynamic parameters (2 4). For patients with acute coronary syndromes, impressive data have been generated for BNP in the prediction of outcome. Under these conditions BNP provides information on survival and incident heart failure incremental to that of anthropometric data and clinical variables (5,6). For long-term mortality assessment BNP
From the *Department of Medicine II and Department of Clinical Chemistry and Laboratory Medicine, Johannes Gutenberg University, Mainz, Germany; INSERM U525, Facult de Mdecine Piti-Salptrire, Paris, France; and the Innere Abteilung, Bundeswehrzentralkrankenhaus, Koblenz, Germany. Manuscript received June 22, 2005; revised manuscript received September 13, 2005, accepted September 19, 2005.

has proved to be superior to necrosis markers (7). Elevated BNP obviously does not depend on acute necrosis but may also indicate stable states of coronary artery disease (CAD) characterized by repetitive microischemia under stress without signicant rise of creatine kinase or troponins (8). There is also evidence that N-terminal B-type natriuretic peptide (Nt-proBNP), the inactive fragment of the prohormone, might also be a robust indicator of cardiovascular risk in patients with stable coronary disease (9 13). The aim of the current study was to examine the prognostic impact of BNP in a large group of consecutively enrolled stable angina patients on short-term as well as long-term cardiovascular (CV) outcome to evaluate the potential clinical applicability of BNP measurements in CAD.

METHODS
During the enrollment phase 1,085 consecutive patients presenting with stable angina and at least one stenosis 30% in the larger coronary arteries entered the observational AtheroGene registry at the two recruitment centers: Department of Medicine II of the Johannes Gutenberg University, Mainz, and the Bundeswehrzentralkrankenhaus, Koblenz, Germany.

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Abbreviations and Acronyms BNP B-type natriuretic peptide CAD coronary artery disease CRP C-reactive protein CV cardiovascular EF left ventricular ejection fraction HR hazard ratio

Further details on the concept of the AtheroGene study have been previously described (14). In the present substudy, exclusion criteria were clinical signs of instability (unstable angina Braunwald classication class B or C, acute ST-segment elevation, and nonST-segment elevation myocardial infarction). Further reasons for exclusion were clinical or echocardiographic signs of severe heart failure and additional known hemodynamically relevant cardiac abnormalities which might generate myocyte stress in addition to overt CAD, including severe valvular heart disease, surgery or trauma within the previous month, known cardiomyopathy, manifest carcinoma, chronic inammatory disease states and febrile conditions, and use of oral anticoagulant therapy within the previous four weeks. These exclusion criteria were met by up to 30% of the eligible patients. The history of classic risk factors was assessed as follows. Patients who had received antihypertensive treatment or who had received a diagnosis of hypertension (blood pressure above 160/90 mm Hg) were considered to have hypertension. Patients were classied as currently smoking, as having smoked in the past (if they had stopped more than 4 weeks and less than 40 years earlier), or as never having smoked (if they had never smoked or had stopped 40 or more years earlier). Patients who were receiving dietary treatment or medication for diabetes or who presented with fasting blood glucose levels above 125 mg/dl were dened as diabetic. In 769 patients, left ventricular ejection fraction (EF) was determined by angiography and off-line analysis according to the area-length method (15). Among the 1,085 patients, survival status remained unknown in 11 subjects (1%) who were lost during followup, and the data of 2 patients for whom EF was not available were excluded from analysis owing to a BNP concentration over 1,500 pg/ml, which might indicate severe heart failure. The nal study population consisted of 1,072 individuals who were followed over a median of 2.5 1.2 years (skewness 1). During this time, 35 cardiovascular deaths, 15 deaths from other causes, and 17 nonfatal myocardial infarctions were registered. The primary end point was nonfatal myocardial infarction and cardiovascular death. Follow-up information was obtained from patient charts and death certicates. All data were evaluated by an independent adjudication committee consisting of experienced physicians who were blinded to BNP concentrations. The study was approved by the local ethics committee of the University of Mainz. All patients were Caucasian. Participa-

tion was voluntary, and patients were enrolled after written informed consent was obtained. Laboratory methods. Blood samples were drawn under standardized conditions before coronary angiography was performed when the patients entered the catheterization lab after a minimum 12-h fast. Serum lipids and creatinine were measured immediately by routine methods; low-density lipoprotein was calculated by the Friedewald formula. For all other biomarkers measured in the study population, plasma and serum were stored at 80C immediately after centrifugation. Plasma B-type natriuretic peptide was determined using a uorescence immunoassay (Biosite, San Diego, California). The detection limit reported is 5 pg/ml, the upper limit 5,000 pg/ml. The assay has an interassay coefcient of variation of near 10%, and a recovery of 100% of added peptide was found. Cross-reactivity with other natriuretic peptides is negligible (16). C-reactive protein (CRP) was determined by a highly sensitive, latex particle-enhanced immunoassay (detection range 0 to 20 mg/l; Roche Diagnostics, Mannheim, Germany). Statistical considerations. The mean values and proportions of baseline cardiovascular risk factors, clinical variables, and biomarkers were calculated for study participants according to occurrence of future cardiovascular events. The statistical signicance of differences between the means for the two subgroups was assessed with Student t test, and the signicance of differences in proportions was tested with the chi-squared statistic. Variables with a skewed distribution were presented as medians and Wilcoxon rank sum test was applied. Patients were divided into four subgroups on the basis of their BNP level at the time of enrollment. The cumulative event plots according to quartiles of BNP concentration were estimated by the Kaplan-Meier method and compared with use of the log rank test. All survival analyses were conducted for the primary end point of nonfatal myocardial infarction and cardiovascular death. Data from patients who died from causes not related to cardiovascular disease were censored at the time of death. Hazard ratios for future CV events were estimated by Cox regression models adjusted for potential confounders. All models included the adjustment for age and sex. Further adjustment was performed for classic risk factors (body mass index, high-density lipoprotein cholesterol levels, a history of hypertension, diabetes, and smoking). The second model further comprised clinical variables such as presence of multivessel disease and cardiac medication with angiotensin-converting enzyme inhibitors and statins and the inammatory marker CRP. The nal analyses included EF into the regression models. To compare the predictive power of BNP to known risk measures in stable angina patients, the hazard ratios (HR) found for one standard deviation increase of BNP, CRP, brinogen, and EF were presented for two Cox regression models. A backward stepwise Cox regression approach was taken for the multi-

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variate analyses, with p 0.10 as the critical value for entering and excluding variables in the model. The HR and 95% condence interval (CI) are reported. The p values are two-sided; a p value of less than 0.05 was considered to indicate statistical signicance. All computations were carried out with SPSS software 11.5 (SPSS Inc., Chicago, Illinois).

RESULTS
The mean age of the study population was 61.6 9.4 years, and 79.7% were male. During follow-up, 52 CV events were documented (17 nonfatal myocardial infarctions and 35 CV deaths). BNP levels exhibited a skewed distribution with a

median (25th/75th interquartile range) of 38.3 (11.8/ 100.35) pg/ml. BNP concentration was signicantly higher in patients who suffered from future CV events than in those who remained free of adverse events (119.2 [43.6/ 300.4] vs. 36.2 [11.3/94.6] pg/ml; p 0.001). Baseline levels of BNP in patients who died from non-CV causes (n 15) were not signicantly different from those in event-free individuals (45.5 [5.0/171.4] vs. 36.1 [11.5/93.7] pg/ml; p 0.83). For overall mortality (n 50) it could be demonstrated that BNP concentrations were signicantly higher in the CV event group (119.2 [20.3/315.3] vs. 36.31 [11.6/97.8] pg/ml in event-free subjects; p 0.001). In Table 1 the baseline characteristics of the study population

Table 1. Baseline Characteristics of the Study Population According to Occurrence of Cardiovascular Events
Patients Without Cardiovascular Event n 1,020 61.6 9.4 80.4 27.7 14.8 80.4 21.2 102 (93/116.5) 37.0 46.4 16.7 195 (165/224) 121 (95/149) 48 (41/57) Patients With Cardiovascular Event n 52 61.7 10.4 65.4 27.9 21.0 71.2 40.4 108.5 (94.8/128.3) 28.8 44.2 26.9 203 (166/243) 124 (97/169) 46 (37.3/57.8) 0.29 0.37 0.22 0.74 28.0 31.6 40.4 73.4 15.2 138.0 67.1 69.7 12.0 95.3 15.3 27.1 65.2 14.8 49.6 55.5 63.6 30.8 19.6 (15.0/30.8) 309 (262/365) 36.2 (11.3/94.6) 2.3 (1.2/4.9) 0.94 (0.83/1.06) 25.0 36.5 38.5 77.0 14.7 138.2 31.9 69.6 11.6 95.7 17.0 22.0 56.7 21.0 48.1 48.1 55.8 42.3 24.9 (15.9/33.1) 352 (316/399) 119.2 (43.6/300.4) 4.28 (1.9/9.1) 1.02 (0.82/1.21)

Characteristic Age, yrs Male, % Traditional risk factors Body mass index, kg/m2 History of hypertension, % History of diabetes, % Fasting blood glucose, mg/% Cigarette smoking, % Never Ex-smokers Current smoking Lipid status Total serum cholesterol, mg/dl LDL cholesterol, mg/dl HDL cholesterol, mg/dl Clinical variables Number of diseased vessels, % 1 vessel 2 vessels 3 or more vessels Heart rate at entry, beats/min Systolic blood pressure at entry, mm Hg Diastolic blood pressure at entry, mm Hg MAP at entry, mm Hg PTCA at entry, % Left ventricular ejection fraction, % Medication, % ACE inhibitor Statin Beta-blocker Diuretics Metabolic variables BUN Biomarkers Fibrinogen, mg/dl Plasma B-type natriuretic peptide, pg/ml Plasma C-reactive protein, mg/l Serum creatinine, mg/dl

p Value 0.93 0.009 0.72 0.11 0.001 0.12 0.14

0.16 0.68 0.88 0.99 0.72 0.001 0.83 0.29 0.25 0.08 0.1 0.001 0.001 0.001 0.11

Data presented are percentage of patients, mean standard deviation, or median and 25th/75th interquartile range for skewed variables. For normally distributed variables, p values were computed with Student t test; for skewed variables, p values were computed with the Wilcoxon rank sum test for the difference in medians. For comparison of categorical variables a chi-square test was used. Invasive data were available for 942 (86.2%) subjects. Left ventricular ejection fraction determined by left ventricular angiography was available for 769 individuals. BUN blood urea nitrogen; HDL high-density lipoprotein; LDL low-density lipoprotein; MAP mean arterial pressure; PTCA percutaneous transluminal coronary angioplasty.

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Figure 1. Kaplan-Meier curves showing the cumulative incidence of cardiovascular events during follow-up according to quartiles of BNP plasma levels. Quartile ranges: Q1 11.84; Q2 11.84 to 38.30; Q3 38.30 to 100.35; Q4 100.35 pg/ml. BNP B-type natriuretic peptide.

according to the occurrence of future CV events are outlined. In the event group, the proportion of females was higher and diabetes was signicantly more often seen. Left ventricular ejection fraction was lower in subjects with adverse outcome, although the mean value was within the normal range in both groups. Both groups did not relevantly differ in general hemodynamic parameters measured invasively at study entry. Of the inammatory biomarkers determined, CRP and brinogen were higher in the event group, as expected (p 0.001 for both). Age at baseline was not signicantly different in both groups.

Figure 1 shows the Kaplan-Meier survival curves according to quartiles of baseline BNP concentration. The unadjusted event-free survival decreased in a stepwise fashion across increasing quartiles (plog rank 0.001). A threshold effect appeared for patients in the upper quartile, where a rapid decline in survival rate can be observed. To assess the independent strength of BNP for cardiovascular risk prediction in comparison with known cardiovascular risk factors, three Cox regression models were developed for logtransformed BNP concentration. The age- and genderadjusted HR showed a 3.36-fold (95% CI 2.01 to 5.61; p 0.001) increased risk. After adjustment for risk factors (HR 3.16, 95% CI 1.82 to 5.48; p 0.001) and EF (HR 2.87, 95% CI 1.47 to 5.58; p 0.002), which was available in 769 subjects, this association remained independently signicant. These models were similarly applied to the quartile analysis of BNP (Table 2). For patients in the upper quartile of BNP baseline concentration, an 8.1-fold (p 0.001) increased risk for future CV events could be observed in comparison with subjects in the rst quartile. This predictive power was only slightly diminished after the adjustment for potential confounders such as classic risk factors, clinical variables, CRP, and even EF. Owing to the observation of the fourth quartile border of 100.35 pg/ml, a cut-off value of 100 pg/ml was chosen and several Cox regression models were examined for patients who presented with BNP concentrations above this value at enrollment (Fig. 2). In comparison with patients whose baseline levels did not exceed this concentration, these subjects revealed a 4.4-fold (95% CI 2.4 to 7.8; p 0.001) increased risk of adverse outcome. This association remained stable even after full adjustment for classic risk factors, clinical variables, CRP, and EF.

Table 2. Hazard Ratios for Quartiles of Baseline BNP Concentration in Comparison With the Lowest Quartile
Quartile BNP (pg/ml) Cardiovascular events, n Cardiovascular events, % Age- and gender-adjusted Hazard ratio 95% CI p value Risk factor-adjusted* Hazard ratio 95% CI p value Fully adjusted Hazard ratio 95% CI p value n Q1 268 11.8 5 1.9 1 1.0 1.0 n Q2 268 n Q3 268 n Q4 268 100.3 28 10.4 8.14 2.9822.22 0.001 7.77 2.7322.1 0.001 6.10 2.018.57 0.001 0.001 p Value

11.838.3 7 2.6 1.67 0.525.29 0.39 1.77 0.555.69 0.34 1.34 0.384.82 0.65

38.3100.3 12 4.5 2.85 0.998.23 0.52 3.13 1.079.15 0.037 2.34 0.747.36 0.15

0.001

0.001

*Risk factor adjustment included age and gender, body mass index, C-reactive protein, and high-density lipoprotein as continuous variables. The following parameters entered the models as dichotomized variables: a history of hypertension, diabetes, smoking status, angiotensin-converting enzyme inhibitor therapy, statin therapy, and presence of multivessel disease. Additionally adjusted for ejection fraction. Because of missing values for left ventricular ejection fraction, this model consists of data from only 769 patients. BNP B-type natriuretic peptide; CI condence interval; Q quartile.

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Figure 2. Hazard ratio and 95 percent condence interval (CI) of cardiovascular events associated with BNP concentrations above a chosen cut-off value of 100 pg/ml, the border of the upper quartile in this cohort being 100.35 pg/ml. Adjustment was performed in four consecutive models as outlined. The traditional risk factors (RFs) (models 2 to 4) comprised age, gender, a history of hypertension, diabetes, smoking status, body mass index, and high-density lipoprotein (the last two parameters entered the model as continuous variables). Presence of multivessel disease and therapy with angiotensin-converting enzyme inhibitors and statins entered the Cox regression analysis as clinical variables (models 2 to 4). BNP B-type natriuretic peptide; CRP C-reactive protein; EF angiographically determined left ventricular ejection fraction.

The 13 clinical and laboratory variables that predicted (p 0.1) univariate risk were entered into multivariate Cox regression analyses (Table 3). One SD increase of BNP (HR 1.4, 95% CI 1.1 to 1.7; p 0.004) was selected as an independent predictor of cardiovascular events, together with one SD decrease in EF (HR 1.4, 95% CI 1.1 to 1.9; p 0.012). The nal model further included female gender (HR 0.5, 95% CI 0.2 to 1.0; p 0.04) and statin therapy (HR 0.6, 95% CI 0.3 to 1.1; p 0.08). These results did not differ signicantly when CRP was also introduced into the initial model. To further pose BNP into relation to known risk markers in patients with manifest CAD, the predictive power of one SD increase in BNP levels, CRP, and brinogen and one SD decrease in EF are illustrated in Figure 3. In this group of patients without overt systolic heart failure, the decrease in left ventricular function implied the most prominent increase in risk of future CV events (HR 1.69; p 0.001), followed by BNP (HR 1.53; p 0.001), brinogen (HR 1.49; p 0.001), and CRP (HR 1.22; p 0.002). Similar relations were found after adjustment for classic risk factors and clinical variables. The highest prognostic accuracy could be demonstrated for BNP (maximum area under the receiver operating characteristics curve of 0.671) and the lowest value for EF (0.623). When analyses were performed in the subgroup of patients (n 769) for whom EF data were available, the results were similar.

subjects independent of left ventricular systolic function and inammatory biomarkers. Evidence is accumulating that BNP may serve as an indicator of ischemic disease. Apart from its strong diagnostic and prognostic characteristics in patients with left ventricular dysfunction (11,17), ischemia seems to be a trigger of BNP expression and release (2,4). In acute ischemia the magnitude of BNP increase mirrors the extent of jeopardized myocardium and the tendency toward adverse remodeling more closely than any other current marker. It has been shown that BNP concentration provides information independent of necrosis markers and more adequately reects myocardial territory at risk under acute ischemia. Similar conditions seem to apply for reversible ischemia under stress testing, because the proportion of ischemic territory without overt necrosis is consistently reected in BNP levels (18). However, generalization has to be considered with caution, because BNP is not specic enough as a measure of ischemia. In community-based cohorts, a prospective association between BNP levels and a range of CV outcomes and overall mortality has been reported in asymptomatic individuals with BNP thresholds well below those used to diagnose heart failure (19). In the primary prevention screening it will be difcult to provide therapeutically clear directives facing the multitude of causes leading to a moderate increase in BNP. Under the precondition of diagnosed CAD the situation might be different. First evidence thus suggests an advantageous role of BNP in secondary risk stratication. BNP seems to reliably diagnose those patients with adverse outcome with a four-fold increased risk for individuals with BNP levels elevated above a potential cut-off value of 100 pg/ml. Although median BNP concentrations in the general CAD population were found to be far below those observed in acute heart failure (20), the concentration to rule out heart failure might get a new dimension, because stable angina patients who present with BNP above this level were at high risk to experience an adverse cardiovascular outcome during follow-up and should attract special attention.
Table 3. Final Model of a Backward Multiple Stepwise Regression Analysis for Cardiovascular Risk Predictors
Variable BNP (1 SD increase) LV ejection fraction (1 SD decrease) Female gender Statin intake Hazard Ratio 1.36 1.45 0.45 0.56 95% CI 1.111.68 1.081.93 0.250.97 0.291.07 p Value 0.004 0.012 0.04 0.08

DISCUSSION
This large-scale prospective study demonstrates the high prognostic value of BNP for long-term outcome in stable angina patients in a Caucasian cohort of consecutive CAD

Thirteen variables were introduced into a multiple stepwise backward regression model: age (dichotomized for the age of 65), gender, body mass index, a history of hypertension, diabetes, smoking, presence of multivessel disease, cardiac medication (ACE inhibitors, statins, and beta-blocker), one standard deviation (SD) increase in B-type natriuretic peptide (BNP), high-density lipoprotein cholesterol, and one SD decrease in left ventricular (LV) ejection fraction. A stepwise backward regression was calculated. p 0.1 was chosen as the critical value for entering and excluding variables in the model. Hazard ratios and 95% condence intervals are reported with two-tailed probability values.

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Figure 3. Hazard ratio associated with an increase of one standard deviation in the outlined variables. Model 1 is adjusted for age and gender. Model 2 additionally includes traditional risk factors (a history of hypertension, diabetes, smoking status, body mass index, and high density lipoprotein as continuous parameter) and clinical variables (multivessel disease and therapy with angiotensin-converting-enzyme inhibitors and statins). In addition, the adjusted areas under the receiver operating characteristics curve (AUC) are provided for the four variables assessed in the Cox regression model. It has to be noted that the nal model included only 767 patients because of missing data for ejection fraction and C-reactive protein. Abbreviations as in Figure 2.

Further investigations have to be undertaken to standardize Nt-proBNP and BNP data, determine cut-off values, and derive therapeutic implications. The value of additional BNP determination becomes obvious in comparison with anthropometric and metabolic variables. B-type natriuretic peptide retained its strong and independent predictive power after adjustment for age, gender, and renal function, which are associated with BNP concentrations and are potent risk factors themselves (2123). The data from our cohort of consecutive unselected stable angina pectoris patients show that routine applicability seems to be practicable without loss of validity. Importantly, the risk information provided by BNP proved to be independent of angiographically dened severity of CAD and cardiac functional parameters, which further underlines the value of additional BNP determination. Backward regression analysis revealed BNP and EF as the strongest predictors of future CV events, which demonstrates that risk information gained by BNP determination is complementary and obviously incremental to systolic left ventricular performance (6). Study limitations. As a limitation it must be mentioned that for this cohort only single measurements at enrollment can be investigated. Serial measurements of BNP concentrations would be of great interest for elucidating effective-

ness of therapeutic strategies and evaluating whether initially determined cardiac risk can be modied by therapeutic interventions. Furthermore, as expected, only a small number of events were registered during follow-up in this intermediate-risk population, which reduces statistical power. Despite the relatively low event rate, BNP provided strong results after adjustment for known risk predictors, underlining the strength of this novel biomarker. Conclusions. The present data support the view that BNP might develop into a biomarker for many cardiac seasons (24). Responsible for the ne tuning of cardiac homeostasis, it is involved in a variety of cardiac abnormalities. Until its pathophysiologic background is entirely understood, an increasing number of novel clinical indications and benets can be expected. The results of the present study, taken together with recent data on Nt-proBNP, provide a promising basis for further investigations into risk stratication in stable CAD where BNP has been shown to improve prognosis assessment in this intermediate-risk group independent of and incremental to classical risk factors. Acknowledgments The test assay for BNP was kindly performed by Biosite, San Diego, California. We are indebted to Margot Neuser for her graphical work.

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and prediction of benet from carvedilol in chronic ischemic left ventricular dysfunction. Australia-New Zealand Heart Failure Group. J Am Coll Cardiol 2001;37:17817. Richards AM, Doughty R, Nicholls MG, et al. Neurohumoral prediction of benet from carvedilol in ischemic left ventricular dysfunction. Australia-New Zealand Heart Failure Group. Circulation 1999;99:786 92. Omland T, Richards AM, Wergeland R, Vik-Mo H. B-type natriuretic peptide and long-term survival in patients with stable coronary artery disease. Am J Cardiol 2005;95:24 8. Blankenberg S, Rupprecht HJ, Bickel C, et al. Glutathione peroxidase 1 activity and cardiovascular events in patients with coronary artery disease. N Engl J Med 2003;349:160513. Dodge HT, Sandler H, Baxley WA, Hawley RR. Usefulness and limitations of radiographic methods for determining left ventricular volume. Am J Cardiol 1966;18:10 24. Cabanes L, Richaud-Thiriez B, Fulla Y, et al. Brain natriuretic peptide blood levels in the differential diagnosis of dyspnea. Chest 2001;120: 204750. Talwar S, Squire IB, Davies JE, Barnett DB, Ng LL. Plasma N-terminal pro-brain natriuretic peptide and the ECG in the assessment of left-ventricular systolic dysfunction in a high risk population. Eur Heart J 1999;20:1736 44. Marumoto K, Hamada M, Hiwada K. Increased secretion of atrial and brain natriuretic peptides during acute myocardial ischaemia induced by dynamic exercise in patients with angina pectoris. Clin Sci (Lond) 1995;88:551 6. 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;350:655 63. Maisel AS, Krishnaswamy P, Nowak RM, et al. Rapid measurement of B-type natriuretic peptide in the emergency diagnosis of heart failure. N Engl J Med 2002;347:1617. Anavekar NS, McMurray JJ, Velazquez EJ, et al. Relation between renal dysfunction and cardiovascular outcomes after myocardial infarction. N Engl J Med 2004;351:128595. Yerkey MW, Kernis SJ, Franklin BA, Sandberg KR, McCullough PA. Renal dysfunction and acceleration of coronary disease. Heart 2004; 90:961 6. McGregor DO, Troughton RW, Frampton C, et al. Hypotensive and natriuretic actions of adrenomedullin in subjects with chronic renal impairment. Hypertension 2001;37:1279 84. Mark DB, Felker GM. B-type natriuretic peptidea biomarker for all seasons? N Engl J Med 2004;350:718 20.

Reprint requests and correspondence: Dr. Renate Schnabel, Johannes Gutenberg-University, Cardiology, Langenbeckstrasse 1, Mainz, Rheinland-Pfalz 55131, Germany. E-mail: schnabelr@ gmx.de.

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