Early brain natriuretic peptide increase reflects acute myocardial ischemia in patients with ongoing chest pain

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1 International Journal of Cardiology 101 (2005) Early brain natriuretic peptide increase reflects acute myocardial ischemia in patients with ongoing chest pain Nikolaos I. Nikolaou a, *, Zenon S. Kyriakides b, Elias P. Tsaglis a, Dionysios G. Antonatos a, Eustathios C. Kartsagoulis c, Dimitrios L. Tsigas a a Cardiology Department, Agia Olga General Hospital, Athens, Greece b Cardiology Department, Red Cross General Hospital, Athens, Greece c Cardiology Department, Thriasio General Hospital, Athens, Greece Received 8 September 2003; received in revised form 27 January 2004; accepted 3 March 2004 Available online 2 July 2004 Abstract Background: Plasma brain natriuretic peptide levels increase during acute ischemic events. In this study we tested the diagnostic performance of brain natriuretic peptide measurements in the detection of acute myocardial ischemia. Methods: Blood brain natriuretic peptide was measured in 101 patients with ongoing chest pain but no heart failure or an ST-segment elevation myocardial infarction on arrival at the emergency department (baseline) and at 2 and 6 h later. After diagnostic testing and 1-month follow-up for ischemia, patients were classified as either ischemic or non-ischemic. Results: In the ischemic group median (25th, 75th percentiles) brain natriuretic peptide values (pg/ml) were 122 (20, 349) at baseline, 116 (36, 347) at 2 h, increasing to 148 (52, 428) at 6 h ( p < vs. baseline). Non-ischemic patients had 12 (5, 32) at baseline, 9 (6, 30) at 2 h, and 13 (5, 29) at 6 h ( p < vs. corresponding values of the ischemic group). Receiver operator characteristic curves were constructed for brain natriuretic peptide values at baseline 2 and 6 h and for the increase of peptide levels from baseline to 6 h. All areas under curve indicated a significant diagnostic ability for the detection of ischemia. The 6-h measurement had better diagnostic performance than baseline and 2-h measurements. The subgroup of ischemic patients without myocardial necrosis also had higher brain natriuretic peptide values and could thus be discriminated from non-ischemic subjects. Conclusions: Brain natriuretic peptide values may detect acute myocardial ischemia in patients with ongoing chest pain but without ST-segment elevation, and distinguish ischemic patients from those with pain of non-ischemic origin. D 2004 Elsevier Ireland Ltd. All rights reserved. Keywords: Natriuretic peptides; Diagnosis; Myocardium; Ischemia 1. Introduction Brain natriuretic peptide (BNP) is a hormone released by the heart primarily in response to the increased wall tension accompanying myocardial dysfunction and contributes to the maintenance of cardiovascular homeostasis through its significant vasodilatory, natriuretic and diuretic properties [1]. Increased BNP concentrations have been demonstrated in a variety of cardiac disorders in comparison to healthy people, and this has led to the evaluation of its measurement as a means for the detection of left ventricular dysfunction in * Corresponding author. 106 Marathonodromon Street, GR , Marousi, Greece. Tel.: ; fax: address: nikosnik@otenet.gr (N.I. Nikolaou). several clinical settings [2,3]. Determination of BNP levels is an established method for screening people with symptoms suggestive of heart failure in the primary care setting [4]. It has also been proposed as a diagnostic tool for the detection of asymptomatic left ventricular dysfunction [3], acute allograft rejection [5] and arrhythmogenic right ventricular dysplasia [6]. BNP levels also increase in patients with unstable angina and acute myocardial infarction, in comparison to control subjects, within 48 h from the last episode of ischemic chest pain [7,8]. Recently, we demonstrated that BNP increases acutely, over a period of minutes, and more prominently than atrial natriuretic peptide, during acute ischemia induced during coronary angioplasty [9]. Also, it was shown that, in patients with chest pain compatible with ischemia and normal electrocardiogram, the use of troponin and BNP /$ - see front matter D 2004 Elsevier Ireland Ltd. All rights reserved. doi: /j.ijcard

2 224 N.I. Nikolaou et al. / International Journal of Cardiology 101 (2005) together provides better results than either troponin or BNP alone for the identification of patients with significant coronary lesions [10]. The aim of the present study was to investigate the value of BNP to detect myocardial ischemia in patients with ongoing chest pain suggestive of myocardial ischemia but without ST-segment elevation. 2. Materials and methods 2.1. Patient selection This was a prospectively organized observational study. Its population consisted of 101 consecutive patients, age >40 years, who were examined in the emergency department of a community hospital between March 15 and November 1, 2002, because of continuing chest pain suggestive of acute myocardial ischemia. Patients were enrolled into the study if the underlying diagnosis was not suggested by either ST-segment elevation on the presenting electrocardiogram or the findings in a portable chest X-ray film. Exclusion criteria were evidence of past or overt heart failure, left ventricular dysfunction, and significant valvular disease during initial evaluation. The Hospital Ethics Committee approved the study, and all subjects gave informed consent. All patients were prospectively evaluated for the presence of acute ischemia as the cause of chest pain and were finally classified into one of the study groups: the ischemic group and the non-ischemic group Initial hospital evaluation Eligibility for the study was assessed by the first author (NN) upon patient arrival at the emergency department. Standard hospital evaluation procedures were followed, including clinical examination, continuous monitoring of the cardiac rhythm, frequent 12-lead electrocardiographic recordings, and measurements of troponin I and creatine phosphokinase-mb mass. Chest pain was considered to be ischemic if it was identical to previously documented ischemic symptoms. Electrocardiographic diagnosis of ischemia was made if new or presumed new ST-segment depression ( z 0.5 mm) or T wave inversion ( z 1 mm) occurred in two or more contiguous leads within 12 h from patient arrival. An acute myocardial infarction was diagnosed if (1) new pathologic Q waves evolved in at least two contiguous leads, (2) troponin I and/or creatine phosphokinase-mb mass typical rise and fall occurred after the index event and (3) evidence of an acute myocardial infarction was present at autopsy [11]. Unstable angina was diagnosed in patients with myocardial ischemia without evidence of infarction. Markers of myocardial necrosis had to remain within normal limits for at least 12 h after initiation of symptoms in order to rule out myocardial infarction Non-invasive testing Individuals without an established diagnosis of ischemia during the initial evaluation had standard exercise testing within the next 72 h. If the baseline ECG was not interpretable for myocardial ischemia, radionuclear perfusion imaging was performed, while patients unable to walk had a dobutamine imaging test. Criteria to define an abnormal study included 1 mm of horizontal or downsloping ST-segment depression 80 ms after the J point during standard treadmill testing, a perfusion defect by myocardial perfusion imaging and worsening regional wall motion by echocardiography. At the same time, an echocardiogram, including twodimensional and pulsed Doppler examination, was performed using a General Electric Vigmed Ultrasound unit. Left ventricular ejection fraction was measured using the mean value of three measurements obtained using Simpson s biplane method. Doppler measurements were calculated from the average of five consecutive cardiac cycles. To assess left ventricular diastolic function the ratio of early (E) to late (A) peak transmitral velocities, isovolumic relaxation time, and peak early filling (E) wave velocity deceleration time was measured. If a definite conclusion about the etiology of chest pain could not be reached using non-invasive testing, coronary arteriography was performed. Severity of coronary narrowing was determined using a digital electronic calliper. Coronary artery disease was considered to be present when lesions were obstructing z 50% of the coronary lumen diameter One-month follow-up Patients without evidence of myocardial ischemia during the aforementioned evaluation procedures were programmed for 1-month follow-up examination and if necessary they were referred to a specialty clinic to establish non-cardiac causes of pain. They were followed for the occurrence of death, non-fatal myocardial infarction, acute heart failure, out-of-hospital cardiac arrest, and any evidence of myocardial ischemia documented during repeat hospitalization, and/or further testing beyond that scheduled initially Patient classification into the study groups After the 1-month follow-up was completed patients were classified into the study groups. A patient was classified into the non-ischemic group if there was (1) no evidence of myocardial ischemia or infarction during the initial hospital evaluation or non-invasive testing, (2) absence of significant or unstable coronary lesions on the coronary angiogram and (3) absence of an acute ischemic event during the 1-month follow-up period. Otherwise, the patient was classified into the ischemic group.

3 N.I. Nikolaou et al. / International Journal of Cardiology 101 (2005) Blood sampling Blood samples for baseline BNP measurements were drawn upon arrival in the emergency department before the initiation of therapy and at 2 (BNP at 2 h) and 6 h (BNP at 6 h) thereafter. The samples were put in tubes containing ethylenediamine-tetraacetic acid (1 mg/ml of blood). Samples for troponin I and CK-MB mass were put into 5-cm 3 glass vacutainers containing lithium and heparin Laboratory analysis Specially trained personnel who were unaware of the individual patients clinical characteristics analyzed all samples within 60 min after draw time in the coronary care unit. Equipment was under the supervision of the central hospital laboratory. Whole blood samples for BNP measurement were analyzed using TriageR System for BNP (Biosite Diagnostics, La Jolla, CA, USA). The average 95% confidence limit of the analytical sensitivity of the triage BNP test is pg/ml. Coefficients of variation are 10.1%, 12.4% and 16.2% for mean values 28.8, and pg/ml, respectively. The median value of three consecutive readings of the same test device was used for the final analysis. Cardiac troponin I and creatine phosphokinase-mb mass were determined using quantitative radial partition immunoassays in combination with StratusR CS STAT Fluorometric Analyzer (Dade Behring). Analytical sensitivity is 0.03 ng/ ml for cardiac troponin I and 0.3 ng/ml for creatine phosphokinase-mb mass. Total coefficients of variation are 4.5% at 0.1 ng/ml for troponin I and 4% at 3.7 ng/ml for creatine phosphokinase-mb Statistical analysis All continuous variables are summarized using the median and the interquartile range (25th and 75th percentiles). For comparisons of continuous data between the two study groups the Mann Whitney U test was used. Differences in proportions were judged by chi-square analysis. The presence of significant differences between BNP measurements at 2 and 6 h in comparison with baseline BNP values was tested separately for each study group using Friedman analysis of variance by ranks. If analysis of variance suggested the presence of significant differences then posthoc comparisons were done using the Wilcoxon matched pairs test. For hypothesis testing p values < 0.05 were considered significant. Unadjusted associations between BNP values and independent variables were tested using Spearman s rank R. Adjusted associations were tested using multiple linear regression. To study the performance of BNP values in the diagnosis of ischemia, receiver operator characteristic curves were constructed, plotting sensitivity against 1 minus specificity for every distinct BNP value. A variable was considered to be of diagnostic significance if the 95% confidence interval for the area under the corresponding receiver operator characteristic curve did not include the 0.5 value. The point with the best discriminatory value was identified as the BNP value that had the fewest false test results. 3. Results During the enrolment period 131 patients presented in the emergency department for the evaluation of ongoing chest pain without ST-segment elevation on the presenting ECG and no identifiable cause in a portable X-ray film. Of these, 14 were excluded from the study due to concomitant acute heart failure, eight due to a history of congestive heart failure and/or cardiomyopathy and three due to significant valvular heart disease. Five patients (four without evidence of ischemia and one with evidence of a non-q-wave myocardial infarction) declined to participate. The characteristics of the latter were not different than those who were enrolled in the study. Of the 101 patients who were finally enrolled, after in-hospital and 1-month follow-up evaluation 31 were assigned to the ischemic group (14 had evidence of acute myocardial infarction) and 70 to the non-ischemic group. Etiologies of pain in the non-ischemic group were musculoskeletal pain (n = 20), psychiatric causes (n = 12), gastrointestinal (n = 8), pulmonary embolism (n = 1), pericarditis (n = 1), other/no diagnosis (n = 29). One of these patients had two diagnoses (psychiatric background, musculoskeletal pain). None of the included patients exhibited an ST-segment elevation ECG pattern during the first 6 h from arrival into the emergency department. Patients in the ischemic group (Table 1) were older and had a higher frequency of hypertension, diabetes mellitus and known coronary artery disease. Their systolic and diastolic left ventricular performance, estimated by echocardiography, was worse than those of the non-ischemic group, as shown by a lower ejection fraction, longer isovolumic relaxation time and more prolonged deceleration time. The study groups did not differ significantly with respect to gender, smoking, hypercholesterolemia and family history of coronary artery disease. Similarly, there were no differences in the duration of chest pain, blood pressure or heart rate measured simultaneously with BNP measurements. BNP levels were higher in the ischemic vs. non-ischemic group at all time points of measurement (Table 2). At 6 h a highly significant increase in BNP values vs. baseline was evident only in the ischemic group. Higher BNP concentration and a significant increase at 6 h were evident both in ischemic patients with and without evidence of myocardial necrosis. BNP levels did not increase above baseline values at 2 h in either ischemic or non-ischemic group. Unadjusted correlation analysis showed that baseline BNP levels were correlated positively with age (R = 0.6, p < ), history of arterial hypertension (R =0.26,

4 226 N.I. Nikolaou et al. / International Journal of Cardiology 101 (2005) Table 1 Characteristics of the two groups Ischemic group (n = 31) p = 0.01), isovolumic relaxation time (R = 0.32, p = 0.01), presence of myocardial ischemia (R = 0.50, p < ) and inversely with left ventricular ejection fraction (R = 0.34, p = 0.001). As shown in Table 3, the presence of myocardial ischemia was an independent predictor of BNP values upon admission, after adjustment for the effects of age, history of arterial hypertension, left ventricular ejection fraction and isovolumic relaxation time. The BNP increase at 6 h was positively correlated with the presence of ischemia (R = 0.62, p < ), history of arterial hypertension (R = 0.22, p = 0.04) and inversely with left ventricular ejection fraction (R = 0.34, p = 0.001). As shown in Table 4, ischemia was Table 2 Time course of whole blood brain natriuretic peptide (BNP) levels (pg/ml) and results of Friedman analysis of variance in the two study groups N Baseline 2 h 6 h Friedman v 2 ( p) Non-ischemic group Ischemic group Myocardial infarction Unstable angina (5, 32) (20, 349 )* (28, 349 )* (20, 490)* Values expressed as median (25th, 75th percentile). * p < vs. non-ischemic group. y p < vs. baseline BNP and BNP at 2 h. Non-ischemic group (n = 70) Male gender, n (%) 18 (58) 49 (70) Current smoker, n (%) 15 (48) 38 (54) Hypertension, n (%) 22 (71) 27 (38)** Hypercholesterolemia, n (%) 17 (55) 35 (50) Diabetes mellitus, n (%) 12 (39) 10 (14)** Family history of CAD, n (%) 9 (29) 12 (17) Known CAD, n (%) 16 (52) 12 (17)*** Age (years) 65 (60, 76) 57 (48, 68)** Duration of pain (min) 60 (30, 150) 45 (25, 120) SBP upon arrival (mmhg) 140 (125, 180) 130 (120, 170) SBP at 2 h (mmhg) 120 (115, 150) 110 (100, 140) SBP at 6 h (mmhg) 120 (105, 140) 115 (110, 135) HR upon arrival (min 1 ) 82 (66, 97) 79 (70, 90) HR at 2 h (min 1 ) 72 (63, 79) 70 (69, 78) HR at 6 h (min -1 ) 73 (61, 80) 68 (50, 80) Ejection fraction (%) 55 (46, 60) 64 (58, 68)*** E/A 0.8 (0.7, 1) 0.9 (0.8, 1.1) Isovolumic relaxation time (ms) 126 (105, 176) (93, 123)* Deceleration time (ms) 222 (185, 258) 194 (160, 212)* Data are presented as median (25th, 75th percentile) unless stated otherwise. n = number of observations, CAD = coronary artery disease, SBP = systolic blood pressure, HR = heart rate, E/A ratio = early to late left ventricular peak filling velocities. * p < 0.05 vs. ischemic group. ** p < 0.01 vs. ischemic group. *** p < vs. ischemic group. 9 (6, 30) 13 (5, 29) 0.97 (0.61) (36, 347)* (52, 428) *,y ( < ) (43, 308)* (72, 418) *,y ( < ) (34, 503)* (47, 648) *,y ( < ) Table 3 Regression results of baseline brain natriuretic peptide values on age, history of arterial hypertension, allocation into the ischemic group, left ventricular ejection fraction and isovolumic relaxation time Beta SE beta T p Age Hypertension Ischemia EF IVRT Beta = standardized regression coefficients, SE = standard error, EF = left ventricular ejection fraction, IVRT = left ventricular isovolumic relaxation time. by far the most powerful predictive indicator of BNP increase at 6 h. Left ventricular ejection fraction was an independent predictor as well. The results of receiver operator characteristic curve analysis are shown in Table 5. Area under curve showed a significant diagnostic performance of BNP values at all measurement time points. As indicated in Fig. 1, areas under curve were greater at 6 h than at 2 h (difference between areas = 0.04, standard error of difference = 0.017, p = 0.03) and at baseline (difference between areas = 0.09, standard error of difference = 0.02, p = ). This is reflected in the augmented specificity and positive predictive value that is observed as we proceed from baseline BNP to those at 6 h. BNP levels remained diagnostic for myocardial ischemia even if only patients with unstable angina and no evidence of myocardial necrosis were included in the analysis (Fig. 2). This became evident from corresponding areas under curve (95% confidence limits) which were 0.83 (0.74, 0.90) for BNP levels at baseline, 0.87 (0.77, 0.93) at 2 h, 0.89 (0.81, 0.95) at 6 h and 0.86 (0.77, 0.93) for peptide level increase to 6 h. 4. Discussion The present study is one of the first to investigate the diagnostic performance of BNP concentrations for the detection of acute ischemia in patients presenting with ongoing chest pain. It demonstrated that whole blood BNP level measurements might help in the detection of acute ischemia in these patients. Table 4 Regression results of brain natriuretic peptide value increase from baseline to 6 h on left ventricular ejection fraction, history of arterial hypertension and allocation into the ischemic group Beta SE beta T p EF Hypertension Ischemia Beta = standardized regression coefficients, SE = standard error, EF = left ventricular ejection fraction.

5 N.I. Nikolaou et al. / International Journal of Cardiology 101 (2005) Table 5 Diagnostic performance characteristics of brain natriuretic peptide measurements for the detection of myocardial ischemia in patients with continuing chest pain Baseline 2 h 6 h 6 h baseline Area under curve (95% CL) Positivity criterion (pg/ml) 0.81 (0.72, 0.88) 0.87 (0.78, 0.93) 0.9 (0.83, 0.95) >26 >28 >41 >6 Sensitivity Specificity Positive predictive value Negative predictive value CL = confidence limits (0.81, 0.94) 4.1. Whole blood BNP levels BNP measurements were made during a time interval that is important for the establishment of the diagnosis in patients with suspected myocardial ischemia. BNP concentrations were higher in patients who turned out to be ischemic vs. non-ischemic after in-hospital and 1-month evaluation at all the time points of measurement. Elevated plasma BNP levels highly predicted the diagnosis of myocardial ischemia, and the association was independent of the effects of age and hypertension, which are known to be positively correlated with BNP levels [12 14]. These findings are in agreement with previous reports which have shown that BNP levels are increased in the course of unstable angina and acute myocardial infarction [15]. Increased global [16] and/or regional wall stress in the Fig. 1. Receiver operator characteristic curves of brain natriuretic peptide values at baseline and at 2 and 6 h after patient arrival in the emergency department, for the diagnosis of acute ischemic events. Fig. 2. Receiver operator characteristic curves of brain natriuretic peptide values at baseline and at 2 and 6 h after patient arrival in the emergency department, for the diagnosis of unstable angina. ischemic ventricle have been suggested as stimuli for augmented BNP release in such patients. It has also been speculated that BNP is secreted as an acute phase reactant to vascular injury [17]. The effect of ischemia on baseline BNP levels was also independent and far outweighed the effects of left ventricular ejection fraction and isovolumic relaxation time. This could be due to the dynamic nature of left ventricular dysfunction during the course of acute ischemic events, which may not be represented by a single measurement performed within 72 h from patient s arrival into the emergency department. It is also possible that early after the initiation of ischemia, mechanisms such as the increase of regional wall stress may predominate for the elevation of BNP levels. As time from the onset of the ischemic event passes, however, left ventricular ejection fraction becomes an independent explanatory variable for BNP increase. BNP elevation in our ischemic patients may therefore be explained at least in part by the effect of myocardial ischemia and necrosis on the diastolic and systolic properties of the left ventricle. Increased age is another factor contributing to elevated BNP levels in the ischemic group. Age has consistently been shown to be positively associated with BNP levels and it has been suggested that this should be considered when BNP is used as a diagnostic tool [12,13]. Nevertheless, increased BNP levels with age may represent an alternative way of expressing the increasing risk for coronary artery disease with age and therefore they may not adversely affect BNP diagnostic performance. As ischemia seems to be etiologically associated with acute elevation of BNP levels it is not surprising that BNP

6 228 N.I. Nikolaou et al. / International Journal of Cardiology 101 (2005) increased only in the ischemic group of our study. In a report concerning patients admitted to the coronary care unit for chest pain, Jernberg et al. [18] reported that N-terminal pro-brain natriuretic peptide, a molecule derived in an equimolar basis from the same parent molecule as brain natriuretic peptide, increases during the first 6 h after admission in patients with unstable angina or acute myocardial infarction. However, in this study in contrast to our findings N-terminal pro-bnp also increased in the group of patients with non-cardiac/unknown causes of pain. This may be explained by the higher prevalence of pulmonary embolism and other causes associated with increased BNP [19], which was reported by Jenberg et al. [18] in the non-cardiac pain subgroup. In our study only one patient turned out to suffer a pulmonary embolism. Initial BNP levels were elevated and increased further during the first 6 h in a manner that was indiscernible from that of ischemic patients. Although increasing BNP levels may alert the clinician for an ongoing serious condition, for the purpose of our study, i.e., to diagnose the presence of myocardial ischemia, it was clearly a false positive BNP elevation Whole blood BNP level measurement as a diagnostic tool in acute ischemia It is clearly evident from receiver operator characteristic curve analysis that BNP measurement at all time points yields diagnostic information for the detection of patients with acute myocardial ischemia. Traditional cardiac biomarkers can detect acute ischemic events only if myocardial ischemia is severe enough to cause myocardial necrosis. In contrast, evidence from our study as well as studies of BNP during percutaneous coronary interventions [9], exercise [20], and acute ischemic events [21,22] shows that BNP synthesis is augmented by the presence of myocardial ischemia even in the absence of myocardial necrosis. Its measurement might therefore help in the evolution of diagnostic strategies beyond those based on the detection of myocardial necrosis. As BNP levels become higher over time only in the group of patients with acute ischemia, the diagnostic performance of measurements at 6 h is better than that of baseline and 2-h measurements. This translates into higher cut-off points and improved specificity and positive predictive value, while sensitivity is relatively unchanged. For the same reason, BNP increase at 6 h vs. baseline is the most specific marker for the presence of myocardial ischemia. Cut-off points selected as BNP values with the lowest false test results fall, especially for BNP measurements at baseline and 2 h, within values that have been reported to be normal for elderly patients and women [11], and are considerably lower than BNP values reported as cut-off points for the detection of congestive heart failure [23]. This may reflect differences in age, sex or other baseline characteristics of our study population compared to those of the aforementioned studies. Although such low cut-off points are limited by low specificity and positive predictive value they may be particularly useful for the exclusion of disease, in view of their high negative predictive values, in populations with a high prevalence of ischemia [24]. Given the previously mentioned association of BNP levels with age, we believe that further studies are needed in order to determine whether different criterion values should be selected for various age groups. In our study the diagnostic performance of BNP levels was calculated against the diagnosis of myocardial ischemia, which was done by the interpretation of the results of appropriate tests. In the setting of the emergency department, failure to diagnose ischemia and inappropriate patient discharge may have detrimental effects [25]. Therefore, very strict criteria were used in order to define the non-ischemic group. All individuals should be free of ischemic events for 1 month and patients with borderline evidence of ischemia and high-risk coronary anatomy were included in the ischemic group. This may have led to the inclusion of an occasional patient with coronary artery disease but without ischemia in the ischemic group and this in turn to the underestimation of differences of BNP levels between the ischemic and non-ischemic groups. We think, however, that this tactic was appropriate in order to avoid, in the long run, the inclusion of high-risk individuals in a group with the potential of early discharge from the emergency department. 5. Conclusion Whole blood BNP levels are increased in patients without ST-segment elevation, acute myocardial infarction or heart failure, presenting with ongoing ischemic pain upon arrival at the emergency department in comparison to those with pain of non-ischemic origin with a further increase during the next 6 h. BNP values are of diagnostic significance for the detection of acute ischemia at all time points. The subgroup of ischemic patients without a myocardial infarction could also be discriminated from non-ischemic patients using BNP measurement. Nevertheless, the diagnostic performance of BNP, i.e., an enhanced specificity and positive predictive value, is superior for peptide levels at 6 h. 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