N-Terminal Pro-BNP in Acute Coronary Syndrome Patients with ST Elevation versus Non ST Elevation Myocardial Infarction

doi:10.4236/ijcm.2011.23036

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International Journal of Clinical Medicine, 2011, 2, 218-223

doi:10.4236/ijcm.2011.23036 Published Online July 2011 (http://www.SciRP.org/journal/ijcm)

N-Terminal Pro-BNP in Acute Coronary

Syndrome Patients with ST Elevation versus

Non ST Elevation Myocardial Infarction

Ragaa H. M. Salama1*, Alaa E. A. El-Moniem2, Nour El-Hefney2, Tarek Samor3

Department of 1Biochemistry; 2Medicine, College of Medicine, Qassim University, Qassim, Kingdom of Saudi Arabia; 3Consultant

of Coronary Care Unite, King Fahed Specialist Hospital, Kingdom of Saudi Arabia.

Email: *[email protected]

Received August 25th, 2010; revised January 11th, 2011; accepted January 28th, 2011.

ABSTRACT

The study aimed to evaluate the differences in secretion of NT-proBNP and conventional cardiac markers in patients

with STE-ACS vs NSTE-ACS as a trial to solve the dilemma of the early detection of myocardial ischemia in NSTE-ACS.

Sixty two patients with acute coronary syndrome (ACS) divided into 2 groups according to ECG: group 1 with elevated

ST segment in ECG (STE-ACS) and group 2 with non elevated ST segment (NSTE-ACS). Twenty healthy subjects with

matched age and sex were enrolled as control group in this study. In the sera of all subjects, levels of NT-proBNP,

CK-MB and troponin-T were measured by different kits. CK-MB and TnT were both significantly higher in STE-ACS

patients compared to NSTE-ACS patients. Conversely , NT-proBNP was significantly higher in NSTE-ACS patients than

STE-ACS especially within 4 hours from onset of chest pain. Comparison between NT-proBNP, TnT and CK-MB levels

by ROC curves revealed area under the curves = 0.68, 0.31, 0.17 respectively. NT-proBNP at cutoff 415 pg/mL in

NSTE-ACS patients had higher sensitivity and specificity (92%, 39%; respectively) than other markers that will help in

early diagnosis of NSTE-ACS.

Keywords: NT-proPNB, Acute Coronary Syndrome, ST Segment, Cardiac Markers

1. Introduction

The serum level of N-terminal B-type natriuretic peptide

(NT-proBNP) was elevated in patients with left ven-

tricular (LV) dysfunction and showed a close correlation

with the BNP level. Many reports declared that the ab-

solute increment of NT-proBNP exceeded that of BNP,

and that NT-proBNP would be a more discerning marker

for the detection and evaluation of cardiac dysfunction

than BNP [1]. B-type natriuretic peptide (BNP) and

NT-proBNP can help to identify and accurately dis-

criminated CHF from respiratory disease and non-car-

diac causes of acute dyspnea [2,3]. NT-proBNP meas-

urement act as a guide to current treatment strategies, as

well as novel strategies, in patients with acute myocar-

dial infarction and as markers for the severity of heart

failure [4,5]. NT-proBNP provided information that may

be superior to clinical judgment for the diagnostic

evaluation of the patient with possible HF. It was a sur-

rogate biomarker for prognosis of myocardial damage as

assessed by contrast-enhanced Cardiac MRI [6]. It was

an independent predictor of survival in patients with

hypertension and increased left ventricular mass [7].

CK-MB was a marker of cytosolic damage that reflected

the area at risk and the resultant size of the infarction.

Whereas Tn-T was a marker of myofibril damage and

elevated in proportion to infarct size per se. The clinical

spectrum of ACS consists of ST elevated (STE) myo-

cardial infarction (MI) (STEMI) and non-STE (NSTE)

MI (NSTEMI)/or unstable angina (UA), which are clas-

sified from the acute phase electrocardiography (ECG)

changes and the development of myocardial necrosis.

STEMI caused by acute total coronary occlusion,

whereas NSTEMI associated with vulnerable plaque and

subocclusive thrombosis [8].

This study aimed to evaluate the clinical utility

NT-proBNP in Saudi patients and early detection of

myocardial ischemia in NSTE-ACS and the best time for

treatment of the disease by synthetic peptide molecule.

2. Materials and Methods

This is a prospective case control hospital based study

N-Terminal Pro-BNP in Acute Coronary Syndrome Patients with ST Elevation versus Non ST 219

Elevation Myocardial Infarction

included 62 selected patients with acute chest pain or

dyspnea. The informed consent was obtained from every

patient. Those patients diagnosed as ACS according to

Braunwald’s classification [9], or acute MI (AMI) ac-

cording to the redefined ESC/ACC Committee criteria

were admitted to Coronary Care Unit (CCU), King

Fahed Spealist Hospital in the duration from January to

June 2009. Fifty four of them were males and 8 were

females with ages ranged 27 - 65 years. All patients pre-

sented to CCU within 10 hours from onset of chest pain.

Also, 20 healthy subjects served as control group with

matched age and sex. The patients had cardiopulmonary

resuscitation before admission, serum creatinine level >

2.0 mg/dl, overt pump failure (≥NYHA class II) or hy-

pertension were excluded, in order to focus on the effect

of myocardial ischemia per se on the release of

NT-pro-BNP. All patients subjected to standard 12-lead

ECG immediately after admission. The patients were

classified into STE and NSTE groups based on the ECG

findings on admission. Patients with ST segment eleva-

tion at the J point in 2 or more consecutive leads (with

the cut-off point being >0.2 mV in leads V1, V2, or V3,

and >0.1 mV in the other leads) were defined as having

STE-ACS while patients with ST segment depression, T

wave inversion, or no ECG abnormalities were defined

as having NSTE-ACS, 17 of them diagnosed as unstable

angina. Transthoracic 2-dimensional echocardiography

was performed within 24 h of admission. The LV

end-diastolic (LVEDD) and left ventricular end-systolic

diameters (LVESD) were measured according to the

guidelines of the American Society of Echocardiography

[10]. The LV ejection fraction (LVEF) was calculated

by the modified Simpson’s method. Coronary angiogra-

phy was done for determination of the affected vessel.

The study was approved by the ethical committee of

Kingdom of Saudi Arabia, Qassium province, Ministry

of Health.

Blood samples were taken from every patient imme-

diately after admission, centrifuged for 20 min at 2000

xg on 4˚C, and sera were separated divided into aliquots,

kept at –70˚C for biochemical measurements of CK-MB,

TnT and NT-proBNP.

Serum CK-MB levels measured kinetically by UV

method (Stein and Bohner, 1985). Serum level of Tn-T

measured by an electrochemiluminescence assay (Elec-

sys 2010, Roche Diagnostics Germany). NT-proBNP

was measured by using sandwich enzyme immunoassay

kit for the quantitative determination of N-terminal

proBNP human in serum from Alpco diagnostics™ USA.

Catalog # (SK-1204 BNP fragment EIA).

3. Statistical Analysis

SPSS version 16 was used in analysis of the data. The

cardiac markers expressed as mean ± standard error. The

NSTE-ACS and STE-ACS groups compared by the

Mann-Whitney U test. While ANOVA test used to

compare between different cardiac markers. Correlation

coefficient calculated to asses the relation between

NT-proBNP and CK-MB, TnT. Differences of percent-

ages were compared by the chi-square test. ROC curves

done and area under the curves determined. The cardiac

markers and NT-proBNP levels on admission were

grouped according to the time from onset of chest pain

to admission of hospital, and the values compared be-

tween NSTE-ACS and STE-ACS patients by independ-

ent T-test at cut point 4 hours, 6 hours and 8 hours to

detect the peck point of secretion of NT-proBNP. A

p-value equal or less than 0.05 was considered statisti-

cally significant.

4. Results

The data of all patients (62) with acute coronary syn-

drome (ACS) were shown in Table 1. The number of

STE-ACS was 36 while NSTE-ACS was 26 patients.

There was no statistical significant difference in age,

DM, smokers, previous MI, hyperlipidemia, EF% or

angiography between STE-ACS and NSTE-ACS. How-

ever, the female was significantly increased in STE-ACS

while smokers are higher in STE-ACS but, didn’t reach

significant level. NT-proBNP level on admission was

significantly higher in the NSTE-ACS compared to

STE-ACS as shown in Figure 1. However, the conven-

tional cardiac markers (CK-MB and Tn-T) levels on

admission were significantly higher in STE-ACS pa-

tients than NSTE-ACS as shown in Figures 2, 3 respec-

tively and Table 2.

Table 1. Baseline characteristics of the patients with acute

coronary syndrome (ACS).

STE-ACS, ST elevation acute coronary syndrome; NSTE-ACS, non-ST

elevation acute coronary syndrome; EF%, ejection fraction; MI, myocardial

infarction. *statistically significance, p < 0.05 by chi square test.

STE-ACS

(n = 36)

NSTE-ACS

(n = 26)

Age, years 60.72 ± 0.9 62.38 ± 0.8

Male/female 28/8 26/0*

Smoking n (%) 20 (55.5%) 10 (38%)

DM, n (%) 20 (55.5%) 12 (46.1%)

Hyperlipidemia, n (%) 28 (77.7%) 18 (69.2%)

Previous MI, n (%) 12 (33.3%) 12 (46.15)

EF% (57.1% ± 9.8%) (56.6% ± 10.9%)

Coronary angiography:

One vessels disease

Two vessels disease

Three vessels disease

24 (66.7%)

8 (22.2%)

4 (11.1%)

16 (61.5%)

8 (30.7%)

2 (7.8%)

N-Terminal Pro-BNP in Acute Coronary Syndrome Patients with ST Elevation versus Non ST

Elevation Myocardial Infarction

220

In Figure 4, ROC curves of STE-ACS patients

showed that CK-MB had higher sensitivity and specific-

ity, followed by Tn-T then NT-proBNP (cut-off = 415

pg/mL, 61%, 8%, respectively). The area under the curve

was 0.82, 0.69, 0.32, respectively. On the other hand, in

Figure 5, ROC curves of NSTE-ACS patients showed

that NT-proBNP had higher sensitivity and specificity

(cut-off = 415 pg/mL, 92%, 39%, respectively), fol-

lowed by Tn-T (cut-off = 0.045 ng/mL) and CK-MB,

(cut-off = 5.7 IU/L ), for both (84%, 6%, respectively)

as shown in Table 3 . The area under the curves was 0.68,

0.31, 0.17, for NT-proBNP, Tn-T, CK-MB, respectively.

In Figure 5, NT-proBNP had clinical significance, p =

0.02, at 95% confidence interval, the lower bound = 0.52

and the upper bound = 0.82). There was a correlation

between Tn-T and CK-MB (r = 0.3, p = 0.01) and in-

verse correlation between NT-BNP and CK-MB (r =

–0.2, p = 0.03), positive correlation between smoking

and dyslipidymia (r = 0.4, p = 0.01), inverse correlation

between number of vessels affected and smoking (r =

–0.34, p = 0.01). There was no significant difference in

the LVEF determined by echocardiography between

NSTE-ACS patients (57.1% ± 9.8%) and STE-ACS pa-

tients (56.6% ± 10.9%) because we excluded patients

with pump failure (≥Killip class II). NT-proBNP in-

creased in NSTE-ACS patients in the early phase of ACS

Figure 1. NT-proBNP in STE-ACS and NST-ACS.

Figure 2. CK-MB in STE-ACS and NST-ACS.

Figure 4. ROC Curve in STE-ACS.

Figure 3. Tn-T in STE-ACS and NST-ACS.

Table 2. Comparison of cardiac markers in all patients (62) with ACS by ANOVA test.

percentiles

Mean ± SE p Minimum Maximum Mode

(frequency) 25th 50th (median) 75th

NT-proBNP (pg/mL) 1124.35 ± 103.9 0.001 200 2800 2400

(10) 380 680 2000

CK-MB (IU/L) 10.75 ± 0.6 0.000 5.60 19.20 5.6, 18

(6) 6.1 9.2 15

Tn-T (ng/mL) 0.41 ± 0.02 0.002 0.01 0.80 0.6

(6) 0.32 0.45 0.6

N-Terminal Pro-BNP in Acute Coronary Syndrome Patients with ST Elevation versus Non ST 221

Elevation Myocardial Infarction

Table 3. Sensitivity and specificity of cardiac markers.

STE-ACS

Sensitivity specificity

NT-proBNP

cut-off = 415 pg/mL

61% 8%

CK-MB

cut-off = 5.7 IU/L

94% 6%

Tn-T

cut-off = 0.045 ng/mL

94% 6%

NSTE-ACS

NT-proBNP

cut-off = 415 pg/mL

92% 39%

CK-MB

cut-off = 5.7 IU/L

84% 6%

Tn-T

cut-off = 0.045 ng/mL

84% 6%

and it was inversely proportional to the duration of chest

pain. It was more significant increased when the dura-

tion of chest pain was ≤4 hours than ≤6 or ≤8 hours as

shown Figures 6-8 respectively.

5. Discussion

Cardiac markers, such as troponin T (TnT), and creatine

kinase (CK)-MB isozyme, detect the development of

minor myocardial necrosis, and have emerged as pow-

erful predictors of risk in patients with ACS [11,12].

Pro-BNP was synthesized as a pro-hormone by cardiac

myocytes then cleaved by enzyme to N-teminal proBNP

(NT-proBNP) and BNP. NT-proBNP levels predicted

long term survival in patients. The highest NT pro-BNP

quartile was twice as likely to die when compared to

patients with left ventricular hypertrophy in the lowest

NT-ptoBNP quartile [7].

In this study, Nt-proBNP was significantly higher in

NSTE-ACS patients than in STE-ACS patients despite

lower values of the conventional cardiac markers

CK-MB and Tn-T in NSTE-ACS patients. The incre-

ment of NT-proBNP in NSTE-ACS patients was in-

versely proportional to the duration of chest pain. It was

more significant increased when the duration of chest

pain was ≤4 hours than ≤6 or ≤8 hours. It increased dur-

ing the hyperacute phase in NSTE-ACS patients, and

wasn’t raised by the process of myocardial necrosis but

the ischemic insult per se. This may be explained on the

basis that the release kinetics of cardiac markers, espe-

cially NT-proBNP, in patients with NSTE-ACS differed

from those in STE-ACS patients. The ischemic area or

area at risk showed different spectrum in these 2 groups.

The massive elevations of NT-pro-BNP observed in the

early phase of coronary syndrome seemed to be inde-

pendent of ventricular performance. Also, STEMI was

caused by acute total coronary occlusion, whereas

NSTEMI was associated with vulnerable plaque and

Figure 5. ROC Curve in NSTE-ACS.

Figure 6. NT-proBNP in all patients with ACS.

Figure 7. CK-MB in in all patients with ACS.

N-Terminal Pro-BNP in Acute Coronary Syndrome Patients with ST Elevation versus Non ST

222

Elevation Myocardial Infarction

Figure 8. Tn-T in all patients with ACS.

subocclusive thrombosis [8]. The myocardial ischemia

was also a stimulus for the release of BNP and

NT-proBNP [13,14]. The underlying pathomechanism

was not fully understood, but a direct release of BNP

from ischemic cardiomyocytes in addition to ischemia

induced by increase in ventricular wall stress was postu-

lated and, moreover, there was evidence suggested a

protective role of BNP on the myocardium. BNP and

other natriuretic peptides limit the extent of tissue in-

farction during ischaemia and reperfusion. The mecha-

nism of cytoprotection is related to cGMP accumulation

and opening of ATP-sensitive K(+) channels [15,16].

The early activation of the natriuretic peptide recep-

tor/cGMP signalling system may be an important auto-

crine/paracrine response in cardiac ischaemia. This in-

cludes inotropic effects, acute regulation of coronary

vascular tone and attenuation of the susceptibility of

myocardium to ischaemic injury, suppression of growth

and proliferative responses in a variety of myocardial

and vascular cells. In ischaemic myocardium, acute

treatment with BNP prior to and during coronary artery

occlusion exerts a markedly protective, concentration-

dependent infarct-limiting action. This cytoprotective

effect of the natriuretic peptide signalling pathway might

conceivably represent an alternative endogenous salvage

pathway in myocardium which is potentially exploitable

therapeutically. Taken together, the acute actions of na-

triuretic peptides on the coronary vasculature and in

myocardial ischaemia suggest a profile of activity that

may be therapeutically beneficial in the management of

patients with acute coronary syndromes [17]. Thus may

be according to our data, treatment with BNP or

NT-BNP peptide within 4 hours from onset of chest pain

will give best results of protection. Age stratification of

NT-proBNP using cut points of 450, 900, and 1,800

ng/L (for age groups of <50, 50 - 75, and >75 years)

reduced false-negative findings in younger patients, re-

duced false-positive findings in older patients, and im-

proved the overall positive predictive value of the

marker without a change in overall sensitivity or speci-

ficity [18]. In this study, the elevation of NT-proBNP

was much higher in the NSTE-ACS patients than STE-

ACS patients (506 pg/mL vs 201 pg/ml). NT-pro- BNP

was higher in NSTE-ACS patients than STE-ACS pa-

tients (758 pg/mL vs 258 pg/mL). Such early increased

would reflect the amount of ischemic insult to the myo-

cardium rather than the actual extent of myocardial

damage or degree of heart failure [19]. A correlation

between LVEF and plasma levels of BNP (r = –0.44, p =

0.002) was detected [6]. However, in this study, this

correlation couldn’t detect because we exclude the heart

failure. The use of NT-proBNP for the evaluation of the

patient with suspected acute HF is useful, cost-effective,

and may reduce adverse outcomes compared with stan-

dard clinical evaluation without natriuretic peptide test-

ing [20].

In a multivariate Cox regression model, N-BNP added

prognostic information above and beyond Killip class,

patient age, and left ventricular ejection fraction. Ad-

justment for peak troponin T levels did not markedly

alter the relation between N-BNP and mortality. In pa-

tients with no evidence of clinical heart failure, N-BNP

remained a significant predictor of mortality after ad-

justment for age and ejection fraction. N-BNP is a pow-

erful indicator of long-term mortality in patients with

ACS and provided prognostic information above and

beyond conventional risk markers [21,22].

6. Conclusions

NT-proBNP is an early sensitive marker of ACS as it

increased significantly in the early phase of ACS (less

than 8 hours), with much increment when the chest pain

duration less than 4 hours. It is very sensitive and spe-

cific than other traditional cardiac markers (CK-MB and

TnT) in the early diagnosis of NSTE-ACS which caused

very big problem in the early diagnosis than STE-ACS.

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