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The value of apelin-36 and brain natriuretic peptide measurements in patients with first ST-elevation myocardial infarction
Clinica Chimica Acta 411 (2010) 2014–2018
Contents lists available at ScienceDirect
Clinica Chimica Acta j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / c l i n c h i m
The value of apelin-36 and brain natriuretic peptide measurements in patients with first ST-elevation myocardial infarction☆ Agnieszka M. Tycinska a,⁎, Bozena Sobkowicz a, Barbara Mroczko b, Robert Sawicki a, Wlodzimierz J. Musial a, Slawomir Dobrzycki c, Ewa Waszkiewicz a, Malgorzata A. Knapp a, Maciej Szmitkowski b a b c
Department of Cardiology, Medical University, Bialystok, Poland Department of Biochemical Diagnostics, Medical University, Bialystok, Poland Department of Invasive Cardiology, Medical University, Bialystok, Poland
a r t i c l e
i n f o
Article history: Received 29 June 2010 Received in revised form 14 August 2010 Accepted 17 August 2010 Available online 22 August 2010 Keywords: Apelin-36 BNP STEMI
a b s t r a c t Background: We aimed to assess apelin—novel endogenous ligand for the angiotensin-like 1 receptor in patients with ST-elevation myocardial infarction (STEMI) and to compare its value with B-type natriuretic peptide (BNP). Methods: In 78 consecutive patients with first STEMI treated with primary PCI, plasma apelin-36 (RIA) and BNP (MEIA) concentrations were measured twice: on admission and on the fifth day of hospitalization. Left ventricle ejection fraction (LVEF) was assessed on admission and composite endpoint (CEP)—after 1 year follow-up. Results: During the 5-day interval median plasma BNP level significantly increased and median plasma apelin concentration significantly decreased. BNP, but not apelin, correlated with low LVEF (b 50%). In ROC analysis only BNP measurements were diagnostic for low LVEF. In ANOVA test, in patients with CEP, a significant decrease in apelin (but not BNP) concentrations measured in 5-day interval was found. ROC analysis identified only second BNP measurement as significant to estimate adverse outcome 0.627 in the prediction of CEP (95% confidence interval = 0.507–0.736). Conclusion: Following STEMI there is a decrease of plasma apelin-36 concentration and an increase of plasma BNP concentration. BNP is better, than apelin diagnostic value for the detection of impaired LVEF. Both BNP and apelin have prognostic value, although both needs further evaluation. © 2010 Elsevier B.V. All rights reserved.
1. Introduction Apelin—a recently isolated novel endogenous ligand for the angiotensin-like 1 receptor (APJ), has been reported to be involved in the regulation of cardiovascular homeostasis. However, the roles of apelin and APJ in cardiovascular system as well as their effects on different human organs have not been completely explained. Only animal studies concern the role of apelin in myocardial ischemia. In humans apelin has been investigated particularly in heart failure [1]. Still it is unknown, if apelin may be useful as marker of prognosis in acute myocardial infarction. B-type natriuretic peptide (BNP) is released from the cardiac ventricles in response to increased wall stress [2]. An acute ischemia may lead to a transient decrease in systolic function. However BNP release may reflect not only the underlying impairment of left
☆ Grant supported by Medical University in Bialystok, Poland, No 3-53710L. ⁎ Corresponding author. Department of Cardiology, Medical University of Bialystok, ul. Sklodowskiej-Curie 24a, 15-276 Bialystok, Poland. Tel.: + 48 857468656; fax: + 48 857468604. E-mail address: [email protected] (A.M. Tycinska). 0009-8981/$ – see front matter © 2010 Elsevier B.V. All rights reserved. doi:10.1016/j.cca.2010.08.024
ventricular function, but also the severity of acute ischemic event [3]. Besides BNP holds promise for risk stratification in this group of patients. The aim of the study was to assess and compare the value of plasma apelin-36 and BNP measurements concerning the diagnosis of left ventricular impairment as well as prognostic value in a group of patients with first ST-elevation myocardial infarction (STEMI) treated with primary percutaneous coronary intervention (pPCI). 2. Materials and methods 2.1. Patient population Seventy-eight patients (54 men, mean age 65.9± 10.4 years and 24 women, mean age 69.5 ± 13.5 years), admitted to our department with first STEMI and treated with pPCI within the first 12 h from the onset of chest pain, were included in the study. The exclusion criteria were: any history of previous myocardial infarction, severe valvular disease, cardiomyopathy, any form of congenital cardiac disease or symptoms of chronic heart failure. The study patients were selected out of the 187 consecutive STEMI patients. The diagnosis of STEMI was made on the
A.M. Tycinska et al. / Clinica Chimica Acta 411 (2010) 2014–2018
basis of typical chest pain, ST-segment elevation of N0.2 mV in precordial or 0.1 mV in limb leads in at least 2 contiguous leads in standard 12-lead electrocardiogram and typical elevation of myocardial creatine kinase (CK-MB). Following 24 h after admission each of the patients underwent standard transthoracic echocardiography (TTE) with the assessment of left ventricle ejection fraction (LVEF). For the purpose of the study the patients were divided into two subgroups: with preserved (≥50%) and impaired (b50%) LVEF. The study design was compliant with the Helsinki Declaration of 1975 as revised in 1996 and it was approved by the local institutional committee on human research (Institutional Review Board-Local Bioethics Committee of Bialystok Medical University). Informed consent from all participants studied for the report was obtained. 2.2. Primary percutaneous angioplasty and pharmacotherapy during hospitalization Before invasive treatment (pPCI) all patients received aspirin at a dose of 300 mg (followed by 75 mg daily) and clopidogrel (300 mg), as well as bolus of weight adjusted unfractionated heparin. Antiplatelet treatment with clopidogrel (75 mg daily) was continued for at least 1 month after the procedure. 2.3. Blood sampling and measurements of BNP and apelin Venous blood samples were collected using the S-Monovette blood collection system with EDTA as anticoagulant for determination of BNP and apelin-36. Blood samples for BNP and apelin-36 were centrifuged in 3500 ×g to obtain plasma samples. Plasma samples were separated, aliquoted and stored at −80 °C until assayed. Apelin-36 and BNP were measured twice: on admission and on the fifth day of hospitalization. Plasma levels of BNP were measured by microparticle enzyme immunoassay kits (MEIA, Abbott, Chicago, Illinois, USA, Architect Ci8200). The intra-assay CV % for BNP is claimed by manufacturer of assay kits to be 5.9% at BNP mean concentration of 29.2 pmol/L, SD = 6.0. In the ROC report the cutoff value was corresponding to the highest accuracy (minimal false-negative and false-positive results). Apelin-36 concentrations were measured with a radioimmunoassay kit (RIA, Phoenix, Cat-No. RK-057-15, LKB-Wallace Mini Gamma 1275, Turku, Finland). The selection of method for assessing apelin has been based on the recent publications: RIA method has been successfully used to measure apelin concentrations in plasma as well as supernatants extracted from myocardium and aorta [1,4,5]. According to the manufacturer, this radioimmunoassay is specific for apelin-36 with no cross-reactivity to apelin-16 or apelin-13. The lowest detection limit was 4.8 pmol/L. 2.4. Follow-up and composite endpoint Composite endpoint (CEP), assessed after 12 months follow-up, was the appearance of any major cardiovascular adverse event: death, stroke and documented symptoms of recurrent ischemic event (including myocardial infarction and reintervention). 2.5. Statistical analysis Results were expressed as means±SD or as medians with 25% to 75% interquartile ranges as appropriate (continuous variables) or as proportions (categorical variables). Associations between continuous and categorical variables were examined using the independent-samples Student's t-test or U Mann–Whitney test (respectively to parameter's distribution) and associations between categorical variables using χ2 test. Logistic regression was used to determinate associations between endpoints for CVD and independent variables with criteria pb 0.05 for entry and pN 0.1 for exit. This method was used to identify the best
2015
predictor. The receiver operating characteristic (ROC) curves were constructed. The area under curve (AUC), a measure of the efficiency, was also computed. All analyses were carried out using Statistica 6.0 (StatSoft, Tulsa, OK, USA) and MedCalc 8.0 (MedCalc Software, Mariakerke, Belgium). pb 0.05 was considered statistically significant. 3. Results Seventy-eight patients, mean age 67.0 ± 11.5 years with median LVEF 45% (quartile range 25%–75%: 39.0–53.0) were evaluated. Median BNP level on admission (first day of STEMI), was 32.1 pmol/L (25th–75th percentile:13.8–84.9) and on the fifth day of hospitalization was 77.0 pmol/L (25th–75th percentile: 34.3–162.9). Median apelin-36 concentration on the first day was 509.6 pmol/L (25th–75th percentile: 464.5–565.3) and on the fifth day was 478.6 pmol/L (25th–75th percentile: 416.5–545). During the 5-day interval the changes in BNP and apelin-36 concentrations were significant (p b 0.001 and p = 0.002, respectively). 3.1. BNP, apelin-36 and LVEF Patients with lower LVEF were older and anterior STEMI was in prevalence in comparison with patients with normal LVEF. Both BNP concentrations, but not apelin-36, were significantly higher in patients with lower LVEF. However frequency of CEP was similar in both groups (Table 1). In ANOVA test there were significant differences according to BNP measurements in patients with high and low LVEF (for both first and fifth days BNP measurements p = 0.017). In these two groups of patients BNP level increased in 5-day interval (Fig. 1), however the difference did not reach statistical significance. In contrast, we did not find significant differences according to apelin-36 measurements on the first and fifth days in patients with high and low LVEF, however in both groups there were significant reduction in apelin-36 concentrations measured in 5-day interval (p = 0.008, and p = 0.040, accordingly; Fig. 1). Only BNP measurements correlated with lower LVEF: for the first measurement—r=−0.39, and even better for the second one—r=−0.51, pb 0.050. We did not find such a significant correlation either to the first or second apelin-36 measurements. In multivariate regression analysis BNP obtained on the fifth day influenced LVEF value (beta=−0.56, pb 0.001). Besides, both—obtained on the first and fifth days—BNP measurements were good for prediction of poor LVEF (p = 0.010 and p b 0.001, respectively). However, we did not find any significance according to apelin-36 measurements (p=0.90 and p=0.30, respectively). Table 1 Characteristics of patients with preserved and impaired LVEF. LVEF ≥50% Age, years Median (25%; 75%) 62.0 Sex (male), % 67.7 STEMI location Anterior, % 19.3 Inferior, % 74.2 Admission BNP, pmol/L, Median (25%; 75%) 21.0 Five-day BNP, pmol/L Median (25%; 75%) 36.6 Admission apelin-36, pmol/L, Median (25%; 75%) 506.8 Five-day apelin-36, pmol/L, Median (25%; 75%) 489.0 CEP, % 22.6
(56.0; 69.0)
LVEF b 50%
p value
71.0 (61.0; 80.0) 70.2
0.020 0.820
55.3 40.4
0.005
(10.2; 54.4)
46.3 (16.2;113.5)
0.010
(17.2; 87.7)
621.4 (54.4; 207.5)
b 0.001
(464.0; 568.4)
88.9 (469.2; 564.6)
0.90
(435.3; 551.1)
466.6 (414.7; 543.9) 19.1
0.40 0.60
LVEF—left ventricle ejection fraction. STEMI—ST-elevation myocardial infarction. BNP—B-type natriuretic peptide. CEP—composite endpoint.
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Fig. 2. Receiver operating characteristic curve for ability of BNP and apelin-36 (both measurements) to predict LVEF. BNP—B-type natriuretic peptide. LVEF—left ventricle ejection fraction.
the second BNP measurement was predictive for CEP: the value of area under the receiver operator characteristic (ROC) curve (AUC) was 0.627 (95% confidence interval 0.507–0.736; Fig. 4). 4. Discussion
Fig. 1. Changes in BNP and apelin-36 measurements in patients with preserved and impaired LVEF (ANOVA test, values shown as mean ± SD). BNP—B-type natriuretic peptide. LVEF—left ventricle ejection fraction. SD—standard deviation.
In ROC analysis only BNP measurements were diagnostic for lower (b50%) LVEF: area under the ROC curve [AUC]—0.652 (95% confidence interval [CI] 0.533 to 0.759) and 0.744 (95% CI 0.630 to 0.837), respectively (Fig. 2). 3.2. BNP, apelin-36 and CEP After 1 year follow-up 19 (24.3%) patients reached composite endpoint. Only one patient died. Symptoms of recurrent ischemia leading to the reintervention were reported in 9 (11.5%) patients. The median baseline concentrations of BNP and apelin-36 were higher in a group of patients who reached CEP compared with those without CEP: 40.3 pmol/L (25th–75th percentile 21.4–75.4) vs 29.0 pmol/L (25th–75th percentile: 10.8–84.9) and 540.4 pmol/L (25th–75th percentile: 492.6–567.7) vs 502.9 (25th–75th percentile: 464.0–564.6), but these values did not reach any significance (respectively, for both parameters p=0.380, and p=0.310). In ANOVA test we did not find any significant differences according to BNP measurements and the occurrence of CEP (Fig. 3). Apelin-36 concentrations decreased in both groups of patients: those who reached and did not reach CEP (p = 0.013 and p = 0.044, respectively; Fig. 3). In ROC analysis of all parameters taken into account, like age, sex, infarct location, LVEF, both BNP and apelin-36 measurements, only
Recently, cardiac apelin has been suggested to contribute to the pathophysiology of heart failure in humans. This novel peptide acts as an endogenous ligand for the previously orphaned G-protein-coupled receptor, angiotensin-like 1 receptor (APJ). Apelin mRNA expression and peptide immunoreactivity have been described in a variety of tissues including gastrointestinal tract, adipose tissue, brain, kidney, liver, lung and at various sites within the cardiovascular system. Apelin is strongly expressed in the heart, but also present in the large vessels, coronary vessels and endothelial cells. In preclinical models, apelin causes nitric oxide-dependent vasodilation, reduces ventricular preload and afterload and increases cardiac contractility in rats with normal and failing hearts [6]. In animal experiments its infusion improved systolic as well as diastolic LV function [7]. In humans the role of apelin has been investigated particularly in heart failure. Most of the studies demonstrated lower plasma concentration of the apelin in patients with left ventricular dysfunction compared to the normal controls [8]. Circulating levels of apelin are reported to decrease in heart failure and to rise in response of LV function improvement [8,9]. It is unclear, if apelin may serve as marker of prognosis in acute myocardial infarction [10]. In our study group, we have noticed the trend to decrease the values of apelin-36 within the first 5-day interval, regardless to LV dysfunction. However, this biomarker did not correlate with LV function. To date only animal studies concern the role of the apelin-APJ system in myocardial ischemia. In vivo and in vitro studies demonstrated an up regulation of APJ gene expression in response to ischemia [10]. Perhaps the apelin–APJ system may be involved in myocardial protection during an acute myocardial ischemia and thus our study reveals the decrease of the peptide within the first 5 days of the ischemic episode. To investigate the value of apelin measurements in ischemic myocardial injury, we decided to compare diagnostic and prognostic significance of apelin with BNP. High level of BNP is a powerful marker of LV systolic dysfunction and poor prognosis after MI [11]. However, patients with ischemic heart disease also exhibit increased plasma BNP concentrations despite preserved cardiac function [12]. Moreover, elevated NT-pro-BNP and BNP are strong
A.M. Tycinska et al. / Clinica Chimica Acta 411 (2010) 2014–2018
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Fig. 4. Receiver operating characteristic curve for ability of BNP and apelin-36 (both measurements) to predict long-term events (patients with CEP vs without CEP). BNP—B-type natriuretic peptide. CEP—composite endpoint.
plasma apelin-36 concentrations and the increase of plasma BNP concentrations could be found in the first days after the onset of myocardial infarction. BNP measurements, especially the second one, are better, than apelin-36 diagnostic value for the detection of LV dysfunction. In this group of patients BNP and apelin-36 have prognostic values, although detailed clinical investigation is now required to establish especially the role of apelin, alone or together with other biomarkers, in patients with ischemic episodes.
5. Study limitations
Fig. 3. Changes in BNP and apelin-36 measurements in patients with and without CEP (ANOVA test, values shown as mean±SD). BNP—B-type natriuretic peptide. CEP—composite endpoint. SD—standard deviation.
independent predictors of clinical events in patients with heart failure and preserved LV function [13]. Most of our study patients had preserved LV function. Although, both BNP measurements (second even better) correlated and predicted poor LVEF, we did not find any significance according to apelin-36 measurements. These results were confirmed in the ROC analysis. Although apelin-36 was not predictive, we found significant decrease of its values in a group of patients who reached CEP. Besides, although not significant, the median baseline concentrations of BNP and apelin-36 were higher in a group of patients who reached CEP compared with those without. However, only the second BNP measurement was predictive. One of the latest published studies has shown that the combination of several biomarkers, including BNP assessed on admission, in each or in combination, had only minimal impact for the prediction of long-term cardiovascular events after primary stenting in STEMI patients [14]. We assessed the similar group of low risk first STEMI patients previously. BNP obtained early after admission had the strongest predictive value, compared to traditional tools for risk stratification [15]. In summary, our study provides information that in low risk STEMI patients, treated with pPCI and with preserved LVEF the decrease of
The main limitation of this study is the relatively small number of patients enrolled, which is related to strict inclusion and exclusion criteria. However, the aim of the study was to examine selected group of first STEMI patients with preserved LVEF. We aimed to investigate upright effect of ischemia on apelin and BNP concentrations. The patients were included prospectively and were investigated thoroughly, so the authors consider the results obtained as being representative.
References [1] Miettinen KH, Magga J, Vuoltenaho O, et al. Utility of plasma apelin and other indices of cardiac dysfunction in the clinical assessment of patients with dilated cardiomyopathy. Regul Pept 2007;140:178–84. [2] de Lemos JA, McGuire DK, Drazner MH. B-type natriuretic peptide in cardiovascular disease. Lancet 2003;362:316–22. [3] Sabatine MS, Morrow DA, de Lemos JA, et al. Elevation of B-type natriuretic peptide in the setting of myocardial ischemia. Circulation 2001;104:II-485 Suppl. II:. [4] Zhang J, Ren CX, Qi YF, et al. Exercise training promotes expression of apelin and APJ of cardiovascular tissues in spontaneously hypertensive rats. Life Sci 2006;79: 1153–9. [5] Goetze JP, Rehfeld JF, Carlsen J, et al. Apelin: A new plasma marker of cardiopulmonary disease. Regul Pept 2006;133:134–8. [6] Japp AG, Newby DE. The apelin–APJ system in heart failure: pathophysiologic relevance and therapeutic potential. Biochem Pharmacol 2008;75:1882–92. [7] Iwanaga Y, Kihara Y, Takenaka H, Kita T. Down-regulation of cardiac apelin system in hypertrophied and failing hearts: possible role of angiotensin II-angiotensin type 1 receptor system. J Moll Cell Cardiol 2006;41:798–806. [8] Chong KS, Gardner RS, Morton JJ, Ashley EA, McDonagh TA. Plasma concentrations of the novel peptide apelin are decreased in patients with chronic heart failure. Eur J Heart Fail 2006;8:355–60. [9] Francia P, Salvati A, Balla C, et al. Cardiac resynchronization therapy increases plasma levels of the endogenous inotrope apelin. Eur J Heart Fail 2007;9:306–9. [10] Japp AG, Cruden NL, Amer DA, et al. Vascular effects of apelin in vivo in man. J Am Coll Cardiol 2008;52:908–13.
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[11] Güneş Y, Okçün B, Kavlak E, Erbaş C, Karcier S. Value of brain natriuretic peptide after acute myocardial infarction. Anadolu Kardiyol Derg 2008;8:182–7. [12] Goetze JP, Gore A, Møller CH, Steinbrüchel DA, Rehfeld JF, Nielsen LB. Acute myocardial hypoxia increases BNP gene expression. FASEB J 2004;18:1928–30. [13] Grewal J, McKelvie RS, Persson H, et al. Usefulness of N-terminal pro-brain de and brain natriuretic peptide to predict cardiovascular outcomes in patients with heart failure and preserved left ventricular ejection fraction. Am J Cardiol 2008;102:733–77.
[14] Jeong YH, Lee SW, Lee CW, et al. Biomarkers on admission for the prediction of cardiovascular events after primary stenting in patients with ST-elevation myocardial infarction. Clin Cardiol 2008;31:572–9. [15] Kuklinska AM, Sobkowicz B, Mroczko B, et al. Prognostic significance of the admission plasma B-type natriuretic peptide measurement in patients with first ST-elevation myocardial infarction in comparison with C-reactive protein and TIMI risk score. Clin Chim Acta 2007;382:106–11.
Contents lists available at ScienceDirect
Clinica Chimica Acta j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / c l i n c h i m
The value of apelin-36 and brain natriuretic peptide measurements in patients with first ST-elevation myocardial infarction☆ Agnieszka M. Tycinska a,⁎, Bozena Sobkowicz a, Barbara Mroczko b, Robert Sawicki a, Wlodzimierz J. Musial a, Slawomir Dobrzycki c, Ewa Waszkiewicz a, Malgorzata A. Knapp a, Maciej Szmitkowski b a b c
Department of Cardiology, Medical University, Bialystok, Poland Department of Biochemical Diagnostics, Medical University, Bialystok, Poland Department of Invasive Cardiology, Medical University, Bialystok, Poland
a r t i c l e
i n f o
Article history: Received 29 June 2010 Received in revised form 14 August 2010 Accepted 17 August 2010 Available online 22 August 2010 Keywords: Apelin-36 BNP STEMI
a b s t r a c t Background: We aimed to assess apelin—novel endogenous ligand for the angiotensin-like 1 receptor in patients with ST-elevation myocardial infarction (STEMI) and to compare its value with B-type natriuretic peptide (BNP). Methods: In 78 consecutive patients with first STEMI treated with primary PCI, plasma apelin-36 (RIA) and BNP (MEIA) concentrations were measured twice: on admission and on the fifth day of hospitalization. Left ventricle ejection fraction (LVEF) was assessed on admission and composite endpoint (CEP)—after 1 year follow-up. Results: During the 5-day interval median plasma BNP level significantly increased and median plasma apelin concentration significantly decreased. BNP, but not apelin, correlated with low LVEF (b 50%). In ROC analysis only BNP measurements were diagnostic for low LVEF. In ANOVA test, in patients with CEP, a significant decrease in apelin (but not BNP) concentrations measured in 5-day interval was found. ROC analysis identified only second BNP measurement as significant to estimate adverse outcome 0.627 in the prediction of CEP (95% confidence interval = 0.507–0.736). Conclusion: Following STEMI there is a decrease of plasma apelin-36 concentration and an increase of plasma BNP concentration. BNP is better, than apelin diagnostic value for the detection of impaired LVEF. Both BNP and apelin have prognostic value, although both needs further evaluation. © 2010 Elsevier B.V. All rights reserved.
1. Introduction Apelin—a recently isolated novel endogenous ligand for the angiotensin-like 1 receptor (APJ), has been reported to be involved in the regulation of cardiovascular homeostasis. However, the roles of apelin and APJ in cardiovascular system as well as their effects on different human organs have not been completely explained. Only animal studies concern the role of apelin in myocardial ischemia. In humans apelin has been investigated particularly in heart failure [1]. Still it is unknown, if apelin may be useful as marker of prognosis in acute myocardial infarction. B-type natriuretic peptide (BNP) is released from the cardiac ventricles in response to increased wall stress [2]. An acute ischemia may lead to a transient decrease in systolic function. However BNP release may reflect not only the underlying impairment of left
☆ Grant supported by Medical University in Bialystok, Poland, No 3-53710L. ⁎ Corresponding author. Department of Cardiology, Medical University of Bialystok, ul. Sklodowskiej-Curie 24a, 15-276 Bialystok, Poland. Tel.: + 48 857468656; fax: + 48 857468604. E-mail address: [email protected] (A.M. Tycinska). 0009-8981/$ – see front matter © 2010 Elsevier B.V. All rights reserved. doi:10.1016/j.cca.2010.08.024
ventricular function, but also the severity of acute ischemic event [3]. Besides BNP holds promise for risk stratification in this group of patients. The aim of the study was to assess and compare the value of plasma apelin-36 and BNP measurements concerning the diagnosis of left ventricular impairment as well as prognostic value in a group of patients with first ST-elevation myocardial infarction (STEMI) treated with primary percutaneous coronary intervention (pPCI). 2. Materials and methods 2.1. Patient population Seventy-eight patients (54 men, mean age 65.9± 10.4 years and 24 women, mean age 69.5 ± 13.5 years), admitted to our department with first STEMI and treated with pPCI within the first 12 h from the onset of chest pain, were included in the study. The exclusion criteria were: any history of previous myocardial infarction, severe valvular disease, cardiomyopathy, any form of congenital cardiac disease or symptoms of chronic heart failure. The study patients were selected out of the 187 consecutive STEMI patients. The diagnosis of STEMI was made on the
A.M. Tycinska et al. / Clinica Chimica Acta 411 (2010) 2014–2018
basis of typical chest pain, ST-segment elevation of N0.2 mV in precordial or 0.1 mV in limb leads in at least 2 contiguous leads in standard 12-lead electrocardiogram and typical elevation of myocardial creatine kinase (CK-MB). Following 24 h after admission each of the patients underwent standard transthoracic echocardiography (TTE) with the assessment of left ventricle ejection fraction (LVEF). For the purpose of the study the patients were divided into two subgroups: with preserved (≥50%) and impaired (b50%) LVEF. The study design was compliant with the Helsinki Declaration of 1975 as revised in 1996 and it was approved by the local institutional committee on human research (Institutional Review Board-Local Bioethics Committee of Bialystok Medical University). Informed consent from all participants studied for the report was obtained. 2.2. Primary percutaneous angioplasty and pharmacotherapy during hospitalization Before invasive treatment (pPCI) all patients received aspirin at a dose of 300 mg (followed by 75 mg daily) and clopidogrel (300 mg), as well as bolus of weight adjusted unfractionated heparin. Antiplatelet treatment with clopidogrel (75 mg daily) was continued for at least 1 month after the procedure. 2.3. Blood sampling and measurements of BNP and apelin Venous blood samples were collected using the S-Monovette blood collection system with EDTA as anticoagulant for determination of BNP and apelin-36. Blood samples for BNP and apelin-36 were centrifuged in 3500 ×g to obtain plasma samples. Plasma samples were separated, aliquoted and stored at −80 °C until assayed. Apelin-36 and BNP were measured twice: on admission and on the fifth day of hospitalization. Plasma levels of BNP were measured by microparticle enzyme immunoassay kits (MEIA, Abbott, Chicago, Illinois, USA, Architect Ci8200). The intra-assay CV % for BNP is claimed by manufacturer of assay kits to be 5.9% at BNP mean concentration of 29.2 pmol/L, SD = 6.0. In the ROC report the cutoff value was corresponding to the highest accuracy (minimal false-negative and false-positive results). Apelin-36 concentrations were measured with a radioimmunoassay kit (RIA, Phoenix, Cat-No. RK-057-15, LKB-Wallace Mini Gamma 1275, Turku, Finland). The selection of method for assessing apelin has been based on the recent publications: RIA method has been successfully used to measure apelin concentrations in plasma as well as supernatants extracted from myocardium and aorta [1,4,5]. According to the manufacturer, this radioimmunoassay is specific for apelin-36 with no cross-reactivity to apelin-16 or apelin-13. The lowest detection limit was 4.8 pmol/L. 2.4. Follow-up and composite endpoint Composite endpoint (CEP), assessed after 12 months follow-up, was the appearance of any major cardiovascular adverse event: death, stroke and documented symptoms of recurrent ischemic event (including myocardial infarction and reintervention). 2.5. Statistical analysis Results were expressed as means±SD or as medians with 25% to 75% interquartile ranges as appropriate (continuous variables) or as proportions (categorical variables). Associations between continuous and categorical variables were examined using the independent-samples Student's t-test or U Mann–Whitney test (respectively to parameter's distribution) and associations between categorical variables using χ2 test. Logistic regression was used to determinate associations between endpoints for CVD and independent variables with criteria pb 0.05 for entry and pN 0.1 for exit. This method was used to identify the best
2015
predictor. The receiver operating characteristic (ROC) curves were constructed. The area under curve (AUC), a measure of the efficiency, was also computed. All analyses were carried out using Statistica 6.0 (StatSoft, Tulsa, OK, USA) and MedCalc 8.0 (MedCalc Software, Mariakerke, Belgium). pb 0.05 was considered statistically significant. 3. Results Seventy-eight patients, mean age 67.0 ± 11.5 years with median LVEF 45% (quartile range 25%–75%: 39.0–53.0) were evaluated. Median BNP level on admission (first day of STEMI), was 32.1 pmol/L (25th–75th percentile:13.8–84.9) and on the fifth day of hospitalization was 77.0 pmol/L (25th–75th percentile: 34.3–162.9). Median apelin-36 concentration on the first day was 509.6 pmol/L (25th–75th percentile: 464.5–565.3) and on the fifth day was 478.6 pmol/L (25th–75th percentile: 416.5–545). During the 5-day interval the changes in BNP and apelin-36 concentrations were significant (p b 0.001 and p = 0.002, respectively). 3.1. BNP, apelin-36 and LVEF Patients with lower LVEF were older and anterior STEMI was in prevalence in comparison with patients with normal LVEF. Both BNP concentrations, but not apelin-36, were significantly higher in patients with lower LVEF. However frequency of CEP was similar in both groups (Table 1). In ANOVA test there were significant differences according to BNP measurements in patients with high and low LVEF (for both first and fifth days BNP measurements p = 0.017). In these two groups of patients BNP level increased in 5-day interval (Fig. 1), however the difference did not reach statistical significance. In contrast, we did not find significant differences according to apelin-36 measurements on the first and fifth days in patients with high and low LVEF, however in both groups there were significant reduction in apelin-36 concentrations measured in 5-day interval (p = 0.008, and p = 0.040, accordingly; Fig. 1). Only BNP measurements correlated with lower LVEF: for the first measurement—r=−0.39, and even better for the second one—r=−0.51, pb 0.050. We did not find such a significant correlation either to the first or second apelin-36 measurements. In multivariate regression analysis BNP obtained on the fifth day influenced LVEF value (beta=−0.56, pb 0.001). Besides, both—obtained on the first and fifth days—BNP measurements were good for prediction of poor LVEF (p = 0.010 and p b 0.001, respectively). However, we did not find any significance according to apelin-36 measurements (p=0.90 and p=0.30, respectively). Table 1 Characteristics of patients with preserved and impaired LVEF. LVEF ≥50% Age, years Median (25%; 75%) 62.0 Sex (male), % 67.7 STEMI location Anterior, % 19.3 Inferior, % 74.2 Admission BNP, pmol/L, Median (25%; 75%) 21.0 Five-day BNP, pmol/L Median (25%; 75%) 36.6 Admission apelin-36, pmol/L, Median (25%; 75%) 506.8 Five-day apelin-36, pmol/L, Median (25%; 75%) 489.0 CEP, % 22.6
(56.0; 69.0)
LVEF b 50%
p value
71.0 (61.0; 80.0) 70.2
0.020 0.820
55.3 40.4
0.005
(10.2; 54.4)
46.3 (16.2;113.5)
0.010
(17.2; 87.7)
621.4 (54.4; 207.5)
b 0.001
(464.0; 568.4)
88.9 (469.2; 564.6)
0.90
(435.3; 551.1)
466.6 (414.7; 543.9) 19.1
0.40 0.60
LVEF—left ventricle ejection fraction. STEMI—ST-elevation myocardial infarction. BNP—B-type natriuretic peptide. CEP—composite endpoint.
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Fig. 2. Receiver operating characteristic curve for ability of BNP and apelin-36 (both measurements) to predict LVEF. BNP—B-type natriuretic peptide. LVEF—left ventricle ejection fraction.
the second BNP measurement was predictive for CEP: the value of area under the receiver operator characteristic (ROC) curve (AUC) was 0.627 (95% confidence interval 0.507–0.736; Fig. 4). 4. Discussion
Fig. 1. Changes in BNP and apelin-36 measurements in patients with preserved and impaired LVEF (ANOVA test, values shown as mean ± SD). BNP—B-type natriuretic peptide. LVEF—left ventricle ejection fraction. SD—standard deviation.
In ROC analysis only BNP measurements were diagnostic for lower (b50%) LVEF: area under the ROC curve [AUC]—0.652 (95% confidence interval [CI] 0.533 to 0.759) and 0.744 (95% CI 0.630 to 0.837), respectively (Fig. 2). 3.2. BNP, apelin-36 and CEP After 1 year follow-up 19 (24.3%) patients reached composite endpoint. Only one patient died. Symptoms of recurrent ischemia leading to the reintervention were reported in 9 (11.5%) patients. The median baseline concentrations of BNP and apelin-36 were higher in a group of patients who reached CEP compared with those without CEP: 40.3 pmol/L (25th–75th percentile 21.4–75.4) vs 29.0 pmol/L (25th–75th percentile: 10.8–84.9) and 540.4 pmol/L (25th–75th percentile: 492.6–567.7) vs 502.9 (25th–75th percentile: 464.0–564.6), but these values did not reach any significance (respectively, for both parameters p=0.380, and p=0.310). In ANOVA test we did not find any significant differences according to BNP measurements and the occurrence of CEP (Fig. 3). Apelin-36 concentrations decreased in both groups of patients: those who reached and did not reach CEP (p = 0.013 and p = 0.044, respectively; Fig. 3). In ROC analysis of all parameters taken into account, like age, sex, infarct location, LVEF, both BNP and apelin-36 measurements, only
Recently, cardiac apelin has been suggested to contribute to the pathophysiology of heart failure in humans. This novel peptide acts as an endogenous ligand for the previously orphaned G-protein-coupled receptor, angiotensin-like 1 receptor (APJ). Apelin mRNA expression and peptide immunoreactivity have been described in a variety of tissues including gastrointestinal tract, adipose tissue, brain, kidney, liver, lung and at various sites within the cardiovascular system. Apelin is strongly expressed in the heart, but also present in the large vessels, coronary vessels and endothelial cells. In preclinical models, apelin causes nitric oxide-dependent vasodilation, reduces ventricular preload and afterload and increases cardiac contractility in rats with normal and failing hearts [6]. In animal experiments its infusion improved systolic as well as diastolic LV function [7]. In humans the role of apelin has been investigated particularly in heart failure. Most of the studies demonstrated lower plasma concentration of the apelin in patients with left ventricular dysfunction compared to the normal controls [8]. Circulating levels of apelin are reported to decrease in heart failure and to rise in response of LV function improvement [8,9]. It is unclear, if apelin may serve as marker of prognosis in acute myocardial infarction [10]. In our study group, we have noticed the trend to decrease the values of apelin-36 within the first 5-day interval, regardless to LV dysfunction. However, this biomarker did not correlate with LV function. To date only animal studies concern the role of the apelin-APJ system in myocardial ischemia. In vivo and in vitro studies demonstrated an up regulation of APJ gene expression in response to ischemia [10]. Perhaps the apelin–APJ system may be involved in myocardial protection during an acute myocardial ischemia and thus our study reveals the decrease of the peptide within the first 5 days of the ischemic episode. To investigate the value of apelin measurements in ischemic myocardial injury, we decided to compare diagnostic and prognostic significance of apelin with BNP. High level of BNP is a powerful marker of LV systolic dysfunction and poor prognosis after MI [11]. However, patients with ischemic heart disease also exhibit increased plasma BNP concentrations despite preserved cardiac function [12]. Moreover, elevated NT-pro-BNP and BNP are strong
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Fig. 4. Receiver operating characteristic curve for ability of BNP and apelin-36 (both measurements) to predict long-term events (patients with CEP vs without CEP). BNP—B-type natriuretic peptide. CEP—composite endpoint.
plasma apelin-36 concentrations and the increase of plasma BNP concentrations could be found in the first days after the onset of myocardial infarction. BNP measurements, especially the second one, are better, than apelin-36 diagnostic value for the detection of LV dysfunction. In this group of patients BNP and apelin-36 have prognostic values, although detailed clinical investigation is now required to establish especially the role of apelin, alone or together with other biomarkers, in patients with ischemic episodes.
5. Study limitations
Fig. 3. Changes in BNP and apelin-36 measurements in patients with and without CEP (ANOVA test, values shown as mean±SD). BNP—B-type natriuretic peptide. CEP—composite endpoint. SD—standard deviation.
independent predictors of clinical events in patients with heart failure and preserved LV function [13]. Most of our study patients had preserved LV function. Although, both BNP measurements (second even better) correlated and predicted poor LVEF, we did not find any significance according to apelin-36 measurements. These results were confirmed in the ROC analysis. Although apelin-36 was not predictive, we found significant decrease of its values in a group of patients who reached CEP. Besides, although not significant, the median baseline concentrations of BNP and apelin-36 were higher in a group of patients who reached CEP compared with those without. However, only the second BNP measurement was predictive. One of the latest published studies has shown that the combination of several biomarkers, including BNP assessed on admission, in each or in combination, had only minimal impact for the prediction of long-term cardiovascular events after primary stenting in STEMI patients [14]. We assessed the similar group of low risk first STEMI patients previously. BNP obtained early after admission had the strongest predictive value, compared to traditional tools for risk stratification [15]. In summary, our study provides information that in low risk STEMI patients, treated with pPCI and with preserved LVEF the decrease of
The main limitation of this study is the relatively small number of patients enrolled, which is related to strict inclusion and exclusion criteria. However, the aim of the study was to examine selected group of first STEMI patients with preserved LVEF. We aimed to investigate upright effect of ischemia on apelin and BNP concentrations. The patients were included prospectively and were investigated thoroughly, so the authors consider the results obtained as being representative.
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[11] Güneş Y, Okçün B, Kavlak E, Erbaş C, Karcier S. Value of brain natriuretic peptide after acute myocardial infarction. Anadolu Kardiyol Derg 2008;8:182–7. [12] Goetze JP, Gore A, Møller CH, Steinbrüchel DA, Rehfeld JF, Nielsen LB. Acute myocardial hypoxia increases BNP gene expression. FASEB J 2004;18:1928–30. [13] Grewal J, McKelvie RS, Persson H, et al. Usefulness of N-terminal pro-brain de and brain natriuretic peptide to predict cardiovascular outcomes in patients with heart failure and preserved left ventricular ejection fraction. Am J Cardiol 2008;102:733–77.
[14] Jeong YH, Lee SW, Lee CW, et al. Biomarkers on admission for the prediction of cardiovascular events after primary stenting in patients with ST-elevation myocardial infarction. Clin Cardiol 2008;31:572–9. [15] Kuklinska AM, Sobkowicz B, Mroczko B, et al. Prognostic significance of the admission plasma B-type natriuretic peptide measurement in patients with first ST-elevation myocardial infarction in comparison with C-reactive protein and TIMI risk score. Clin Chim Acta 2007;382:106–11.