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Intermedin as a prognostic factor for major adverse cardiovascular events in patients with ST-segment elevation acute myocardial infarction
Peptides 58 (2014) 98–102
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Intermedin as a prognostic factor for major adverse cardiovascular events in patients with ST-segment elevation acute myocardial infarction Bei Tang, Ze Zhong ∗ , Hong-Wei Shen, Hui-Ping Wu, Peng Xiang, Bin Hu Department of Critical Care Medicine, The First People’s Hospital of Jiande City, 599 Yanzhou Main Road, Jiande 311600, China
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Article history: Received 26 May 2014 Received in revised form 6 June 2014 Accepted 6 June 2014 Available online 23 June 2014 Keywords: Intermedin Acute myocardial infarction Major adverse cardiovascular event Prognosis Biomarker
a b s t r a c t Intermedin functions systemically as a potent vasodilator and its plasma levels have been shown to be elevated in patients with acute myocardial infarction. This study aimed to evaluate the prognostic value of plasma intermedin level in the patients with ST-segment elevation acute myocardial infarction. Plasma intermedin concentrations of 128 patients and 128 healthy controls were determined using a radioimmunoassay. Patients were followed up for 6 months for major adverse cardiovascular events (MACE) consisting of cardiovascular mortality, reinfarction, hospitalization for decompensated heart failure, and lift-threatening arrhythmia. The association of plasma intermedin levels with MACE was investigated by univariate and multivariate analyses. Plasma intermedin levels were significantly higher in patients than in healthy subjects. Elevated plasma level of intermedin was identified as an independent predictor of MACE. Receiver operating characteristic curve analysis showed that plasma intermedin levels had high predictive value for MACE. Moreover, its predictive value was similar to Global Registry of Acute Coronary Events scores’ based on area under curve. Meantime, it obviously improved Global Registry of Acute Coronary Events scores’ predictive value in a combined logistic-regression model. In multivariate Cox’s proportional hazard analysis, plasma intermedin level emerged as an independent predictor of MACE-free survival. Thus, our results suggest that high plasma intermedin level is associated with poor outcomes of patients and may be a useful prognostic biomarker in ST-segment elevation acute myocardial infarction. © 2014 Elsevier Inc. All rights reserved.
Introduction Acute myocardial infarction, especially ST-segment elevation myocardial infarction (STEMI), is a leading cause of mortality and morbidity worldwide [4]. The risk stratification of patients with STEMI can help to identify those individuals at maximum risk of adverse outcomes who may benefit from early aggressive therapy [9]. Currently, clinical risk assessment tool such as Global Registry of Acute Coronary Events (GRACE) score is the most commonly used method of risk stratification [12]. Nevertheless, plasma biomarkers have been the subject of research in recent years [23]. Intermedin (IMD), also known as adrenomedullin 2, is a novel peptide, recently discovered simultaneously by 2 groups in 2004 [24,31]. IMD is expressed in many organ systems including gastrointestinal tract, lungs, cardiovascular and renal systems, hypothalamus, pituitary gland, adrenal gland, placenta, uterus, and ovaries [7,8,27,29–31]. IMD functions systemically as a potent
∗ Corresponding author. Tel.: +86 0571 64096607; fax: +86 0571 64096607. E-mail address: [email protected] (Z. Zhong). http://dx.doi.org/10.1016/j.peptides.2014.06.009 0196-9781/© 2014 Elsevier Inc. All rights reserved.
vasodilator, delays gastric emptying and enhances angiogenesis [27,29,30]. IMD may exert cardioprotection in experimental heart disease models including congestive heart failure [13] and ischemia/reperfusion injury [34], as well as, can ameliorate atherosclerosis in apoE null mice by modifying lipid profiles of mice [35]. Blood levels of IMD have been associated with severity of coronary stenosis in acute coronary syndrome [22]. Recently, a significant increase in plasma IMD following acute myocardial infarction has been demonstrated to be associated with oxidative stress and the severity of the coronary stenosis [17]. Thus, plasma IMD level may be a promising prognostic tool in STEMI. This study was designed to clarify the association between the plasma levels of IMD and STEMI outcomes. Materials and methods Study population This was a prospective observational study of STEMI patients consecutively admitted to Department of Critical Care Medicine, The First People’s Hospital of Jiande City, China, from February 2011
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to May 2013. STEMI diagnosis was made according to the following criteria [16]: (1) typical chest pain with a duration >30 min; (2) electrocardiographic ST-segment elevation ≥0.1 mV in either two or more limb leads, or ≥0.2 mV in either two or more precordial leads; (3) and an elevation of serum creatine phosphokinase more than two times the upper limit of the normal range. The exclusion criteria were rheumatic heart disease, valvular heart disease, chronic liver, renal and respiratory diseases, malignancy, and age ≥80 years. Healthy controls included a group of age- and sex-matched volunteers who had no previous diagnosis of hypertension, diabetes mellitus and other chronic disease, and had not received any pharmacological therapy during the month prior to the study. This study was permitted by Ethnic Committee in The First People’s Hospital of Jiande City. All participants or their kin provided their written informed consent to participate in this study and to publish these case details. Assessment On admission, we recorded the information on demographics, previous cardiovascular disease and cardiovascular risk factors. The Killip classification was determined by the first cardiology specialist to examine the patient [15]. Estimated glomerular filtration rate was calculated from the simplified Modification of Diet in Renal Disease formula [26]. Transthoracic echocardiography was performed. A 16-segment left ventricular wall motion index score was determined based on the American Society of Echocardiography method [25]. The left ventricular ejection fraction was calculated using the biplane method of disks formula. Impaired left ventricular systolic function was defined as either a left ventricular ejection fraction <40% or a ventricular wall motion index score >1.8 [20]. Based on an international observational database of patients with cute coronary syndromes, Global Registry of Acute Coronary Events (GRACE) score can be calculated to predict in-hospital morality or 6-month death and/or re-myocardial infarction [11]. We used GRACE scores to predict 6-month major adverse cardiovascular events (MACE) consisting of cardiovascular mortality, reinfarction, hospitalization for decompensated heart failure, and lift-threatening arrhythmia [2]. Immunoassay methods Peripheral blood samples were taken for healthy individuals at study entry and for patients at 12–24 h after chest pain. Samples were placed on ice, centrifuged at 3000 × g, and plasma aliquoted and frozen at −70 ◦ C. Plasma samples were extracted through a SepPak C18 cartridge (Waters, Milford, MA, USA) following the method of Morimoto et al. [19]. Plasma extracts were assayed in duplicate using IMD radioimmunoassay kit (Phoenix Pharmaceuticals, Belmont, CA, USA). The person carrying the assays was completely blinded to the clinical information. Statistical analysis All statistical analyses were performed with the use of SPSS 15.0 (SPSS Inc., Chicago, IL, USA) and MedCalc 9.6.4.0. (MedCalc Software, Mariakerke, Belgium). The results were reported as counts (percentage) for the categorical variables, mean ± standard deviation for the continuous variables. Chi-square tests (or Fisher exact tests) and t tests were performed for intergroup comparisons. To analyze association of IMD to MACE during follow-up, multivariate analysis was performed in a binary logistic-regression model with calculated odds ratio (OR) and 95% confidence interval (CI). Receiver operating characteristic (ROC) curves were used to describe the predictive values with the estimated optimal cutoff point and the calculated area under curve (AUC). According to
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previous methods [5,10,33], a combined logistic-regression model was configured, and then, the additive benefit of intermedin to GRACE scores was estimated. MACE-free survival was estimated using the Kaplan–Meier method and the intergroup differences in survival time were tested using the log-rank test. Multivariate Cox’s proportional hazard analysis was carried out to compare and identify independent prognostic factors for MACE-free survival and to calculate hazard ratios (HR) and 95% CI. All significant parameters in the univariate analysis were entered into a multivariate model. All P values less than 0.05 were considered as statistically significant with a 2-tailed test. Results Study population characteristics This study included 128 STEMI patients and 128 age- and sexmatched healthy controls. Table 1 shows patients’ clinical and laboratory characteristics. 35 patients (27.3%) had MACE. Plasma IMD levels were statistically significantly higher in patients than in healthy controls (185.7 ± 30.1 pg/mL vs. 116.5 ± 22.2 pg/mL; P < 0.001). MACE prediction Tables 1 and 2 show that some risk factors were correlated with 6-month MACE of STEMI patients. A multivariate analyses selected plasma IMD levels (OR, 1.032; 95% CI, 1.014–1.051; P = 0.001) and GRACE score (OR, 1.049; 95% CI, 1.025–1.074; P < 0.001) as the independent predictors for 6-month MACE. In addition, plasma IMD levels were bifurcated at mean value (185.7 pg/mL) and values of >185.7 pg/mL indicated high level of IMD. Furthermore, A multivariate analyses showed high level of IMD (OR, 3.942; 95% CI, 1.416–10.979; P = 0.009) and GRACE score (OR, 1.053; 95% CI, 1.029–1.077; P < 0.001) as the independent predictors for 6-month MACE. Fig. 1A shows that plasma IMD levels had high predictive value for 6-month MACE (AUC, 0.812; 95% CI, 0.733–0.876). Compared with AUC of GRACE score (AUC, 0.838; 95% CI, 0.762–0.897), the difference was not statistically significant (P = 0.653). Moreover, in Fig. 1B, a combined logistic-regression model was configured and it was demonstrated that IMD statistically significantly improved the AUC of GRACE score to 0.882 (95% CI, 0.814–0.932; P = 0.047). MACE-free survival analysis Table 2 shows that some risk factors were correlated with MACE-free survival of STEMI patients during 6-month follow-up. A multivariate analyses selected plasma IMD levels (OR, 1.031; 95% CI, 1.018–1.044; P < 0.001) and GRACE score (OR, 1.034; 95% CI, 1.022–1.046; P < 0.001) as the independent predictors for MACEfree survival. In addition, plasma IMD levels were bifurcated at mean value (185.7 pg/mL) and values of >185.7 pg/mL indicated high level of IMD. Furthermore, A multivariate analyses showed high level of IMD (OR, 3.045; 95% CI, 1.389–6.673; P = 0.005) and GRACE score (OR, 1.038; 95% CI, 1.026–1.050; P < 0.001) as the independent predictors for MACE-free survival. Fig. 2 shows that patients with high level of IMD had significantly shorter MACE-free survival than those with low level of IMD. Discussion The current study showed that elevated plasma IMD level was associated with MACE risk independently from other known risk factors for STEMI. Furthermore, plasma IMD level also emerged
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Table 1 Patients’ characteristics and the factors associated with MACE during follow-up. Characteristics
All patients
MACE Positive
Number Demographics Age (years) Male Body mass index (kg/m2 ) Previous cardiovascular disease Myocardial infarction Angina pectoris Heart failure Cardiovascular risk factors Hypertension Diabetes mellitus Hypercholesterolemia Current/ex-smoker Risk markers Killip class > 1 Glucose (mmol/L) Troponin T (ng/L) WBC (×109 ) C-reactive protein (mg/L) Creatine kinase MB (ng/mL) Intermedin (pg/mL) High level of intermedin eGFR (ml/min/1.73 m2 ) Ilvsf GRACE score Medications Aspirin Beta-blocker ACE-inhibitor or ARB Statin Admission time (h) Plasma-sampling time (h)
128
P values Negative
35
93
66.2 ± 9.5 92 (71.9%) 25.8 ± 2.4
69.4 ± 8.6 21 (60.0%) 26.3 ± 2.6
65.0 ± 9.5 71 (76.3%) 25.7 ± 2.3
0.018 0.067 0.206
28 (21.9%) 30 (23.4%) 4 (3.1%)
14 (40.0%) 14 (40.0%) 2 (5.7%)
14 (15.1%) 16 (17.2%) 2 (2.2%)
0.002 0.007 0.302
70 (54.7%) 29 (22.7%) 45 (35.2%) 82 (64.1%)
26 (74.3%) 14 (40.0%) 15 (42.9%) 24 (68.6%)
44 (47.3%) 15 (16.1%) 30 (32.3%) 58 (62.4%)
0.006 0.004 0.263 0.514
48 (37.5%) 9.8 ± 3.5 909.8 ± 855.6 7.4 ± 2.8 10.6 ± 3.6 87.7 ± 78.4 185.7 ± 30.1 49 (38.3%) 64.8 ± 19.8 54 (42.2%) 121.3 ± 36.4
20 (57.1%) 11.6 ± 4.3 1455.0 ± 1008.2 9.0 ± 3.3 12.6 ± 4.6 138.3 ± 109.5 211.2 ± 34.4 24 (68.6%) 56.5 ± 21.3 22 (62.9%) 155.5 ± 35.0
28 (30.1%) 9.2 ± 2.9 704.6 ± 692.3 6.9 ± 2.4 9.8 ± 2.8 68.7 ± 52.1 176.1 ± 21.7 25 (26.9%) 67.9 ± 18.4 32 (34.4%) 108.4 ± 27.6
0.005 0.004 <0.001 0.001 0.001 <0.001 <0.001 <0.001 0.003 0.004 <0.001
22 (62.9%) 24 (68.6%) 19 (54.3%) 20 (57.1%) 5.3 ± 2.6 16.8 ± 3.9
80 (86.0%) 79 (85.0%) 77 (82.8%) 75 (80.7%) 5.5 ± 2.8 17.4 ± 4.0
0.004 0.037 0.001 0.007 0.654 0.438
102 (79.7%) 103 (80.5%) 96 (75.0%) 95 (74.2%) 5.4 ± 2.7 17.3 ± 4.0
Variables were presented as mean ± standard deviation or counts (percentage). Intergroup comparisons were completed by unpaired Student’s t test, chi-square test or Fisher exact test. MACE indicates major adverse cardiovascular events; WBC, white blood cell; eGFR, estimated glomerular filtration rate; GRACE, Global Registry of Acute Coronary Events; ACE, angiotensin-converting enzyme; ARB, angiotensin II receptor blocker; iLVSF, impaired left ventricular systolic function. Plasma intermedin levels were bifurcated at mean value (185.7 pg/mL). Values of >185.7 pg/mL indicated high level of intermedin.
as an independent predictor of MACE-free survival. ROC analysis demonstrated that its predictive value was similar to GRACE score and meantime, it improved the predictive value of GRACE score. To date, to the best of our knowledge, this is the first epidemiologic study to evaluate the prognostic significance of plasma IMD level
in STEMI. This study therefore revealed that elevated plasma IMD level had potential to predict poor prognosis in STEMI patients. IMD is a member of the calcitonin gene-related peptide/calcitonin family of peptides and was discovered in 2004 [24,31]. It is extensively distributed throughout the body
Fig. 1. The receiver operating characteristic curve analysis of plasma intermedin level (A) and combination of plasma intermedin level with GRACE score (B) for major adverse cardiovascular events in ST-segment elevation myocardial infarction patients. GRACE indicates Global Registry of Acute Coronary Events. GRACE score + Intermedin means combination of GRACE score and intermedin to predict major adverse cardiovascular events based on a combined logistic-regression model and receiver operating characteristic curve.
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Table 2 The factors associated with MACE and MACE-free survival during follow-up. Characteristics
MACE Odds ratio (95% confidence interval)
Demographics Age (years) Male Body mass index (kg/m2 ) Previous cardiovascular disease Myocardial infarction Angina pectoris Heart failure Cardiovascular risk factors Hypertension Diabetes mellitus Hypercholesterolemia Current/ex-smoker Risk markers Killip class > 1 Glucose (mmol/L) Troponin T (ng/L) WBC (×109 ) C-reactive protein (mg/L) Creatine kinase MB (ng/mL) Intermedin (pg/mL) High level of intermedin eGFR (ml/min/1.73 m2 ) iLVSF GRACE score Medications Aspirin Beta-blocker ACE-inhibitor or ARB Statin Admission time (h) Plasma-sampling time (h)
MACE-free survival P values
Hazard ratio (95% confidence interval)
P values
1.057 (1.008–1.108) 0.465 (0.203–1.064) 1.118 (0.949–1.318)
0.021 0.070 0.183
1.059 (1.015–1.105) 0.547 (0.278–1.076) 1.107 (0.965–1.270)
0.008 0.081 0.145
3.762 (1.555–9.100) 3.208 (1.352–7.616) 2.758 (0.373–20.376)
0.003 0.008 0.320
2.836 (1.440–5.588) 2.446 (1.243–4.814) 2.651 (0.635–11.063)
0.003 0.010 0.181
3.217 (1.361–7.606) 3.467 (1.448–8.302) 1.575 (0.709–3.499) 1.317 (0.575–3.013)
0.008 0.005 0.265 0.515
2.733 (1.280–5.838) 2.732 (1.388–5.378) 1.480 (0.758–2.891) 1.194 (0.585–2.437)
0.009 0.004 0.251 0.627
3.095 (1.387–6.908) 1.248 (1.093–1.424) 2.694 (1.695–4.374) 1.301 (1.125–1.506) 1.252 (1.111–1.410) 1.012 (1.006–1.019) 1.043 (1.026–1.061) 5.935 (2.541–13.860) 0.971 (0.951–0.991) 3.226 (1.438–7.238) 1.056 (1.033–1.079)
0.006 0.001 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001 0.005 0.005 <0.001
2.556 (1.307–4.998) 1.200 (1.087–1.325) 1.914 (1.418–2.584) 1.235 (1.100–1.387) 1.210 (1.110–1.318) 1.007 (1.004–1.010) 1.040 (1.029–1.052) 4.833 (2.363–9.887) 0.976 (0.960–0.993) 2.763 (1.391–5.489) 1.044 (1.032–1.056)
0.006 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001 0.005 0.004 <0.001
0.275 (0.112–0.678) 0.387 (0.155–0.963) 0.247 (0.105–0.581) 0.320 (0.138–0.744) 0.966 (0.832–1.122) 0.961 (0.869–1.062)
0.005 0.041 0.001 0.008 0.651 0.435
0.363 (0.182–0.722) 0.467 (0.229–0.953) 0.302 (0.155–0.588) 0.397 (0.203–0.777) 0.971 (0.854–1.103) 0.966 (0.887–1.053)
0.004 0.037 <0.001 0.007 0.647 0.437
Univariate logistic-regression analysis was used to calculate the odds ratio and 95% confidence interval for prediction of MACE. Univariate Cox regression analysis was used to calculate the hazard ratio and 95% confidence interval for analysis of MACE-free survival. MACE indicates major adverse cardiovascular events; WBC, white blood cell; eGFR, estimated glomerular filtration rate; GRACE, Global Registry of Acute Coronary Events; ACE, angiotensin-converting enzyme; ARB, angiotensin II receptor blocker; iLVSF, impaired left ventricular systolic function. Plasma intermedin levels were bifurcated at mean value (185.7 pg/mL). Values of >185.7 pg/mL indicated high level of intermedin.
[7,8,27,29–31]. It causes hypotension when given peripherally, but when given into the central nervous system, it increases blood pressure and causes sympathetic activation. It also increases prolactin release, is anti-diuretic and natriuretic and reduces food intake [14]. Plasma IMD levels are elevated in various human diseases including acute myocardial infarction [17] and acute coronary syndrome [22], and it is also secreted by leukocytes of patients with chronic heart failure at different stages of the disease [18]. Previous study has shown that elevated plasma concentrations of IMD reflect severity of coronary stenosis in the patients with acute coronary syndrome [22]. It is a paracrine/autocrine factor secreted by myocardium and up-regulated during the pathophysiologic process in some animal models and is considered a potential endogenous
Fig. 2. The survival curves for MACE-free survival in ST-segment elevation myocardial infarction patients according to plasma intermedin levels. MACE indicates major adverse cardiovascular events.
protector of the heart [13,34,35]. Furthermore, IMD 1-53 exerts potent cardioprotective effects against oxidative stress [36], inhibiting endoplasmic reticulum stress via PI3 kinase-Akt signaling [32], and activating cardioprotective Akt/GSK-3beta signaling, decreasing mitochondrial-mediated myocardial apoptosis [28]. Thus, these neuroprotective properties of IMD may be beneficial in suppressing myocardial ischemic injury and an increase in plasma IMD level may reflect a counter-regulatory or compensatory mechanism in STEMI. It is hypothesized that close and reproducible relation of IMD levels to the degree of myocardial injury is the basis of its unique usefulness as a prognostic biomarker. Myocardial injury is associated with the activation of a range of neurohormonal systems in proportion to the severity of myocardial injury. Up-regulated hormones include natriuretic peptides (Atype natriuretic peptide, B-type natriuretic peptide and N-terminal pro-brain natriuretic peptide) and adrenomedullin [1,3,6,21]. Although these blood markers were of potential clinical prognostic predictive value, to my best knowledge, none of the very plausible biomarkers added a clinically useful degree of prediction of MACE after STEMI to that provided by the measurement of the simple clinical variable like GRACE score. Previous study has demonstrated high plasma IMD level may be associated with the severity of the coronary stenosis after STEMI [20]. This study analyzed MACE and MACE-free survival and showed that plasma IMD level, presented as continuous or categorical variable, was identified as an independent prognostic factor. ROC curve showed high predictive value of plasma IMD level for MACE. Interestingly, IMD improved the predictive value of GRACE score based on AUC. These accumulating evidences showed that IMD may play a role as a prognostic biomarker in STEMI. Furthermore, more prospective multicenter
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investigations are needed to confirm the predictive value of plasma IMD levels on MACE after STEMI. Conclusions This study suggests that IMD may be a useful prognostic tool for the prediction of MACE in patients with STEMI. Conflict of interest The authors declare that they have no conflict of interest. Acknowledgement This study was supported by a grant from Zhejiang Province Medical and Health Project (No. 2013KYA176) and Hangzhou City Medical and Health Project (No. 2012B051). References [1] Aldous SJ. Cardiac biomarkers in acute myocardial infarction. Int J Cardiol 2013;164:282–94. [2] Aslan S, Ikitimur B, Cakmak HA, Karadag B, Tufekcioglu EY, Ekmekci H, et al. Prognostic utility of serum vitronectin levels in acute myocardial infarction. Herz 2014, http://dx.doi.org/10.1007/s00059-014-4105-2. [3] Banerjee AK, Dastidar DG. Biochemical markers in acute myocardial infarction. Indian Heart J 2011;63:33–8. [4] Boateng S, Sanborn T. Acute myocardial infarction. Dis Mon 2013;59:83–96. [5] Cai JY, Lu C, Chen MH, Ba HJ, Chen XD, Lin JH, et al. Predictive value of phosphorylated axonal neurofilament subunit H for clinical outcome in patients with acute intracerebral hemorrhage. Clin Chim Acta 2013;424:182–6. [6] Chan D, Ng LL. Biomarkers in acute myocardial infarction. BMC Med 2010;8:34. [7] Chauhan M, Elkins R, Balakrishnan M, Yallampalli C. Potential role of intermedin/adrenomedullin 2 in early embryonic development in rats. Regul Pept 2011;170:65–71. [8] Chauhan M, Yallampalli U, Dong YL, Hankins GD, Yallampalli C. Expression of adrenomedullin 2 (ADM2)/intermedin (IMD) in human placenta: role in trophoblast invasion and migration. Biol Reprod 2009;81:777–83. [9] Cheng CI, Hsueh SK, Lee FY, Wu CJ, Fang CY, Sheu JJ, et al. Clinical presentation and prognostic factors of patients with acute ST-segment elevation myocardial infarction following emergent revascularization for left main coronary artery obstruction. Circ J 2008;72:1598–604. [10] Du Q, Yang DB, Shen YF, Yu WH, Zhang ZY, Zhu Q, et al. Plasma leptin level predicts hematoma growth and early neurological deterioration after acute intracerebral hemorrhage. Peptides 2013;45:35–9. [11] Eagle KA, Lim MJ, Dabbous OH, Pieper KS, Goldberg RJ, Van de Werf F, et al. A validated prediction model for all forms of acute coronary syndrome: estimating the risk of 6-month postdischarge death in an international registry. J Am Med Assoc 2004;291:2727–33. [12] Fox KA, Dabbous OH, Goldberg RJ, Pieper KS, Eagle KA, Van de Werf F, et al. Prediction of risk of death and myocardial infarction in the six months after presentation with acute coronary syndrome: prospective multinational observational study (GRACE). Br Med J 2006;333:1091. [13] Hirose T, Totsune K, Mori N, Morimoto R, Hashimoto M, Nakashige Y, et al. Increased expression of adrenomedullin 2/intermedin in rat hearts with congestive heart failure. Eur J Heart Fail 2008;10:840–9. [14] Hong Y, Hay DL, Quirion R, Poyner DR. The pharmacology of adrenomedullin 2/intermedin. Br J Pharmacol 2012;166:110–20. [15] Killip 3rd T, Kimball JT. Treatment of myocardial infarction in a coronary care unit. A two year experience with 250 patients. Am J Cardiol 1967;20:457–64.
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Peptides journal homepage: www.elsevier.com/locate/peptides
Intermedin as a prognostic factor for major adverse cardiovascular events in patients with ST-segment elevation acute myocardial infarction Bei Tang, Ze Zhong ∗ , Hong-Wei Shen, Hui-Ping Wu, Peng Xiang, Bin Hu Department of Critical Care Medicine, The First People’s Hospital of Jiande City, 599 Yanzhou Main Road, Jiande 311600, China
a r t i c l e
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Article history: Received 26 May 2014 Received in revised form 6 June 2014 Accepted 6 June 2014 Available online 23 June 2014 Keywords: Intermedin Acute myocardial infarction Major adverse cardiovascular event Prognosis Biomarker
a b s t r a c t Intermedin functions systemically as a potent vasodilator and its plasma levels have been shown to be elevated in patients with acute myocardial infarction. This study aimed to evaluate the prognostic value of plasma intermedin level in the patients with ST-segment elevation acute myocardial infarction. Plasma intermedin concentrations of 128 patients and 128 healthy controls were determined using a radioimmunoassay. Patients were followed up for 6 months for major adverse cardiovascular events (MACE) consisting of cardiovascular mortality, reinfarction, hospitalization for decompensated heart failure, and lift-threatening arrhythmia. The association of plasma intermedin levels with MACE was investigated by univariate and multivariate analyses. Plasma intermedin levels were significantly higher in patients than in healthy subjects. Elevated plasma level of intermedin was identified as an independent predictor of MACE. Receiver operating characteristic curve analysis showed that plasma intermedin levels had high predictive value for MACE. Moreover, its predictive value was similar to Global Registry of Acute Coronary Events scores’ based on area under curve. Meantime, it obviously improved Global Registry of Acute Coronary Events scores’ predictive value in a combined logistic-regression model. In multivariate Cox’s proportional hazard analysis, plasma intermedin level emerged as an independent predictor of MACE-free survival. Thus, our results suggest that high plasma intermedin level is associated with poor outcomes of patients and may be a useful prognostic biomarker in ST-segment elevation acute myocardial infarction. © 2014 Elsevier Inc. All rights reserved.
Introduction Acute myocardial infarction, especially ST-segment elevation myocardial infarction (STEMI), is a leading cause of mortality and morbidity worldwide [4]. The risk stratification of patients with STEMI can help to identify those individuals at maximum risk of adverse outcomes who may benefit from early aggressive therapy [9]. Currently, clinical risk assessment tool such as Global Registry of Acute Coronary Events (GRACE) score is the most commonly used method of risk stratification [12]. Nevertheless, plasma biomarkers have been the subject of research in recent years [23]. Intermedin (IMD), also known as adrenomedullin 2, is a novel peptide, recently discovered simultaneously by 2 groups in 2004 [24,31]. IMD is expressed in many organ systems including gastrointestinal tract, lungs, cardiovascular and renal systems, hypothalamus, pituitary gland, adrenal gland, placenta, uterus, and ovaries [7,8,27,29–31]. IMD functions systemically as a potent
∗ Corresponding author. Tel.: +86 0571 64096607; fax: +86 0571 64096607. E-mail address: [email protected] (Z. Zhong). http://dx.doi.org/10.1016/j.peptides.2014.06.009 0196-9781/© 2014 Elsevier Inc. All rights reserved.
vasodilator, delays gastric emptying and enhances angiogenesis [27,29,30]. IMD may exert cardioprotection in experimental heart disease models including congestive heart failure [13] and ischemia/reperfusion injury [34], as well as, can ameliorate atherosclerosis in apoE null mice by modifying lipid profiles of mice [35]. Blood levels of IMD have been associated with severity of coronary stenosis in acute coronary syndrome [22]. Recently, a significant increase in plasma IMD following acute myocardial infarction has been demonstrated to be associated with oxidative stress and the severity of the coronary stenosis [17]. Thus, plasma IMD level may be a promising prognostic tool in STEMI. This study was designed to clarify the association between the plasma levels of IMD and STEMI outcomes. Materials and methods Study population This was a prospective observational study of STEMI patients consecutively admitted to Department of Critical Care Medicine, The First People’s Hospital of Jiande City, China, from February 2011
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to May 2013. STEMI diagnosis was made according to the following criteria [16]: (1) typical chest pain with a duration >30 min; (2) electrocardiographic ST-segment elevation ≥0.1 mV in either two or more limb leads, or ≥0.2 mV in either two or more precordial leads; (3) and an elevation of serum creatine phosphokinase more than two times the upper limit of the normal range. The exclusion criteria were rheumatic heart disease, valvular heart disease, chronic liver, renal and respiratory diseases, malignancy, and age ≥80 years. Healthy controls included a group of age- and sex-matched volunteers who had no previous diagnosis of hypertension, diabetes mellitus and other chronic disease, and had not received any pharmacological therapy during the month prior to the study. This study was permitted by Ethnic Committee in The First People’s Hospital of Jiande City. All participants or their kin provided their written informed consent to participate in this study and to publish these case details. Assessment On admission, we recorded the information on demographics, previous cardiovascular disease and cardiovascular risk factors. The Killip classification was determined by the first cardiology specialist to examine the patient [15]. Estimated glomerular filtration rate was calculated from the simplified Modification of Diet in Renal Disease formula [26]. Transthoracic echocardiography was performed. A 16-segment left ventricular wall motion index score was determined based on the American Society of Echocardiography method [25]. The left ventricular ejection fraction was calculated using the biplane method of disks formula. Impaired left ventricular systolic function was defined as either a left ventricular ejection fraction <40% or a ventricular wall motion index score >1.8 [20]. Based on an international observational database of patients with cute coronary syndromes, Global Registry of Acute Coronary Events (GRACE) score can be calculated to predict in-hospital morality or 6-month death and/or re-myocardial infarction [11]. We used GRACE scores to predict 6-month major adverse cardiovascular events (MACE) consisting of cardiovascular mortality, reinfarction, hospitalization for decompensated heart failure, and lift-threatening arrhythmia [2]. Immunoassay methods Peripheral blood samples were taken for healthy individuals at study entry and for patients at 12–24 h after chest pain. Samples were placed on ice, centrifuged at 3000 × g, and plasma aliquoted and frozen at −70 ◦ C. Plasma samples were extracted through a SepPak C18 cartridge (Waters, Milford, MA, USA) following the method of Morimoto et al. [19]. Plasma extracts were assayed in duplicate using IMD radioimmunoassay kit (Phoenix Pharmaceuticals, Belmont, CA, USA). The person carrying the assays was completely blinded to the clinical information. Statistical analysis All statistical analyses were performed with the use of SPSS 15.0 (SPSS Inc., Chicago, IL, USA) and MedCalc 9.6.4.0. (MedCalc Software, Mariakerke, Belgium). The results were reported as counts (percentage) for the categorical variables, mean ± standard deviation for the continuous variables. Chi-square tests (or Fisher exact tests) and t tests were performed for intergroup comparisons. To analyze association of IMD to MACE during follow-up, multivariate analysis was performed in a binary logistic-regression model with calculated odds ratio (OR) and 95% confidence interval (CI). Receiver operating characteristic (ROC) curves were used to describe the predictive values with the estimated optimal cutoff point and the calculated area under curve (AUC). According to
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previous methods [5,10,33], a combined logistic-regression model was configured, and then, the additive benefit of intermedin to GRACE scores was estimated. MACE-free survival was estimated using the Kaplan–Meier method and the intergroup differences in survival time were tested using the log-rank test. Multivariate Cox’s proportional hazard analysis was carried out to compare and identify independent prognostic factors for MACE-free survival and to calculate hazard ratios (HR) and 95% CI. All significant parameters in the univariate analysis were entered into a multivariate model. All P values less than 0.05 were considered as statistically significant with a 2-tailed test. Results Study population characteristics This study included 128 STEMI patients and 128 age- and sexmatched healthy controls. Table 1 shows patients’ clinical and laboratory characteristics. 35 patients (27.3%) had MACE. Plasma IMD levels were statistically significantly higher in patients than in healthy controls (185.7 ± 30.1 pg/mL vs. 116.5 ± 22.2 pg/mL; P < 0.001). MACE prediction Tables 1 and 2 show that some risk factors were correlated with 6-month MACE of STEMI patients. A multivariate analyses selected plasma IMD levels (OR, 1.032; 95% CI, 1.014–1.051; P = 0.001) and GRACE score (OR, 1.049; 95% CI, 1.025–1.074; P < 0.001) as the independent predictors for 6-month MACE. In addition, plasma IMD levels were bifurcated at mean value (185.7 pg/mL) and values of >185.7 pg/mL indicated high level of IMD. Furthermore, A multivariate analyses showed high level of IMD (OR, 3.942; 95% CI, 1.416–10.979; P = 0.009) and GRACE score (OR, 1.053; 95% CI, 1.029–1.077; P < 0.001) as the independent predictors for 6-month MACE. Fig. 1A shows that plasma IMD levels had high predictive value for 6-month MACE (AUC, 0.812; 95% CI, 0.733–0.876). Compared with AUC of GRACE score (AUC, 0.838; 95% CI, 0.762–0.897), the difference was not statistically significant (P = 0.653). Moreover, in Fig. 1B, a combined logistic-regression model was configured and it was demonstrated that IMD statistically significantly improved the AUC of GRACE score to 0.882 (95% CI, 0.814–0.932; P = 0.047). MACE-free survival analysis Table 2 shows that some risk factors were correlated with MACE-free survival of STEMI patients during 6-month follow-up. A multivariate analyses selected plasma IMD levels (OR, 1.031; 95% CI, 1.018–1.044; P < 0.001) and GRACE score (OR, 1.034; 95% CI, 1.022–1.046; P < 0.001) as the independent predictors for MACEfree survival. In addition, plasma IMD levels were bifurcated at mean value (185.7 pg/mL) and values of >185.7 pg/mL indicated high level of IMD. Furthermore, A multivariate analyses showed high level of IMD (OR, 3.045; 95% CI, 1.389–6.673; P = 0.005) and GRACE score (OR, 1.038; 95% CI, 1.026–1.050; P < 0.001) as the independent predictors for MACE-free survival. Fig. 2 shows that patients with high level of IMD had significantly shorter MACE-free survival than those with low level of IMD. Discussion The current study showed that elevated plasma IMD level was associated with MACE risk independently from other known risk factors for STEMI. Furthermore, plasma IMD level also emerged
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Table 1 Patients’ characteristics and the factors associated with MACE during follow-up. Characteristics
All patients
MACE Positive
Number Demographics Age (years) Male Body mass index (kg/m2 ) Previous cardiovascular disease Myocardial infarction Angina pectoris Heart failure Cardiovascular risk factors Hypertension Diabetes mellitus Hypercholesterolemia Current/ex-smoker Risk markers Killip class > 1 Glucose (mmol/L) Troponin T (ng/L) WBC (×109 ) C-reactive protein (mg/L) Creatine kinase MB (ng/mL) Intermedin (pg/mL) High level of intermedin eGFR (ml/min/1.73 m2 ) Ilvsf GRACE score Medications Aspirin Beta-blocker ACE-inhibitor or ARB Statin Admission time (h) Plasma-sampling time (h)
128
P values Negative
35
93
66.2 ± 9.5 92 (71.9%) 25.8 ± 2.4
69.4 ± 8.6 21 (60.0%) 26.3 ± 2.6
65.0 ± 9.5 71 (76.3%) 25.7 ± 2.3
0.018 0.067 0.206
28 (21.9%) 30 (23.4%) 4 (3.1%)
14 (40.0%) 14 (40.0%) 2 (5.7%)
14 (15.1%) 16 (17.2%) 2 (2.2%)
0.002 0.007 0.302
70 (54.7%) 29 (22.7%) 45 (35.2%) 82 (64.1%)
26 (74.3%) 14 (40.0%) 15 (42.9%) 24 (68.6%)
44 (47.3%) 15 (16.1%) 30 (32.3%) 58 (62.4%)
0.006 0.004 0.263 0.514
48 (37.5%) 9.8 ± 3.5 909.8 ± 855.6 7.4 ± 2.8 10.6 ± 3.6 87.7 ± 78.4 185.7 ± 30.1 49 (38.3%) 64.8 ± 19.8 54 (42.2%) 121.3 ± 36.4
20 (57.1%) 11.6 ± 4.3 1455.0 ± 1008.2 9.0 ± 3.3 12.6 ± 4.6 138.3 ± 109.5 211.2 ± 34.4 24 (68.6%) 56.5 ± 21.3 22 (62.9%) 155.5 ± 35.0
28 (30.1%) 9.2 ± 2.9 704.6 ± 692.3 6.9 ± 2.4 9.8 ± 2.8 68.7 ± 52.1 176.1 ± 21.7 25 (26.9%) 67.9 ± 18.4 32 (34.4%) 108.4 ± 27.6
0.005 0.004 <0.001 0.001 0.001 <0.001 <0.001 <0.001 0.003 0.004 <0.001
22 (62.9%) 24 (68.6%) 19 (54.3%) 20 (57.1%) 5.3 ± 2.6 16.8 ± 3.9
80 (86.0%) 79 (85.0%) 77 (82.8%) 75 (80.7%) 5.5 ± 2.8 17.4 ± 4.0
0.004 0.037 0.001 0.007 0.654 0.438
102 (79.7%) 103 (80.5%) 96 (75.0%) 95 (74.2%) 5.4 ± 2.7 17.3 ± 4.0
Variables were presented as mean ± standard deviation or counts (percentage). Intergroup comparisons were completed by unpaired Student’s t test, chi-square test or Fisher exact test. MACE indicates major adverse cardiovascular events; WBC, white blood cell; eGFR, estimated glomerular filtration rate; GRACE, Global Registry of Acute Coronary Events; ACE, angiotensin-converting enzyme; ARB, angiotensin II receptor blocker; iLVSF, impaired left ventricular systolic function. Plasma intermedin levels were bifurcated at mean value (185.7 pg/mL). Values of >185.7 pg/mL indicated high level of intermedin.
as an independent predictor of MACE-free survival. ROC analysis demonstrated that its predictive value was similar to GRACE score and meantime, it improved the predictive value of GRACE score. To date, to the best of our knowledge, this is the first epidemiologic study to evaluate the prognostic significance of plasma IMD level
in STEMI. This study therefore revealed that elevated plasma IMD level had potential to predict poor prognosis in STEMI patients. IMD is a member of the calcitonin gene-related peptide/calcitonin family of peptides and was discovered in 2004 [24,31]. It is extensively distributed throughout the body
Fig. 1. The receiver operating characteristic curve analysis of plasma intermedin level (A) and combination of plasma intermedin level with GRACE score (B) for major adverse cardiovascular events in ST-segment elevation myocardial infarction patients. GRACE indicates Global Registry of Acute Coronary Events. GRACE score + Intermedin means combination of GRACE score and intermedin to predict major adverse cardiovascular events based on a combined logistic-regression model and receiver operating characteristic curve.
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Table 2 The factors associated with MACE and MACE-free survival during follow-up. Characteristics
MACE Odds ratio (95% confidence interval)
Demographics Age (years) Male Body mass index (kg/m2 ) Previous cardiovascular disease Myocardial infarction Angina pectoris Heart failure Cardiovascular risk factors Hypertension Diabetes mellitus Hypercholesterolemia Current/ex-smoker Risk markers Killip class > 1 Glucose (mmol/L) Troponin T (ng/L) WBC (×109 ) C-reactive protein (mg/L) Creatine kinase MB (ng/mL) Intermedin (pg/mL) High level of intermedin eGFR (ml/min/1.73 m2 ) iLVSF GRACE score Medications Aspirin Beta-blocker ACE-inhibitor or ARB Statin Admission time (h) Plasma-sampling time (h)
MACE-free survival P values
Hazard ratio (95% confidence interval)
P values
1.057 (1.008–1.108) 0.465 (0.203–1.064) 1.118 (0.949–1.318)
0.021 0.070 0.183
1.059 (1.015–1.105) 0.547 (0.278–1.076) 1.107 (0.965–1.270)
0.008 0.081 0.145
3.762 (1.555–9.100) 3.208 (1.352–7.616) 2.758 (0.373–20.376)
0.003 0.008 0.320
2.836 (1.440–5.588) 2.446 (1.243–4.814) 2.651 (0.635–11.063)
0.003 0.010 0.181
3.217 (1.361–7.606) 3.467 (1.448–8.302) 1.575 (0.709–3.499) 1.317 (0.575–3.013)
0.008 0.005 0.265 0.515
2.733 (1.280–5.838) 2.732 (1.388–5.378) 1.480 (0.758–2.891) 1.194 (0.585–2.437)
0.009 0.004 0.251 0.627
3.095 (1.387–6.908) 1.248 (1.093–1.424) 2.694 (1.695–4.374) 1.301 (1.125–1.506) 1.252 (1.111–1.410) 1.012 (1.006–1.019) 1.043 (1.026–1.061) 5.935 (2.541–13.860) 0.971 (0.951–0.991) 3.226 (1.438–7.238) 1.056 (1.033–1.079)
0.006 0.001 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001 0.005 0.005 <0.001
2.556 (1.307–4.998) 1.200 (1.087–1.325) 1.914 (1.418–2.584) 1.235 (1.100–1.387) 1.210 (1.110–1.318) 1.007 (1.004–1.010) 1.040 (1.029–1.052) 4.833 (2.363–9.887) 0.976 (0.960–0.993) 2.763 (1.391–5.489) 1.044 (1.032–1.056)
0.006 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001 0.005 0.004 <0.001
0.275 (0.112–0.678) 0.387 (0.155–0.963) 0.247 (0.105–0.581) 0.320 (0.138–0.744) 0.966 (0.832–1.122) 0.961 (0.869–1.062)
0.005 0.041 0.001 0.008 0.651 0.435
0.363 (0.182–0.722) 0.467 (0.229–0.953) 0.302 (0.155–0.588) 0.397 (0.203–0.777) 0.971 (0.854–1.103) 0.966 (0.887–1.053)
0.004 0.037 <0.001 0.007 0.647 0.437
Univariate logistic-regression analysis was used to calculate the odds ratio and 95% confidence interval for prediction of MACE. Univariate Cox regression analysis was used to calculate the hazard ratio and 95% confidence interval for analysis of MACE-free survival. MACE indicates major adverse cardiovascular events; WBC, white blood cell; eGFR, estimated glomerular filtration rate; GRACE, Global Registry of Acute Coronary Events; ACE, angiotensin-converting enzyme; ARB, angiotensin II receptor blocker; iLVSF, impaired left ventricular systolic function. Plasma intermedin levels were bifurcated at mean value (185.7 pg/mL). Values of >185.7 pg/mL indicated high level of intermedin.
[7,8,27,29–31]. It causes hypotension when given peripherally, but when given into the central nervous system, it increases blood pressure and causes sympathetic activation. It also increases prolactin release, is anti-diuretic and natriuretic and reduces food intake [14]. Plasma IMD levels are elevated in various human diseases including acute myocardial infarction [17] and acute coronary syndrome [22], and it is also secreted by leukocytes of patients with chronic heart failure at different stages of the disease [18]. Previous study has shown that elevated plasma concentrations of IMD reflect severity of coronary stenosis in the patients with acute coronary syndrome [22]. It is a paracrine/autocrine factor secreted by myocardium and up-regulated during the pathophysiologic process in some animal models and is considered a potential endogenous
Fig. 2. The survival curves for MACE-free survival in ST-segment elevation myocardial infarction patients according to plasma intermedin levels. MACE indicates major adverse cardiovascular events.
protector of the heart [13,34,35]. Furthermore, IMD 1-53 exerts potent cardioprotective effects against oxidative stress [36], inhibiting endoplasmic reticulum stress via PI3 kinase-Akt signaling [32], and activating cardioprotective Akt/GSK-3beta signaling, decreasing mitochondrial-mediated myocardial apoptosis [28]. Thus, these neuroprotective properties of IMD may be beneficial in suppressing myocardial ischemic injury and an increase in plasma IMD level may reflect a counter-regulatory or compensatory mechanism in STEMI. It is hypothesized that close and reproducible relation of IMD levels to the degree of myocardial injury is the basis of its unique usefulness as a prognostic biomarker. Myocardial injury is associated with the activation of a range of neurohormonal systems in proportion to the severity of myocardial injury. Up-regulated hormones include natriuretic peptides (Atype natriuretic peptide, B-type natriuretic peptide and N-terminal pro-brain natriuretic peptide) and adrenomedullin [1,3,6,21]. Although these blood markers were of potential clinical prognostic predictive value, to my best knowledge, none of the very plausible biomarkers added a clinically useful degree of prediction of MACE after STEMI to that provided by the measurement of the simple clinical variable like GRACE score. Previous study has demonstrated high plasma IMD level may be associated with the severity of the coronary stenosis after STEMI [20]. This study analyzed MACE and MACE-free survival and showed that plasma IMD level, presented as continuous or categorical variable, was identified as an independent prognostic factor. ROC curve showed high predictive value of plasma IMD level for MACE. Interestingly, IMD improved the predictive value of GRACE score based on AUC. These accumulating evidences showed that IMD may play a role as a prognostic biomarker in STEMI. Furthermore, more prospective multicenter
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investigations are needed to confirm the predictive value of plasma IMD levels on MACE after STEMI. Conclusions This study suggests that IMD may be a useful prognostic tool for the prediction of MACE in patients with STEMI. Conflict of interest The authors declare that they have no conflict of interest. Acknowledgement This study was supported by a grant from Zhejiang Province Medical and Health Project (No. 2013KYA176) and Hangzhou City Medical and Health Project (No. 2012B051). References [1] Aldous SJ. Cardiac biomarkers in acute myocardial infarction. Int J Cardiol 2013;164:282–94. [2] Aslan S, Ikitimur B, Cakmak HA, Karadag B, Tufekcioglu EY, Ekmekci H, et al. Prognostic utility of serum vitronectin levels in acute myocardial infarction. Herz 2014, http://dx.doi.org/10.1007/s00059-014-4105-2. [3] Banerjee AK, Dastidar DG. Biochemical markers in acute myocardial infarction. Indian Heart J 2011;63:33–8. [4] Boateng S, Sanborn T. Acute myocardial infarction. Dis Mon 2013;59:83–96. [5] Cai JY, Lu C, Chen MH, Ba HJ, Chen XD, Lin JH, et al. Predictive value of phosphorylated axonal neurofilament subunit H for clinical outcome in patients with acute intracerebral hemorrhage. Clin Chim Acta 2013;424:182–6. [6] Chan D, Ng LL. Biomarkers in acute myocardial infarction. BMC Med 2010;8:34. [7] Chauhan M, Elkins R, Balakrishnan M, Yallampalli C. Potential role of intermedin/adrenomedullin 2 in early embryonic development in rats. Regul Pept 2011;170:65–71. [8] Chauhan M, Yallampalli U, Dong YL, Hankins GD, Yallampalli C. Expression of adrenomedullin 2 (ADM2)/intermedin (IMD) in human placenta: role in trophoblast invasion and migration. Biol Reprod 2009;81:777–83. [9] Cheng CI, Hsueh SK, Lee FY, Wu CJ, Fang CY, Sheu JJ, et al. Clinical presentation and prognostic factors of patients with acute ST-segment elevation myocardial infarction following emergent revascularization for left main coronary artery obstruction. Circ J 2008;72:1598–604. [10] Du Q, Yang DB, Shen YF, Yu WH, Zhang ZY, Zhu Q, et al. Plasma leptin level predicts hematoma growth and early neurological deterioration after acute intracerebral hemorrhage. Peptides 2013;45:35–9. [11] Eagle KA, Lim MJ, Dabbous OH, Pieper KS, Goldberg RJ, Van de Werf F, et al. A validated prediction model for all forms of acute coronary syndrome: estimating the risk of 6-month postdischarge death in an international registry. J Am Med Assoc 2004;291:2727–33. [12] Fox KA, Dabbous OH, Goldberg RJ, Pieper KS, Eagle KA, Van de Werf F, et al. Prediction of risk of death and myocardial infarction in the six months after presentation with acute coronary syndrome: prospective multinational observational study (GRACE). Br Med J 2006;333:1091. [13] Hirose T, Totsune K, Mori N, Morimoto R, Hashimoto M, Nakashige Y, et al. Increased expression of adrenomedullin 2/intermedin in rat hearts with congestive heart failure. Eur J Heart Fail 2008;10:840–9. [14] Hong Y, Hay DL, Quirion R, Poyner DR. The pharmacology of adrenomedullin 2/intermedin. Br J Pharmacol 2012;166:110–20. [15] Killip 3rd T, Kimball JT. Treatment of myocardial infarction in a coronary care unit. A two year experience with 250 patients. Am J Cardiol 1967;20:457–64.
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