- Email: [email protected]
The value of novel serum biomarkers in risk stratification of the patients with acute coronary syndromes
228
Letters to the Editor
References [1] Henein M, Nicoll R. Atherosclerosis and extensive arterial calcification: the same condition? Int J Cardiol 2010;141:1–2. [2] Beckman JA, Ganz J, Creager MA, Ganz P, Kinlay S. Relationship of clinical presentation and calcification of culprit coronary artery stenoses. Arterioscler Thromb Vasc Biol 2001;21(10):1618–22.
[3] Inaba S, Okayama H, Funada JI, Hashida H, Hiasa G, Sumimoto T, Takata Y, Nishimura K, Inoue K, Ogimoto A, Ohtsuka T, Higaki J. Relationship between smaller calcifications and lipid-rich plaques on integrated backscatter-intravascular ultrasound. Int J Cardiol 2010;145:347–8. [4] Coats AJ. Ethical authorship and publishing. Int J Cardiol 2009;131:149–50.
0167-5273/$ – see front matter © 2010 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.ijcard.2010.04.063
The value of novel serum biomarkers in risk stratification of the patients with acute coronary syndromes Turgay Celik a,⁎, Murat Celik a, U. Cagdas Yuksel b, Baris Bugan a, Atila Iyisoy a a b
Gulhane Military Medical Academy, School of Medicine, Department of Cardiology, Etlik-Ankara, Turkey Sarikamis Army District Hospital, Department of Cardiology, Sarikamis, Turkey
a r t i c l e
i n f o
Article history: Received 10 May 2010 Accepted 18 May 2010 Available online 20 June 2010 Keywords: Acute coronary syndromes Risk stratification Novel serum biomarkers
In their recently well-presented article Fernández-Bergés and coworkers tried to compare the prognostic value of two clinical risk scores (RS) i.e.Thrombolysis in Myocardial Infarction (TIMI) and physician's risk assessment (PRA) in unstable angina or non-ST-segment elevation myocardial infarction (UA/NSTEMI) patients and to assess whether serum biomarkers can increase the prognostic accuracy of these RS [1]. They prospectively assessed 610 consecutive UA/NSTEMI patients. In all RS patients, high sensitivity C-reactive protein, CD40 ligand, IL6, IL10, IL18, E-selectin, P-selectin, white blood cell count, neopterin and NTproBNP were assessed at study entry. The primary study endpoint was death and non-fatal MI at 30 and 360 days of follow-up. For both RS, the study endpoint occurred more commonly in patients at a “higher risk” compared to those classified as being at a “lower risk”. TIMI RS, however, was a better predictor of events than PRA at both 30- and 360-day followup. The inflammatory biomarkers assessed in the study did not significantly improve the predictive value of RS. Although the authors examined almost all well-known serum biomarkers used in risk strafication of patients with UA/NSTEMI there are novel biomarkers found to have prognostic significance in the management of those patients. Heart-type fatty acid binding protein (H-FABP) is a small cytosolic protein that functions as the principle transporter of long chain fatty acids in cardiac muscle cells [2]. It is released into the circulation in response to myocardial injury, and may provide added value to other cardiac biomarkers for the early diagnosis of myocardial infarction [3]. The ability of H-FABP to predict cardiovascular outcomes was evaluated in 2287 patients with acute coronary syndrome
⁎ Corresponding author. Department of Cardiology, Gulhane School of Medicine, 06018 Etlik-Ankara, Turkey. Tel.: + 90 312 3044268; fax: + 90 312 3044250. E-mail address: [email protected] (T. Celik).
(ACS) enrolled in the OPUS-TIMI 16 trial [4]. H-FABP was elevated in 15% of patients. These patients had, at 10 month follow-up, a significant increase in the rate of the composite end point of death, recurrent MI, or heart failure (multivariable adjusted HR 1.9). H-FABP elevation provided incremental information for risk stratification to troponins or BNP. Pentraxin 3 (PTX3), which is the first identified long pentraxin, conserves the C-terminal pentraxin domain of the classical short pentraxins but differs with the presence of an unrelated long N-terminal domain. It differs from classical short pentraxins in gene organization, cellular source, and ligands recognized [5,6]. PTX3 is synthesized locally at the inflammatory sites by endothelial and smooth muscle cells or by monocytes/ macrophages upon exposure to primary inflammatory signals such as IL-1, tumor necrosis factor-α, oxidized low-density lipoprotein, and bacterial products, but not IL-6 [5,7,8]. Furthermore, PTX3 is highly expressed in vascular cells and vascular inflammatory cells of human atherosclerotic lesions [9,10]. In addition, plasma PTX3 increases in patients with ACS [11,12]. Recent studies have reported that plasma PTX3 is elevated in patients with UA/NSTEMI [12]. Matsui and coworkers prospectively investigated the prognostic value of PTX3 in patients with UA/NSTEMI [13]. PTX3, hs-CRP, NT-proBNP, and cardiac troponin I were measured on admission in 204 consecutive patients hospitalized for UA/NSTEMI within 24 h after the onset of chest symptoms. In a stepwise Cox regression analysis including 18 wellknown clinical and biochemical predictors of ACS outcome, both PTX3 (relative risk 3.86 per 10-fold increment, P = 0.01) and NT-proBNP (relative risk 2.16 per 10-fold increment, P =0.02), but not hsCRP, were independently associated with the 6-month cardiac event. The cardiac event rate was higher in patients with increased PTX3 (≥3.1 ng/mL of median value) than those without (20% vs. 5.8%, P = 0.003). A Kaplan– Meier analysis revealed that patients with increased PTX3 had a higher risk for cardiac events than those without (P = 0.002). PTX3 and NTproBNP may be potent and independent predictors for 6-month cardiac events in patients hospitalized for UA/NSTEMI within 24 h after the onset. The use of multiple markers appears to have additive prognostic value. This was demonstrated in the CHECKMATE study in which combined bedside multimarker testing (serum CK-MB, cTnI, and myoglobin) were compared to local laboratory testing of a single marker measured at baseline and multiple times in the next 16 to 24 h [14]. Patients with either all 3 tests positive or only CK-MB and cTnI positive had a higher rate of death or infarction at 30 days compared to positive single marker testing in the local laboratory (18.8% and 21.9% versus 5.5%). The value of the multimarker approach reflects
Letters to the Editor
somewhat different mechanisms of enzyme release from ischemic myocardial cells or, with myoglobin, with hypoperfusion-induced release from skeletal muscle cells [15]. Elevations in serum hs-CRP and BNP are also of prognostic importance and assess different pathophysiologic mechanisms than cardiac enzymes in myocardial ischemia. Risk stratification based upon an additive effect of cTnI, CRP, and BNP was evaluated in a study of 450 patients with ACS without ST segment elevation in the OPUS-TIMI 16 trial and validated in 1635 patients in the TACTICS-TIMI 18 trial [16]. The number of elevated markers was a significant predictor of the composite end point of death, MI, or heart failure in both trials. In TACTICS-TIMI 18, the end point at six months was increased 2.1-, 3.1-, and 3.7-fold in those with 1, 2, or 3 elevated biomarkers compared to no biomarker elevations. In a similar analysis of data on 6809 patients from the GUSTO IV ACS trial, independent predictors of mortality at one year included N-pro-BNP, cTnT, CRP, heart rate, and creatinine clearance [17]. The two-marker combination of N-pro-BNP in the top quartile (>1869 ng/L) plus any of the other markers in their top quartiles (cTnT >0.47 µg/L, CRP >9.62 mg/L, heart rate > 79 bpm, or creatinine clearance ≤51 mL/ min) predicted a one-year mortality of 22% to 26%, while N-pro-BNP in the bottom quartile plus any other marker in the bottom quartile predicted a 1-year mortality of less than 2%. In conclusion despite the increased use of coronary revascularization, patients with UA/NSTEMI remain at risk for subsequent cardiac and arrhythmic events. As a result, ongoing risk stratification remains to be important. Women with a non-ST elevation ACS are more likely to have elevations of CRP and BNP, and less likely to have elevations of troponins and CK-MB, than men, despite similar levels of risk. As a result, a multimarker approach that incorporates CRP and BNP as well as troponins may more accurately predict risk for both genders. A number of serum biomarkers can be measured to assist in risk stratification of those patients. The two most commonly used are serum troponins and CK-MB. Other biomarkers, such as myoglobin, hs-CRP, PTX-3, H-FABP and BNP, also have prognostic significance; their role, alone or in combination, in clinical decision making is not yet clearly established. The authors of this manuscript have certified that they comply with the Principles of Ethical Publishing in the International Journal of Cardiology [18]. References [1] Fernández-Bergés D, Bertomeu-Gonzalez V, Sánchez PL, et al. Clinical scores and patient risk stratification in non-ST elevation acute coronary syndrome. Int J Cardiol 2011;146(2):219–24 (this issue). [2] Glatz JF, Kleine AH, van Nieuwenhoven FA, Hermens WT, van Dieijen-Visser MP, van der Vusse GJ. Fatty-acid-binding protein as a plasma marker for the estimation of myocardial infarct size in humans. Br Heart J 1994;71:135–40.
0167-5273/$ – see front matter © 2010 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.ijcard.2010.05.040
229
[3] Seino Y, Ogata K, Takano T, et al. Use of a whole blood rapid panel test for hearttype fatty acid-binding protein in patients with acute chest pain: comparison with rapid troponin T and myoglobin tests. Am J Med 2003;115:185–90. [4] O'Donoghue M, de Lemos JA, Morrow DA, et al. Prognostic utility of heart-type fatty acid binding protein in patients with acute coronary syndromes. Circulation 2006;114:550–7. [5] Garlanda C, Bottazzi B, Bastone A, Mantovani A. Pentraxins at the crossroads between innate immunity, inflammation, matrix deposition, and female fertility. Annu Rev Immunol 2005;23:337–66. [6] Presta M, Camozzi M, Salvatori G, Rusnati M. Role of the soluble pattern recognition receptor PTX3 in vascular biology. J Cell Mol Med 2007;11:723–38. [7] Basile A, Sica A, d'Aniello E, et al. Characterization of the promoter for thehuman long pentraxin PTX3. Role of NF-kappaB in tumor necrosis factor-alpha and interleukin-1beta regulation. J Biol Chem 1997;272:8172–8. [8] Kravitz MS, Pitashny M, Shoenfeld Y. Protective molecules—C-reactive protein (CRP), serum amyloid P (SAP), pentraxin3 (PTX3), mannose-binding lectin (MBL), and apolipoprotein A1 (Apo A1), and their autoantibodies: prevalence and clinical significance in autoimmunity. J Clin Immunol 2005;25:582–91. [9] Rolph MS, Zimmer S, Bottazzi B, Garlanda C, Mantovani A, Hansson GK. Production of the long pentraxin PTX3 in advanced atherosclerotic plaques. Arterioscler Thromb Vasc Biol 2002;22:e10–4. [10] Savchenko A, Imamura M, Ohashi R, et al. Expression of pentraxin 3 (PTX3) in human atherosclerotic lesions. J Pathol 2008;215:48–55. [11] Peri G, Introna M, Corradi D, et al. PTX3, A prototypical long pentraxin, is an early indicator of acute myocardial infarction in humans. Circulation 2000;102:636–41. [12] Inoue K, Sugiyama A, Reid PC, et al. Establishment of a high sensitivity plasma assay for human pentraxin3 as a marker for unstable angina pectoris. Arterioscler Thromb Vasc Biol 2007;27:161–7. [13] Matsui S, Ishii J, Kitagawa F, et al. Pentraxin 3 in unstable angina and non-STsegment elevation myocardial infarction. Atherosclerosis 2010;210:220–5. [14] Newby LK, Storrow AB, Gibler WB, et al. Bedside multimarker testing for risk stratification in chest pain units. The Chest Pain Evaluation by Creatine Kinase-MB, Myoglobin, and Troponin I (CHECKMATE) study. Circulation 2001;103:1832–7. [15] de Lemos JA, Morrow DA, Gibson CM, et al. The prognostic value of serum myoglobin in patients with non-ST-segment elevation acute coronary syndromes. Results from the TIMI 11B and TACTICS-TIMI 18 studies. J Am Coll Cardiol 2002;40:238–44. [16] Sabatine MS, Morrow DA, de Lemos JA, et al. Multimarker approach to risk stratification in non-ST elevation acute coronary syndromes: simultaneous assessment of troponin I, C-reactive protein, and B-type natriuretic peptide. Circulation 2002;105:1760–3. [17] James SK, Lindahl B, Siegbahn A, et al. N-terminal pro-brain natriuretic peptide and other risk markers for the separate prediction of mortality and subsequent myocardial infarction in patients with unstable coronary artery disease: a Global Utilization of Strategies To Open occluded arteries (GUSTO)-IV substudy. Circulation 2003;108:275–81. [18] Coats AJ. Ethical authorship and publishing. Int J Cardiol 2009;131:149–50.
Letters to the Editor
References [1] Henein M, Nicoll R. Atherosclerosis and extensive arterial calcification: the same condition? Int J Cardiol 2010;141:1–2. [2] Beckman JA, Ganz J, Creager MA, Ganz P, Kinlay S. Relationship of clinical presentation and calcification of culprit coronary artery stenoses. Arterioscler Thromb Vasc Biol 2001;21(10):1618–22.
[3] Inaba S, Okayama H, Funada JI, Hashida H, Hiasa G, Sumimoto T, Takata Y, Nishimura K, Inoue K, Ogimoto A, Ohtsuka T, Higaki J. Relationship between smaller calcifications and lipid-rich plaques on integrated backscatter-intravascular ultrasound. Int J Cardiol 2010;145:347–8. [4] Coats AJ. Ethical authorship and publishing. Int J Cardiol 2009;131:149–50.
0167-5273/$ – see front matter © 2010 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.ijcard.2010.04.063
The value of novel serum biomarkers in risk stratification of the patients with acute coronary syndromes Turgay Celik a,⁎, Murat Celik a, U. Cagdas Yuksel b, Baris Bugan a, Atila Iyisoy a a b
Gulhane Military Medical Academy, School of Medicine, Department of Cardiology, Etlik-Ankara, Turkey Sarikamis Army District Hospital, Department of Cardiology, Sarikamis, Turkey
a r t i c l e
i n f o
Article history: Received 10 May 2010 Accepted 18 May 2010 Available online 20 June 2010 Keywords: Acute coronary syndromes Risk stratification Novel serum biomarkers
In their recently well-presented article Fernández-Bergés and coworkers tried to compare the prognostic value of two clinical risk scores (RS) i.e.Thrombolysis in Myocardial Infarction (TIMI) and physician's risk assessment (PRA) in unstable angina or non-ST-segment elevation myocardial infarction (UA/NSTEMI) patients and to assess whether serum biomarkers can increase the prognostic accuracy of these RS [1]. They prospectively assessed 610 consecutive UA/NSTEMI patients. In all RS patients, high sensitivity C-reactive protein, CD40 ligand, IL6, IL10, IL18, E-selectin, P-selectin, white blood cell count, neopterin and NTproBNP were assessed at study entry. The primary study endpoint was death and non-fatal MI at 30 and 360 days of follow-up. For both RS, the study endpoint occurred more commonly in patients at a “higher risk” compared to those classified as being at a “lower risk”. TIMI RS, however, was a better predictor of events than PRA at both 30- and 360-day followup. The inflammatory biomarkers assessed in the study did not significantly improve the predictive value of RS. Although the authors examined almost all well-known serum biomarkers used in risk strafication of patients with UA/NSTEMI there are novel biomarkers found to have prognostic significance in the management of those patients. Heart-type fatty acid binding protein (H-FABP) is a small cytosolic protein that functions as the principle transporter of long chain fatty acids in cardiac muscle cells [2]. It is released into the circulation in response to myocardial injury, and may provide added value to other cardiac biomarkers for the early diagnosis of myocardial infarction [3]. The ability of H-FABP to predict cardiovascular outcomes was evaluated in 2287 patients with acute coronary syndrome
⁎ Corresponding author. Department of Cardiology, Gulhane School of Medicine, 06018 Etlik-Ankara, Turkey. Tel.: + 90 312 3044268; fax: + 90 312 3044250. E-mail address: [email protected] (T. Celik).
(ACS) enrolled in the OPUS-TIMI 16 trial [4]. H-FABP was elevated in 15% of patients. These patients had, at 10 month follow-up, a significant increase in the rate of the composite end point of death, recurrent MI, or heart failure (multivariable adjusted HR 1.9). H-FABP elevation provided incremental information for risk stratification to troponins or BNP. Pentraxin 3 (PTX3), which is the first identified long pentraxin, conserves the C-terminal pentraxin domain of the classical short pentraxins but differs with the presence of an unrelated long N-terminal domain. It differs from classical short pentraxins in gene organization, cellular source, and ligands recognized [5,6]. PTX3 is synthesized locally at the inflammatory sites by endothelial and smooth muscle cells or by monocytes/ macrophages upon exposure to primary inflammatory signals such as IL-1, tumor necrosis factor-α, oxidized low-density lipoprotein, and bacterial products, but not IL-6 [5,7,8]. Furthermore, PTX3 is highly expressed in vascular cells and vascular inflammatory cells of human atherosclerotic lesions [9,10]. In addition, plasma PTX3 increases in patients with ACS [11,12]. Recent studies have reported that plasma PTX3 is elevated in patients with UA/NSTEMI [12]. Matsui and coworkers prospectively investigated the prognostic value of PTX3 in patients with UA/NSTEMI [13]. PTX3, hs-CRP, NT-proBNP, and cardiac troponin I were measured on admission in 204 consecutive patients hospitalized for UA/NSTEMI within 24 h after the onset of chest symptoms. In a stepwise Cox regression analysis including 18 wellknown clinical and biochemical predictors of ACS outcome, both PTX3 (relative risk 3.86 per 10-fold increment, P = 0.01) and NT-proBNP (relative risk 2.16 per 10-fold increment, P =0.02), but not hsCRP, were independently associated with the 6-month cardiac event. The cardiac event rate was higher in patients with increased PTX3 (≥3.1 ng/mL of median value) than those without (20% vs. 5.8%, P = 0.003). A Kaplan– Meier analysis revealed that patients with increased PTX3 had a higher risk for cardiac events than those without (P = 0.002). PTX3 and NTproBNP may be potent and independent predictors for 6-month cardiac events in patients hospitalized for UA/NSTEMI within 24 h after the onset. The use of multiple markers appears to have additive prognostic value. This was demonstrated in the CHECKMATE study in which combined bedside multimarker testing (serum CK-MB, cTnI, and myoglobin) were compared to local laboratory testing of a single marker measured at baseline and multiple times in the next 16 to 24 h [14]. Patients with either all 3 tests positive or only CK-MB and cTnI positive had a higher rate of death or infarction at 30 days compared to positive single marker testing in the local laboratory (18.8% and 21.9% versus 5.5%). The value of the multimarker approach reflects
Letters to the Editor
somewhat different mechanisms of enzyme release from ischemic myocardial cells or, with myoglobin, with hypoperfusion-induced release from skeletal muscle cells [15]. Elevations in serum hs-CRP and BNP are also of prognostic importance and assess different pathophysiologic mechanisms than cardiac enzymes in myocardial ischemia. Risk stratification based upon an additive effect of cTnI, CRP, and BNP was evaluated in a study of 450 patients with ACS without ST segment elevation in the OPUS-TIMI 16 trial and validated in 1635 patients in the TACTICS-TIMI 18 trial [16]. The number of elevated markers was a significant predictor of the composite end point of death, MI, or heart failure in both trials. In TACTICS-TIMI 18, the end point at six months was increased 2.1-, 3.1-, and 3.7-fold in those with 1, 2, or 3 elevated biomarkers compared to no biomarker elevations. In a similar analysis of data on 6809 patients from the GUSTO IV ACS trial, independent predictors of mortality at one year included N-pro-BNP, cTnT, CRP, heart rate, and creatinine clearance [17]. The two-marker combination of N-pro-BNP in the top quartile (>1869 ng/L) plus any of the other markers in their top quartiles (cTnT >0.47 µg/L, CRP >9.62 mg/L, heart rate > 79 bpm, or creatinine clearance ≤51 mL/ min) predicted a one-year mortality of 22% to 26%, while N-pro-BNP in the bottom quartile plus any other marker in the bottom quartile predicted a 1-year mortality of less than 2%. In conclusion despite the increased use of coronary revascularization, patients with UA/NSTEMI remain at risk for subsequent cardiac and arrhythmic events. As a result, ongoing risk stratification remains to be important. Women with a non-ST elevation ACS are more likely to have elevations of CRP and BNP, and less likely to have elevations of troponins and CK-MB, than men, despite similar levels of risk. As a result, a multimarker approach that incorporates CRP and BNP as well as troponins may more accurately predict risk for both genders. A number of serum biomarkers can be measured to assist in risk stratification of those patients. The two most commonly used are serum troponins and CK-MB. Other biomarkers, such as myoglobin, hs-CRP, PTX-3, H-FABP and BNP, also have prognostic significance; their role, alone or in combination, in clinical decision making is not yet clearly established. The authors of this manuscript have certified that they comply with the Principles of Ethical Publishing in the International Journal of Cardiology [18]. References [1] Fernández-Bergés D, Bertomeu-Gonzalez V, Sánchez PL, et al. Clinical scores and patient risk stratification in non-ST elevation acute coronary syndrome. Int J Cardiol 2011;146(2):219–24 (this issue). [2] Glatz JF, Kleine AH, van Nieuwenhoven FA, Hermens WT, van Dieijen-Visser MP, van der Vusse GJ. Fatty-acid-binding protein as a plasma marker for the estimation of myocardial infarct size in humans. Br Heart J 1994;71:135–40.
0167-5273/$ – see front matter © 2010 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.ijcard.2010.05.040
229
[3] Seino Y, Ogata K, Takano T, et al. Use of a whole blood rapid panel test for hearttype fatty acid-binding protein in patients with acute chest pain: comparison with rapid troponin T and myoglobin tests. Am J Med 2003;115:185–90. [4] O'Donoghue M, de Lemos JA, Morrow DA, et al. Prognostic utility of heart-type fatty acid binding protein in patients with acute coronary syndromes. Circulation 2006;114:550–7. [5] Garlanda C, Bottazzi B, Bastone A, Mantovani A. Pentraxins at the crossroads between innate immunity, inflammation, matrix deposition, and female fertility. Annu Rev Immunol 2005;23:337–66. [6] Presta M, Camozzi M, Salvatori G, Rusnati M. Role of the soluble pattern recognition receptor PTX3 in vascular biology. J Cell Mol Med 2007;11:723–38. [7] Basile A, Sica A, d'Aniello E, et al. Characterization of the promoter for thehuman long pentraxin PTX3. Role of NF-kappaB in tumor necrosis factor-alpha and interleukin-1beta regulation. J Biol Chem 1997;272:8172–8. [8] Kravitz MS, Pitashny M, Shoenfeld Y. Protective molecules—C-reactive protein (CRP), serum amyloid P (SAP), pentraxin3 (PTX3), mannose-binding lectin (MBL), and apolipoprotein A1 (Apo A1), and their autoantibodies: prevalence and clinical significance in autoimmunity. J Clin Immunol 2005;25:582–91. [9] Rolph MS, Zimmer S, Bottazzi B, Garlanda C, Mantovani A, Hansson GK. Production of the long pentraxin PTX3 in advanced atherosclerotic plaques. Arterioscler Thromb Vasc Biol 2002;22:e10–4. [10] Savchenko A, Imamura M, Ohashi R, et al. Expression of pentraxin 3 (PTX3) in human atherosclerotic lesions. J Pathol 2008;215:48–55. [11] Peri G, Introna M, Corradi D, et al. PTX3, A prototypical long pentraxin, is an early indicator of acute myocardial infarction in humans. Circulation 2000;102:636–41. [12] Inoue K, Sugiyama A, Reid PC, et al. Establishment of a high sensitivity plasma assay for human pentraxin3 as a marker for unstable angina pectoris. Arterioscler Thromb Vasc Biol 2007;27:161–7. [13] Matsui S, Ishii J, Kitagawa F, et al. Pentraxin 3 in unstable angina and non-STsegment elevation myocardial infarction. Atherosclerosis 2010;210:220–5. [14] Newby LK, Storrow AB, Gibler WB, et al. Bedside multimarker testing for risk stratification in chest pain units. The Chest Pain Evaluation by Creatine Kinase-MB, Myoglobin, and Troponin I (CHECKMATE) study. Circulation 2001;103:1832–7. [15] de Lemos JA, Morrow DA, Gibson CM, et al. The prognostic value of serum myoglobin in patients with non-ST-segment elevation acute coronary syndromes. Results from the TIMI 11B and TACTICS-TIMI 18 studies. J Am Coll Cardiol 2002;40:238–44. [16] Sabatine MS, Morrow DA, de Lemos JA, et al. Multimarker approach to risk stratification in non-ST elevation acute coronary syndromes: simultaneous assessment of troponin I, C-reactive protein, and B-type natriuretic peptide. Circulation 2002;105:1760–3. [17] James SK, Lindahl B, Siegbahn A, et al. N-terminal pro-brain natriuretic peptide and other risk markers for the separate prediction of mortality and subsequent myocardial infarction in patients with unstable coronary artery disease: a Global Utilization of Strategies To Open occluded arteries (GUSTO)-IV substudy. Circulation 2003;108:275–81. [18] Coats AJ. Ethical authorship and publishing. Int J Cardiol 2009;131:149–50.