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Plasma Concentration of Soluble Vascular Cell Adhesion Molecule-1 and Oncoming Cardiovascular Risk in Patients With Unstable Angina Pectoris and Non–ST-Segment Elevation Myocardial Infarction
Plasma Concentration of Soluble Vascular Cell Adhesion Molecule-1 and Oncoming Cardiovascular Risk in Patients With Unstable Angina Pectoris and Non–ST-Segment Elevation Myocardial Infarction Göknur Tekin, MDa,*, Abdullah Tekin, MDa, I˙lke Sipahi, MDb, Ays¸em Kaya, PhDc, and Vedat Sansoy, MDb In patients who had unstable angina pectoris and non–ST-segment elevation myocardial infarction, initial blood levels of soluble vascular cell adhesion molecule-1 were found not to be higher than those in asymptomatic patients who had coronary artery disease. Although troponin T and high-sensitivity C-reactive protein were found to have prognostic value, blood levels of soluble vascular cell adhesion molecule-1 were not predictive of an increased risk of major cardiac events during 6-month follow-up. © 2005 Elsevier Inc. All rights reserved. (Am J Cardiol 2005;96: 379 –381) Unstable angina pectoris (UAP) and non–ST-segment elevation myocardial infarction (NSTEMI) results mainly from the development of a thrombus that is superimposed on the rupture of an atherosclerotic plaque.1 Inflammation has a pivotal role in disruption of this plaque and subsequent thrombus-generating events.2 Inflammatory stimuli result in generation of cytokines that trigger the increased production of cellular adhesion molecules.3,4 Vascular cell adhesion molecule-1 (VCAM-1) is the 1 of these adhesion molecules and belongs to the immunoglobulin superfamily. It is found on endothelial cells, lymphoid dendritic cells, tissue macrophages, and renal tubular epithelial cells.5 The interaction between VCAM-1 on endothelial cells and integrins on leukocytes helps to firm binding and transendothelial migration of leukocytes to the arterial intima. There are studies that have examined the relation between event rates due to coronary heart disease event and levels of soluble VCAM-1 (sVCAM-1) in apparently healthy adults6,7 and in patients who have coronary artery disease.8 Less is known about the prognostic significance of sVCAM-1 in acute coronary syndromes.9 In this prospective study, we assessed and compared the prognostic significance of sVCAM-1, high-sensitivity C-reactive protein, and troponin T in patients with UAP and NSTEMI. •••
The study group consisted of 70 patients who presented with UAP or NSTEMI and 18 asymptomatic patients who had angiographically proved coronary artery disease. The UAP group consisted of patients who had typical angina at
a
Department of Cardiology, Faculty of Medicine, Bas¸kent University, Adana; and bInstitute of Cardiology, Department of Cardiology and cDepartment of Biochemistry, Cerrahpas¸a Medical Faculty, Istanbul University, Istanbul, Turkey. Manuscript received December 28, 2004; revised manuscript received and accepted March 28, 2005. * Corresponding author: Tel.: 322-231-07-91; fax: 322-327-12-76. E-mail address: [email protected] (G. Tekin). 0002-9149/05/$ – see front matter © 2005 Elsevier Inc. All rights reserved. doi:10.1016/j.amjcard.2005.03.080
rest within the previous 48 hours with ST-segment changes that suggested ischemia. The NSTEMI group had similar diagnostic criteria in addition to biochemical evidence of myocardial damage. Patients who had a history of acute coronary syndrome, a cerebrovascular event, major surgery, or percutaneous coronary intervention within the previous 6 months were excluded. Patients who had any inflammatory condition, liver disease, kidney disease, thyroid disease, or cancer or used anticoagulant therapy were also excluded from the study. Patients who had UAP or NSTEMI were followed for 6 months for the occurrence of major adverse cardiac events, which were cardiac death, nonfatal myocardial infarction, and recurrent ischemic chest pain. Blood was drawn at the time of presentation, before any antithrombotic or anticoagulant therapy. Concentrations of sVCAM-1 were detected with enzyme-linked immunosorbent assay kits (R&D Systems, Abingdon, United Kingdom). Blood levels of troponin T were measured in heparinized blood by an immunosandwich reaction (CARDIAC T Quantitative, Roche Diagnostics, Germany). Patients who had troponin T concentrations ⬎0.01 ng/ml were considered positive for troponin T. Serum levels of high-sensitivity C-reactive protein were determined nephelometrically (Dade Behring Holding GmbH, Marburg, Germany). Statistical analysis was performed with SPSS 9.0 for Windows (SPSS, Inc., Chicago, Illinois). Variables are presented as mean ⫾ SD for continuous data and as proportions for categorical data. Continuous variables with normal distribution were analyzed by unpaired t test. Continuous variables with non-normal distribution were analyzed by the Mann-Whitney test. The Kolmogorov-Smirnov test was used to identify whether continuous variables were normally distributed. Categorical parameters were analyzed by chi-square or Fischer’s exact test, whichever was appropriate. Two-sided p values ⬍0.05 were considered statistically significant. Patients’ clinical features are presented in Table 1. There www.AJConline.org
380
The American Journal of Cardiology (www.AJConline.org)
Table 1 Baseline characteristics of study population
Age (yrs) Men/Women Diabetes mellitus Systemic hypertension Hypercholesterolemia Smoker Myocardial infarct (healed) Coronary angioplasty Coronary bypass hs-CRP (mg/dl)
Patients With UAP or NSTEMI (n ⫽ 70)
Patients With Stable CAD (n ⫽ 18)
p Value
60 ⫾ 10 55/15 18 (26%) 24 (34%) 33 (47%) 49 (70%) 23 (33%) 8 (11%) 15 (21%) 1.24 ⫾ 1.93
60 ⫾ 10 14/4 4 (22%) 6 (33%) 10 (56%) 8 (44%) 12 (67%) 6 (33%) 7 (39%) 0.50 ⫾ 0.30
NS NS NS NS NS 0.042 0.014 0.034 NS 0.006
CAD ⫽ coronary artery disease; hs-CRP ⫽ high-sensitivity C-reactive protein.
Figure 1. Comparison of blood levels of sVCAM-1 between patients who had UAP or NSTEMI and asymptomatic patients who had coronary artery disease (CAD).
Figure 2. Comparison of blood levels of sVCAM-1 between cardiac event and nonevent groups.
were 29 patients who had NSTEMI and 41 who had UAP. Patients who had UAP or NSTEMI were categorized into cardiac event and nonevent groups. Event and nonevent groups had similar baseline clinical characteristics. There were 4 deaths; 3 occurred within the first month of presentation and 1 occurred 46 days after presentation. During the 6-month follow-up, 3 patients developed a nonfatal myocardial infarction and 15 had recurrent ischemic chest pain. Blood levels of sVCAM-1 were found be no higher in patients who had UAP or STEMI than in patients who had stable coronary artery disease (784 ⫾ 280 vs 732 ⫾ 120 ng/ml, p ⫽ 0.642; Figure 1). There was no significant difference in concentrations of sVCAM-1 between event and nonevent groups (731 ⫾ 164 vs 779 ⫾ 320 ng/ml, p ⫽ 0.786; Figure 2). Blood levels of high-sensitivity C-reactive protein were significantly higher in the event than in the nonevent group (2.54 ⫾ 2.81 vs 0.65 ⫾ 0.89 mg/dl, p ⬍0.001; Figure 3). Concentrations of high-sensitivity C-reactive protein were also significantly increased in patients who experienced cardiac death (4.77 ⫾ 5.74 vs 1.03 ⫾ 1.27
mg/dl, p ⬍0.001). Patients who were not positive for troponin T but developed a major cardiovascular event also had significantly increased concentrations of high-sensitivity C-reactive protein (1.36 ⫾ 0.97 vs 0.49 ⫾ 0.26 mg/dl, p ⫽ 0.02). There were proportionally more patients who were positive for troponin T in the event than in the nonevent group (12 of 22 vs 10 of 48, p ⫽ 0.01). •••
In this study, we found that concentrations of sVCAM-1 were not higher in patients who had UAP or NSTEMI at presentation than in patients who had stable coronary heart disease. Further, blood levels of sVCAM-1 at presentation were not predictive of an adverse cardiac event. Adhesion molecules facilitate the recruitment of circulating leukocytes to sites of inflammation.10 As a result, augmented expression of adhesion molecules in vascular endothelium might be expected in acute coronary syndromes. Soluble forms of adhesion molecules in the supernatant of cultured endothelial cells has been shown to reflect its expression on endothelial cell surfaces.11 Concentrations of soluble forms
Coronary Artery Disease/Soluble Vascular Cell Adhesion Molecule-1
381
prognostic significance of high-sensitivity C-reactive protein and troponin T in the course of UAP and NSTEMI. Our findings also indicate that high levels of high-sensitivity C-reactive protein may predict an adverse cardiac event, even in patients whose initial troponin T level is negative. As a result, measurement of sVCAM-1 at the presentation of UAP and NSTEMI is less likely to supply much predictive information to that provided by more established risk factors such as high-sensitivity C-reactive protein and troponin T in patients who have a stable clinical picture for the previous 6 months.
Figure 3. Comparison of blood levels of high-sensitivity C-reactive protein (hs-CRP) between cardiac event and nonevent groups.
of adhesion molecules in blood may indicate the degree of inflammatory state involved in pathogenesis of UAP and NSTEMI. Our study is concordant with the findings of Ghasias et al12 and Parker et al13 who found no difference in sVCAM-1 concentrations between patients who had unstable coronary artery disease and those who had stable disease. Some other studies have shown significantly increased sVCAM-1 levels in patients who had UAP and NSTEMI compared with healthy controls.9,12,14 We were unable to show any relation between sVCAM-1 levels and adverse cardiac events, which is different from the findings of Mulvihill et al.9 This might partly be due to the different background of our study. We did not include patients who had an acute coronary syndrome within the previous 6 months because of an observation that sVCAM-1 concentrations may remain increased up to 6 months after an acute coronary syndrome.14 Therefore, it is questionable whether increased levels of sVCAM-1 in the event group in the previous study reflects previous unresolved intense inflammation in coronary artery endothelium, which causes recurrent instability. The time that elapsed from the initiation of chest pain to the collection of blood might also affect sVCAM-1 concentrations.15 sVCAM-1 levels in blood at a particular time during the course of disease may have a link with adverse cardiac events, although this has not been proved. Moreover, levels of sVCAM-1 may not correctly reflect expression of membrane-bound VCAM on vascular endothelium, which is believed to be a function of poor understanding of the process of “shedding” from the cell surface. This study also supports the growing evidence of the
1. Fuster V, Badimon L, Badimon JJ, Chesebro JH. The pathogenesis of coronary artery disease and the acute coronary syndromes. N Engl J Med 1992;326:242–250. 2. Libby P, Ridker PM, Maseri A. Inflammation and atherosclerosis. Circulation 2002;105:1135–1143. 3. Gearing A, Newman W. Circulating adhesion molecules in disease. Immunol Today 1993;14:506 –512. 4. Jang Y, Lincoff A, Plow E, Topol E. Cell adhesion molecules in coronary artery disease. J Am Coll Cardiol 1994;24:1591–1601. 5. Stad RK, Burman WA. Current views on structure and function of endothelial adhesion molecules. Cell Adhes Commun 1994;2:261–268. 6. de Lemos JA, Hennekens CH, Ridker PM. Plasma concentration of soluble vascular adhesion molecule-1 and subsequent cardiovascular risk. J Am Coll Cardiol 2000;36:423– 426. 7. Malik I, Danesh J, Whincup P, Bhatia V, Papacosta O, Walker M, Lennon L, Thomson A, Haskard D. Soluble adhesion molecules and prediction of coronary artery disease: a prospective study and metaanalysis. Lancet 2001;358:971–975. 8. Blankenberg S, Rupprect HJ, Bickel C, Peetz D, Hafner G, Tiret L, Meyer J, for the AtheroGene Investigators. Circulating cell adhesion molecules and death in patients with coronary artery disease. Circulation 2001;104:1336 –1342. 9. Mulvihill NT, Foley JB, Murphy RT, Curtin R, Crean PA, Walsh M. Risk stratification in unstable angina and non–Q wave myocardial infarction using soluble cell adhesion molecules. Heart 2001;85:623– 627. 10. Springer TA. Traffic signals for lymphocyte recirculation and leukocyte emigration: the multistep paradigm. Cell 1994;76:301–314. 11. Piggot R, Dillon LP, Hemingway IH, Gearing AJ. Soluble forms of E-selectin, ICAM-1 and VCAM-1 in the supernatants of cytokine activated cultured endothelial cells. Biochem Biophys Res Commun 1992;187:584 –589. 12. Ghasias NK, Shahi CN, Foley B, Goggins M, Crean P, Kelly A, Kelleher D, Walsh M. Elevated levels of circulating soluble adhesion molecules in peripheral blood of patients with unstable angina. Am J Cardiol 1997;80:617– 619. 13. Parker C, Vita JA, Freedman JE. Soluble adhesion molecules and unstable coronary artery disease. Atherosclerosis 2001;156:417– 424. 14. Mulvihill NT, Foley JB, Murphy R, Crean P, Walsh M. Evidence of prolonged inflammation in unstable angina and non–Q wave myocardial infarction. J Am Coll Cardiol 2000;36:1210 –1216. 15. Kerner T, Ahlers O, Reschreiter H, Bührer C, Möckel M, Gerlach H. Adhesion molecules in different treatments of acute myocardial infarction. Crit Care 2001;5:145–150.
The study group consisted of 70 patients who presented with UAP or NSTEMI and 18 asymptomatic patients who had angiographically proved coronary artery disease. The UAP group consisted of patients who had typical angina at
a
Department of Cardiology, Faculty of Medicine, Bas¸kent University, Adana; and bInstitute of Cardiology, Department of Cardiology and cDepartment of Biochemistry, Cerrahpas¸a Medical Faculty, Istanbul University, Istanbul, Turkey. Manuscript received December 28, 2004; revised manuscript received and accepted March 28, 2005. * Corresponding author: Tel.: 322-231-07-91; fax: 322-327-12-76. E-mail address: [email protected] (G. Tekin). 0002-9149/05/$ – see front matter © 2005 Elsevier Inc. All rights reserved. doi:10.1016/j.amjcard.2005.03.080
rest within the previous 48 hours with ST-segment changes that suggested ischemia. The NSTEMI group had similar diagnostic criteria in addition to biochemical evidence of myocardial damage. Patients who had a history of acute coronary syndrome, a cerebrovascular event, major surgery, or percutaneous coronary intervention within the previous 6 months were excluded. Patients who had any inflammatory condition, liver disease, kidney disease, thyroid disease, or cancer or used anticoagulant therapy were also excluded from the study. Patients who had UAP or NSTEMI were followed for 6 months for the occurrence of major adverse cardiac events, which were cardiac death, nonfatal myocardial infarction, and recurrent ischemic chest pain. Blood was drawn at the time of presentation, before any antithrombotic or anticoagulant therapy. Concentrations of sVCAM-1 were detected with enzyme-linked immunosorbent assay kits (R&D Systems, Abingdon, United Kingdom). Blood levels of troponin T were measured in heparinized blood by an immunosandwich reaction (CARDIAC T Quantitative, Roche Diagnostics, Germany). Patients who had troponin T concentrations ⬎0.01 ng/ml were considered positive for troponin T. Serum levels of high-sensitivity C-reactive protein were determined nephelometrically (Dade Behring Holding GmbH, Marburg, Germany). Statistical analysis was performed with SPSS 9.0 for Windows (SPSS, Inc., Chicago, Illinois). Variables are presented as mean ⫾ SD for continuous data and as proportions for categorical data. Continuous variables with normal distribution were analyzed by unpaired t test. Continuous variables with non-normal distribution were analyzed by the Mann-Whitney test. The Kolmogorov-Smirnov test was used to identify whether continuous variables were normally distributed. Categorical parameters were analyzed by chi-square or Fischer’s exact test, whichever was appropriate. Two-sided p values ⬍0.05 were considered statistically significant. Patients’ clinical features are presented in Table 1. There www.AJConline.org
380
The American Journal of Cardiology (www.AJConline.org)
Table 1 Baseline characteristics of study population
Age (yrs) Men/Women Diabetes mellitus Systemic hypertension Hypercholesterolemia Smoker Myocardial infarct (healed) Coronary angioplasty Coronary bypass hs-CRP (mg/dl)
Patients With UAP or NSTEMI (n ⫽ 70)
Patients With Stable CAD (n ⫽ 18)
p Value
60 ⫾ 10 55/15 18 (26%) 24 (34%) 33 (47%) 49 (70%) 23 (33%) 8 (11%) 15 (21%) 1.24 ⫾ 1.93
60 ⫾ 10 14/4 4 (22%) 6 (33%) 10 (56%) 8 (44%) 12 (67%) 6 (33%) 7 (39%) 0.50 ⫾ 0.30
NS NS NS NS NS 0.042 0.014 0.034 NS 0.006
CAD ⫽ coronary artery disease; hs-CRP ⫽ high-sensitivity C-reactive protein.
Figure 1. Comparison of blood levels of sVCAM-1 between patients who had UAP or NSTEMI and asymptomatic patients who had coronary artery disease (CAD).
Figure 2. Comparison of blood levels of sVCAM-1 between cardiac event and nonevent groups.
were 29 patients who had NSTEMI and 41 who had UAP. Patients who had UAP or NSTEMI were categorized into cardiac event and nonevent groups. Event and nonevent groups had similar baseline clinical characteristics. There were 4 deaths; 3 occurred within the first month of presentation and 1 occurred 46 days after presentation. During the 6-month follow-up, 3 patients developed a nonfatal myocardial infarction and 15 had recurrent ischemic chest pain. Blood levels of sVCAM-1 were found be no higher in patients who had UAP or STEMI than in patients who had stable coronary artery disease (784 ⫾ 280 vs 732 ⫾ 120 ng/ml, p ⫽ 0.642; Figure 1). There was no significant difference in concentrations of sVCAM-1 between event and nonevent groups (731 ⫾ 164 vs 779 ⫾ 320 ng/ml, p ⫽ 0.786; Figure 2). Blood levels of high-sensitivity C-reactive protein were significantly higher in the event than in the nonevent group (2.54 ⫾ 2.81 vs 0.65 ⫾ 0.89 mg/dl, p ⬍0.001; Figure 3). Concentrations of high-sensitivity C-reactive protein were also significantly increased in patients who experienced cardiac death (4.77 ⫾ 5.74 vs 1.03 ⫾ 1.27
mg/dl, p ⬍0.001). Patients who were not positive for troponin T but developed a major cardiovascular event also had significantly increased concentrations of high-sensitivity C-reactive protein (1.36 ⫾ 0.97 vs 0.49 ⫾ 0.26 mg/dl, p ⫽ 0.02). There were proportionally more patients who were positive for troponin T in the event than in the nonevent group (12 of 22 vs 10 of 48, p ⫽ 0.01). •••
In this study, we found that concentrations of sVCAM-1 were not higher in patients who had UAP or NSTEMI at presentation than in patients who had stable coronary heart disease. Further, blood levels of sVCAM-1 at presentation were not predictive of an adverse cardiac event. Adhesion molecules facilitate the recruitment of circulating leukocytes to sites of inflammation.10 As a result, augmented expression of adhesion molecules in vascular endothelium might be expected in acute coronary syndromes. Soluble forms of adhesion molecules in the supernatant of cultured endothelial cells has been shown to reflect its expression on endothelial cell surfaces.11 Concentrations of soluble forms
Coronary Artery Disease/Soluble Vascular Cell Adhesion Molecule-1
381
prognostic significance of high-sensitivity C-reactive protein and troponin T in the course of UAP and NSTEMI. Our findings also indicate that high levels of high-sensitivity C-reactive protein may predict an adverse cardiac event, even in patients whose initial troponin T level is negative. As a result, measurement of sVCAM-1 at the presentation of UAP and NSTEMI is less likely to supply much predictive information to that provided by more established risk factors such as high-sensitivity C-reactive protein and troponin T in patients who have a stable clinical picture for the previous 6 months.
Figure 3. Comparison of blood levels of high-sensitivity C-reactive protein (hs-CRP) between cardiac event and nonevent groups.
of adhesion molecules in blood may indicate the degree of inflammatory state involved in pathogenesis of UAP and NSTEMI. Our study is concordant with the findings of Ghasias et al12 and Parker et al13 who found no difference in sVCAM-1 concentrations between patients who had unstable coronary artery disease and those who had stable disease. Some other studies have shown significantly increased sVCAM-1 levels in patients who had UAP and NSTEMI compared with healthy controls.9,12,14 We were unable to show any relation between sVCAM-1 levels and adverse cardiac events, which is different from the findings of Mulvihill et al.9 This might partly be due to the different background of our study. We did not include patients who had an acute coronary syndrome within the previous 6 months because of an observation that sVCAM-1 concentrations may remain increased up to 6 months after an acute coronary syndrome.14 Therefore, it is questionable whether increased levels of sVCAM-1 in the event group in the previous study reflects previous unresolved intense inflammation in coronary artery endothelium, which causes recurrent instability. The time that elapsed from the initiation of chest pain to the collection of blood might also affect sVCAM-1 concentrations.15 sVCAM-1 levels in blood at a particular time during the course of disease may have a link with adverse cardiac events, although this has not been proved. Moreover, levels of sVCAM-1 may not correctly reflect expression of membrane-bound VCAM on vascular endothelium, which is believed to be a function of poor understanding of the process of “shedding” from the cell surface. This study also supports the growing evidence of the
1. Fuster V, Badimon L, Badimon JJ, Chesebro JH. The pathogenesis of coronary artery disease and the acute coronary syndromes. N Engl J Med 1992;326:242–250. 2. Libby P, Ridker PM, Maseri A. Inflammation and atherosclerosis. Circulation 2002;105:1135–1143. 3. Gearing A, Newman W. Circulating adhesion molecules in disease. Immunol Today 1993;14:506 –512. 4. Jang Y, Lincoff A, Plow E, Topol E. Cell adhesion molecules in coronary artery disease. J Am Coll Cardiol 1994;24:1591–1601. 5. Stad RK, Burman WA. Current views on structure and function of endothelial adhesion molecules. Cell Adhes Commun 1994;2:261–268. 6. de Lemos JA, Hennekens CH, Ridker PM. Plasma concentration of soluble vascular adhesion molecule-1 and subsequent cardiovascular risk. J Am Coll Cardiol 2000;36:423– 426. 7. Malik I, Danesh J, Whincup P, Bhatia V, Papacosta O, Walker M, Lennon L, Thomson A, Haskard D. Soluble adhesion molecules and prediction of coronary artery disease: a prospective study and metaanalysis. Lancet 2001;358:971–975. 8. Blankenberg S, Rupprect HJ, Bickel C, Peetz D, Hafner G, Tiret L, Meyer J, for the AtheroGene Investigators. Circulating cell adhesion molecules and death in patients with coronary artery disease. Circulation 2001;104:1336 –1342. 9. Mulvihill NT, Foley JB, Murphy RT, Curtin R, Crean PA, Walsh M. Risk stratification in unstable angina and non–Q wave myocardial infarction using soluble cell adhesion molecules. Heart 2001;85:623– 627. 10. Springer TA. Traffic signals for lymphocyte recirculation and leukocyte emigration: the multistep paradigm. Cell 1994;76:301–314. 11. Piggot R, Dillon LP, Hemingway IH, Gearing AJ. Soluble forms of E-selectin, ICAM-1 and VCAM-1 in the supernatants of cytokine activated cultured endothelial cells. Biochem Biophys Res Commun 1992;187:584 –589. 12. Ghasias NK, Shahi CN, Foley B, Goggins M, Crean P, Kelly A, Kelleher D, Walsh M. Elevated levels of circulating soluble adhesion molecules in peripheral blood of patients with unstable angina. Am J Cardiol 1997;80:617– 619. 13. Parker C, Vita JA, Freedman JE. Soluble adhesion molecules and unstable coronary artery disease. Atherosclerosis 2001;156:417– 424. 14. Mulvihill NT, Foley JB, Murphy R, Crean P, Walsh M. Evidence of prolonged inflammation in unstable angina and non–Q wave myocardial infarction. J Am Coll Cardiol 2000;36:1210 –1216. 15. Kerner T, Ahlers O, Reschreiter H, Bührer C, Möckel M, Gerlach H. Adhesion molecules in different treatments of acute myocardial infarction. Crit Care 2001;5:145–150.