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Increased plasma levels of soluble selectins in patients with unstable angina
International Journal of Cardiology 78 (2001) 69–73 www.elsevier.com / locate / ijcard
Increased plasma levels of soluble selectins in patients with unstable angina ~ ¨ a , Kenan Ovunc ¨ ¨ ¸ a, ˘ b , Necla Ozer Enver Atalar a , *, Kudret Aytemir a , Ibrahim Haznedaroglu a a ¨ ¨ Serdar Aksoyek , Sırrı Kes a , S¸erafettin Kirazlı b , Ferhan Ozmen a
b
Cardiology Department, Hacettepe University School of Medicine, Ankara, Turkey Haematology Department, Hacettepe University School of Medicine, Ankara, Turkey
Received 25 July 2000; received in revised form 13 November 2000; accepted 6 December 2000
Abstract Background: Inflammation plays an important role in the pathogenesis of unstable angina. Adhesion molecules, such as selectins, mediate the interactions between leukocytes, platelets and endothelial cells during inflammation and thrombogenesis. Hypothesis: The purpose of this study was to determine whether soluble E-selectin, P-selectin and L-selectin levels are increased in patients with unstable angina (UA). Methods: Soluble E-, P- and L-selectin levels were measured by enzyme-linked immunoassay in the peripheral blood of 23 patients with UA, 26 patients with stable angina (SA) and 15 control patients with angiographically normal coronary arteries. Results: Soluble E-selectin levels were significantly higher in patients with UA (45611 ng / ml) than in controls (3068 ng / ml, P,0.001), or patients with SA (3468 ng / ml, P50.001). Similarly, plasma levels of P- and L-selectin were significantly higher in patients with UA (4276144 and 7726160 ng / ml, respectively) than in patients with SA (278679 and 643694 ng / ml, respectively, P,0.005 vs. UA for both), or control patients (189643 and 6016126 ng / ml, respectively, P50.001 vs. UA for both). Conclusions: Plasma levels of soluble selectins were increased in patients with UA compared with patients with SA or patients without angiographically visible coronary artery disease. Measurements of these adhesion molecules may be helpful as non-invasive markers of coronary plaque destabilization in UA. 2001 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Unstable angina; Soluble adhesion molecule; Acute coronary syndrome; Selectin
1. Introduction Coronary atherosclerosis is a chronic inflammatory process with acute exacerbations leading to unstable coronary syndromes. A previously stable atherosclerotic plaque is ruptured or eroded in most instances of acute coronary syndrome, leading to thrombus formation [1–3]. While the mechanism of rupture remains uncertain, the process is associated ¨ *Corresponding author. Present address: Koymenevler Koop. 2. Blok No: 4, C ¸ ayyolu-Ankara, 06530 Turkey. Tel.: 190-312-241-01-67; fax: 190-312-325-50-10. E-mail address: [email protected] (E. Atalar).
with acute inflammatory manifestations, including the adhesion of neutrophils and monocytes to coronary endothelial cells, and subsequent increase in the number of activated leukocytes [2,4–6]. It is also well established that the activation of leukocytes promotes platelet aggregation, while platelet activation products may facilitate the accumulation of neutrophils at inflammatory sites [7]. Thrombus formation follows as a consequence of platelet adhesion and aggregation [4–8]. During inflammation and thrombogenesis, an important role is played by interactions among platelets, leukocytes and endothelial cells [9,10]. Cell adhesion
0167-5273 / 01 / $ – see front matter 2001 Elsevier Science Ireland Ltd. All rights reserved. PII: S0167-5273( 00 )00473-3
70
E. Atalar et al. / International Journal of Cardiology 78 (2001) 69 – 73
molecules, such as selectins, mediate cell-to-cell interactions and modulate the adherence of blood platelets and leukocytes to the vascular endothelium. The expression of P-, E- and L-selectins is increased on the surface of activated platelets, endothelial cells and leukocytes, respectively, and their enhanced expression has also been observed in human atherosclerotic plaques [9–13]. Furthermore, increased concentrations of circulating, soluble E-, P- and L-selectins (sE- sP- and sL-selectins) indicate the activation of endothelial cells, platelets and leukocytes, respectively [9,10,14]. The purpose of this study was to determine whether soluble E-, P- and L-selectin levels are increased in patients with unstable angina. Accordingly, plasma sE-, sP- and sL-selectin concentrations were measured in the peripheral blood of patients with unstable angina, stable angina and in patients with normal coronary arteries.
2. Material and methods
2.1. Patient population and methods The study population consisted of a group of patients with unstable angina, a group of patients with stable exertional angina, and a control group. All patients underwent diagnostic coronary angiography within 1–2 weeks after entry into the study. Detailed clinical information, including history of angina pectoris, coronary artery disease risk factors, medication, and prior interventions were prospectively collected. All patients had granted their written informed consent to participate. Patients with ongoing infections, diabetes mellitus, malignancy, chronic liver disease, renal insufficiency, connective tissue disease, or being treated with anti-inflammatory or anticoagulant drugs, were excluded from the study. Patients who had sustained a myocardial infarction within 6 weeks, or had undergone coronary artery bypass graft surgery within 6 months were also excluded.
patients with elevated CK-MB enzyme and troponin I were excluded from the study. The remaining 13 men and nine women (mean age55468 years) had $75% luminal diameter stenosis of at least one coronary artery.
2.3. Stable angina group The 19 men and seven women (mean age55666 years) included in the stable angina group had typical exertional angina, no angina at rest, a positive exercise test, and $75% luminal diameter stenosis of at least one coronary artery.
2.4. Control group The control group consisted of nine men and six women (mean age55268 years) who had typical exertional angina, no angina at rest, a positive exercise test and no angiographically visible coronary artery disease.
2.5. Blood sampling and measurement of adhesion molecules In patients with unstable angina, venous blood was collected immediately after their admission to the emergency department, before initiation of anticoagulant therapy. In patients with stable angina and in control subjects, blood samples were collected at the time of coronary angiography. All free-flowing blood samples were obtained from an antecubital vein. The plasma was separated and stored at 2808C for measurements of adhesion molecules. Concentrations of sE-selectin, sP-selectin and sL-selectin in stored plasma were measured with enzyme-linked immunosorbent assay kits (R&D Systems, Abington, UK). The ranges of intra- and interassay coefficient of variation in our laboratory were 5.3–7.8, and 6.4– 9.1%, respectively.
2.6. Statistical analysis 2.2. Unstable angina group Patients admitted to the emergency department with typical angina at rest and ST segment depression on the electrocardiogram had a diagnosis of unstable angina. From a group of 48 patients screened, 26
Values of plasma soluble E-, P- and L-selectin concentrations, age, serum cholesterol, and plasma triglyceride levels are presented as mean6S.D. Plasma soluble E-, P- and L-selectin levels among the three groups were compared by one-way ANOVA.
E. Atalar et al. / International Journal of Cardiology 78 (2001) 69 – 73
Statistically significant differences were further tested by Scheffe’s test for multiple comparisons. A Pvalue,0.05 was considered statistically significant.
Table 2 Circulating plasma soluble adhesion molecule levels in unstable angina (UA), stable angina (SA) and control patients
UA SA Controls
3. Results
3.1. Characteristics of the study group and angiographic data Table 1 presents the baseline clinical and coronary angiographic characteristics of patients with unstable angina, stable angina, and of the control patients. There were no significant differences among the three groups with respect to age, sex, prevalence of hypertension or obesity, smoking history, or plasma total cholesterol or serum triglyceride levels. The angiographic extent of coronary disease was comparable in patients with unstable angina versus patients with stable angina. Likewise, there were no differences in the use of medications, including long acting nitrates, calcium channel blockers, beta-adrenergic blockers, and aspirin among the three patient groups.
3.2. Plasma sE-, sP- and sL-selectin levels The concentrations of plasma soluble P-, E- and L-selectin in the three groups of patients are pre-
71
sP-selectin (ng / ml)
sE-selectin (ng / ml)
sL-selectin (ng / ml)
4276144 a,d 278679 e 189643
45611 a,c 3468 3068
7726160 b,d 643694 6016126
a
P50.001 versus stable angina. P50.004 versus stable angina. c P,0.001 versus control group. d P50.001 versus control group. e P50.03 versus control group. b
sented in Table 2. The mean plasma sE-selectin level was significantly higher in patients with unstable angina than in patients with stable angina and control patients (P50.001 and ,0.001, respectively). The mean plasma sE-selectin levels measured in stable angina versus control patients were not significantly different (P50.3, Fig. 1). Likewise, the mean plasma sL-selectin levels were significantly higher in patients with unstable angina than in patients with stable angina, or in control patients (P50.004 and 0.001, respectively). The mean plasma sL-selectin levels measured in stable angina versus control patients were not significantly different (P50.6, Fig. 2). Finally, the mean plasma sP-selectin levels measured in patients with unstable angina were significantly
Table 1 Baseline characteristics of the study groups a
Age (mean6S.D.) Men / women (n) Previous MI ([ of patients) Family history of CAD ([ of patients) Hypertension history ([ of patients) Smoking history ([ of patients) BMI.25 ([ of patients) Serum total cholesterol (mmol / l) Serum triglyceride (mmol / l) $ 75% CAS ([ of patients) 1-vessel 2-vessel 3-vessel Medication history ([ of patients) Beta blockers Long-acting nitrates Calcium channel blockers Aspirin a
Unstable angina (n523)
Stable angina (n526)
Controls (n515)
5468 13 / 9 3 7 10 19 7 5.6460.75 5.0260.72
5666 19 / 7 6 11 12 22 10 5.5460.77 4.9460.90
5268 9/6 0 3 6 11 7 5.3860.95 4.8660.93
7 10 6
13 8 5
0 0 0
3 16 6 20
4 21 11 26
1 12 7 15
MI, myocardial infarction; CAD, coronary artery disease; BMI, body mass index; CAS, coronary artery stenosis.
72
E. Atalar et al. / International Journal of Cardiology 78 (2001) 69 – 73
Fig. 1. Plots of peripheral venous plasma concentrations of sE-selectin in patients with unstable angina (UA), stable angina (SA), and control patients (Control). The top of the box represents the 75th percentile and the bottom the 25th percentile. The vertical line inside the box represents the median value, and the lines above and below the box are whiskers to the 90th and the 10th percentiles, respectively.
Fig. 3. Plots of peripheral venous plasma concentrations of soluble P-selectin in patients with unstable angina (UA), stable angina (SA), and in control patients (Control). See Fig. 1 for additional explanations.
4. Discussion higher than in patients with stable angina or in control patients (P50.001 and 0.001, respectively). The mean sP-selectin levels in patients with stable angina were also significantly higher than in control patients (P50.03, Fig. 3).
Fig. 2. Plots of peripheral venous plasma concentrations of soluble L-selectin in patients with unstable angina (UA), stable angina (SA), and in control patients (Control). See Fig. 1 for additional explanations.
In the present study, plasma levels of soluble P-, Land E-selectin were higher in patients with unstable angina than in patients with stable angina and in patients without angiographically visible coronary artery disease. These observations suggest that activation of leukocytes, endothelial cells, and platelets takes place in the circulation during unstable angina. Coronary plaque disruption resulting in thrombus formation and / or platelet aggregation is considered the most important mechanism responsible for the development of acute coronary syndromes, including unstable angina [4,8]. Recent studies have shown that unstable angina is associated with acute activation of monocytes, an observation in support of the important role played by coronary arterial inflammation, followed by plaque rupture, in its pathogenesis [2,8,15]. The finding of higher levels of sL-selectin, in our study may be an important indicator of active inflammation and unstable coronary plaque. Increased levels of sP- and sE-selectin in patients with unstable angina have been similarly measured in previous studies [16–18]. The increase in P-selectin levels may be due to plaque rupture and thrombus formation, as well as to an interaction of platelets by activated leukocytes before plaque disruption. The
E. Atalar et al. / International Journal of Cardiology 78 (2001) 69 – 73
increase in sE-selectin may be a consequence of plaque rupture and / or interactions between activated leukocytes and platelets. Stefanadis et al. [19] have recently reported an increase in thermal heterogeneity within human atherosclerotic coronary arteries of patients with unstable angina and acute myocardial infarction, indicating active inflammation. The detection of increased heat released by activated inflammatory cells in atherosclerotic plaques may predict plaque rupture and thrombosis. A possible correlation between increased sL-selectin levels and thermal heterogeneity of the coronary arteries is worth pursuing in further studies. In conclusion, this study confirmed the presence of elevated circulating sP-, sL- and sE-selectin levels in patients with unstable angina, as a result of the activation of platelets, leukocytes, and endothelial cells, respectively. Therefore, increases in soluble selectin levels may serve as a non-invasive marker of coronary plaque destabilization.
References [1] Fuster V, Badimon L, Cohen M, Ambrose JA, Badimon JJ, Chesebro J. Insights into the pathogenesis of acute ischemic syndromes. Circulation 1988;77:1213–20. [2] van der Wal AC, Becker AE, van der Loos CM, Das PK. Site of intimal rupture or erosion of thrombosed coronary atherosclerotic plaques is characterized by an inflammatory process irrespective of the dominant plaque morphology. Circulation 1994;89:36–44. [3] Falk E, Fuster V. Angina pectoris and disease progression. Circulation 1995;92:2033–5. [4] Buja LM, Willerson JT. Role of inflammation in coronary plaque disruption. Circulation 1994;89:503–5. [5] Moreno PR, Falk E, Palacios IF, Newell JB, Fuster V, Fallon JT. Macrophage infiltration in acute coronary syndromes. Implications for plaque rupture. Circulation 1994;90:775–8.
73
[6] Ricevuti G, Mazzone G, Pasotti D, de Servi S, Specchia G. Role of granulocytes in endothelial injury in coronary artery disease in humans. Atherosclerosis 1991;91:1–14. [7] Theroux P, Latour JG, Leger-Gauthier C, De Lara J. Fibrinopeptide A and platelet factor levels in unstable angina. Circulation 1987;75:156–62. [8] Fuster V, Badimon L, Badimon JJ, Chesebro J. The pathogenesis of coronary artery disease and the acute coronary syndromes. New Engl J Med 1992;326:242–50. [9] Carlos TM, Harlan JM. Leukocyte-endothelial adhesion molecules. Blood 1994;84:2068–101. [10] Jang Y, Lincoff M, Plow EF, Topol EJ. Cell adhesion molecules in coronary artery disease. J Am Coll Cardiol 1994;24:1591–601. [11] Davies MJ, Gordon LJ, Gearing HJ et al. The expression of the adhesion molecules ICAM-1, VCAM-1, PECAM, and E-selectin in human atherosclerosis. J Pathol 1993;171:223–9. [12] Johnson-Tidey RR, McGregor JL, Taylor PR, Poston RN. Increase in the adhesion molecule P-selectin in endothelium overlying atherosclerotic plaques. Coexpression with intercellular adhesion molecule-1. Am J Pathol 1994;144:952–61. [13] Tenaglia AN, Buda AJ, Wilkins RG, Barron MK, Jeffords PR, Vo K, Jordan MO, Kusnick B, Lefer DJ. Levels of expression of Pselectin, E-selectin, and intercellular adhesion molecule-1 in coronary atherectomy specimens from patients with stable and unstable angina pectoris. Am J Cardiol 1997;79:742–7. [14] Blann AD, Lip GY, Beevers G, McCollum CN. Soluble P-selectin in atherosclerosis: a comparison with endothelial cell and platelet markers. Thromb Haemost 1997;77:1077–80. [15] Neri Serneri GG, Abbate R, Gori AM et al. Transient intermittent lymphocyte activation is responsible for the instability of angina. Circulation 1992;86:790–7. [16] Kaikita K, Ogawa H, Yasue H et al. Soluble P-selectin is released into the coronary circulation after coronary spasm. Circulation 1995;92:1726–30. [17] Ikeda H, Takajo Y, Ichiki K et al. Increased soluble form of P-selectin in patients with unstable angina. Circulation 1995;92:1693–6. [18] Ghaisas NK, Shahi CN, Foley B et al. Elevated levels of circulating soluble adhesion molecules in peripheral blood of patients with unstable angina. Am J Cardiol 1997;80:617–9. [19] Stefanadis C, Diamantopoulos L, Vlachopoulos C et al. Thermal heterogeneity within human atherosclerotic coronary arteries detected in vivo: A new method of detection by application of a special thermography catheter. Circulation 1999;99:1965–71.
Increased plasma levels of soluble selectins in patients with unstable angina ~ ¨ a , Kenan Ovunc ¨ ¨ ¸ a, ˘ b , Necla Ozer Enver Atalar a , *, Kudret Aytemir a , Ibrahim Haznedaroglu a a ¨ ¨ Serdar Aksoyek , Sırrı Kes a , S¸erafettin Kirazlı b , Ferhan Ozmen a
b
Cardiology Department, Hacettepe University School of Medicine, Ankara, Turkey Haematology Department, Hacettepe University School of Medicine, Ankara, Turkey
Received 25 July 2000; received in revised form 13 November 2000; accepted 6 December 2000
Abstract Background: Inflammation plays an important role in the pathogenesis of unstable angina. Adhesion molecules, such as selectins, mediate the interactions between leukocytes, platelets and endothelial cells during inflammation and thrombogenesis. Hypothesis: The purpose of this study was to determine whether soluble E-selectin, P-selectin and L-selectin levels are increased in patients with unstable angina (UA). Methods: Soluble E-, P- and L-selectin levels were measured by enzyme-linked immunoassay in the peripheral blood of 23 patients with UA, 26 patients with stable angina (SA) and 15 control patients with angiographically normal coronary arteries. Results: Soluble E-selectin levels were significantly higher in patients with UA (45611 ng / ml) than in controls (3068 ng / ml, P,0.001), or patients with SA (3468 ng / ml, P50.001). Similarly, plasma levels of P- and L-selectin were significantly higher in patients with UA (4276144 and 7726160 ng / ml, respectively) than in patients with SA (278679 and 643694 ng / ml, respectively, P,0.005 vs. UA for both), or control patients (189643 and 6016126 ng / ml, respectively, P50.001 vs. UA for both). Conclusions: Plasma levels of soluble selectins were increased in patients with UA compared with patients with SA or patients without angiographically visible coronary artery disease. Measurements of these adhesion molecules may be helpful as non-invasive markers of coronary plaque destabilization in UA. 2001 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Unstable angina; Soluble adhesion molecule; Acute coronary syndrome; Selectin
1. Introduction Coronary atherosclerosis is a chronic inflammatory process with acute exacerbations leading to unstable coronary syndromes. A previously stable atherosclerotic plaque is ruptured or eroded in most instances of acute coronary syndrome, leading to thrombus formation [1–3]. While the mechanism of rupture remains uncertain, the process is associated ¨ *Corresponding author. Present address: Koymenevler Koop. 2. Blok No: 4, C ¸ ayyolu-Ankara, 06530 Turkey. Tel.: 190-312-241-01-67; fax: 190-312-325-50-10. E-mail address: [email protected] (E. Atalar).
with acute inflammatory manifestations, including the adhesion of neutrophils and monocytes to coronary endothelial cells, and subsequent increase in the number of activated leukocytes [2,4–6]. It is also well established that the activation of leukocytes promotes platelet aggregation, while platelet activation products may facilitate the accumulation of neutrophils at inflammatory sites [7]. Thrombus formation follows as a consequence of platelet adhesion and aggregation [4–8]. During inflammation and thrombogenesis, an important role is played by interactions among platelets, leukocytes and endothelial cells [9,10]. Cell adhesion
0167-5273 / 01 / $ – see front matter 2001 Elsevier Science Ireland Ltd. All rights reserved. PII: S0167-5273( 00 )00473-3
70
E. Atalar et al. / International Journal of Cardiology 78 (2001) 69 – 73
molecules, such as selectins, mediate cell-to-cell interactions and modulate the adherence of blood platelets and leukocytes to the vascular endothelium. The expression of P-, E- and L-selectins is increased on the surface of activated platelets, endothelial cells and leukocytes, respectively, and their enhanced expression has also been observed in human atherosclerotic plaques [9–13]. Furthermore, increased concentrations of circulating, soluble E-, P- and L-selectins (sE- sP- and sL-selectins) indicate the activation of endothelial cells, platelets and leukocytes, respectively [9,10,14]. The purpose of this study was to determine whether soluble E-, P- and L-selectin levels are increased in patients with unstable angina. Accordingly, plasma sE-, sP- and sL-selectin concentrations were measured in the peripheral blood of patients with unstable angina, stable angina and in patients with normal coronary arteries.
2. Material and methods
2.1. Patient population and methods The study population consisted of a group of patients with unstable angina, a group of patients with stable exertional angina, and a control group. All patients underwent diagnostic coronary angiography within 1–2 weeks after entry into the study. Detailed clinical information, including history of angina pectoris, coronary artery disease risk factors, medication, and prior interventions were prospectively collected. All patients had granted their written informed consent to participate. Patients with ongoing infections, diabetes mellitus, malignancy, chronic liver disease, renal insufficiency, connective tissue disease, or being treated with anti-inflammatory or anticoagulant drugs, were excluded from the study. Patients who had sustained a myocardial infarction within 6 weeks, or had undergone coronary artery bypass graft surgery within 6 months were also excluded.
patients with elevated CK-MB enzyme and troponin I were excluded from the study. The remaining 13 men and nine women (mean age55468 years) had $75% luminal diameter stenosis of at least one coronary artery.
2.3. Stable angina group The 19 men and seven women (mean age55666 years) included in the stable angina group had typical exertional angina, no angina at rest, a positive exercise test, and $75% luminal diameter stenosis of at least one coronary artery.
2.4. Control group The control group consisted of nine men and six women (mean age55268 years) who had typical exertional angina, no angina at rest, a positive exercise test and no angiographically visible coronary artery disease.
2.5. Blood sampling and measurement of adhesion molecules In patients with unstable angina, venous blood was collected immediately after their admission to the emergency department, before initiation of anticoagulant therapy. In patients with stable angina and in control subjects, blood samples were collected at the time of coronary angiography. All free-flowing blood samples were obtained from an antecubital vein. The plasma was separated and stored at 2808C for measurements of adhesion molecules. Concentrations of sE-selectin, sP-selectin and sL-selectin in stored plasma were measured with enzyme-linked immunosorbent assay kits (R&D Systems, Abington, UK). The ranges of intra- and interassay coefficient of variation in our laboratory were 5.3–7.8, and 6.4– 9.1%, respectively.
2.6. Statistical analysis 2.2. Unstable angina group Patients admitted to the emergency department with typical angina at rest and ST segment depression on the electrocardiogram had a diagnosis of unstable angina. From a group of 48 patients screened, 26
Values of plasma soluble E-, P- and L-selectin concentrations, age, serum cholesterol, and plasma triglyceride levels are presented as mean6S.D. Plasma soluble E-, P- and L-selectin levels among the three groups were compared by one-way ANOVA.
E. Atalar et al. / International Journal of Cardiology 78 (2001) 69 – 73
Statistically significant differences were further tested by Scheffe’s test for multiple comparisons. A Pvalue,0.05 was considered statistically significant.
Table 2 Circulating plasma soluble adhesion molecule levels in unstable angina (UA), stable angina (SA) and control patients
UA SA Controls
3. Results
3.1. Characteristics of the study group and angiographic data Table 1 presents the baseline clinical and coronary angiographic characteristics of patients with unstable angina, stable angina, and of the control patients. There were no significant differences among the three groups with respect to age, sex, prevalence of hypertension or obesity, smoking history, or plasma total cholesterol or serum triglyceride levels. The angiographic extent of coronary disease was comparable in patients with unstable angina versus patients with stable angina. Likewise, there were no differences in the use of medications, including long acting nitrates, calcium channel blockers, beta-adrenergic blockers, and aspirin among the three patient groups.
3.2. Plasma sE-, sP- and sL-selectin levels The concentrations of plasma soluble P-, E- and L-selectin in the three groups of patients are pre-
71
sP-selectin (ng / ml)
sE-selectin (ng / ml)
sL-selectin (ng / ml)
4276144 a,d 278679 e 189643
45611 a,c 3468 3068
7726160 b,d 643694 6016126
a
P50.001 versus stable angina. P50.004 versus stable angina. c P,0.001 versus control group. d P50.001 versus control group. e P50.03 versus control group. b
sented in Table 2. The mean plasma sE-selectin level was significantly higher in patients with unstable angina than in patients with stable angina and control patients (P50.001 and ,0.001, respectively). The mean plasma sE-selectin levels measured in stable angina versus control patients were not significantly different (P50.3, Fig. 1). Likewise, the mean plasma sL-selectin levels were significantly higher in patients with unstable angina than in patients with stable angina, or in control patients (P50.004 and 0.001, respectively). The mean plasma sL-selectin levels measured in stable angina versus control patients were not significantly different (P50.6, Fig. 2). Finally, the mean plasma sP-selectin levels measured in patients with unstable angina were significantly
Table 1 Baseline characteristics of the study groups a
Age (mean6S.D.) Men / women (n) Previous MI ([ of patients) Family history of CAD ([ of patients) Hypertension history ([ of patients) Smoking history ([ of patients) BMI.25 ([ of patients) Serum total cholesterol (mmol / l) Serum triglyceride (mmol / l) $ 75% CAS ([ of patients) 1-vessel 2-vessel 3-vessel Medication history ([ of patients) Beta blockers Long-acting nitrates Calcium channel blockers Aspirin a
Unstable angina (n523)
Stable angina (n526)
Controls (n515)
5468 13 / 9 3 7 10 19 7 5.6460.75 5.0260.72
5666 19 / 7 6 11 12 22 10 5.5460.77 4.9460.90
5268 9/6 0 3 6 11 7 5.3860.95 4.8660.93
7 10 6
13 8 5
0 0 0
3 16 6 20
4 21 11 26
1 12 7 15
MI, myocardial infarction; CAD, coronary artery disease; BMI, body mass index; CAS, coronary artery stenosis.
72
E. Atalar et al. / International Journal of Cardiology 78 (2001) 69 – 73
Fig. 1. Plots of peripheral venous plasma concentrations of sE-selectin in patients with unstable angina (UA), stable angina (SA), and control patients (Control). The top of the box represents the 75th percentile and the bottom the 25th percentile. The vertical line inside the box represents the median value, and the lines above and below the box are whiskers to the 90th and the 10th percentiles, respectively.
Fig. 3. Plots of peripheral venous plasma concentrations of soluble P-selectin in patients with unstable angina (UA), stable angina (SA), and in control patients (Control). See Fig. 1 for additional explanations.
4. Discussion higher than in patients with stable angina or in control patients (P50.001 and 0.001, respectively). The mean sP-selectin levels in patients with stable angina were also significantly higher than in control patients (P50.03, Fig. 3).
Fig. 2. Plots of peripheral venous plasma concentrations of soluble L-selectin in patients with unstable angina (UA), stable angina (SA), and in control patients (Control). See Fig. 1 for additional explanations.
In the present study, plasma levels of soluble P-, Land E-selectin were higher in patients with unstable angina than in patients with stable angina and in patients without angiographically visible coronary artery disease. These observations suggest that activation of leukocytes, endothelial cells, and platelets takes place in the circulation during unstable angina. Coronary plaque disruption resulting in thrombus formation and / or platelet aggregation is considered the most important mechanism responsible for the development of acute coronary syndromes, including unstable angina [4,8]. Recent studies have shown that unstable angina is associated with acute activation of monocytes, an observation in support of the important role played by coronary arterial inflammation, followed by plaque rupture, in its pathogenesis [2,8,15]. The finding of higher levels of sL-selectin, in our study may be an important indicator of active inflammation and unstable coronary plaque. Increased levels of sP- and sE-selectin in patients with unstable angina have been similarly measured in previous studies [16–18]. The increase in P-selectin levels may be due to plaque rupture and thrombus formation, as well as to an interaction of platelets by activated leukocytes before plaque disruption. The
E. Atalar et al. / International Journal of Cardiology 78 (2001) 69 – 73
increase in sE-selectin may be a consequence of plaque rupture and / or interactions between activated leukocytes and platelets. Stefanadis et al. [19] have recently reported an increase in thermal heterogeneity within human atherosclerotic coronary arteries of patients with unstable angina and acute myocardial infarction, indicating active inflammation. The detection of increased heat released by activated inflammatory cells in atherosclerotic plaques may predict plaque rupture and thrombosis. A possible correlation between increased sL-selectin levels and thermal heterogeneity of the coronary arteries is worth pursuing in further studies. In conclusion, this study confirmed the presence of elevated circulating sP-, sL- and sE-selectin levels in patients with unstable angina, as a result of the activation of platelets, leukocytes, and endothelial cells, respectively. Therefore, increases in soluble selectin levels may serve as a non-invasive marker of coronary plaque destabilization.
References [1] Fuster V, Badimon L, Cohen M, Ambrose JA, Badimon JJ, Chesebro J. Insights into the pathogenesis of acute ischemic syndromes. Circulation 1988;77:1213–20. [2] van der Wal AC, Becker AE, van der Loos CM, Das PK. Site of intimal rupture or erosion of thrombosed coronary atherosclerotic plaques is characterized by an inflammatory process irrespective of the dominant plaque morphology. Circulation 1994;89:36–44. [3] Falk E, Fuster V. Angina pectoris and disease progression. Circulation 1995;92:2033–5. [4] Buja LM, Willerson JT. Role of inflammation in coronary plaque disruption. Circulation 1994;89:503–5. [5] Moreno PR, Falk E, Palacios IF, Newell JB, Fuster V, Fallon JT. Macrophage infiltration in acute coronary syndromes. Implications for plaque rupture. Circulation 1994;90:775–8.
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