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(Circulation. 1995;92:1693-1696.)
© 1995 American Heart Association, Inc.

Articles

Increased Soluble Form of P-Selectin in Patients With Unstable Angina

Hisao Ikeda, MD; Yoshinori Takajo, MD; Kazuya Ichiki, MD; Takafumi Ueno, MD; Sanae Maki, MD; Takehiko Noda, MD; Kenzo Sugi, MD; Tsutomu Imaizumi, MD

From the Third Department of Internal Medicine (H.I., Y.T., K.I., T.U., S.M., T.I.), Kurume University School of Medicine, and the Division of Cardiology (T.N., K.S.), Sugi Hospital, Omuta, Japan.

Correspondence to Hisao Ikeda, MD, The Third Department of Internal Medicine, Kurume University School of Medicine, 67 Asahi-machi, Kurume 830, Japan.

	Abstract

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Background P-selectin in platelets and endothelial cells mediates adhesive interaction with leukocytes to form thrombi. The purpose of the present study was to investigate the plasma levels of P-selectin in patients with unstable angina and in those with stable effort angina of different pathophysiologies.

Methods and Results Plasma P-selectin levels were determined by a monoclonal antibody–based enzyme immunoassay on plasma samples taken from 12 patients with unstable angina, 11 patients with stable effort angina, and 15 healthy volunteers. Patients with unstable angina had angina at rest associated with ECG changes. In patients with unstable angina, plasma P-selectin levels within 1 hour (361±90 ng/mL) and at 3 hours (282±56 ng/mL) after angina were significantly (P<.05) higher than those in volunteers (177±31 ng/mL). Plasma P-selectin levels at 5 hours after attack (242±46 ng/mL) did not differ from those in volunteers. Although patients with stable effort angina developed angina with ST-segment depressions by treadmill exercise, their plasma P-selectin levels did not change (before, 178±45; immediately after, 186±36; and 1 hour after the exercise, 179±34 ng/mL).

Conclusions Plasma P-selectin levels after angina increased significantly in patients with unstable angina but did not in patients with stable effort angina. These findings may contribute to understanding of the pathophysiology of the acute coronary syndrome of unstable angina.

Key Words: P-selectin • angina

	Introduction

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Platelet aggregation and thrombus formation secondary to plaque disruption have been implicated as major pathogenic mechanisms underlying the acute coronary syndrome of unstable angina.^{1 2} This pathophysiology of unstable angina is different from that of effort-induced angina due to increased myocardial oxygen demand. The hypothesis of the disease process in unstable angina has been strongly supported by results of previous studies obtained in serial coronary angiographic,³ angioscopic,⁴ and pathological studies^{5 6} and in experimental studies using an animal model of coronary arterial thrombosis.^{7 8} The disease process of unstable angina appears to involve a transient thrombus formation mediated by a complex cascade of cellular interactions between the vascular endothelium and platelets at the atherosclerotic coronary artery.

Cell adhesion molecules play a key role in cellular interactions in diverse disease processes, including coronary thrombosis, atherosclerosis, restenosis after coronary angioplasty, and reperfusion injury.⁹ P-selectin is a member of the selectin family and is an integral membrane glycoprotein found in both -granules of platelets¹⁰ and Weibel-Palade bodies of endothelial cells.^{11 12} These molecules contain an N-terminal lectin-like domain, an epidermal growth factor–like domain, a variable number of consensus repeats of a sequence found in complement regulatory proteins, a transmembrane domain, and a short cytoplasmic tail.¹² After cellular activation by agonists such as thrombin, P-selectin is rapidly redistributed to the cell surface and binds a sialylated carbohydrate structure expressed on neutrophils and monocytes through a calcium-dependent lectin-like mechanism.^{13 14} Thus, P-selectin mediates platelet-leukocyte and endothelial cell–leukocyte adhesive interactions. Recent studies using a monoclonal antibody-based enzyme immunoassay have demonstrated that the soluble form of P-selectin is present in normal circulation.^{15 16 17} We previously documented that the soluble form of P-selectin increased markedly in patients with evolving acute myocardial infarction.¹⁸ In the present study, we examined the plasma level of P-selectin in patients with unstable angina to further understand the pathophysiology of this syndrome, in which complex interactions between the endothelium, platelets, and neutrophils may occur to form coronary thrombi. We also examined the plasma P-selectin in patients with stable effort angina.

	Methods

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Study Patients
We analyzed the soluble form of P-selectin in the peripheral blood of 12 patients with unstable angina hospitalized in the coronary care unit: 11 men and 1 woman, 53 to 72 years old (mean, 67 years). The diagnosis of unstable angina was defined as ischemic chest pain at rest with no definite evidence of myocardial necrosis by enzymatic techniques. Transient ST-segment depression and/or T-wave inversion associated with angina was present in all patients. We studied only patients in whom blood sampling was possible after onset of chest pain. Patients who presented with ST-segment elevation or new Q waves on the ECG were excluded. Standard medications, including long-acting nitrates, calcium channel blockers, ß-blockers, and aspirin were usually started on the first day of admission if patients did not already take them. Sublingual or intravenous nitroglycerin was administered for the relief of angina attacks. No thrombolytic agents were used. Cardiac catheterization and coronary arteriography were performed by a standard technique within 1 to 2 weeks after admission. We confirmed that all patients had significant coronary artery stenosis.

We also analyzed the soluble form of P-selectin in peripheral blood of patients with stable angina. Stable angina was defined as effort angina without evidence of recent deterioration or rest pain in the previous 6 months. These were 9 men and 2 women, 48 to 77 years old (mean, 68 years). All medications as described above were continued on the day of the treadmill exercise test when blood samples were obtained. A treadmill test was done according to the Bruce protocol. All patients developed typical chest pain with horizontal ST-segment depression of 1 mm during the exercise test. These patients were matched to the unstable angina patients for age, sex, and other clinical variables. A medical history regarding previous myocardial infarction, hypertension, smoking, and diabetes mellitus was carefully obtained in patients. Patients with stable effort angina also underwent coronary angiography. Plasma P-selectin levels were determined in 15 healthy volunteers: 10 men and 5 women, 41 to 83 years old (mean, 63 years). Written informed consent was obtained from all subjects.

Blood Sampling
Whole blood was obtained by venipuncture of the peripheral vein in all subjects. If a patient with unstable angina had an anginal attack after hospitalization, a blood sample (5 mL) was collected within 1 hour and at 3 and 5 hours after the attack. In patients with stable angina, plasma P-selectin levels were determined before, immediately after, and 1 hour after the exercise test. Whole blood for plasma preparation was immediately anticoagulated with 1/10 volume of 1% EDTA-2Na. After being centrifuged at 3000g at 4°C for 10 minutes, plasma was frozen at -80°C until assay.

Enzyme Immunoassay for Soluble Form of P-Selectin
The plasma level of P-selectin was determined according to a previously described method^{15 16} with a P-selectin kit (Takara Biomedicals). Briefly, 100 µL of plasma was added to 96-well plates coated with the first monoclonal antibody (WGA-1) and then blocked with 1% BSA. A volume of 100 µL of standard P-selectin (0, 10, 20, 40, 80, 160, and 320 ng/mL) or blood sample was added to each well. The plates were incubated for 1 hour at 37°C and washed with PBS. We then added 100 µL of solution of the second monoclonal antibody (PL7-6) labeled with horseradish peroxidase to each well and incubated the plate for 1 hour at 37°C. After PBS washing, 100 µL of 5.5 mmol/L o-phenylenediamine · 2HCl solution was added as a substrate, and the mixture was left for 15 minutes at room temperature. The enzyme reaction was stopped by the addition of 100 µL of 1N H₂SO₄, and absorbance at 492 nm was measured in a microplate reader.

Statistics
Values are presented as mean±SD. The clinical characteristics of the two study groups described in the Table were compared by unpaired Student's t test, ² test, or Fisher's exact probability test. The values of plasma P-selectin levels obtained at different time periods were compared by repeated-measures ANOVA with the Scheffé test. Differences were considered statistically significant at P<.05.

View this table: [in this window] [in a new window]   Table 1. Clinical Characteristics of the Two Study Groups

	Results

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Clinical Characteristics
The clinical characteristics of patients with unstable and stable angina were similar for age, sex distribution, and major risk factors (Table). A history of previous myocardial infarction was not noted in patients in the unstable angina group, but one patient in the stable angina group had such a history. The angiographic characteristics were similar between the two groups. Patients with unstable and stable angina did not differ in the use of ß-blockers (33% versus 45%), long-acting nitrates (83% versus 82%), calcium channel blockers (92% versus 100%), and aspirin (100% versus 100%). There were no significant differences in the frequency of smoking or in serum cholesterol levels between the patients with unstable angina, those with stable angina, and the healthy volunteers.

Plasma P-Selectin Levels in Unstable Angina
Fig 1A shows the plasma P-selectin levels in 15 healthy volunteers and in 12 patients with unstable angina. Plasma P-selectin levels in volunteers were 177±31 ng/mL. Plasma P-selectin levels in patients with unstable angina within 1 hour and at 3 and 5 hours after onset of anginal attack were 361±90, 282±56, and 242±46 ng/mL, respectively. Plasma P-selectin levels within 1 hour and at 3 hours after anginal attack were both significantly higher than those in control subjects (P<.05). Plasma P-selectin levels at 5 hours after anginal attack were significantly (P<.05) lower than those at 1 hour and did not differ from those in control subjects.

View larger version (19K): [in this window] [in a new window]   Figure 1. A, Bar graph showing time course of the plasma concentration of P-selectin in patients with unstable angina. Plasma P-selectin levels within 1 hour and at 3 hours after anginal attack were significantly higher than those in control subjects. Plasma P-selectin levels at 5 hours after attacks decreased significantly compared with those within 1 hour and did not differ from those in control subjects. *P<.05 compared with those in control subjects; P<.05 compared with those within 1 hour. B, Bar graph showing plasma concentration of P-selectin before and after exercise stress test in patients with stable effort angina. Although exercise-induced ischemia was observed in all patients during the exercise test, there were no significant increases in plasma P-selectin levels.

Plasma P-Selectin Levels Before and After Exercise Test in Patients With Stable Angina
Fig 1B shows the plasma P-selectin levels before and after treadmill exercise test in 11 patients with stable angina. Plasma P-selectin levels before, immediately after, and 1 hour after exercise test were 178±45, 186±36, and 179±34 ng/mL, respectively. Plasma P-selectin levels before exercise test did not differ from those in control subjects. Plasma P-selectin levels did not change with exercise test (P=NS).

	Discussion

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In the present study, plasma P-selectin levels after anginal attacks were significantly elevated in patients with unstable angina compared with those in patients with stable effort angina and in control subjects. The levels decreased toward the control value within several hours after the cessation of rest angina. In contrast, patients with stable effort angina did not show any change in plasma P-selectin levels after exercise test, although these patients clearly showed evidence of exercise-induced ischemia, with typical ischemic chest pain and horizontal ST-segment depressions. Thus, the present findings may suggest that the pathophysiology of unstable angina is closely related to coronary arterial thrombi through the cellular interactions among platelets, leukocytes, and endothelial cells.

In the present study, we measured plasma P-selectin using the sandwich enzyme immunoassay with two different anti–P-selectin murine monoclonal antibodies. The specificity of these monoclonal antibodies for P-selectin was previously demonstrated by Katayama et al,¹⁵ who demonstrated that these monoclonal antibodies bound to different antigenic epitopes on human P-selectin in a noncompetitive manner and showed no cross-reaction with human E-selectin and L-selectin. These investigators confirmed that the P-selectin levels in platelet-poor plasma were similar to the P-selectin levels in whole blood obtained by standard blood sampling procedures, indicating that the P-selectin detected in plasma is an in vivo product rather than the result of in vitro platelet aggregation.¹⁶ The plasma level obtained in healthy subjects was 177±31 ng/mL, which was similar to those reported by Dunlop et al¹⁷ (175±63 in women and 251±43 ng/mL in men), those reported by Katayama et al¹⁶ (121±84 ng/mL), and those reported by us¹⁸ (178±44 ng/mL), indicating stable and reliable measurements of P-selectin by our method.

We measured the plasma level of P-selectin on the assumption that plasma contains only water-soluble molecules and that immunochemical reaction with monoclonal antibody is specific for the soluble molecule. However, analysis of the complementary DNA demonstrated the possible presence of a soluble form of P-selectin that possesses a deleted transmembrane segment derived from alternative splicing of mRNA.¹⁹ Thus, it is possible that the P-selectin detected in the present study is a mixture of a soluble form and a membrane form produced by alternative splicing of mRNA.

The acute inflammatory reaction may occur at the site of atherosclerotic coronary obstruction in acute coronary syndromes.²⁰ In the present study, P-selectin, an increase of which indicates inflammation, was elevated after anginal attacks in patients with unstable angina. Although it is difficult to determine the exact source of plasma P-selectin in the present study, there are several possibilities to account for increased levels of plasma P-selectin in unstable angina. It is well known that thrombin is the principal mediator of thrombus formation at the site of vascular injury in vivo.²¹ Thrombin can rapidly induce the expression of a membrane form of P-selectin on the surface of platelet and endothelial cell.^{10 13} A recent study by Palabrica et al²² demonstrated that the presence of leukocytes in thrombi is mediated by P-selectin in vivo and that these leukocytes promote fibrin deposition. These findings indicate that the membrane form of P-selectin is an important adhesion molecule on platelets in mediating platelet-leukocyte binding in vivo. Once platelets and leukocytes are thus activated, vasoactive substances such as thromboxane A₂ and leukotrienes are released and further induce platelet aggregation and vasoconstriction. The present data, therefore, suggest that platelets and/or endothelial cells might be activated through interactions with leukocytes during anginal attacks in patients with unstable angina. In contrast to the membrane form of P-selectin, a soluble form of P-selectin is shown to prevent leukocyte ß₂-integrin adhesion, suggesting that this form may serve to limit thrombosis and inflammatory reactions.²³ Thus, the increased levels of plasma P-selectin in unstable angina observed in the present study may play an important role in limiting coronary thrombosis.

The present study demonstrated no significant changes in plasma P-selectin levels after exercise-induced anginal attacks in patients with stable effort angina, even though these patients clearly showed evidence of exercise-induced ischemia. This observation suggested that plasma increases in P-selectin did not result from exercise-induced ischemia and that increased plasma P-selectin in unstable angina might be related to a transient thrombus formation through interactions between leukocytes and platelets and/or endothelial cells.

In the present study, patients with unstable angina had significant increases in plasma P-selectin levels, which gradually decayed to normal levels several hours after the cessation of rest angina. The concentration range and the time course of the elevations in plasma P-selectin levels in patients with unstable angina were different from those we reported previously in patients with acute myocardial infarction.¹⁸ Plasma P-selectin levels on day 1 in patients with acute myocardial infarction ranged from 320 to 1458 ng/mL, twofold to threefold higher than those in patients with unstable angina. Thus, these observations may suggest the different severities of coronary artery thrombosis between unstable angina and acute myocardial infarction.

The present study demonstrates for the first time, to the best of our knowledge, that plasma P-selectin levels increase significantly after anginal attacks in patients with unstable angina. Since mRNA encoding the soluble form exists in both platelets¹⁹ and endothelium,¹² measurements of plasma P-selectin may help us to understand the pathophysiology of unstable angina and may be clinically useful as a new molecular marker of platelet aggregation and thrombus formation in acute coronary syndromes.

	Acknowledgments

 
This work was supported in part by a grant-in-aid for Scientific Research (20217938) from the Ministry of Education, Science, and Culture, Tokyo, Japan.

Received May 4, 1995; revision received July 11, 1995; accepted July 26, 1995.

	References

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				A. H.B. Wu, F. S. Apple, W. B. Gibler, R. L. Jesse, M. M. Warshaw, and R. Valdes Jr. National Academy of Clinical Biochemistry Standards of Laboratory Practice: Recommendations for the Use of Cardiac Markers in Coronary Artery Diseases Clin. Chem., July 1, 1999; 45(7): 1104 - 1121. [Abstract] [Full Text] [PDF]

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				H. Ikeda, T. Ueyama, T. Murohara, H. Yasukawa, N. Haramaki, H. Eguchi, A. Katoh, Y. Takajo, I. Onitsuka, T. Ueno, et al. Adhesive Interaction Between P-Selectin and Sialyl Lewisx Plays an Important Role in Recurrent Coronary Arterial Thrombosis in Dogs Arterioscler. Thromb. Vasc. Biol., April 1, 1999; 19(4): 1083 - 1090. [Abstract] [Full Text] [PDF]

				H. Eguchi, H. Ikeda, T. Murohara, H. Yasukawa, N. Haramaki, S. Sakisaka, and T. Imaizumi Endothelial Injuries of Coronary Arteries Distal to Thrombotic Sites : Role of Adhesive Interaction Between Endothelial P-Selectin and Leukocyte Sialyl LewisX Circ. Res., March 19, 1999; 84(5): 525 - 535. [Abstract] [Full Text] [PDF]

				K. A. Ault, C. P. Cannon, J. Mitchell, J. McCahan, R. P. Tracy, W. F. Novotny, J. D. Reimann, and E. Braunwald Platelet activation in patients after an acute coronary syndrome: results from the TIMI-12 trial J. Am. Coll. Cardiol., March 1, 1999; 33(3): 634 - 639. [Abstract] [Full Text] [PDF]

				A. J. Palazzo, S. P. Jones, W. G. Girod, D. C. Anderson, D. N. Granger, and D. J. Lefer Myocardial ischemia-reperfusion injury in CD18- and ICAM-1-deficient mice Am J Physiol Heart Circ Physiol, December 1, 1998; 275(6): H2300 - H2307. [Abstract] [Full Text] [PDF]

				N. Aoki and H. Tomoda Plasma Soluble P-Selectin in Acute Myocardial Infarction: Effects of Coronary Recanalization Therapy Angiology, September 1, 1998; 49(9): 807 - 813. [Abstract] [PDF]

				G S Hillis and A D Flapan Cell adhesion molecules in cardiovascular disease: a clinical perspective Heart, May 1, 1998; 79(5): 429 - 431. [Full Text]

				G. Davi, M. Romano, A. Mezzetti, A. Procopio, S. Iacobelli, T. Antidormi, T. Bucciarelli, P. Alessandrini, F. Cuccurullo, and G. B. Bon Increased Levels of Soluble P-Selectin in Hypercholesterolemic Patients Circulation, March 17, 1998; 97(10): 953 - 957. [Abstract] [Full Text] [PDF]

				V. Fuster, M. Poon, and J. T. Willerson Learning From the Transgenic Mouse : Endothelium, Adhesive Molecules, and Neointimal Formation Circulation, January 13, 1998; 97(1): 16 - 18. [Full Text] [PDF]