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(Circulation. 1995;92:1726-1730.)
© 1995 American Heart Association, Inc.

Articles

Soluble P-Selectin Is Released Into the Coronary Circulation After Coronary Spasm

Koichi Kaikita, MD; Hisao Ogawa, MD; Hirofumi Yasue, MD; Tomohiro Sakamoto, MD; Hisakazu Suefuji, MD; Hitoshi Sumida, MD; Ken Okumura, MD

From the Division of Cardiology, Kumamoto University School of Medicine, Kumamoto, Japan.

Correspondence to Hisao Ogawa, MD, Division of Cardiology, Kumamoto University School of Medicine, 1-1-1 Honjo, Kumamoto City 860, Japan.

	Abstract

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Background The glycoprotein P-selectin is an adhesion molecule involved in the property change of leukocytes at the initiation of the inflammatory process. The purpose of the present study was to determine whether acute myocardial ischemia induced by coronary spasm causes an acute inflammatory response in the coronary circulation.

Methods and Results We examined plasma soluble P-selectin levels in the coronary sinus and the aortic root simultaneously in 16 patients with coronary spastic angina before and after left coronary artery spasm induced by intracoronary injection of acetylcholine and in 15 patients with stable exertional angina before and after acute myocardial ischemia induced by rapid atrial pacing. Ten control patients with chest pain but normal coronary arteries and no coronary spasm also received intracoronary acetylcholine. Plasma soluble P-selectin levels were increased significantly in the coronary sinus (32.8±3.6 to 52.8±5.9 ng/mL, P<.001) and in the aortic root (34.6±3.7 to 41.9±4.4 ng/mL, P<.05) after the attacks in the coronary spastic angina group but remained unchanged in the stable exertional angina group after the attacks and in the control group after the administration of acetylcholine. Furthermore, the coronary sinus–arterial difference of soluble P-selectin increased significantly after the attacks in the coronary spastic angina group (-1.8±2.2 to 10.9±2.7 ng/mL, P<.001).

Conclusions Our data indicate that soluble P-selectin is released into the coronary circulation after coronary artery spasm. We conclude that coronary artery spasm may induce the leukocyte adhesion in the coronary circulation and may lead to myocardial damage.

Key Words: ischemia • glycoproteins

	Introduction

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Tissues exposed to ischemia and reperfusion have an acute inflammatory response that is characterized by an increased adherence and emigration of leukocytes in vessels.^{1 2 3 4 5 6 7 8} The selectins belong to an identified family of cell surface glycoproteins that have important roles as adhesion molecules and appear to be the initial adhesion molecules that influence the properties of leukocytes at the initiation of the inflammatory process.^{9 10 11 12 13 14 15 16} Although all the selectins retard the movement of leukocytes in the microvasculature and cause them to roll, P-selectin (GMP-140) is rapidly involved in mediating rolling after ischemia and reperfusion.^{4 9} Two variant forms of P-selectin have been identified by analysis of cDNA, one predicting a soluble form of the molecule lacking the transmembrane domain and the other predicting a molecule containing eight instead of nine consensus repeats.^{17 18} These two forms appear to be generated by alternative splicing of mRNA.^{17 18} Soluble forms of P-selectin recently have been shown to be present in human plasma using an immunoenzymometric method.^{19 20 21}

Coronary artery spasm has been implicated in the pathogenesis of unstable angina^{22 23} or acute myocardial infarction.^{24 25 26} We also have shown that coronary artery spasm induces thrombin generation and may lead to thrombus formation in the coronary artery involved.^{27 28 29} Coronary artery spasm appears to be a clinical counterpart of myocardial ischemia and reperfusion. Whether coronary artery spasm can cause acute inflammatory response in the coronary circulation is unknown.

The purpose of the present study was to determine whether acute myocardial ischemia induced by coronary artery spasm or by rapid atrial pacing causes acute inflammatory response as reflected by plasma soluble P-selectin levels in the coronary circulation. We examined plasma soluble P-selectin levels before and after left coronary artery spasm induced by intracoronary injection of acetylcholine³⁰ in patients with coronary spastic angina and before and after atrial pacing in patients with stable exertional angina involving the left coronary artery.

	Methods

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Study Population
Patients included in this study were divided into coronary spastic angina, stable exertional angina, and control groups. The coronary spastic angina group consisted of 16 patients (13 men and 3 women; mean age, 57±2 years) who had attacks of chest pain associated with ST segment elevation or depression on the ECG occurring at rest and in whom spasm of the left coronary artery was induced by injection of acetylcholine into the left coronary artery. In the present study, coronary spasm was defined as total or subtotal occlusion of the coronary artery associated with ischemic ST segment changes with or without chest pain on the ECG. The stable exertional angina group consisted of 15 patients (12 men and 3 women; mean age, 63±2 years) who had typical exertional angina and 90% narrowing of the left coronary artery. The control group consisted of 10 patients (8 men and 2 women; mean age, 61±3 years) who had no significant coronary artery stenosis (<25% of luminal diameter), and no coronary spasm was demonstrated by the intracoronary injection of acetylcholine. The three groups were matched for age and sex. The patients with myocardial infarction or those receiving heparin, coumarin anticoagulant, or antiplatelet agents were excluded from this study. The study protocol was approved by the ethics committee at our institution, and written informed consent was obtained from each patient and his or her family.

Procedures for Catheterization and Blood Sampling
All drugs were withdrawn 72 hours before cardiac catheterization except for sublingual nitroglycerin, which also was withdrawn 2 hours before catheterization. The study was performed in the morning while the patients were in the fasting state. A 6F Goodale-Lubin catheter (USCI) for blood sampling was positioned in the coronary sinus through the right antecubital vein. The position of the catheter was confirmed by occasional injection of the contrast medium. Coronary arteriography was performed using the Sones technique. All patients were given 5000 U of heparin at the insertion of the Sones catheter. Blood samples for soluble P-selectin and lactate then were collected from the coronary sinus and the aortic root simultaneously at the same speed.

Acetylcholine Provocation Test
After control blood sampling, 20 to 100 µg of acetylcholine was injected into the left coronary artery to induce coronary spasm.³⁰ In the patients with coronary spastic angina and control subjects, a coronary arteriogram was obtained when ST segment changes or chest pain appeared or 2 minutes after each injection. After angiograms, blood samples were taken again simultaneously from the coronary sinus and the aortic root.

Pacing Stress Test
After control blood sampling, atrial pacing was commenced in the patients with stable exertional angina. The pacing rate was begun at 100 beats per minute and was increased until the patients experienced angina that was sustained for 3 or 5 minutes. Blood samples then were collected.

Assays of Soluble P-Selectin and Lactate
Soluble P-selectin was measured using a commercially available ELISA kit (Takara Shuzo Co).¹⁹ The two monoclonal antibodies (WGA-1 and PL7-6) against P-selectin used in this kit did not cross-react with human E-selectin.¹⁹ First, 96-well plates coated with monoclonal antibodies WGA-1, reactive only with thrombin-stimulated human platelet, were blocked with BSA. PL7-6 was labeled with horseradish peroxidase (Boehringer Mannheim) according to a previous method.³¹ To each well, 100 µL of standard P-selectin (0, 10, 20, 40, 80, 160, 320, and 640 ng/mL) or samples were added. P-selectin standard was diluted in PBS containing 1% BSA to various noted concentrations. The plate was incubated for 1 hour at 37°C and washed with PBS. Peroxidase-labeled monoclonal antibody solution (100 µL) then was added to each well and the plate incubated for 1 hour at 37°C. After washing in PBS, 100 µL of 5.5 mmol/L o-phenylenediamine·2HCl (Sigma Chemical Co.) solution was added as substrate and the mixture left for 10 minutes at room temperature. The enzyme reaction was stopped by the addition of 100 µL of 1N H₂SO₄, and the absorbance at 492 nm was measured in a microplate reader, MPR-A4 i II (TOSOH Co). The variabilities of intra-assay and interassay for soluble P-selectin were 6.7% and 7.2%, respectively.

We measured the plasma concentration of lactate in duplicate with use of lactate oxidase combined with N-ethyl-N-(3-methylphenyl)-N'-acetyl-ethylenediamine,³² using an enzyme system assay kit, Determiner LA (Kyowa Medics Co). Myocardial lactate extraction ratio was calculated by the following formula: myocardial lactate extraction ratio (%)=[(L_Ao-L_CS)/L_Ao]x100, where L_Ao and L_CS represent plasma lactate concentration (milligrams per deciliter) in the aortic root and in the coronary sinus, respectively.

Statistics
Values for soluble P-selectin and lactate levels are given as mean±SEM. The two-tailed paired Student's t test was used in the analysis of changes in soluble P-selectin and lactate levels in each group. Comparisons of soluble P-selectin levels, age, serum cholesterol, and serum triglycerides among the three groups were performed with one-way ANOVA followed by Scheffé's test. The clinical characteristics of the three groups shown in Table 1, except age, serum cholesterol, and serum triglyceride, were compared by a ² test. Probability levels <.05 were considered to be statistically significant.

View this table: [in this window] [in a new window]   Table 1. Characteristics of the Study Groups (mean±SEM)

	Results

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Characteristics of the Study Group and Angiographic Data
Table 1 shows the clinical characteristics of patients with coronary spastic angina, patients with stable exertional angina, and control subjects. There were no significant differences among the three groups in the following variables: age, sex, hypertension, smoking, diabetes mellitus, obesity, serum cholesterol, and serum triglycerides. Six patients with coronary spastic angina had significant organic stenosis (75% of luminal diameter). Four had one-vessel disease, one had two-vessel disease, and one had three-vessel disease. All the patients with stable exertional angina had major coronary arteries with 90% diameter stenosis. The control subjects had no significant organic stenosis (25% of luminal diameter) in their coronary arteries, and no coronary artery spasm was induced by intracoronary injection of acetylcholine in any of them.

Percent Myocardial Lactate Extraction
The percent myocardial lactate extraction during the attacks was decreased significantly in the patients with coronary spastic angina (29.8±3.9% to -2.6±7.0%, P<.001) and in those with stable exertional angina (26.9±13.4% to -7.1±13.7%, P<.001) but remained unchanged in the control subjects (Table 2).

View this table: [in this window] [in a new window]   Table 2. Soluble P-Selectin and Lactate Data

Plasma Soluble P-Selectin Levels
The plasma soluble P-selectin levels at baseline were not significantly different among the three groups (Table 2). The plasma soluble P-selectin levels after the attacks in the patients with coronary spastic angina were increased significantly in the coronary sinus (32.8±3.6 to 52.8±5.9 ng/mL, P<.001) and in the aortic root (34.6±3.7 to 41.9±4.4 ng/mL, P<.05). On the other hand, these values remained unchanged in the patients with stable exertional angina before and after rapid atrial pacing (28.0±4.5 to 31.8±4.1 ng/mL in the coronary sinus and 27.4±3.7 to 27.3±4.9 ng/mL in the aortic root) and in the control subjects before and after intracoronary injection of acetylcholine (25.9±6.8 to 26.3±5.8 ng/mL in the coronary sinus and 22.5±5.2 to 25.1±5.3 ng/mL in the aortic root) (Table 2 and Fig 1). The time intervals between catheter insertion and blood sampling were from 15 minutes to 25 minutes in all three patient groups. The coronary sinus–arterial differences of plasma soluble P-selectin levels were increased significantly after the attacks in the coronary spastic angina group (-1.8±2.2 to 10.9±2.7 ng/mL, P<.001) but remained unchanged in the stable exertional angina group (0.5±2.2 to 4.5±2.8 ng/mL) and in the control subjects (3.5±2.3 to 1.2±2.8 ng/mL) (Table 2 and Fig 2).

View larger version (20K): [in this window] [in a new window]   Figure 1. Graphs illustrate plots of plasma soluble P-selectin levels in the coronary sinus (CS) and in the aortic root (Ao) at baseline and after acetylcholine (ACh) provocation in control subjects (left), in patients with coronary spastic angina (CSA) (middle), and at baseline and after rapid atrial pacing in patients with stable exertional angina (SEA) (right).

View larger version (28K): [in this window] [in a new window]   Figure 2. Graphs illustrate plots of coronary sinus–arterial differences of plasma soluble P-selectin levels at baseline and after acetylcholine (ACh) provocation in control subjects (left), in patients with coronary spastic angina (CSA) (middle), and at baseline and after rapid atrial pacing in patients with stable exertional angina (SEA) (right).

	Discussion

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The glycoprotein P-selectin is located in -granules of platelets^{33 34} and Weibel-Palade bodies of endothelial cells^{35 36} and is translocated within seconds to minutes to the cell surface without the need for new protein synthesis after ischemia and reperfusion.^{4 9} It recently has been shown that P-selectin mediates the interaction of granulocytes with platelets and stimulated endothelium in the region of tissue injury,^{37 38} leading to platelet leukocyte binding and granulocyte/endothelium-mediated fibrin deposition in inflammation and thrombosis.³⁹ Coronary artery spasm, which appears to be a clinical counterpart of myocardial ischemia and reperfusion, has been implicated in the pathogenesis of unstable angina^{22 23} or acute myocardial infarction,^{24 25 26} and in previous studies, we have shown that coronary artery spasm induces thrombin generation.^{27 28 29} Acute inflammation caused by leucocyte adhesion in the coronary circulation has been suggested to play an important role in the formation of coronary thrombosis.⁴⁰ The role of adhesion or activation of leukocytes in ischemic myocardium also has been reported in experimental animal models^{1 2 3 4 5 6} and in patients with unstable angina.^{41 42 43} However, it is not yet clear whether coronary spasm initiates the acute inflammatory response.

In the present study, the plasma soluble P-selectin levels were increased significantly in the coronary sinus and in the aortic root, and the coronary sinus–arterial differences of plasma soluble P-selectin levels were increased significantly after the attacks in the coronary spastic angina group but remained unchanged in the stable exertional angina group after the attacks and the control group after administration of acetylcholine. Percent myocardial lactate extraction during the attacks was decreased significantly to the same degree in both the coronary spastic angina group and in the stable exertional angina group. It is considered that the differences of plasma levels of soluble P-selectin and lactate between coronary sinus and aortic root reflect the amounts released mainly from the ischemic area induced by the left coronary artery spasm or by rapid atrial pacing because coronary sinus drains blood mainly from the left coronary artery. These findings indicate that soluble P-selectin is increased in the coronary circulation after acute myocardial ischemia induced by coronary spasm and that coronary spasm may induce the soluble P-selectin into the coronary circulation in the coronary artery involved. Because coronary spasm persisted 1 to 2 minutes in the patients with coronary spastic angina, the coronary artery was considered to be reperfused at the time of blood sampling. We generally inject 100 to 200 µg of nitroglycerin into the coronary artery involved when induced coronary spasm does not resolve spontaneously within 5 minutes or hemodynamic instability occurs as a result of coronary spasm. In the present study, we did not use nitroglycerin in all patients with coronary spastic angina because coronary spasm resolved spontaneously within 1 to 2 minutes. The release of soluble P-selectin into the coronary circulation was not observed after pacing-induced ischemia in the patients with stable exertional angina. The duration of pacing-induced ischemia was similar to that of ischemia induced by coronary spasm, and the percent myocardial lactate extraction during pacing-induced ischemia was decreased significantly to the same degree in the patients with stable exertional angina as in the patients with coronary spastic angina. Thus, it is possible that the induction of P-selectin is not associated with the pacing-induced ischemia related to increased oxygen demand versus reduced oxygen supply in the ischemic myocardium but to ischemia and reperfusion by coronary spasm. The role of the soluble form of P-selectin is unclear at present. Johnston et al¹⁷ and McEver¹⁸ have demonstrated that the molecules of P-selectin contain an N-terminal lectin–like domain, an epidermal growth factor–like domain, consensus repeats related to those in complement binding proteins, a transmembrane domain, and a cytoplasmic tail. Two variant forms for P-selectin have been identified by analysis of the cDNA, one predicting a soluble form of the molecule lacking the transmembrane domain and the other predicting a molecule containing eight instead of nine consensus repeats, and these two forms appear to be generated by alternative splicing of mRNA.^{17 18} Furthermore, they explain that transcripts encoding the putative soluble form of P-selectin may be as common as those encoding the membrane form.^{17 18} Thus, the induction of the soluble form of P-selectin may reflect the total P-selectin upregulation on the stimulated endothelial cells or activated platelets. Lefer et al⁹ explain in a recent review that the soluble form of P-selectin may be due to an overflow of P-selectin, that it may be a barometer of P-selectin upregulation at any point in time or may be a feedback mechanism to curtail intravascular adhesion, and that it may indicate the state of activation of P-selectin in the course of the disease processes.

In vitro studies have shown that thrombin or platelet activating factor induces receptor-mediated fusion of Weibel-Palade bodies with the plasma membrane within seconds to minutes, leading to rapid redistribution of P-selectin to the endothelial cell surface.^{33 34 35 44 45 46 47} Moreover, in a previous study, we have shown that coronary artery spasm induces thrombin generation and may lead to thrombus formation in the coronary artery involved.^{27 28 29} It is possible that increased soluble P-selectin levels are associated with thrombin generation into the coronary circulation after acute myocardial ischemia and reperfusion induced by coronary spasm. The present study shows that soluble P-selectin is increased in the coronary circulation after coronary spasm. Thus, coronary spasm may induce leukocyte adhesion in the coronary circulation and may lead to myocardial damage.

	Acknowledgments

 
This study was supported in part by a Grant-in-Aid for Scientific Research from the Ministry of Education, a Smoking Research Foundation Grant for Biomedical Research, Tokyo, Japan, and a grant from Japan Cardiovascular Research Foundation, Osaka, Japan.

Received January 31, 1995; revision received April 19, 1995; accepted May 3, 1995.

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