Hisakazu Suefuji

The variation of plasma concentrations of a novel, adipocyte derived protein, adiponectin, in patients with acute myocardial infarction

Adiponectin is a new member of adipocyte derived proteins belonging to the soluble defence collagens.1 Plasma adiponectin concentrations in obese subjects are decreased in spite of an adipose specific expression.1 More interestingly, the patients with chronic coronary artery disease exhibited lower plasma adiponectin concentrations compared to body mass index (BMI) matched control subjects.2 On the other hand, adiponectin accumulates in the vascular subendothelial space when the endothelial barrier is damaged.3 In vitro, adiponectin suppresses the expression of adhesion molecules in the vascular endothelial cells and cytokine production from macrophages.2,4 Therefore, the molecule may be involved in the inflammation and tissue repairing processes. Acute coronary syndrome is often precipitated by acute thrombosis.5 It is commonly accepted that the rupture or the erosion of plaques by the inflammatory process leads to coronary thrombosis and acute myocardial infarction (AMI). The C reactive protein (CRP) concentrations in the acute phase are suggested to reflect pre-existing coronary plaque instability associated with the onset of AMI. The significance of adiponectin in acute coronary syndrome has never been investigated. In the present study, we examined the serial change in plasma adiponectin concentrations and its relation to plasma CRP concentration in …

Increased plasma tissue factor levels in acute myocardial infarction

BACKGROUND Tissue factor (TF) is a low molecular weight glycoprotein that initiates the clotting cascade and is considered to be a major regulator of coagulation, hemostasis, and thrombosis. METHODS AND RESULTS We examined plasma TF levels in 31 consecutive patients with acute myocardial infarction (AMI) (within 6 hours after the onset of symptoms), 27 patients with stable exertional angina, and 27 control subjects. Ten patients with AMI had a history of unstable angina before infarction, and 21 had a sudden onset of infarction. The plasma TF level was higher in the AMI group than in the stable exertional angina and control groups (240 +/- 112 vs 184 +/- 46 pg/ml [p < 0.05] vs 177 +/- 37 pg/ml, p < 0.01, respectively). TF levels were decreased in the chronic phase (2 weeks after admission) compared with the acute phase of infarction (from 240 +/- 112 pg/ml to 222 +/- 97 pg/ml, p < 0.05). In addition, plasma TF levels were higher in patients with AMI with prodromal unstable angina than in patients with a sudden onset of infarction (300 +/- 169 pg/ml vs 212 +/- 57 pg/ml, p < 0.05). TF levels were similar in the acute and chronic phases in the patients with AMI with prodromal unstable angina (300 +/- 169 pg/ml vs 290 +/- 136 pg/ml, p = not significant) but were decreased in the chronic phase in the patients with AMI with sudden onset (from 212 +/- 57 pg/ml to 190 +/- 49 pg/ml, p < 0.05). CONCLUSION Increased plasma TF levels in patients with AMI may reflect enhanced intravascular procoagulant activity. The higher TF levels in patients with AMI with prodramol unstable angina may be associated with repeated episodes of myocardial ischemia and reperfusion.

Comparison of Plasma Tissue Factor Levels in Unstable and Stable Angina Pectoris

We have reported that the plasma levels of plasma fibrinopeptide A and plasminogen activator inhibitor activity increase in patients with unstable angina and acute myocardial infarction. Tissue factor (TF) is a low-molecular-weight glycoprotein that binds to and acts on essential cofactor VII, and the resulting complex activates factors IX and X, initiating the coagulation cascade. We measured plasma TF antigen levels in 21 patients with unstable angina (on admission and after treatment), 27 patients with stable exertional angina, and 27 control subjects. The 3 groups were matched for age, gender, and other clinical variables. The plasma TF antigen levels were higher in the unstable angina group than in the stable exertional angina and control groups (240 +/- 75 vs 184 +/- 46 and 177 +/- 37 pg/ml, p < 0.01). There were no significant differences in the plasma TF antigen levels between the stable exertional angina and the control groups. Furthermore, the plasma TF antigen levels were reexamined after treatment in the 21 patients with unstable angina. The mean level in these 21 patients decreased after 2 weeks of treatment (from 240 +/- 75 to 206 +/- 57 pg/ml, p < 0.01). This study suggests that the plasma TF antigen levels correlate with disease activity in patients with unstable angina. The increased plasma TF antigen levels in patients with unstable angina may reflect intravascular procoagulant activity.

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

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.

Co‐localization of tissue factor and tissue factor pathway inhibitor in coronary atherosclerosis

Tissue factor (TF) initiates the extrinsic pathway of blood coagulation by acting as a cofactor for Factor VII. Inhibition of the Factor VIIa–TF complex is mediated by the tissue factor pathway inhibitor (TFPI), which is a serine protease inhibitor with three Kunitz‐type domains. The localization of TF and TFPI protein has been examined immunohistochemically in various atherosclerotic lesions of coronary arteries from 22 autopsy cases and their messenger RNA expression has been confirmed by reverse transcription‐polymerase chain reaction. Four types of atherosclerotic lesion (types I, II, III, and IV) were classified according to the method described by Stary et al. TF and TFPI were localized in endothelial cells, macrophages, macrophage‐derived foam cells, and smooth muscle cells in the intimal lesions, medial smooth muscle cells, and endothelial cells of the microvessels in the adventitia. Immunohistochemical double staining revealed the co‐localization of TF and TFPI in the endothelial cells and macrophages in four types of atherosclerotic lesions. In type III and IV lesions, the number of TF‐ and TFPI‐positive cells was increased, accompanied by extracellular localization of TF and TFPI in the lipid core of atherosclerotic plaques. Fibrin deposition was found around TF‐ and TFPI‐positive macrophages and in the lipid core of atherosclerotic plaques. TF and TFPI messenger RNA were detected more frequently in coronary arteries with type III and IV lesions than in those with type I and II lesions. The co‐localization of TF and TFPI was demonstrated in various atherosclerotic lesions of coronary arteries and was shown to be intimately related to fibrin deposition in advanced atherosclerotic plaques. The co‐localization of TF and TFPI may thus be closely associated with thrombogenicity in atherosclerotic lesions of coronary arteries. Copyright

Plasma soluble intercellular adhesion molecule-1 levels in coronary circulation in patients with unstable angina

It has been suggested that active inflammation plays an important role in the pathogenesis of acute coronary syndromes, including unstable angina. Intracellular adhesion molecule-1 (ICAM-1) is a major ligand on the endothelial cells for adherence of the activated polymorphonuclear leukocytes. Recently, it has been demonstrated that the soluble form of ICAM-1 has been detected in human serum and has been increased in many other inflammatory or autoimmune disorders. To evaluate the involvement of ICAM-1 in unstable angina, we examined plasma soluble ICAM-1 (sICAM-1) levels in coronary circulation. The plasma sICAM-1 levels in the coronary sinus and aortic root were simultaneously examined in 20 patients with unstable angina, 19 patients with stable exertional angina, and 16 control subjects. The plasma levels of sICAM-1 were measured by enzyme-linked immunosorbent assay. The mean plasma sICAM-1 levels (nanograms per milliliter) both in the coronary sinus and aortic root were significantly higher (p <0.01) in patients with unstable angina than in those with stable exertional angina and in control subjects (217+/-14 vs 126+/-8; 120+/-10 in the coronary sinus, 202+/-13 vs 125+/-9; 123+/-10 in the aortic root). Furthermore, the mean value was higher in the coronary sinus than in the aortic root in patients with unstable angina. There were no significant differences in the values between in the coronary sinus and aortic root in patients with stable exertional angina and control subjects. Thus, sICAM-1 release is increased, especially in coronary circulation in unstable angina.

The effects of the angiotensin-converting enzyme inhibitor imidapril on plasma plasminogen activator inhibitor activity in patients with acute myocardial infarction

This study sought to determine whether early treatment with angiotensin-converting enzyme (ACE) inhibitors in patients with acute myocardial infarction (AMI) is useful for the improvement of fibrinolytic function, as well as left ventricular function. This study was designed to examine the levels of plasma plasminogen activator inhibitor (PAI) activity and serum ACE activity during the course of 2 weeks in 40 patients with AMI within 12 hours after the onset of the symptom and who randomly received early treatment with either the ACE inhibitor imidapril or a placebo (20 patients in the imidapril group and 20 in the placebo group). The levels of serum ACE activity in the imidapril group decreased significantly (p < 0.01) 8 hours after the administration of imidapril, and the levels 24 hours after administration were significantly lower than those in the placebo group (3.6 +/- 0.6 IU/L vs 7.4 +/- 0.8 IU/L; p < 0.001). The plasma PAI activity increased gradually to peak levels 16 hours after the administration of imidapril and placebo. The levels in the placebo group decreased gradually but remained high during the study period. On the other hand, the levels of PAI activity in the imidapril group decreased rapidly and those 48 hours after administration were significantly lower than those in the placebo group (7.9 +/- 1.9 IU/ml vs 18.4 +/- 3.5 IU/ml; p < 0.01). The levels of left ventricular ejection fraction about 2 weeks after admission were significantly higher in the imidapril group than in the placebo group (65.9% +/- 2.5% vs 49.1% +/- 4.4%; p < 0.01). This study showed that imidapril, an ACE inhibitor, might be useful for the improvement of fibrinolytic function and left ventricular function in the acute phase of myocardial infarction.

Increased Blood Vascular Endothelial Growth Factor Levels in Patients with Acute Myocardial Infarction

Vascular endothelial growth factor (VEGF) is a growth factor for vascular endothelial cells in vitro. The present study was designed to determine whether serum VEGF levels increase in patients with acute myocardial infarction (AMI) compared with patients with stable exertional angina and control subjects, and to examine the serial changes of serum VEGF levels in patients with AMI. We examined serum VEGF levels by using antibody prepared from serum immunized with human VEGF121. The serum VEGF level (pg/ml) was higher (p < 0.0001) on admission in the patients with AMI (177 ± 19) than in those with stable exertional angina (61 ± 7) and control subjects (62 ± 6). The serum VEGF level (pg/ml) of the patients with AMI was 177 ± 19 on admission, 125 ± 9 on day 3, 137 ± 11 on day 5, 242 ± 18 at 1 week, and 258 ± 22 at 2 weeks after admission. The value was higher on admission than on day 3 after admission (p = 0.014), the values were higher at 1 week and 2 weeks than on admission, on day 3, and 5 (p < 0.01). Furthermore, there were correlations between peak VEGF levels at 1 week or 2 weeks after admission and peak creatine kinase levels. The increase of VEGF on admission in the patients with AMI may be due to the hypoxia of acute myocardial ischemia. The elevation at 1 week and 2 weeks from the onset may cause the development of collateral circulation in relation to the healing of the infarction site.

Effects of enalapril on tissue factor in patients with uncomplicated acute myocardial infarction.

In a randomized, double-blind, placebo-controlled study beginning 4 weeks after uncomplicated acute myocardial infarction, it was established that the baseline plasma tissue factor antigen level was significantly higher in patients with myocardial infarction than in control subjects, and enalapril therapy significantly reduced the elevated plasma tissue factor antigen level. This may be associated with the reduction in the risk of coronary thrombosis seen with the use of angiotensin-converting enzyme inhibitors.

Increased plasminogen activator inhibitor activity and diabetes predict subsequent coronary events in patients with angina pectoris

BACKGROUND. Plasminogen activator inhibitor (PAI) is a marker of recurrence of myocardial infarction. Diabetes mellitus is also an important risk factor of coronary artery disease, including myocardial infarction and angina pectoris. AIM. We examined baseline plasma PAI activity levels, clinical variables, and angiographic findings and assessed them as prospective values for subsequent coronary events, such as sudden death, nonfatal myocardial infarction and coronary revascularization by percutaneous transluminal coronary angioplasty or coronary artery bypass surgery during the follow-up period. METHODS. We conducted a prospective study for 4 years of 249 consecutive patients admitted with angina pectoris. Blood samples for PAI were drawn at discharge. RESULTS. In the multivariate Cox proportional hazard model, PAI activity and diabetes mellitus were significant and independent risk factors (the risk increased by 10% in those with a higher PAI concentration and by 70% in diabetic patients). Event-free survival was reduced by higher PAI activity (≥ 8.4 lU/mL) and the presence of diabetes. The patients with higher PAI activity and diabetes had a 4.2-fold risk in comparison with the patients with lower PAI activity and no diabetes. However, patients with lower PAI activity were less likely to have coronary events even when they had diabetes. CONCLUSIONS. Higher PAI activity and diabetes predict subsequent coronary events in patients with angina pectoris. Diabetes has less prognostic value for subsequent coronary events in patients with lower PAI activity.