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Background: Accurate evaluation of thrombogenicity helps to prevent thrombosis and excessive bleeding. The total thrombus-formation analysis system (T-TAS) was developed for quantitative analysis of platelet thrombus formation by the use of microchips with thrombogenic surfaces (collagen, platelet chip [PL-chip]; collagen plus tissue factor, atherome chip [AR-chip]). We examined the utility of the T-TAS in the assessment of the efficacy of antiplatelet therapy in patients with coronary artery disease (CAD)., Methods and Results: In this cross-sectional study, 372 consecutive patients admitted to the cardiovascular department were divided into three groups: patients not receiving any antiplatelet therapy (control, n = 56), patients receiving aspirin only (n = 69), and patients receiving aspirin and clopidogrel (n = 149). Blood samples were used for the T-TAS to measure the platelet thrombus-formation area under the curve (AUC) at various shear rates (1500 s(-1) [PL18 -AUC10 ] and 2000 s(-1) [PL24 -AUC10 ] for the PL-chip; 300 s(-1) [AR10 -AUC30 ] for the AR-chip). The on-clopidogrel platelet aggregation was measured by the use of P2Y12 reaction units (PRUs) with the VerifyNow system. The mean PL24 -AUC10 levels were 358 ± 111 (± standard deviation) (95% confidence interval [CI] 328.9-387.1) in the control group, 256 ± 108 (95% CI 230.5-281.5) in the aspirin group, and 113 ± 91 (95% CI 98.4-127.6) in the aspirin/clopidogrel group. In the aspirin/clopidogrel group, the PL24 -AUC10 was higher in poor metabolizers (PMs) with cytochrome P450 2C19(CYP2C19) polymorphisms (152 ± 112, 95% CI 103.4-200.6) than in the non-PM group (87 ± 74, 95% CI 73.8-100.2)., Conclusions: Our findings suggest that the PL24 -AUC10 level measured by the T-TAS is a potentially suitable index for the assessment of antiplatelet therapy in CAD patients., (© 2016 International Society on Thrombosis and Haemostasis.)

Background: Long-term inhibition of nitric oxide synthase (NOS) is known to induce hypertension and perivascular fibrosis. Recent evidence also suggests that long-term NOS inhibition induces expression of plasminogen activator inhibitor-1 (PAI-1) in vascular tissues and that PAI-1 may contribute to the development of fibrosis after chemical or ionizing injury. On the basis of these observations, we hypothesized that PAI-1 may influence the vascular response to long-term NOS inhibition by N(omega)-nitro-L-arginine methyl ester (L-NAME)., Methods and Results: We compared the temporal changes in systolic blood pressure and coronary perivascular fibrosis in PAI-1-deficient (PAI-1(-/-)) and wild-type (WT) male mice (N=6 per group). At baseline, there were no significant differences in blood pressure between groups. After initiation of L-NAME, systolic blood pressure increased in both groups at 2 weeks. Over an 8-week study period, systolic blood pressure increased to 141+/-3 mm Hg in WT animals versus 112+/-4 mm Hg in PAI-1(-/-) mice (P<0.0001). The extent of coronary perivascular fibrosis increased significantly in L-NAME-treated WT mice (P<0.01 versus PAI-1(-/-) mice). Cardiac type I collagen mRNA expression was greater in control (P<0.01) and L-NAME-treated PAI-1(-/-) (P<0.05) groups than in control WT mice, indicating that PAI-1 deficiency prevents the increase of collagen deposition by promoting matrix degradation., Conclusions: These findings suggest that PAI-1 deficiency alone is sufficient to protect against the structural vascular changes that accompany hypertension in the setting of long-term NOS inhibition. Direct inhibition of vascular PAI-1 activity may provide a new therapeutic strategy for the prevention of arteriosclerotic cardiovascular disease.

Background: E-selectin, also known as endothelial cell leukocyte adhesion molecule-1, is a member of the selectin family of adhesion molecules and is expressed on vascular endothelial cells in inflammatory reactions. The induction of surface E-selectin expression by endothelial cells is considered a marker of activation., Methods and Results: We examined the plasma soluble E-selectin (sE-selectin) level in 41 patients within 6 hours after the onset of acute myocardial infarction (AMI) and in 37 patients with stable exertional angina and 27 control patients. Blood samples were obtained on admission, after reperfusion therapy, and at 4 hours, 8 hours, 12 hours, 24 hours, 48 hours, 3 days, 5 days, 1 week, and 2 weeks after admission in the AMI group. In this group, 21 patients had a history of prodromal unstable angina before infarction and 20 had sudden onset of infarction. The plasma sE-selectin level (ng/mL) on admission was higher in the AMI group than in the stable exertional angina group and control group (38.5 +/- 3.1 vs 28.5 +/- 1.5, P <.01, 26.0 +/- 1.8, P <.01, respectively). In addition, plasma sE-selectin levels were higher in the patients with AMI with prodromal unstable angina than in those with a sudden onset of infarction on admission (44.7 +/- 5.4 vs 32.0 +/- 2.1, P <.05). The plasma sE-selectin level decreased slowly during the chronic phase both in patients with AMI with prodromal unstable angina (from 44.7 +/- 5.4 to 33.8 +/- 3.4, P <.01) and those with a sudden onset of infarction (from 32.0 +/- 2.1 to 24.9 +/- 2.4, P <.01)., Conclusions: These results suggest that an increase of sE-selectin may reflect enhanced endothelial cell activation in patients with AMI. The higher sE-selectin level in patients with AMI with prodromal unstable angina may have been associated with repeated episodes of myocardial ischemia and reperfusion.

The cell surface expression of intercellular adhesion molecule-1 (ICAM-1) is upregulated following activation during inflammatory responses, mediating both cell migration and activation. The involvement of inflammation in unstable angina is suggested by the presence of activated circulating leukocytes. To examine whether plasma soluble ICAM-1 (sICAM-1) levels increase in the coronary circulation of patients with coronary organic stenosis and coronary spasm, plasma sICAM-1 levels were measured in the coronary sinus (CS) and the aortic root (Ao) simultaneously in 10 patients with 90% or more coronary narrowing and coronary spasm (coronary spastic angina (CSA) with organic stenosis), in 11 patients with coronary spasm and no significant coronary narrowing (CSA without organic stenosis), in 16 patients with stable exertional angina, and in 13 control subjects. The plasma sICAM-1 levels (ng/ml) in the CS increased in CSA with organic stenosis (230+/-26) as compared with CSA without organic stenosis (158+/-14), stable exertional angina (130+/-9) and control subjects (121+/-10) (p<0.01). The levels in the Ao also increased in CSA with organic stenosis (208+/-24) as compared with CSA without organic stenosis (149+/-13), stable exertional angina (130+/-11) and control subjects (121+/-10) (p<0.01). Furthermore, the plasma sICAM-1 levels were higher in the CS than in the Ao only in CSA with organic stenosis. These results suggest that activation of leukocytes occurs through the induction of ICAM-1 in the coronary circulation in the patients with CSA with organic stenosis.

Plasminogen activator inhibitor activity was higher in 18 patients with multivessel spasm than in 20 patients with 1-vessel spasm and in 22 control patients. Tissue plasminogen activator antigen was also higher in patients with multivessel spasm than in those with 1-vessel spasm and control patients. The increased plasminogen activator inhibitor activity in patients with multivessel spasm indicates that the fibrinolytic system is more impaired in such patients than in those with 1-vessel coronary spasm; this may be related to the higher incidence of refractory angina during hospitalization and cardiac events during the follow-up period.

Objectives: We investigated the effects of enalapril therapy on plasma tissue factor (TF), tissue factor pathway inhibitor (TFPI) and monocyte chemoattractant protein-1 (MCP-1) levels in patients with acute myocardial infarction., Background: Macrophages express TF in human coronary atherosclerotic plaques. Both TF and TFPI are major regulators of coagulation and thrombosis. Monocyte chemoattractant protein-1 is a monocyte and macrophage chemotactic and activating factor., Methods: In a randomized, double-blind, placebo-controlled study beginning about two weeks after myocardial infarction, 16 patients received four weeks of placebo (placebo group) and another 16 patients received four weeks of enalapril 5 mg daily therapy (enalapril group). We performed blood sampling after administration of the doses., Results: There were no significant differences in the serum angiotensin-converting enzyme (ACE) activity, plasma TF, free TFPI or MCP-1 levels before administration between the enalapril and placebo groups. In the enalapril group, ACE activity (IU/liter) (14.0 before, 5.2 on day 3, 5.8 on day 7, 6.3 on day 28), TF levels (pg/ml) (223, 203, 182, 178) and MCP-1 levels (pg/ml) (919, 789, 790, 803) significantly decreased by day 28. However, the free TFPI levels (ng/ml) (28.2, 26.5, 26.8, 28.4) did not change. These four variables were unchanged during the study period in the placebo group., Conclusions: This study demonstrated that administration of enalapril reduces the increased procoagulant activity in patients with myocardial infarction associated with inhibition of the activation and accumulation of macrophages and monocytes.

Protein C is one of the most important antithrombotic components. After activation by the thrombin-thrombomodulin complex on endothelial cells, activated protein C (APC) inactivates factors Va and VIIIa, which leads to the inhibition of thrombin formation. We examined the association of plasma levels of APC with the responsiveness to coronary thrombolytic therapy of the infarct-related coronary artery in patients with acute myocardial infarction (AMI). Plasma levels of APC, thrombin-antithrombin III complex (TAT), and plasminogen activator inhibitor (PAI) activity were measured in 32 consecutive AMI patients who underwent coronary angiography followed by thrombolytic therapy, and compared to the measurements in 23 control subjects. On admission, APC levels (ng/mL) were significantly elevated in patients with AMI, as compared with controls (2.5+/-0.4 vs. 1.2+/-0.2, 1.3+/-0.2, respectively, p<0.01). At discharge, plasma levels in AMI patients decline to values not significantly different from those in controls. (1.2+/-0.2, 1.3+/-0.2, respectively). TAT levels (ng/mL) were different among the groups in a fashion similar to that of APC (14.1+/-3.1 on admission vs. 3.3+/-0.4 at discharge, 1.8+/-0.1 in the control subjects, respectively, p<0.01). PAI activity levels (IU/mL) were higher on admission than at discharge and higher than the control subjects (19.7+/-1.8 vs. 10.5+/-1.0, 5.4 +/- 0.7, respectively, p<0.01). Thirty-two patients with AMI were classified into two groups according to the results of thrombolysis: the success group (24 patients) and the failure group (eight patients). APC levels were higher in the failure group than in the success group (5.1+/-0.7 vs. 1.6+/-0.2, p<0.01). TAT levels were also higher in the failure group than in the success group (30.8+/-9.6 vs. 8.6+/-1.7, p<0.01). PAI activity levels (IU/mL) were lower in the failure group than in the success group (13.5+/-3.1 vs. 21.7+/-2.1, p<0.05). There were correlations between APC and TAT levels both on admission (r=0.75, p<0.0001) and at discharge (r=0.71, p<0.0001). Elevated APC was thought to correlate with increased thrombin generation in patients with AMI. This study demonstrated that there was a significant relation between plasma APC level and the responsiveness to thrombolytic therapy of the infarct artery. This study may also indicate that increased thrombin generation is a cause of the resistance to thrombolytic therapy.

Background: This study was designed to evaluate the plasma levels of tissue factor (TF) and tissue factor pathway inhibitor (TFPI) in patients with unstable angina and investigate whether there is a relationship between these levels and unfavorable outcome., Methods and Results: The plasma TF and free TFPI antigen levels were determined in plasma samples taken from 51 patients with unstable angina, 56 with stable exertional angina, and 55 with chest pain syndrome. The plasma TF and free TFPI antigen levels were higher in the unstable angina group than in the stable exertional angina and chest pain syndrome group. There was a good correlation between TF and TFPI. We established borderline as maximum level in the patients with chest pain syndrome. Seven patients (of the 22 in the high TF group) required revascularization to control their unstable angina during in-hospital stay. On the other hand, only 1 of the 29 patients in the low TF group required myocardial revascularization. Four patients of the 14 patients in the high free TFPI group required myocardial revascularization during in-hospital stay, and 4 of the 37 patients in the low free TFPI group required myocardial revascularization. We compared the TF and free TFPI levels between the cardiac event (+) group and cardiac event (-) group. TF levels were significantly higher in the cardiac event (+) group than in the cardiac event (-) group., Conclusions: We have demonstrated that not only the plasma TF levels but also the plasma-free TFPI levels are elevated in patients with unstable angina. Patients with unstable angina and heightened TF and free TFPI are at increased risk for unfavorable outcomes. The heightened TF level was a more important predictor in patients with unstable angina.

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 1999 John Wiley & Sons, Ltd.)

The hypercoagulability is associated with expression of tissue factor in patients with angina. Tissue factor pathway inhibitor regulates the extrinsic coagulation pathway mediated by tissue factor. Plasma samples were obtained from 14 patients with angina pectoris and 9 with chest pain syndrome before and 5, 30, 60, and 120 minutes after administration of heparin (50 IU/kg). The tissue factor and prothrombin fragment 1+2 levels before administration were elevated in patients with angina pectoris and were reduced to the levels of chest pain syndrome after the administration. The free tissue factor pathway inhibitor levels after the administration were higher in patients with angina pectoris than in patients with chest pain syndrome. Plasma tissue factor pathway inhibitor levels correlated positively with plasma tissue factor and prothrombin fragment 1+2 levels. We showed that plasma-free TFPI levels after administration of heparin, which may indicate endothelial cell associated TFPI levels, increased in patients with angina pectoris compared with patients with chest pain syndrome. Increased endothelial cell associated TFPI was associated with hypercoagulability in patients with angina pectoris. These may help to explain the reduction in thrombotic risk associated with the use of heparin.

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 present study examines whether an acute inflammatory response occurs during acute myocardial infarction (AMI) by measuring soluble P-selectin levels. We examined plasma soluble P-selectin levels in 16 consecutive patients with AMI, in 15 patients with angina, and in 13 control subjects with chest pain but normal coronary arteries and no coronary spasm. In patients with AMI, blood samples were obtained immediately after admission and at 1, 4, 24, and 48 hours, and 1 week after initiation of reperfusion therapy. The plasma soluble P-selectin levels were significantly higher in the AMI group on admission than in the other 2 groups (83 +/- 13 ng/ml, p < 0.01). The plasma soluble P-selectin levels at baseline were not significantly different between the angina and control groups (28 +/- 4 vs 24 +/- 5 ng/ml, p = NS). Plasma soluble P-selectin levels reached their peak significantly at 4 hours after initiation of the reperfusion therapy in patients with AMI. The peak level was significantly higher than the level on admission (115 +/- 17 vs 83 +/- 13 ng/ml, p < 0.05). The plasma soluble P-selectin levels were higher in the AMI group than in the angina and control groups over the time course (p < 0.01). Our data indicate that the plasma soluble P-selectin levels are increased in patients with AMI, and that the levels are increases after reperfusion therapy more than before reperfusion. We suggest that the increase in the plasma soluble P-selectin levels may be caused by the activation of endothelial cells and platelets after myocardial ischemia and reperfusion during AMI.

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.

Tissue factor is a membrane-bound glycoprotein that functions in the extrinsic pathway of blood coagulation by acting as a cofactor for factor VII, and the resulting complex leads to thrombin production in vivo. The purpose of the present study is to determine whether macrophages express tissue factor in human coronary atherosclerotic plaques. We examined directional coronary atherectomy specimens from 24 patients with unstable angina and 23 with stable exertional angina. In these specimens, macrophages were detected in 22 (92%) of 24 patients with unstable angina versus 12 (52%) of 23 with stable exertional angina (P = .003). The percentage of macrophage infiltration area was significantly larger in patients with unstable angina than in those with stable exertional angina (17 +/- 3% versus 6 +/- 2%, P = .008). The immunohistochemical double staining revealed the expression of tissue factor on macrophages in 18 (75%) of 24 patients with unstable angina versus 3 (13%) of 23 with stable exertional angina (P < .0001). Thrombus was identified in 20 (83%) of 24 patients with unstable angina versus 12 (52%) of 23 with stable exertional angina (P = .02). Fibrin deposition was mainly observed around macrophages expressing tissue factor in the patients with unstable angina. We have shown that tissue factor expression on macrophages was more frequent in coronary atherosclerotic plaques in patients with unstable angina. Tissue factor expressed on macrophages may play an important role in the thrombogenicity in coronary atherosclerotic plaques of these patients.

Intercellular adhesion molecule-1 (ICAM-1) is a major ligand for 2 members of the CD18 family of leukocyte integrin adhesion molecules and mediates adhesion between leukocytes and stimulated endothelial cells. We examined plasma soluble ICAM-1 (sICAM-1) levels in 30 patients with acute myocardial infarction (AMI) within 6 h of symptom onset, 21 patients with unstable angina (UA), 35 patients with stable exertional angina (SEA) and 21 control subjects. Plasma sICAM-1 levels (ng/ml) were significantly higher in both the acute and chronic phases of AMI and in the UA group than in the SEA and the control groups (195 +/- 14, 198 +/- 16 in the acute and chronic phases of AMI, 188 +/- 11 in the UA group vs 142 +/- 7 in the SEA group, 141 +/- 10 in the control group, p < 0.01). Plasma sICAM-1 levels were significantly higher in AMI patients when preceded by unstable angina than when not preceded by unstable angina at any point over the time course except 1 week after admission (p < 0.01 vs admission, 12 h, 2 days, 3 days, 5 days, 2 weeks, 3 weeks. p < 0.05 vs 24 h). These results suggest that the increase in sICAM-1 is associated with repeated episodes of myocardial ischemia and reperfusion not leading to myocardial necrosis. The increase in sICAM-1 may play an important role as an inflammatory component in the pathogenesis of the ischemic myocardium.

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.

Background: Treatment with an angiotensin-converting enzyme (ACE) inhibitor in patients with myocardial infarction has been shown to modify endogenous fibrinolysis., Hypothesis: We investigated the effects of the ACE inhibitor imidapril on endogenous fibrinolysis in association with the serum ACE activity., Methods: In a randomized, double-blind, placebo-controlled study beginning 4 weeks after uncomplicated myocardial infarction, 15 patients received imidapril (5 mg daily) (imidapril group) and another 15 received placebo therapy (placebo group) for 4 weeks. Blood sampling was performed before the start of administration and on Days 3, 7, and 28 after the start of administration. Serum ACE activity and plasma fibrinolytic variables [plasminogen activator inhibitor (PAI) activity, plasminogen activator inhibitor type 1 (PAI-1) antigen level, and tissue type plasminogen activator (TPA) antigen level] were measured., Results: There was no difference between the imidapril and placebo groups in serum ACE activity or plasma fibrinolytic variables before administration. Serum ACE activity decreased significantly on Days 3, 7, and 28 in the imidapril group. The decrease of PAI activity and PAI-1 antigen levels was significantly less on Days 7 and 28, but not on Day 3. The TPA antigen level in the imidapril group was unchanged. None of the parameters in the placebo group was changed., Conclusion: The ACE inhibitor imidapril modified fibrinolysis, but the effects occurred after the inhibition of serum ACE activity.

Recent clinical trials have demonstrated that the administration of angiotensin-converting enzyme (ACE) inhibitors to patients with myocardial infarction reduces the incidence of recurrent myocardial infarction. It has also been reported that an elevated level of plasminogen activator inhibitor (PAI) appears to constitute a marker of the risk of recurrent coronary thrombosis. To determine whether the ACE inhibitor captopril reduces plasma PAI inhibitor activity, we measured changes in plasma PAI activity (IU/ml), tissue plasminogen activator (t-PA) antigen (ng/ml), and serum ACE activity (IU/L) in 14 survivors of myocardial infarction receiving captopril therapy (37.5 mg daily) and compared them with the values in 15 placebo-treated patients chosen at random. Blood sampling was performed at 07.00 h. In the captopril-treated group, serum ACE activity decreased significantly, from 14.0 +/- 0.8 to 11.5 +/- 1.2 IU/L 24 h after captopril therapy (p < 0.01), and those of PAI activity and t-PA antigen also decreased significantly-from 11.9 +/- 2.8 to 5.5 +/- 2.2 IU/ml (p < 0.02) and from 9.9 +/- 1.0 to 7.5 +/- 0.9 ng/ml (p < 0.05), respectively 48 h after captopril therapy. However, the levels of ACE activity, PAI activity, and t-PA antigen remained unchanged during the study period in the placebo group. Thus, our data indicate that the administration of captopril to patients with acute myocardial infarction may result in a reduced frequency of recurrent coronary thrombosis by increasing fibrinolytic capacity.

Background: Local ACE in the heart may be important in the pathophysiological state after myocardial infarction (MI). It is unknown, however, whether ACE is expressed in myocytes of the human heart., Methods and Results: Using a newly generated polyclonal antibody to a synthetic peptide corresponding to part of the human endothelial ACE sequence, we examined the localization of ACE in left ventricles of patients (n = 10) with MI obtained at left ventricular aneurysmectomy or autopsy and in the hearts of control subjects at autopsy (n = 10). The avidinbiotinylated peroxidase complex method was used for the immunohistochemical staining for ACE. In the left ventricles, positively stained myocytes for ACE were found in 8 of the 10 patients with MI. ACE immunoreactivity was seen in the remaining viable myocytes located near the infarct scar of the aneurysmal left ventricle and in nonmyocytes such as fibroblasts, macrophages, vascular smooth muscle cells, and endothelial cells within the scarred tissue. On the other hand, no immunoreactivity for ACE was detected in the ventricular myocytes of all control hearts obtained at autopsy., Conclusions: We observe immunohistochemical staining for ACE in the left ventricular myocytes of the region adjacent to the infarct scar and in nonmyocytes. These results indicate that ACE is markedly increased on the edge of the infarct scar and suggest that local ACE may be important in the ventricular remodeling after MI.

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.

Background: Lipoprotein (a) [Lp(a)] is an independent risk factor for coronary artery disease and niceritrol (a prodrug of nicotinic acid) is known to reduce Lp(a) levels. Patients with coronary artery disease often have impairment of the fibrinolytic system., Methods: To elucidate the effect of niceritrol on fibrinolysis and Lp(a) levels, we examined plasminogen activator inhibitor (PAI) activity, tissue-type plasminogen activator (t-PA) antigen, and serum Lp(a) levels before and after administration of niceritrol to coronary artery disease patients with high baseline Lp(a) levels (> or = 20 mg/dl). Niceritrol was administered to 26 patients for 12 weeks at 750 mg/day. Fasting blood samples were obtained at 0800 h from each patient before treatment, after administration of niceritrol for 12 weeks and 4 weeks after the discontinuation of therapy., Results: There were significant reductions in PAI activity (9.9 +/- 1.8 compared with 5.4 +/- 1.6 IU/ml, P < 0.01), t-PA antigen levels (10.0 +/- 0.5 compared with 8.8 +/- 0.6 ng/ml, P < 0.05), and Lp(a) levels (49.3 +/- 5.9 compared with 42.5 +/- 5.4 mg/dl, P < 0.01) after 12 weeks of niceritrol administration. Four weeks after the discontinuation of niceritrol treatment, all these parameters returned to baseline., Conclusions: This study demonstrated that niceritrol administration decreases PAI activity and t-PA antigen levels together with Lp(a) levels in patients with coronary artery disease. These observations suggest that niceritrol administration may tend to normalize fibrinolysis in such patients.

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.

5-Fluorouracil (5-FU) is widely used in the treatment of various solid tumors. However, 5-FU cardiotoxicity is being reported with increasing frequency. The main symptom of cardiotoxicity is chest pain at rest with ischemic electrocardiographic changes. Up until now, the underlying mechanism has been suspected to be coronary artery spasm. However, this chest pain associated with 5-FU has several characteristics that are incompatible with coronary artery spasm; eg, inefficacy of calcium-channel blocker and a slow increase in cardiac enzyme levels. We experienced a case of 5-FU-induced cardiotoxicity which showed clinical findings consistent with acute myocardial infarction. Based on the clinical findings, coronary angiography, and left ventricular angiography in a prolonged attack, we concluded that the cardiotoxicity in this case was not due to ischemia caused by coronary artery spasm.