Shinzo Miyamoto

Angiotensin-converting enzyme inhibition reduces monocyte chemoattractant protein-1 and tissue factor levels in patients with myocardial infarction ☆

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.

Prognostic value of plasma levels of secretory type II phospholipase A2 in patients with unstable angina pectoris

Plasma levels of secretory nonpancreatic type II phospholipase A2 (sPLA2) are increased in various chronic inflammatory diseases; this increase is correlated with disease severity. sPLA2 plays a possible role in atherogenesis and is highly expressed in atheromatous plaques. Thus, this study prospectively examined whether plasma levels of sPLA2 may have a prognostic value in patients with unstable angina, which is known to have inflammatory features. Plasma levels of sPLA2 were measured in 52 patients with unstable angina, in 107 patients with stable angina, and in 96 control subjects by radioimmunoassay. sPLA2 levels were significantly higher in patients with unstable angina than in those with stable angina and in control subjects. sPLA2 remained elevated after stabilization of disease. The levels were not increased in the blood in the coronary sinus. Kaplan-Meier analysis demonstrated that patients with unstable angina and with the higher sPLA2 levels had a significantly higher probability of developing clinical coronary events during a follow-up period of 2 years compared with those with the lower levels. In multivariate Cox hazard analysis, the higher levels of sPLA2 were a significant predictor of developing coronary events in patients with unstable angina, independent of other risk factors, including C-reactive protein levels, an established inflammatory predictor. In conclusion, the increase in circulating levels of sPLA2 predicts clinical coronary events independently of other risk factors in patients with unstable angina. sPLA2 levels were persistently elevated but the elevated levels may not be derived from coronary circulation.

Attenuation of Nitrate Tolerance and Oxidative Stress by an Angiotensin II Receptor Blocker in Patients With Coronary Spastic Angina

Background—Nitrates are widely used to treat coronary artery disease, but their therapeutic value is compromised by the rapid development of tolerance. Recently, the renin-angiotensin system has been suggested to play an important role in the development of nitrate tolerance. Methods and Results—Sixty-four patients with coronary spastic angina were investigated to clarify the effect of angiotensin II type 1 receptor blocker (ARB) therapy on nitrate tolerance. Transdermal nitroglycerin (10 mg/d) and an ARB (candesartan, 8 mg/d) were administered to 21 patients (GTN+ARB group) for 3 days, whereas transdermal nitroglycerin and placebo were administered to 19 patients (GTN group). Another 18 patients were treated with placebo skin patches and placebo tablets for 3 days (control group). The brachial artery response to incremental doses of intravenous nitroglycerin (0.01, 0.1, and 1.0 &mgr;g/kg) was measured by ultrasound before and after transdermal nitroglycerin therapy. Before treatment, the arterial diameter was increased by nitroglycerin injection in each group. After treatment, the increase of arterial diameter was significantly suppressed in the GTN group but not in the control or GTN+ARB groups. The plasma level of thioredoxin (a marker of oxidative stress) was increased in the GTN group after treatment (P <0.01) but not in the control or GTN+ARB groups. Conclusions—An ARB suppressed the development of nitrate tolerance during transdermal nitroglycerin therapy. These results suggest that increased oxidative stress induced by activation of angiotensin II may play an important role in the development of nitrate tolerance.

Preference Toward a T-Helper Type 1 Response in Patients With Coronary Spastic Angina

Background—Coronary artery spasm plays an important role in the pathogenesis of ischemic heart diseases such as unstable angina (UA) and acute myocardial infarction. Nitric oxide (NO) plays an important role in coronary artery spasm. We previously reported a deficiency in NO activity in the spasm arteries of patients with coronary spastic angina (CSA). Others have reported that NO influences the immune response. Therefore, we investigated the balance between T-helper type 1 (Th1) and 2 (Th2) responses in patients with CSA by evaluating the frequencies of interferon (IFN)-&ggr;–producing T cells and interleukin (IL)-4–producing T cells in the peripheral blood of such patients. Methods and Results—Peripheral blood mononuclear cells were collected from 50 consecutive patients with CSA, 23 consecutive patients with UA, 36 patients with stable angina (SA), and 21 patients with chest pain syndrome (CPS). Cytokine-producing CD4+ T cells were quantified by 3-color flow cytometry after stimulation with phorbol myristate acetate and ionomycin. UA and CSA were associated with a significant increase in the frequency of CD4+ T cells that produced IFN-&ggr;, whereas these conditions caused no significant difference in the frequency of CD4+ T cells that produced IL-4. Culturing with an NO donor compound for 24 hours before stimulation inhibited the increase in the frequency of CD4+ T cells that produced IFN-&ggr;. Conclusions—We demonstrated that there was a preference toward the Th1-type response in patients with CSA and that T cells showed a reduced Th1-type response after being treated with NO.

Comparison of remnant-like lipoprotein particles in postmenopausal women with and without coronary artery disease and in men with coronary artery disease

It is known that hypertriglyceridemia is a risk factor of coronary artery disease (CAD) in postmenopausal women. This study prospectively examined whether remnant lipoprotein, an atherogenic triglyceride-rich lipoprotein, may have a significant risk and prognostic values in postmenopausal women with angiographically verified CAD. Remnant-like lipoprotein particles cholesterol (RLP cholesterol) levels in fasting serum were measured in 134 consecutive postmenopausal women with (n = 56) or without (n = 78) CAD by an immunoseparation method. The women with CAD were followed for < or =24 months until occurrence of the following clinical coronary events: readmission or coronary revascularization due to recurrent or refractory angina pectoris, nonfatal myocardial infarction, and cardiac death. Multivariate logistic regression analysis showed that high RLP cholesterol levels (>5.7 mg/dl cholesterol; 90th percentile of the distribution of RLP cholesterol levels in controls) were a significant risk factor for the presence of CAD independent of low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, triglycerides, and other traditional risk factors. Kaplan-Meier analysis demonstrated that women with CAD and higher RLP cholesterol levels had a significantly higher probability of developing coronary events (p <0.001). In multivariate Cox hazard analysis, high RLP cholesterol levels as well as diabetes and hypercholesterolemia were a significant predictor of future coronary events independent of other risk factors in women with CAD (odds ratio 9.7, 95% confidence intervals 1.3 to 20.3, p = 0.02). In conclusion, increased levels of RLP cholesterol are a significant and independent risk factor of CAD and predict future coronary events in postmenopausal women with CAD.

Plasma thioredoxin levels and platelet aggregability in patients with acute myocardial infarction

BACKGROUND Oxidative stress is thought to play an important role in atherosclerotic vascular disease. Recently, it has become possible to quantitatively measure thioredoxin, a marker of oxidative stress in human plasma. A platelet aggregometer that uses laser-light scattering enables minimal changes in platelet aggregability to be monitored; however, the relationship between oxidative stress and platelet aggregability in vivo is not well understood. METHODS We investigated plasma thioredoxin levels and platelet aggregability, in particular small platelet aggregates, in 45 patients with acute myocardial infarction (AMI); we compared the results with 33 patients with stable exertional angina (SEA) and 30 patients with chest pain syndrome (CPS). RESULTS The plasma thioredoxin levels and the degree of small platelet aggregates were higher in the AMI group than in the SEA and the CPS groups: in the AMI group, at 4 weeks after admission, both of those parameters were significantly decreased (P <.01), but they were still higher (P <.05) than in the SEA or the CPS group. There was a significant positive correlation between small platelet aggregates and plasma thioredoxin levels (rho = 0.354, P =.0002). We divided the AMI patients into 2 groups according to the 75 percentile of plasma thioredoxin levels on admission. At the chronic phase, the left ventricular ejection fraction was significantly higher in the lower thioredoxin group than in the higher thioredoxin group. CONCLUSIONS We showed that plasma thioredoxin levels and platelet aggregability increased concomitantly in patients with AMI. In these patients, increased plasma thioredoxin was associated with platelet hyperaggregability and lower left ventricular ejection fraction.

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.

Adiponectin is inversely related to plasminogen activator inhibitor type 1 in patients with stable exertional angina

Adipose tissue is a secretory organ producing a variety of bioactive substances, such as adiponectin. Adiponectin has antiatherogenic properties while plasminogen activator inhibitor type 1 (PAI-1) is closely involved in the development of atherosclerosis. The relationship between adiponectin and PAI-1 in patients with coronary artery disease (CAD) has not been clarified. This study examined plasma levels of adiponectin and PAI-1 in 64 patients with stable exertional angina (SEA) and 65 patients with the chest pain syndrome (CPS). Plasma log-adiponectin levels were significantly lower in patients with SEA (0.62+/-0.08 micro g/dL) compared to those with CPS (0.86+/-0.05 micro g/dL) (p<0.0001). The plasma levels of log-PAI-1 were significantly higher in patients with SEA (1.23+/-0.18 ng/mL) compared to those with CPS (1.15+/-0.22 ng/mL) (p<0.05). Plasma log-adiponectin levels correlated negatively with diabetes mellitus (DM), body mass index (BMI), log-PAI-1 (r=-0.284, p<0.001), triglyceride (TG), and remnant-like particles cholesterol (RLP-C), and positively with high-density lipoprotein cholesterol (HDL-C) levels. Plasma levels of log-PAI-1 correlated positively with DM, BMI,TG and RLP-C levels, and negatively with HDL-C levels. Multiple logistic regression analysis identified sex, angina pectoris, and PAI-1 as independent determinants of hyperadiponectinemia (p<0.05). Adiponectin is inversely related to PAI-1. DM, BMI,TG, HDL-C, and RLP-C are common mediators between adiponectin and PAI-1, and treatment for common mediators may prevent the development of CAD by reducing PAI-1 and increasing adiponectin levels.

Comparison of urinary biopyrrin levels in acute myocardial infarction (after reperfusion therapy) versus stable angina pectoris and their usefulness in predicting subsequent cardiac events

We examined the relation between oxidative stress and cardiac events in patients with acute myocardial infarction (AMI). There is now increasing evidence that reactive oxygen species cause reperfusion injury to the previously ischemic myocardium after reperfusion. We measured urinary biopyrrin/creatinine levels, an oxidative stress marker, in 41 patients with AMI, 34 patients with stable angina pectoris (SAP), and 29 control subjects. In the patients with AMI, urine samples were taken before, at 4 and 24 hours, and at 1 and 2 weeks after reperfusion therapy. Of these 41 patients with AMI, 38 received reperfusion therapy, and the urinary biopyrrin/creatinine levels (micromol/g.creatinine) before reperfusion were significantly higher than those of the other 2 groups (AMI 4.24 +/- 0.49, SAP 2.45 +/- 0.15, control subjects 2.31 +/- 0.16; p = 0.0003 vs AMI). The onset of reperfusion significantly increased the levels of urinary biopyrrins/creatinine, and this time course was mapped out, peaking at 4 hours (8.21 +/- 0.96 vs 4.24 +/- 0.49 before, p = 0.0001), and decreasing to control levels between 24 hours and 7 days. The peak levels of urinary biopyrrins/creatinine were higher in the positive cardiac event group than in the negative cardiac event group (11.89 +/- 1.77 vs 7.57 +/- 1.00 micromol/g.creatinine, p = 0.029). These findings add further evidence that oxidative stress contributes to the complications of reperfusion injury, and suggest that urinary assessment of biopyrrins may be useful in predicting subsequent cardiac events after reperfusion in AMI.

Formation of platelet aggregates after attacks of coronary spastic angina pectoris

Using a novel laser-light scattering method, we examined platelet aggregability, especially small-sized platelet aggregates, at baseline and after spontaneous coronary spastic attacks in 14 patients with coronary spastic angina, and before and after anginal attacks during an exercise test in 11 patients with stable exertional angina. The number of small-sized platelet aggregates after coronary spastic anginal attacks increased significantly, but not in patients with stable exertional angina. These results imply that an increase in the number of small-sized platelet aggregates from coronary spasm may be a trigger for coronary thrombosis via medium- and large-sized platelet aggregates.