Ichiro Kajiwara

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.

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 Plasma Levels of Thioredoxin in Patients with Coronary Spastic Angina

To determine whether plasma levels of thioredoxin are associated with coronary spasm, we measured the plasma levels of thioredoxin in 170 patients who had <25% organic stenosis in coronary arteriography. According to the results of cardiac catheterization, we divided the patients into two groups: a coronary spastic angina group (n=84) and a chest pain syndrome group (n=86). The plasma levels of thioredoxin were significantly higher in the coronary spastic angina group than in the chest pain syndrome group (40.7 +/- 4.1 versus 18.2 +/- 1.1 ng/ml, p<0.0001). Furthermore, the increased plasma levels of thioredoxin were associated with high disease activity indicated by the frequency of angina attacks (p=0.0004). In multiple logistic regression analysis, the higher levels of thioredoxin [relative risk 14.8, 95% confidence interval (5.13-42.9), p<0.0001] and current smoking [relative risk 3.39, 95% confidence interval (1.31-8.75), p=0.012] were significant and independent variables associated with coronary spasm. We demonstrated that the plasma levels of thioredoxin were increased in the coronary spastic angina group, and increased levels of thioredoxin were associated with high disease activity. The plasma levels of thioredoxin and current smoking were risk factors for coronary spastic angina, and they were independent from other traditional risk factors.

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.

Prognostic value of plasma high-sensitivity C-reactive protein levels in Japanese patients with stable coronary artery disease: The Japan NCVC-Collaborative Inflammation Cohort (JNIC) Study

High-sensitivity C-reactive protein (hsCRP) levels can predict cardiovascular events among apparently healthy individuals and patients with coronary artery disease (CAD). However, hsCRP levels vary among ethnic populations. We previously reported hsCRP levels in Japanese to be much lower than in Western populations. We investigated the prognostic value of hsCRP levels in Japanese patients with stable CAD. The hsCRP levels were measured in 373 Japanese patients who underwent elective coronary angiography and thereafter decided to receive only medical treatment. Patients were followed up for 2.9+/-1.5 years for major cardiovascular events (death, myocardial infarction, unstable angina, stroke, aortic disease, peripheral arterial disease, or heart failure). The median hsCRP level was 0.70 mg/l. During the follow-up, cardiovascular events occurred in 53 (14%) of the 373 patients. Compared with 320 patients without events, 53 with events had higher hsCRP levels (median 1.06 vs. 0.67 mg/l, P<0.05). To clarify the association between hsCRP levels and cardiovascular events, the 373 study patients were divided into tertiles according to hsCRP levels: lower (<0.4 mg/l), middle (0.4-1.2mg/l), and higher (>1.2mg/l). The Kaplan-Meier analysis demonstrated a significant difference in the event-free survival rate between higher vs. middle or lower tertiles (P<0.05). In multivariate Cox regression analysis, the hsCRP level of >1.0mg/l was an independent predictor for cardiovascular events (hazard ratio, 2.0; 95%CI, 1.1-3.4; P<0.05). Thus, in Japanese patients with stable CAD who received only medical treatment, higher hsCRP levels, even >1.0mg/l, were found to be associated with a significantly increased risk for further cardiovascular events.

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.

Increased Autoantibodies Against Oxidized Low-Density Lipoprotein in Coronary Circulation in Patients with Coronary Spastic Angina

Oxidized low-density lipoproteins are important in the progression of atherosclerosis. Autoantibodies against malondialdehyde-modified low-density lipoproteins have been reported to be predictive of the progression of atherosclerosis. This study sought to examine whether plasma levels of autoantibodies against oxidized low-density lipoprotein increase in the coronary circulation in patients with coronary spastic angina. The authors examined plasma antioxidized low-density lipoprotein antibody levels (activity unit values (AcU)/mL) simulta neously in the coronary sinus and the aortic root in 20 patients with coronary spastic angina, 23 patients with stable exertional angina, and 15 control subjects by measuring plasma levels of immunoglobulin G (IgG) autoantibodies against malondialdehyde-modified low-density lipoproteins by enzyme-linked immunosorbent assay. The plasma antioxidized low-density lipoprotein antibody levels (AcU/mL) in the coronary sinus increased in coronary spastic angina (38 ± 16) compared with stable exertional angina (23 ±7) and control subjects (20 ±6) (p≤0.0001). The levels (AcU/mL) in the aortic root also increased in coronary spastic angina (33 ± 12) compared with stable exertional angina (23 ±7) and control subjects (20 ±6) (p<0.005). Furthermore, the coronary sinus-arterial differences of the levels (AcU/mL) were also higher in coronary spastic angina (5 ±9) than in stable exertional angina (0 ±6) and healthy subjects (-1 ±5) (p < 0.05). The generation of malondialdehyde-modified low-density lipoproteins is reported to be associated with atherothrombosis. These findings suggest that elevated levels of autoantibodies against malondialdehyde-modified oxidized low-density lipoproteins in coronary circulation are associated with the development of atherothrombosis from the progression of atherosclerosis rather than with the extent of coronary atheroscle rosis in patients with coronary spastic angina.

Enhanced platelet aggregation in the coronary circulation after coronary spasm.

A recently developed platelet aggregometer using a laser light scattering method is capable of monitoring the increase in size of small-sized platelet aggregates (diameter 9-25 microm), which cannot be detected with the conventional methods. Whether coronary spasm can cause platelet aggregation in the coronary circulation is unknown. We investigated platelet aggregation, especially small-sized platelet aggregates, simultaneously in the coronary sinus and the aortic root in 18 patients with coronary spastic angina before and after a 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 right atrial pacing. Platelet aggregation in 12 patients with chest pain syndrome was also examined before and after coronary spasms provoked by acetylcholine. The number of small-sized platelet aggregates increased significantly in the coronary sinus [2.0+/-0.6 x 104 to 4.1+/-1.0 x 104 (V), P<.01] and in the aortic root [1.7+/-0.6 x 104 to 3.2+/-0.6 x 104 (V), P<.05], and the coronary sinus-arterial difference in the number of small-sized platelet aggregates [2.3+/-1.9 x 103 to 1.1+/-0.4 x 104 (V), P<.01] increased significantly after attacks in the coronary spastic angina group, but remained the same in the stable exertional angina group after attacks and in the chest pain syndrome group after the administration of acetylcholine. Therefore, we can conclude that acute myocardial ischemia induced by coronary spasm causes platelet aggregation in the coronary circulation.

Differential Effects of Strong and Regular Statins on the Clinical Outcome of Patients With Chronic Kidney Disease Following Coronary Stent Implantation – The Kumamoto Intervention Conference Study (KICS) Registry –

BACKGROUND The aim of this study was to examine the effects of different statins on the clinical outcomes of Japanese patients with coronary stent implants. METHODS AND RESULTS This study included 5,801 consecutive patients (males, 4,160; age, 69.7±11.1 years, mean±SD) who underwent stent implantation between April 2008 and March 2011. They were treated with a strong statin (n=3,042, 52%, atorvastatin, pitavastatin, or rosuvastatin), a regular statin (n=1,082, 19%, pravastatin, simvastatin, or fluvastatin) or no statin (n=1,677, 29%). The patients with chronic kidney disease (CKD) were divided into mild-to-moderate CKD (30≤eGFR<60, n=1,956) and severe CKD (eGFR <30, n=559). Primary endpoints included cardiovascular death and nonfatal myocardial infarction, including stent thrombosis and ischemic stroke. The clinical outcome for the primary endpoint in mild-to-moderate CKD patients treated with a strong statin (hazard ratio 0.50, 95% confidence interval 0.31-0.81; P=0.005) was significantly lower than in those on no statins, but that in the patients treated with a regular statin was not (P=0.160). The clinical outcome for the primary endpoint in severe CKD patients treated with a strong or regular statin was no different than not being on statin therapy (P=0.446, P=0.194, respectively). CONCLUSIONS In patients with mild-to-moderate CKD, only strong statins were associated with lower risk compared with no statin, but regular statins were not. It is possible that taking a strong statin from the early stage of CKD is useful for suppression of cardiovascular events.