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OBJECTIVES We sought to examine whether estradiol (E2) supplementation suppresses anginal attacks in women with variant angina. BACKGROUND Estrogen is known to improve endothelial function. Coronary spasm plays an important role in the pathogenesis of not only variant angina but also ischemic heart disease in general, and endothelial dysfunction seems to be involved in the pathogenesis of coronary spasm. METHODS Fifteen postmenopausal women with variant angina (mean age 54.2 years) were given a hyperventilation (HV) test, a provocation test for coronary spasm, in the early morning of day 1 (baseline), day 3 (after 2-day transdermal E2supplementation, 4 mg) and day 5 (after 2-day placebo administration). We measured the flow-mediated (endothelium-dependent) dilation (FMD) of the brachial artery with the ultrasound technique before each HV test. RESULTS The anginal attacks with ST segment elevation were induced by HV in all patients on days 1 and 5. However, no attacks were induced on day 3. Supplementation with E2augmented FMD (3.5 ± 0.6∗, 8.9 ± 0.7 and 4.0 ± 0.5∗ on days 1, 3 and 5, respectively; ∗p < 0.01 vs. day 3). The serum E2levels on days 1, 3 and 5 were 22.7 ± 2.8∗, 96.2 ± 9.2 and 30.7 ± 7.1∗ pg/ml, respectively (∗p < 0.01 vs. day 3). CONCLUSIONS The present results demonstrated for the first time, to our knowledge, that E2supplementation suppresses the HV-induced attacks in women with variant angina, in part because of the improvement of endothelial function.

OBJECTIVESThe purpose of this study was to evaluate the extent of atherosclerotic changes in angiographically normal coronary arteries using intravascular ultrasound (IVUS) technique in patients with coronary spastic angina.BACKGROUNDNitric oxide activity was shown to be decreased in coronary arteries of patients with coronary spastic angina (CSA). Decrease in nitric oxide causes arterial intimal hyperplasia or thickening. However, it remains unclear whether intimal thickening is diffusely present in coronary arteries of patients with CSA.METHODSThe IVUS study was performed in 26 patients with CSA and with normal coronary angiograms and in 31 control subjects in whom age and gender was matched with those in patients with CSA.RESULTSCompared with control subjects, patients with CSA had significantly larger percent intima + media area (%I + M area), intima + media area and maximal intima + media thickness in all of proximal, middle and distal segments (p < 0.01, respectively). Lumen area was comparable between these groups. The presence of spasm was the most powerful independent predictor of increase in percent intima + media area, in multiple-regression analysis with the traditional risk factors as covariates.CONCLUSIONSIntimal thickening existed entirely in a coronary artery in patients with CSA and with normal angiograms, independently of other traditional risk factors. The diffuse intimal thickening in the spasm coronary arteries is intimately related with coronary spasm.

OBJECTIVES This study was designed to examine the effect of antioxidant supplementation on the endothelial function and insulin sensitivity in patients with coronary spastic angina (CSA). BACKGROUND Insulin resistance may play a key role in coronary heart disease, and there is a possible link between acetylcholine-induced coronary vasoconstriction and hyperinsulinemia in patients with CSA. Endothelial dysfunction is present in the systemic arteries in CSA patients, and reactive oxygen species may cause inactivation of nitric oxide in these patients. METHODS We measured flow-mediated dilation of the brachial artery using ultrasound technique in 22 patients with CSA and 20 control subjects. We also evaluated glucose tolerance using a 75-g oral glucose tolerance test and insulin sensitivity using steady-state plasma glucose (SSPG) methods in the same patients. RESULTS The incidence of impaired glucose tolerance was higher in the CSA group than in the control group. Vitamin C infusion augmented flow-mediated dilation and decreased SSPG levels in the CSA group (from 3.27 ± 0.77% to 7.00 ± 0.59% [p CONCLUSIONS Vitamin C improves both endothelial function and insulin sensitivity in patients with CSA. Thus, reactive oxygen species and/or decreased nitric oxide bioactivity may play an important role in the genesis of both endothelial dysfunction and insulin resistance in patients with CSA.

OBJECTIVES We examined whether endothelial dysfunction occurs when acute hyperglycemia is induced by oral glucose loading. BACKGROUND Endothelial dysfunction has been shown to occur in patients with diabetes mellitus (DM), and chronic hyperglycemia is implicated as a cause of endothelial dysfunction. However, in many patients with Type 2 DM and in those with impaired glucose tolerance (IGT), fasting blood glucose may be within normal limits, and hyperglycemia occurred only post-prandially. METHODS With ultrasound technique, we measured flow-mediated endothelium-dependent vasodilation during oral glucose tolerance test in 58 subjects: (17 patients with normal glucose tolerance [NGT], 24 with IGT, and 17 with type 2 DM). In addition, we measured the levels of thiobarbituric acid reactive substances (TBARS) and nitrite/nitrate. RESULTS Flow-mediated vasodilation decreased after glucose loading (NGT: 7.53 ± 0.40, 4.24 ± 0.28 and 6.35 ± 0.40, in fasting, at 1- and 2-h, respectively, IGT: 6.50 ± 0.48, 1.40 ± 0.41∗∗ and 4.00 ± 0.47∗, respectively; DM: 4.77 ± 0.37, 1.35 ± 0.38∗∗ and 1.29 ± 0.29%∗∗, respectively; ∗p < 0.01 vs. fasting, ∗∗p < 0.005 vs. fasting). The TBARS concentration increased in parallel with plasma glucose level in each group (NGT: 1.43 ± 0.07, 2.03 ± 0.12 and 1.80 ± 0.12, respectively; IGT: 1.65 ± 0.11, 2.46 ± 0.12∗∗ and 1.94 ± 0.08∗, respectively; DM: 1.73 ± 0.07, 2.34 ± 0.08∗∗ and 2.47 ± 0.09∗∗ nmol/ml, respectively; ∗p < 0.05 vs. fasting, ∗∗p < 0.01 vs. fasting). Glucose loading did not change nitrite/nitrate concentration in any of the groups. CONCLUSIONS Hyperglycemia in response to oral glucose loading rapidly suppresses endothelium-dependent vasodilation, probably through increased production of oxygen-derived free radicals. These findings strongly suggest that prolonged and repeated post-prandial hyperglycemia may play an important role in the development and progression of atherosclerosis.

Objectives. This study sought to examine effect of vitamin C, an antioxidant, on the abnormal vasomotor reactivity in spasm coronary arteries.Background. Oxygen free radicals generated in the arterial walls have been shown to cause endothelial vasomotor dysfunction.Methods. Responses of the epicardial arterial diameters of the left coronary arteries to the intracoronary infusion of acetylcholine (ACh) (10 and 50 μg/min) were measured by quantitative coronary angiography before and during combined intracoronary infusion of vitamin C (10 mg/min) or saline as a placebo in 32 patients with coronary spastic angina and in 34 control subjects.Results. Vitamin C infusion suppressed the constrictor response of the epicardial diameter to ACh in spasm coronary arteries but had no significant effect in the control coronary arteries (percent change in distal diameter in response to 10 μg/min of ACh [constriction (−), dilation (+), mean ± SEM] before vitamin C: −8.2 ± 2.9% in spasm arteries, +8.4 ± 2.9%∗ in control arteries; during vitamin C: +0.2 ± 3.8%∗ in spasm arteries, +7.2 ± 1.3%∗ in control arteries [∗p < 0.01 vs. spasm arteries before vitamin C]). The coronary sinus–arterial difference in plasma thiobarbituric acid reactive substances during ACh infusion, an indicator of lipid peroxidation in coronary circulation, was higher in patients with coronary spastic angina than in control subjects (p < 0.01) but was suppressed in patients with coronary spastic angina to comparable levels in control subjects by combined infusion of vitamin C. Saline infusion had no effect.Conclusions. The results indicate that vitamin C attenuates vasomotor dysfunction in epicardial coronary arteries in patients with coronary spastic angina. Oxygen free radicals may at least in part play a role in the abnormal coronary vasomotor reactivity in response to ACh in spasm coronary arteries.

Objectives. We examined whether there is a gender difference in the improvement of endothelium-dependent vasodilation after estrogen supplementation.Background. Estrogen therapy reduces the risk of cardiovascular events in postmenopausal women, and the augmented release of endothelium-derived nitric oxide (NO) by estrogens has been suggested to be one of the mechanisms for the cardioprotective effects of estrogen.Methods. With ultrasound technique, we measured the diameter and blood flow of the brachial artery at rest, during reactive hyperemia after transient occlusion and after nitroglycerin administration before and after estradiol supplementation in 15 postmenopausal women (mean 63 years) and in 15 men matched for age and risk factors for atherosclerosis.Results. Estradiol supplementation augmented the flow-mediated vasodilation and serum level of nitrite/nitrate (metabolites of NO) in women (respectively, from a mean ± SEM of 8.0 ± 0.6% to 12.9 ± 0.6% [p < 0.01 by analysis of variance (ANOVA)] and from 64.9 ± 8.7 to 93.7 ± 9.4 μmol/liter [p < 0.05 by ANOVA]) but not in men (respectively, from 8.1 ± 0.6% to 8.3 ± 0.7% and from 57.8 ± 6.7 to 60.8 ± 5.4 μmol/liter). The increases in blood flow during reactive hyperemia and in diameter after nitroglycerin administration were not affected by estradiol supplementation in either men or women.Conclusions. Estradiol supplementation improves endothelium-dependent vasodilation in women, probably because of augmented NO production/release, but not in men. Thus, there may be gender differences in the effects of estrogen therapy on endothelial functions and NO production/release.

Objectives. This study sought to examine whether flow-dependent dilation is impaired at the site of coronary artery spasm in patients with coronary spastic angina. Background. Physiologic stimuli such as exercise and exposure to cold have been shown to cause an increase in coronary blood flow, leading to flow-dependent dilation of coronary arteries in normal subjects, but cause coronary constriction in patients with coronary spastic angina. Methods. A maximal increase in blood flow was induced selectively in the left anterior descending coronary artery (LAD) by infusion of adenosine through a Doppler flow catheter tip in the midportion of the LAD in 10 patients with coronary spastic angina, all with angiographically demonstrated spasm of the LAD, and in 11 control patients. Coronary artery diameter at the proximal site of the LAD (exposed to increased flow but not to adenosine) was measured by quantitative angiography. Results. Flow-dependent dilation of the proximal LAD was found to be less in spasm arteries than in control arteries. Infusion of NG-monomethyl-l-arginine (l-NMMA) in the proximal LAD suppressed flow-dependent dilation in control arteries but had no significant effect on spasm arteries. The dilator response to nitroglycerin was not impaired in spasm coronary arteries. Conclusions. Our results indicate that flow-dependent coronary dilation is impaired in spasm arteries, partly due to a deficiency in endothelial nitric oxide bioactivity, which in turn may contribute to the increase in coronary tone during physiologic stimuli in patients with coronary spastic angina.

This study sought to examine nitric oxide-mediated regulation of epicardial coronary arterial tone in cigarette smokers.Cigarette smoking is a major risk factor for coronary artery disease and is highly prevalent in patients with coronary spastic angina. Long-term exposure to cigarette smoking has been recently reported to suppress endothelium-dependent arterial relaxation in vivo humans.Responses of epicardial coronary artery diameter to single or combined infusion of acetylcholine and NG-monomethyl-L-arginine (L-NMMA) into the left main coronary artery were examined in 11 current smokers and 17 nonsmokers using quantitative coronary angiography.Acetylcholine dilated one-third of the proximal segments and most of the distal segments of coronary arteries in nonsmokers, whereas it constricted most of the proximal and distal segments in smokers. L-NMMA decreased the basal diameter of coronary arteries in nonsmokers but had minimal effect on the basal diameter in smokers. L-NMMA abolished the dilator response to acetylcholine in the coronary arteries of nonsmokers but had minimal effect on the constrictor response to acetylcholine in the arteries of smokers. The dilator response to nitroglycerin was significantly increased in the coronary arteries of smokers compared with in those of nonsmokers. The constrictor response to L-NMMA at rest was significantly correlated with the dilator response to nitroglycerin and with the diameter changes to acetylcholine in both smokers and nonsmokers.Nitric oxide bioactivity at rest and at acetylcholine-stimulated conditions in smokers was decreased, leading to the supersensitivity of the artery to the dilator effect of nitroglycerin as well as the constrictor effect of acetylcholine in smokers. Cigarette smoking affects nitric oxide-mediated regulation of coronary artery tone.

Objectives We investigated the relationship between the urinary levels of biopyrrins and the severity of heart failure (HF). Background Oxidative stress is evident in heart disease and contributes to the development of ventricular dysfunction in patients with HF. Biopyrrins, oxidative metabolites of bilirubin, have been discovered as potential markers of oxidative stress. Methods We measured the levels of urinary biopyrrins and plasma B-type natriuretic peptide (BNP) in 94 patients with HF (59 men; mean age 65 years) and 47 control subjects (30 men; mean age 65 years). Urine and blood samples were taken after admission in all subjects. Further urine samples were obtained from 40 patients after treatment of HF. Results The urinary biopyrrins/creatinine levels (μmol/g creatinine) were the highest in patients in New York Heart Association (NYHA) class III/IV (n = 26; 17.05 [range 7.85 to 42.91]). The urinary biopyrrins/creatinine levels in patients in NYHA class I (n = 35; 3.46 [range 2.60 to 5.42]) or II (n = 33; 5.39 [range 3.37 to 9.36]) were significantly higher than those in controls (2.38 [range 1.57 to 3.15]). There were significant differences in urinary biopyrrins/creatinine levels among each group. The treatment of HF significantly decreased both urinary biopyrrins/creatinine levels (from 7.43 [range 3.84 to 17.05] to 3.07 [range 2.21 to 5.71]) and NYHA class (from 2.5 ± 0.1 to 1.7 ± 0.1). Log biopyrrins/creatinine levels were positively correlated with log BNP levels (r = 0.650, p Conclusions These results indicate that urinary biopyrrins levels are increased in patients with HF and are elevated in proportion to its severity.

OBJECTIVESThis study sought to examine whether oral intake of alpha-tocopherol, an antioxidant, could improve endothelium-dependent vasorelaxation in patients with high remnant lipoproteins levels.BACKGROUNDRemnant lipoproteins are known to be atherogenic and impair endothelium-dependent arterial relaxation, but the underlying mechanisms remain unclear. Oxidative stress is a common feature of various risk factors for atherosclerosis.METHODSFlow-mediated vasodilation of the brachial artery during reactive hyperemia was examined by high resolution ultrasound technique before and at the end of 4 weeks treatment with oral administration of alpha-tocopherol acetate (300 IU/day) or placebo, which was randomly assigned, in 40 patients with high serum levels of remnants and in 30 patients with low remnants levels in the fasting state (>75th percentile and

Objectives. We examined the effects of oral administration of vitamin E, an antioxidant, on endothelium-dependent vasodilation in patients with coronary spastic angina.Background. We have recently reported that endothelium-dependent vasodilation is impaired in patients with coronary spastic angina (CSA). Furthermore, it is known that oxidative stress may play an important role in the impairment of endothelium-dependent vasodilation in cardiovascular diseases.Methods. With the ultrasound technique, flow-dependent vasodilation of the brachial arteries during reactive hyperemia was examined before and after treatment for a month with either oral administration of vitamin E (α-tocopherol acetate, 300 mg/day) or placebo, which is randomly assigned, in patients with CSA (n = 60).Results. Before treatment, patients with CSA had impaired flow-dependent vasodilation, lower plasma levels of α-tocopherol and higher plasma levels of thiobarbituric acid reactive substances (TBARS), as compared with age- and sex-matched control subjects (n = 60) (flow-dependent vasodilation: 3.1 ± 1.8 vs. 7.1 ± 2.5%, p < 0.001; α-tocopherol levels: 8.9 ± 1.8 vs. 10.8 ± 1.8 μg/ml, p < 0.001). In patients with CSA, treatment with vitamin E restored flow-dependent vasodilation (3.1 ± 1.7 vs. 8.3 ± 2.0%, p < 0.001), and this improvement was associated with the decreases in plasma TBARS levels and anginal attacks.Conclusions. The results indicate that vitamin E treatment improved endothelium-dependent vasodilation and decreased plasma TBARS levels in patients with CSA. Thus, increased oxidative stress may contribute to endothelial dysfunction and anginal attacks in patients with CSA.

ObjectivesThe purpose of this study was to examine whether echolucent carotid plaques predict future coronary events in patients with clinically stable coronary artery disease (CAD).BackgroundAlthough rupture of coronary plaques is considered a major cause of acute coronary syndromes (ACS), the clinical estimation of coronary vulnerability still remains inconclusive. Ultrasound evaluation of carotid plaques with integrated backscatter (IBS) analysis can indicate the consistency/structure of the plaques. Lipid-rich lesions known as “unstable plaques” appear as echolucent plaques with low IBS values using this technique.MethodsWe investigated the echogenicity of carotid plaques using ultrasound with IBS in 286 consecutive CAD patients (71 with ACS and 215 with stable CAD). Coronary plaque complexity was also determined angiographically in stable CAD patients followed up for 30 months or until the occurrence of coronary events.ResultsThe calibrated IBS values of carotid plaques in ACS patients were significantly lower than those in stable CAD patients (p < 0.01). Echolucent carotid plaques accurately predicted the existence of complex coronary plaques (predictive power of 83%). Kaplan-Meier analysis demonstrated a significantly higher probability of coronary events developing in patients with echolucent carotid plaques than in patients without this type of plaque (p < 0.001). The presence of echolucent carotid plaques in stable CAD patients predicted future coronary events independent of other risk factors (odds ratio 7.0, 95% confidence interval 2.3 to 21.4; p < 0.001).ConclusionsEcholucent carotid plaques with low IBS values predicted coronary plaque complexity and the development of future coronary complications in patients with stable CAD. Qualitative evaluation of carotid plaques using ultrasound with IBS is a clinically useful procedure for risk assessment of CAD patients.

Objectives . This study was performed 1) to examine the role of adenosine in the pathogenesis of syndrome X in patients with this syndrome and abnormal results on myocardial scintigrams during exercise, and 2) to determine the susceptibility to myocardial ischemia in this subset of patients with syndrome X. Background . A role for adenosine in the pathogenesis of syndrome X has recently been postulated, but there are few clinical data supporting this hypothesis. Methods . Exercise thallium-201 myocardial scintigraphy after intravenous administration of aminophylline, an adenosine receptor blocking agent, or saline solution and adenosine thallium-201 scintigraphy were performed in 26 patients with syndrome X. Hemodynamic variables during exercise and perfusion defect size after aminophylline and saline infusions were compared. At cardiac catheterization, coronary hemodynamic variables during separate infusions of adenosine and dobutamine were also examined and were compared among patients with abnormal or normal scintigrams and 10 control subjects. Results . Perfusion abnormalities on exercise-thallium-201 scintigraphy occurred in 14 of 26 patients with syndrome X. Intravenous infusion of aminophylline suppressed the scintigraphic perfusion defect and prolonged the time to 1-mm ST segment depression in patients with syndrome X with abnormal exercise scintigrams. Intravenous infusion of adenosine induced a perfusion defect in the same myocardial area where the perfusion defect was observed at exercise in 7 of the 14 patients with syndrome X. At cardiac catheterization, patients with syndrome X with abnormal exercise scintigrams had lower coronary flow reserve and a greater frequency of myocardial lactate production and ST segment depression in response to the infusions of adenosine and dobutamine than did the other two groups. During adenosine infusion, great cardiac vein blood flow and oxygen content were significantly increased and myocardial oxygen consumption and lactate extraction were significantly reduced from baseline without a significant increase in rate-pressure product in this subset of patients with syndrome X. Conclusions . Patients with syndrome X with abnormal exercise scintigrams have high susceptibility to myocardial ischemia during exercise or pharmacologic stress tests, probably owing to reduced coronary flow reserve. A heterogeneous response to endogenous adenosine may contribute to scintigraphic perfusion abnormalities and myocardial ischemia during exercise in this subset of patients with syndrome X.

Objectives The aim of the present study was to investigate whether there is diurnal fluctuation in the endothelial function of patients with variant angina (VA). Background Coronary spasm is induced by acetylcholine and is promptly relieved by nitroglycerin. Thus, it is possible that endothelial dysfunction is involved in the pathogenesis of coronary spasm. Furthermore, the frequency of ischemic episodes is known to display diurnal variation. Methods Flow-mediated, endothelium-dependent vasodilation of the brachial arteries was measured in the early morning (6 am ), afternoon (2 pm ) and evening (8 pm ) in 20 patients with VA (mean age 54.5 years; 10 men and 10 women) and in 20 control subjects (mean age 54.2 years; 10 men and 10 women). All patients underwent 24-h ambulatory electrocardiographic monitoring during the study. Results Flow-mediated vasodilation in patients with VA was deteriorated by the early morning and improved by the afternoon (patients with VA at 8 pm vs. 6 am vs. 2 pm : 7.8 ± 2.1% (p am ) vs. 5.4 ± 2.3% vs. 8.8 ± 1.9% (p am ); control subjects: 9.5 ± 2.8% vs. 9.0 ± 2.2% vs. 9.9 ± 1.9%, respectively). The frequency of spontaneous ischemic episodes was highest from midnight to morning and was lowest from morning to late afternoon (4 pm to midnight: 7 episodes; midnight to 8 am : 25 episodes; 8 am to 4 pm : 3 episodes). Conclusions There is diurnal fluctuation in endothelial function, which is associated with variation in the frequency of ischemic episodes.