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In recent years, transthyretin amyloid cardiomyopathy (ATTR-CM) has received increasing attention; however, the epidemiology of ATTR-CM in Japan is not yet understood. In the Kumamoto Cardiac Amyloid Survey, we evaluated the current incidence, clinical characteristics, diagnostic approaches, and treatment strategies for ATTR-CM and compared tafamidis-prescription hospitals with regional hospitals.We conducted a retrospective multicenter observational cohort study. The registry included patients with ATTR-CM diagnosed in two tafamidis-prescription hospital institutes [Japanese Circulation Society (JCS)-certified facilities] and 15 regional cardiovascular facilities in Kumamoto between January 2018 and December 2020.In total, 174 patients were diagnosed with ATTR-CM. The incidence of ATTR-CM was estimated to be approximately 1 per 10,000 person-years in the elderly population (65 years old) in Kumamoto. Compared with that in the JCS-certified facilities cohort (n=115), age at diagnosis was significantly older (84.5 ± 5.6 vs. 77.5 ± 6.3 years old; p0.01) in the regional hospitals cohort (n=59). Histological (25% vs. 81%; p0.01) and genetic diagnosis (7% vs. 82%) were also less frequently performed. Probable (as indicated by positive bone scintigraphy findings with confirmation of monoclonal protein absence) and possible (as indicated by positive bone scintigraphy findings without confirmation of monoclonal protein absence) ATTR-CM accounted for the majority of cases (75% vs. 19%; p0.01) in the regional hospitals cohort compared to the JCS-certified facilities cohort. There were no cases of hereditary ATTR-CM among the patients who underwent TTR genetic testing (n=98).We confirmed the incidence of ATTR-CM in Kumamoto and the diagnostic approach used in patients with ATTR-CM. Further prospective studies with a larger sample are needed to validate our results and to further shed light on the epidemiology of ATTR-CM in Japan.

Aim Matrix metalloproteinases (MMPs) play critical roles in acute myocardial infarction (AMI). This trial was conducted to determine the potential effects of higher-dose rosuvastatin on circulating MMP levels in patients with AMI. Methods This was a multicenter, open-label, 1:1 randomized, parallel-group study. Patients with AMI were randomly assigned to the appropriate-dose group (10 mg rosuvastatin once daily) or the low-dose group (2.5 mg rosuvastatin once daily) within 24 hours after percutaneous coronary intervention. MMP-2 and MMP-9 levels were measured on day 1 and at week 4, 12, and 24 after enrollment. The primary endpoint was the change in MMP levels at 24 weeks after enrollment. The secondary endpoints were change in MMP levels at day 1 and weeks 4 and 12 after enrollment. Results Between August 2017 and October 2018, 120 patients with AMI from 19 institutions were randomly assigned to either the appropriate-dose or the low-dose group. There were 109 patients who completed the 24-week follow-up. The primary endpoint for both MMP-2 and MMP-9 was not significantly different between the two groups. The change in the active/total ratio of MMP-9 at week 12 after baseline was significantly lower in the appropriate-dose group compared with the low-dose group (0.81 [-52.8-60.1]% vs. 70.1 [-14.5-214.2]%, P=0.004), while the changes in MMP-2 were not significantly different between the two groups during the study period. Conclusions This study could not demonstrate the superiority of appropriate-dose of rosuvastatin in inhibiting serum MMPs levels in patients with AMI.

Background Acute myocardial infarction (AMI) is mainly characterized by the rupture of lipid-rich vulnerable atherosclerotic plaque. The matrix metalloproteinases (MMPs) have been shown to play a critical role in inflammatory processes underlying plaque rupture. Some reports suggested statins inhibit the increased MMP levels after AMI. However, there are a few comparison studies between the different dosages of the same statin and circulating levels of MMPs. Purpose This study will preliminarily investigate the potential effects of appropriate or low dose of rosuvastatin on circulating MMPs levels in AMI patients. Moreover, we will also obtain plasma from patients while undergoing diagnostic angiography to determine differences in various cardiac sites and peripheral vessels. Methods This study is a multicenter, open-label, randomized, parallel-group study to be conducted to compare the appropriate or low dose of rosuvastatin in the effect on serum levels of inflammatory markers in AMI patients. The eligible patients undergoing percutaneous coronary intervention (PCI) will be randomly assigned to receive either appropriate or low-dose rosuvastatin daily using a web-based randomization software within 24 h after PCI. The low-dose group will be treated with rosuvastatin 2.5 mg once daily with a follow-up. The appropriate-dose group will begin treatment with rosuvastatin 5 mg once daily, and the dose of rosuvastatin will be titrated to 10 mg within 4 weeks. During administration of the study treatment, subjects will undergo laboratory testing including MMPs and be monitored for the occurrence of adverse events up to 24 weeks. The primary endpoint will be the change rate of MMPs at 24 weeks after administration. Conclusions INVITATION will compare the appropriate or low dose of rosuvastatin in the effects on serum levels of inflammatory markers including MMPs in AMI patients. This study will provide significant information on rosuvastatin as an anti-inflammatory agent for AMI.

Objective: Endothelial dysfunction is thought to represent the initial stage in the development of atherosclerosis. Recently, noninvasive examination of endothelial function has become possible using flow-mediated endothelium-dependent dilation of the brachial artery (FMD) during reactive hyperemia. We examined whether FMD has prognostic value for the prediction of subsequent cardiovascular events. Methods: Patients were followed prospectively every month until the occurrence of the cardiovascular events. Patients: The study subjects comprised 221 consecutive patients (men 108, mean age 61.4±10.6, ischemic heart disease 152, cardiomyopathy 28, arrhythmia 12, valvular disease 5, congenital heart disease 3, and cardioneurosis 21). The mean FMD was 4.77±2.85% and this value was used to divide the patients into the 2 groups (Group 1: FMD ≥4.7%; Group 2: FMD Results: There were 110 patients in Group 1 (men 36, mean age 60.5±10.9), and 111 patients in Group 2 (men 72, mean age 62.2±10.3). Patients were followed until the occurrence of at least 1 of the major clinical cardiovascular events. Seven cardiovascular events occurred in Group 1 (6.4%, 1.14 events per 100 patient-years), while 16 occurred in Group 2 (2.88 events per 100 patient-years). Kaplan-Meier analysis demonstrated a significantly higher probability of developing cardiovascular events in Group 2 than in Group 1. Conclusion: The present results demonstrated that the magnitude of FMD in the brachial artery was a good predictor of subsequent cardiovascular events.

To determine whether plasma levels of thioredoxin are associated with coronary spasm, we measured the plasma levels of thioredoxin in 170 patients who had

We report a 67-year-old Japanese man who presented with worsening heart failure with asymptomatically transient ischemic ST-segment depression. Left ventriculography showed diffuse hypokinesis; asymptomatic coronary artery spasm was evoked by the acetylcholine provocation test. Endomyocardial biopsy exhibited hypertrophic cardiomyocytes and scattered microscopic focal myocardial necrosis with amyloid-deposition. Transient ST-segment depression improved after treatment with a calcium antagonist, but cardiac contraction was still impaired. We hypothesize that asymptomatic coronary spasm may cause irreversible cardiac damage and heart failure with amyloid-deposition; the presence or absence of coronary spasm in heart failure patients should be clarified in order to determine therapeutic strategy.

The incidence of ischemic heart disease shows a sharp rise after menopause. However, the effects of hormone replacement therapy (HRT) on cardiovascular disease are still controversial. Not only oxidative stress, but also inflammation has been suggested to play an important role in the pathogenesis of cardiovascular events. We compared the effects of HRT on endothelial function, cellular antioxidant system and inflammation between oral and transdermal administration in mild hypercholesterolemic postmenopausal women. Transdermal estradiol replacement was administrated to 12 patients (mean age 53 years) for 12 weeks, and oral conjugated equine estrogen was administrated to 12 patients (mean age 54 years) for 12 weeks. The flow-mediated endothelium-dependent dilation of the brachial artery, serum levels of thioredoxin as a marker of the cytoprotective antioxidant system, and high-sensitivity C-reactive protein (hs-CRP) were measured every 4 weeks. The flow-mediated vasodilation increased with HRT (oral, baseline 4.9 +/- 0.5, 4-week 8.9 +/- 0.7*, 8-week 9.9 +/- 0.6*, 12-week 9.4 +/- 0.7*; transdermal, 4.7 +/- 0.6, 8.3 +/- 0.7*, 9.1 +/- 0.8*, 8.9 +/- 0.9%*, * = p < 0.01 versus baseline). The thioredoxin levels decreased with HRT (oral, 26.1 +/- 7.2, 24.1 +/- 8.2, 22.1 +/- 7.8, 19.1 +/- 7.0*; transdermal, 26.9 +/- 7.4, 23.4 +/- 8.7, 21.1 +/- 7.9, 19.2 +/- 7.2 ng/ml*, * = p < 0.01 versus baseline). There were no differences in the variation of the flow-mediated vasodilation or thioredoxin concentrations between the 2 groups. The hs-CRP levels increased with oral HRT (0.32 +/- 0.12, 0.72 +/- 0.17*, 0.86 +/- 0.23*, 0.88 +/- 0.21 mg/dl*, * = p < 0.01 versus baseline), while transdermal HRT did not elicit any changes (0.35 +/- 0.15, 0.34 +/- 0.17, 0.38 +/- 0.20, 0.36 +/- 0.22 mg/dl). The differences of hs-CRP concentrations between the 2 groups analyzed by 2-way ANOVA were significant (p < 0.01). Oral HRT instigated inflammation, but transdermal did not. Both oral and transdermal HRT, however, improved endothelial function and decreased oxidative stress through affecting the cellular redox state. These differentials in the effects caused by the course of administration may affect the future cardiovascular events.

A 75-year old man was referred to hospital for symptomatic hypoxemia. He did not complain of dyspnea while supine, but while sitting or standing, he experienced dyspnea with severe hypoxemia. He did not have any pulmonary diseases that could cause dyspnea. Transesophageal echocardiography revealed an atrial septal aneurysm with a small atrial septal defect (ASD) and a mild left-to-right shunt through the ASD when the patient was supine. However, when he became upright, a severe right-to-left shunt occurred and the arterial oxygen saturation decreased from 96% to 80% with dyspnea. Cardiac catheterization revealed normal pulmonary artery pressure. He was therefore diagnosed as having platypnea - orthodeoxia syndrome. Magnetic resonance imaging of the chest showed a deformity of the atrium associated with elongation of the ascending aorta. The ASD was closed surgically and the dyspnea and hypoxemia that occurred while he was upright completely resolved.

Hypercholesterolemia impairs endothelial function. However, the production/release of nitric oxide from the hypercholesterolemic aorta is reported to be enhanced rather than impaired in animal studies. L-arginine improves endothelial function in hypercholesterolemic subjects. The goal of the present study was to investigate the effects of L-arginine on endothelial function and oxidative stress in hypercholesterolemic subjects. In 17 hypercholesterolemic male subjects (mean age 41.7 years, mean total cholesterol 264.3 +/- 5.9 mg/dl) and 17 age-matched healthy men as controls (mean total cholesterol 187.1 +/- 6.8 mg/dl), we measured flow-mediated endothelium-dependent vasodilation of the brachial artery during saline infusion and after saline plus L-arginine infusion (30 g for 1 h) with ultrasound technique. In addition, we measured the levels of thiobarbituric acid reactive substances (TBARS), as a marker of lipid peroxide. The flow-mediated vasodilation was lower and the TBARS concentration was higher in the hypercholesterolemic group than in the control group during the saline infusion. The addition of L-arginine increased flow-mediated vasodilation and decreased TBARS concentration in the hypercholesterolemic group (from 3.92 +/- 0.58 to 7.27 +/- 0.53% [P

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.

Although echocardiographically determined left ventricular mass and geometry predict cardiovascular morbid events in patients with hypertension, the mechanisms underlying this relation are unclear. There is considerable evidence that endothelium-dependent vasodilation is impaired in patients with hypertension. Thus, endothelial dysfunction may contribute to the mechanism that causes cardiovascular morbid events. This study was designed to examine the relationship between left ventricular geometry and endothelial function in patients with hypertension. The percentage increase in brachial arterial diameter during reactive hyperemia was examined by a high-resolution ultrasound technique in 49 patients with hypertension and 64 normotensive subjects. Patients with hypertension had an impairment of the percentage increase in brachial arterial diameter during reactive hyperemia and an increase in thiobarbituric acid-reactive substances (TBARS) compared to normotensive subjects (percentage increase in diameter 5.6 ± 3.0 vs. 8.0 ± 2.5%, p < 0.001; TBARS levels 6.1 ± 1.3 vs. 5.3 ± 1.0 nmol/ml, p < 0.001). In patients with hypertension, there was a significant correlation between the left ventricular mass index and the percentage increase in brachial arterial diameter during reactive hyperemia (r = –0.583, p < 0.001), and the percentage increase in brachial arterial diameter during reactive hyperemia varied with the pattern of left ventricular geometry (normal ventricular geometry: 7.7 ± 2.6%; concentric remodeling: 5.2 ± 2.3%; eccentric hypertrophy: 4.2 ± 1.8%; concentric hypertrophy: 2.9 ± 2.6%). We conclude that (1) flow-mediated endothelium-dependent vasodilation in the brachial artery is impaired in patients with hypertension, (2) a relationship exists between the left ventricular mass index and flow-mediated endothelium-dependent vasodilation in the brachial artery in patients with hypertension and (3) increased oxidative stress may play a role in the endothelial dysfunction in patients with hypertension.

Cigarette smoking impairs endothelial function and is one of the major risk factors for atherosclerosis and coronary heart disease. Insulin resistance is associated with major risk factors for atherosclerosis. We examined the effects of vitamin C on insulin sensitivity and endothelial function by measuring steady-state plasma glucose (SSPG) and flow-mediated dilation (FMD) of the brachial artery. We studied 16 current smokers with normal glucose tolerance, 15 nonsmokers with impaired glucose tolerance (IGT), and 17 nonsmokers with normal glucose tolerance as controls. Both SSPG and FMD were blunted in smokers and nonsmokers with IGT compared with controls. In smokers, vitamin C decreased SSPG ( P < 0.01 by ANOVA) with decreasing plasma thiobarbituric acid-reactive substances (TBARS) ( P < 0.05 by ANOVA) and improved FMD ( P < 0.05 by ANOVA). Furthermore, vitamin C improved both SSPG ( P < 0.005 by ANOVA) and FMD ( P < 0.05 by ANOVA) in nonsmokers with IGT. SSPG, FMD, or TBARS in controls did not change after vitamin C infusion. There was a significant correlation between SSPG and FMD both in smokers and nonsmokers with IGT, whereas no correlation was observed in controls. In conclusion, both insulin sensitivity and endothelial function were impaired in smokers and nonsmokers with IGT and were improved by vitamin C. Thus increased reactive oxygen species play an important role in the pathogenesis of insulin resistance as well as endothelial dysfunction in smokers and nonsmokers with IGT.

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.

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, p0.01). 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, p0.01). 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, p0.01). 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, p0.01). TAT levels were also higher in the failure group than in the success group (30.8+/-9.6 vs. 8.6+/-1.7, p0.01). 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, p0.05). There were correlations between APC and TAT levels both on admission (r=0.75, p0.0001) and at discharge (r=0.71, p0.0001). 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.

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.

We investigated the effect of statin therapy on T-cell activation in patients who underwent percutaneous coronary intervention by using flow cytometric analysis. The increased frequency of interferon-γ–positive CD4 + T cells after percutaneous coronary intervention was significant in the group treated without statins but not in the group treated with statins.

The addition of medroxyprogesterone acetate (MPA) is widely accepted to remove the endometrial-cancerogenic effect of estrogen replacement therapy in postmenopausal women. To evaluate the effect of MPA on endothelial function, we measured flow-mediated vasodilation of brachial arteries after transient occlusion in a randomized, double-blind, placebo-controlled study; we concluded that the addition of MPA attenuates the favorable effects of estradiol on endothelium-dependent vasodilation.

Cigarette smoking is one of the major risk factors for atherosclerotic coronary disease, but the precise mechanism(s) by which cigarette smoking promotes atherosclerosis remains unknown. As there is now increasing evidence that atherosclerosis is an inflammatory condition, the present study investigated whether inflammation exists in smokers.The inflammatory markers and lipid profiles were compared among a current-smoker group (210 patients, mean age 61.8 +/- 11.0 years), past-smoker group (115 patients, 67.1 +/- 9.0 years) and never-smoked group (113 patients, 68.2 +/- 10.7 years), all of whom had no apparent signs of inflammation. The respective levels of blood leukocytes, platelets, C-reactive protein and fibrinogen were significantly higher in current-smokers than in the never-smoked group (6,600 +/- 1,723 /microl vs 5,638 +/- 1,313 /microl p0.01; 22.7 +/- 6.8 x 10(4) /microl vs 18.7 +/- 7.4 x 10(4) /microl, p0.01; 3.50+/-4.91 mg/L vs 1.92+/-3.02 mg/L, p0.01; 334.2 +/- 90.9 mg/dl vs 314.7 +/- 80.2 mg/dl, p0.05). The respective levels of plasma triglycerides, remnant-like particle cholesterol and apolipoprotein-B were significantly higher and that of high-density lipoprotein cholesterol significantly lower in the current-smokers than in the never-smoked group (152.4 +/- 96.2 mg/dl vs 120.5 +/- 58.1 mg/dl, p0.01; 5.4+/-6.3 mg/dl vs 3.8 +/- 2.0 mg/dl, p0.05; 101.6 +/- 23.7 mg/dl vs 95.0 +/- 21.2 mg/dl, p0.05; 45.2 +/- 12.3 mg/dl vs 50.6 +/- 15.6 mg/dl, p0.01). Past smokers had intermediate values between those of current-smokers and never-smoked.Low-grade inflammation, atherogenic dyslipidemia, and hypercoagulability are present in smokers compared with those who have never smoked among subjects without apparent inflammation who underwent coronary angiography on suspicion of coronary artery disease.

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 μg/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 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.

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.

The dehydroepiandrosterone (DHEA) concentration decreases with age. There is evidence that DHEA has a protective effect against age-related disorders, including cardiovascular disease. Accordingly, we examined the effect of DHEA supplementation (25 mg/d) on endothelial function, insulin sensitivity, and fibrinolytic activity in 24 men with hypercholesterolemia (mean age, 54 ± 1 yr). All subjects were enrolled in a randomized, double-blind study. Flow-mediated dilation of brachial artery after transient occlusion, which was expressed as the percent change from the baseline value of the diameter, increased significantly with DHEA supplementation [DHEA: baseline, 3.9 ± 0.5%; 4 wk, 6.9 ± 0.7%; 8 wk, 7.9 ± 0.6%; 12 wk, 8.4 ± 0.7% (P < 0.01 vs. baseline for all, by ANOVA); placebo: 4.1 ± 0.6%, 4.5 ± 0.5%, 3.9 ± 0.5%, and 4.4 ± 0.6% (P < 0.01 for all, by ANOVA)]. There was a significant concurrent reduction in the plasma levels of plasminogen activator inhibitor type 1 during DHEA supplementation [DHEA: 9.1 ± 2.2, 6.4 ± 2.3, 5.5 ± 2.8, and 5.1 ± 2.0 IU/ml (P < 0.01 vs. baseline, by ANOVA); placebo: 9.0 ± 2.1, 10.4 ± 2.2, 9.5 ± 2.2, and 9.6 ± 2.1 IU/ml (P < 0.01, by ANOVA)]. DHEA supplementation also decreased steady state plasma glucose [DHEA: baseline, 178.9 ± 12.2; 12 wk, 132.0 ± 12.8 mg/dl (P < 0.01, by ANOVA); placebo: 181.0 ± 13.8 and 179.6 ± 12.4 mg/dl (P < 0.01, by ANOVA)]. In contrast, steady state plasma insulin did not change during the study in either group. The low dose DHEA supplementation improves vascular endothelial function and insulin sensitivity and decreases the plasminogen activator inhibitor type 1 concentration. These beneficial changes have the potential to attenuate the development of age-related disorders such as cardiovascular disease.

Angiographically normal coronary arteries have concealed intimal thickening that importantly contribute to coronary arterial disease activity. Increased plasma levels of plasminogen activator inhibitor (PAI) are associated with myocardial infarction and atherosclerosis. However, it remains unclear whether the PAI contributes to vascular wall thickening detected by intravascular ultrasound (IVUS) in normal coronary angiogram. The aim of this study was to evaluate if the PAI activity contributes to the extent of atherosclerotic changes in angiographically normal coronary arteries using IVUS technique.We studied 33 consecutive patients with normal coronary angiograms. These patients were divided into a high level of plasma PAI activity group (H-PAI; n=12) and a normal range of PAI activity group (N-PAI; n=21), according to the plasma PAI activity levels.The average of "percent intima+media area (%I+M area)" and "maximal intima+media (I+M) thickness" were significantly greater in the H-PAI group as compared with those in the N-PAI group (p0.05). Minimal lumen diameter and lumen area were comparable between these groups. The plasma PAI activity level was the independent predictor of increase in maximal I+M thickness, in multiple regression analysis with the traditional risk factors as covariates.Thickened intima+media of angiographically normal coronary arteries were associated with high plasma level of PAI activity, independently of other traditional risk factors. PAI may contribute to the pathogenesis of coronary intimal thickening that might increase coronary arterial tone.

Background A-Type and B-type natriuretic peptides are cardiac hormones whose circulating levels reflect the severity of heart failure. It is not known how plasma levels of these hormones respond to changes in cardiac function that occur as a result of treatment with angiotensin-converting enzyme (ACE) inhibitors. Methods Enalapril was administered at 5 mg/d for 3 months in 24 patients with chronic heart failure, and for the next 3 months at 15 mg/d in the high-dose group (n = 12) and 5 mg/d in the low-dose group (n = 12). We measured plasma levels of A-type or B-type natriuretic peptides, as well as conventional measures of cardiac function, such as the cardiothoracic ratio, left ventricular end-diastolic volume, and percent fractional shortening. Results Mean (± SD) plasma levels of both hormones decreased promptly after 2 weeks of therapy (A-type natriuretic peptide: 140 ± 107 pg/mL to 81 ± 68 pg/mL, P = 0.01; B-type natriuretic peptide: 305 ± 278 pg/mL to 190 ± 178 pg/mL, P = 0.01). These reductions were sustained throughout therapy. In contrast, the cardiothoracic ratio, left ventricular end-diastolic dimension, and percent fractional shortening had not changed significantly after 3 months of treatment, although improvements were seen after 6 months of treatment. After 6 months, plasma levels of both A-type and B-type natriuretic peptides were significantly lower in the high-dose group than in the low-dose group (A-type natriuretic peptide: 48 ± 25 pg/mL vs. 57 ± 27 pg/mL, P = 0.01; B-type natriuretic peptide: 78 ± 58 pg/mL vs. 139 ± 61 pg/mL, P = 0.005), whereas no significant differences were observed in the other measures of cardiac function. Conclusion Plasma levels of A-type and B-type natriuretic peptides appear to be more sensitive markers of heart failure than conventional echocardiographic parameters and cardiothoracic ratios. Measurement of these hormones might be useful for monitoring the effects of treatment with ACE inhibitors.

A 16-year-old Japanese woman with infective endocarditis was admitted to hospital. An echocardiography exhibited a perivalvular pseudoaneurysm just under the mitral valve. Left ventriculography demonstrated that the aneurysm had a small neck and dyskinetic motion with oppression to the coronary sinus and right coronary artery.

SummaryWe examined the alteration of platelet aggregability in acute hyperglycemia during 75-gram oral glucose tolerance tests (OGTT). Twenty subjects underwent 75-gram OGTT and venous blood samples were obtained before (0 min), 60, 120 and 180 min postload. Platelet aggregability shown as the number of small platelet aggregates was measured with a novel laser-light scattering (LS) method. Platelet aggregability increased in parallel with both glucose and immunoreactive insulin (IRI) levels. The number of mean small aggregates at 60 min (12.30 ± 1.10 × 104) was significantly higher than the one at 0 min (8.32 ± 0.88 × 104, p

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

An elevated level of angiotensin-converting enzyme (ACE) has been demonstrated to increase the risk of myocardial infarction. Plasminogen activator inhibitor (PAI) is the most important physiological inhibitor of tissue plasminogen activator in plasma. An elevated level of PAI has been reported to be associated with decreased fibrinolytic capacity and to constitute a marker of the risk for recurrent coronary thrombosis.We measured the serum ACE activity and plasma PAI activity in 34 patients with recent myocardial infarction, and evaluated the correlation between these two values by linear regression analysis. We also administered captopril (37.5 mg/day) to 17 of these patients and placebo to the other 17 patients at random, and compared the changes in PAI activity and ACE activity in these two groups over a 1-month period.There was a significant correlation between the serum ACE activity and the plasma PAI activity at baseline in the patients (r = 0.498, P0.01). The captopril-treated patients showed significantly reduced PAI activity (P0.01), and a concomitant decrease in ACE activity.These results suggest that elevated ACE activity is associated with impaired fibrinolysis and that treatment with an ACE inhibitor improves the fibrinolytic function in patients with recent myocardial infarction. The results also suggest that the renin-angiotensin system plays a role in the increased risk of ischemic cardiovascular events when it is activated, and in the reduction of risk of recurrent myocardial infarction by ACE inhibition.

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, p0.01). 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, p0.05). The plasma soluble P-selectin levels were higher in the AMI group than in the angina and control groups over the time course (p0.01). 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.

Behçet's disease frequently involves the venous system, usually affecting small vessels, but sometimes large vessels such as the vena cava. Antiphospholipid antibody syndrome is associated with an increased incidence of arterial and venous thrombosis. A 29-year-old male with Behçet's disease developed bilateral leg edema secondary to thrombotic occlusion of the inferior vena cava. Laboratory tests revealed positive antiphospholipid antibodies and lupus anticoagulant. Treatment with steroid and warfarin subsequent to intravenous administration of uro-kinase resulted in improvement of symptoms. The association of antiphospholipid antibody syndrome and Behçet's disease may have caused the total thrombotic occlusion of the vena cava in this case.

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 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.