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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.

ObjectivesTo identify factors associated with plasma D-dimer levels in outpatients with rheumatoid arthritis (RA).MethodsWe consecutively recruited 460 RA patients who visited our hospital for routine follow-ups between June and October 2021. Plasma D-dimer, RA-related characteristics, comorbidities, and cardiovascular and venous thromboembolism (VTE) risk factors were examined at enrolment. Patients with elevated D-dimer levels underwent whole-leg venous ultrasonography to diagnose deep vein thrombosis (DVT).ResultsParticipants had no DVT signs or symptoms. Among them, 252 (54.8%) were positive for plasma D-dimer (≥0.5 μg/ml) and 40 (8.7%) had high D-dimer levels (≥3 μg/ml). The mean was 1.07 μg/ml. After adjustments, age [odds ratio (OR) 1.88 per additional 10 years, P = .003], high and moderate clinical disease activity index (OR 8.79, P ConclusionsClinical disease activity is a major contributor to plasma D-dimer elevation in RA outpatients.

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.

Various oxidative stress markers have been measured to evaluate the status of heart failure (HF). However, the relationships between these markers and the aetiology of HF have not been fully investigated. This study compared 8-hydroxy-2'-deoxyguanosine (8-OHdG) and biopyrrins levels in patients with ischemic and non-ischemic HF. Study subjects were divided into a coronary artery disease (CAD) group (n=70), a non-CAD group (n=61) and a control group (n=33). In the CAD group, 8-OHdG and biopyrrins levels increased with the severity of the New York Heart Association (NYHA) functional class and log BNP levels correlated with 8-OHdG and biopyrrins levels. However, non-CAD patients with NYHA class III/IV had significantly lower 8-OHdG levels than CAD patients with NYHA class III/IV and the levels did not correlate with log BNP levels. In the CAD group, 8-OHdG levels reflected the severity of atherosclerosis. These results indicate that the properties of oxidative stress markers should be carefully taken into consideration for the assessment of HF status.

OBJECTIVES Coronary heart disease is relatively uncommon in premenopausal women but shows a sharp increase after menopause. The decline of endogenous ovarian hormones is commonly assumed to be a major component of this phenomenon. The effects of estrogens on the vasculature have been investigated extensively in previous studies. However, the effects of estrogens on myocardial function have not been evaluated in humans. We sought to examine the effects of hormone therapy (HT) on myocardial function and cardiac natriuretic peptides in postmenopausal women with chest pain and a normal coronary angiogram. DESIGN Transdermal HT (estradiol: 0.72 mg/2 d) was administered to 15 postmenopausal women with chest pain and a normal coronary angiogram (mean age, 53 y) for 12 weeks, and oral HT (conjugated equine estrogens: 0.625 mg/d) was administered to another 15 postmenopausal women (mean age, 54 y) for 12 weeks. Echocardiography or cardiac catheterization showed no cardiac dysfunction in any woman at baseline. Cardiac function was evaluated by echocardiography, and plasma B-type natriuretic peptide was measured every 4 weeks. RESULTS B-type natriuretic peptide levels increased after transdermal HT (baseline: 13.1 +/- 3.1, 4 wk: 22.1 +/- 2.9, 8 wk: 33.2 +/- 3.1, 12 wk: 38.4 +/- 3.3 pg/mL; P < 0.01 vs baseline). The levels were also augmented after oral HT (baseline: 14.1 +/- 3.8, 4 wk: 23.2 +/- 3.3, 8 wk: 35.6 +/- 3.9, 12 wk: 39.6 +/- 3.5 pg/mL; P < 0.01 vs baseline). Serial echocardiography showed no changes in ventricular function in either treatment group. At baseline the serum estradiol levels in the transdermal group were comparable with those in the oral group. CONCLUSIONS The estradiol levels after HT increased in both groups, but there was no significant difference between the two groups. B-type natriuretic peptide levels increased without cardiac dysfunction, and the chest symptoms were relieved in some participants after HT. Thus, estrogen supplementation augments natriuretic peptide levels without harmful effects on ventricular function.

Aims Type 2 diabetes is preceded by a symptom-free period of impaired glucose tolerance (IGT). Pancreatic B-cell function decreases as glucose intolerance develops. In many patients with IGT, fasting blood glucose is within normal limits and hyperglycaemia occurs only postprandially. We examined whether pancreatic B-cell function changes during acute hyperglycaemia induced by oral glucose loading. Methods We calculated the insulinogenic index (I.I.) as an indicator of pancreatic B-cell function and measured serum levels of thioredoxin, a marker of cellular redox state, and 8-hydroxy-2′-deoxyguanosine (8-OHdG), a marker of oxidative stress, during a 75-g oral glucose tolerance test (OGTT) in 45 subjects [24 patients with normal glucose tolerance (NGT), 14 with IGT and seven with Type 2 diabetes]. Results Thioredoxin levels decreased after glucose loading [66.1 ± 23.7, *59.3 ± 22.4, *49.3 ± 21.2 and *37.7 ± 18.0 ng/mL, fasting (0 min) and at 30, 60 and 120 min, respectively; *P < 0.001 vs. fasting]. In contrast, concentrations of 8-OHdG peaked at 30 min and then gradually decreased (0.402 ± 0.123, *0.440 ± 0.120, †0.362 ± 0.119 and †0.355 ± 0.131 ng/mL, *P < 0.05 vs. fasting, †P < 0.01 vs. 30 min). The insulinogenic index correlated with the change in thioredoxin levels (r = 0.34, P < 0.05). However, there was no relationship with the change in 8-OHdG levels from 0 to 30 min. Conclusions Hyperglycaemia in response to oral glucose impairs pancreatic B-cell function with decreasing thioredoxin levels. The augmented oxidative stress induced by hyperglycaemia may affect the cellular redox state. These findings strongly suggest that repeated postprandial hyperglycaemia may play an important role in the development and progression of diabetes mellitus.

Background The effect of edaravone, a free radical scavenger, on long-term prognosis and its efficacy with regards to scavenging injurious free radicals in patients with acute myocardial infarction (AMI) was examined. Methods and Results One hundred and one initial AMI patients were randomly assigned to receive 30 mg edaravone (n=50) or a placebo (n=51) intravenously just before reperfusion. The infarct size, using serum biomarkers and Q-wave formations, and the incidence of reperfusion arrhythmia between the groups were compared. Cardiovascular event-free curves were estimated by using the Kaplan - Meier method. In addition, the serum thioredoxin levels, an oxidative stress marker, to assess the antioxidant effect of edaravone was determined. In all cases, successful reperfusion was obtained within 6 h after the onset of symptoms. Infarct size and reperfusion arrhythmia were significantly attenuated in the edaravone group compared with the placebo group (p=0.035 and p=0.031). The cumulative event-free rate was significantly higher in the edaravone group than in the placebo group (p=0.045). Serum thioredoxin levels were significantly lower in the edaravone group than in the placebo group throughout the acute phase. Conclusions The present study suggests that the edaravone administration just prior to reperfusion might reduce oxidative stress and improve the long-term clinical outcomes of AMI patients. (Circ J 2006; 70: 832 -837)

Plasma levels of human thioredoxin are indicative of the responses against oxidative stress. We measured the plasma thioredoxin levels in patients with unstable angina in order to examine the relationships between subsequent clinical course and plasma thioredoxin levels before and after treatment for unstable angina. Blood was sampled both on admission and after treatment in 44 patients with unstable angina. In addition, blood samples were obtained from 41 patients with stable exertional angina and 41 patients with chest pain syndrome after admission. The plasma levels of thioredoxin were the highest in the unstable angina group among three groups (p

Introduction Inflammation is a key process in atherosclerotic formation. Structural changes in the carotid arterial wall including detection of focal plaques are measured as the intima-media thickness (IMT) providing an index of atheroma. Coronary arterial plaques may be considered as vascular structural changes. Distensibility of the arteries can be assessed by functional changes in pulse wave velocity (PWV) providing an index of sclerosis. Adiponectin has potential antiatherosclerotic properties. We hypothesized that adiponectin was associated with atherosclerotic vascular changes involved in inflammation. Materials and methods We enrolled 142 patients with coronary artery disease (CAD) and 108 control patients, matched for age, sex, and body mass index (BMI) with CAD patients. We investigated the relationship between adiponectin, C-reactive protein (CRP), and atherosclerotic vascular changes. Results CRP ( p =0.0009), high-density lipoprotein cholesterol (HDL-C; p =0.02), and IMTmax ( p =0.02) were determinants of adiponectin independent of glucose intolerance ( p =0.0001), BMI ( p =0.002), and CAD ( p =0.03), all of which have been significantly associated with adiponectin ( r =0.38). Adiponectin was not correlated with PWV. CRP, glucose intolerance, and HDL-C that correlated with adiponectin were inversely correlated with IMTmax and CAD. CRP was negatively correlated with HDL-C ( r =−0.24, p =0.0002) and positively correlated with glucose intolerance ( r =0.15, p =0.01). Conclusions Adiponectin has a close relationship with CRP, IMTmax, CAD, HDL-C, and other established risk factors. CRP, glucose intolerance, and HDL-C are common mediators between adiponectin and atheromatous vascular changes, which are contrary to each other. The exacerbation of atherogenesis may be involved in a decrease of adiponectin through abnormal glyco- and lipid-metabolism by promoting inflammation.

This clinical pilot study was a randomized, controlled, open-label study in 80 patients with acute myocardial infarction and was designed to examine the effects of a novel free radical scavenger, edaravone. Administration of edaravone before myocardial reperfusion was associated with smaller enzymatic infarcts and better clinical outcome.

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

Introduction: The fibrinolytic system has a major role as a defense mechanism against thrombus formation. Net fibrinolytic activity in plasma reflects the balance between tissue-type plasminogen activator and plasminogen activator inhibitor (PAI). PAI is the main factor determining overall fibrinolytic activity. Materials and methods: We examined the effects of oral administration of vitamin E, an antioxidant, on fibrinolytic activity and oxidative stress in patients with coronary spastic angina. Forty patients with coronary spastic angina were randomly assigned into two treatment groups, either vitamin E group (α-tocopherol acetate, 400 mg/day) or placebo group by means of computerized system. PAI activity and thioredoxin, a marker of oxidative stress, levels were measured before and at the end of 1 month treatment. Results: Before treatment, the levels of PAI activity and thioredoxin were increased in patients with coronary spastic angina as compared with control subjects (n=17) (PAI activity levels: 13.6±1.4 vs. 7.6±2.2 IU/ml, p

Background Connective tissue disease, which is an inflammatory condition represented by C-reactive protein (CRP), is a risk factor for ischemic heart disease. The aim of the present study was to examine if there is a relationship between connective tissue disease and coronary spastic angina, and whether the inflammatory condition was associated with ischemic heart disease, even in patients with connective tissue disease. Methods and Results The study group comprised 73 consecutive patients with connective tissue disease who were admitted to the Department of Cardiovascular Medicine between April 2000 and March 2003. Of the 73 patients, 38 (19 men, 19 women) were diagnosed as having an ischemic heart disease (7 patients acute coronary syndrome, 19 patients coronary spastic angina, 12 patients stable exertional angina). In the present study, 19 (50.0%) of the 38 patients of ischemic heart disease were diagnosed as having coronary spastic angina. In the same study period, 151 (38.7%) of 390 patients with ischemic heart disease (without connective tissue disease) were diagnosed as having coronary spastic angina. The frequency of the patients with coronary spastic angina tended to be higher in patients with connective tissue disease than in patients without connective tissue disease. Among the study patients, serum CRP concentrations (mg/dl) were higher in patients with acute coronary syndrome (1.50±1.19, n=7) and those with coronary spastic angina (1.06±1.78, n=19) than in those with non-ischemia (0.35±0.40, n=35, p

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.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).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.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.

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.

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)-γ–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-γ, 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-γ. 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.

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.

Early statin therapy after acute coronary syndrome reduces atherothrombotic vascular events. This study aimed to compare the effects of hydrophilic and hydrophobic statins on myocardial salvage and left ventricular (LV) function in patients with ST-elevated myocardial infarction (STEMI).Seventy-five STEMI patients who had received emergency reperfusion therapy were enrolled and randomized into the hydrophilic statin group (rosuvastatin; 5 mg/day, n = 38) and hydrophobic statin group (atorvastatin; 10 mg/day, n = 37) for 6 months. LV ejection fraction (LVEF), and B-type natriuretic peptide (BNP) and co-enzyme Q10 (CoQ10) levels were measured at baseline and the end of treatment. The myocardial salvage index was assessed by single photon emission computed tomography with (123-)I-β-methyl-iodophenylpentadecanoic acid (ischemic area-at-risk at onset of STEMI: AAR) and (201-)thallium scintigraphy (area-at-infarction at 6 months: AAI) [myocardial salvage index = (AAR-AAI) × 100/AAR (%)].Onset-to-balloon time and maximum creatine phosphokinase levels were comparable between the groups. After 6 months, rosuvastatin (-37.6% ± 17.2%) and atorvastatin (-32.4% ± 22.4%) equally reduced low-density lipoprotein-cholesterol (LDL-C) levels (p = 0.28). However, rosuvastatin (+3.1% ± 5.9%, p0.05), but not atorvastatin (+1.6% ± 5.7%, p = 0.15), improved LVEF. Rosuvastatin reduced BNP levels compared with atorvastatin (-53.3% ± 48.8% versus -13.8% ± 82.9%, p0.05). The myocardial salvage index was significantly higher in the rosuvastatin group than the atorvastatin group (78.6% ± 29.1% versus 52.5% ± 38.0%, p0.05). CoQ10/LDL-C levels at 6 months were increased in the rosuvastatin group (+23.5%, p0.01) and percent changes in CoQ10/LDL-C were correlated with the myocardial salvage index (r = 0.56, p0.01).Rosuvastatin shows better beneficial effects on myocardial salvage than atorvastatin in STEMI patients, including long-term cardiac function, associated with increasing CoQ10/LDL-C.URL http://www.umin.ac.jp/ctr/index.htm Unique Identifier: UMIN000003893.

We investigated whether the assessment of small platelet aggregates before percutaneous coronary intervention (PCI) could predict restenosis after PCI. This was a prospective cohort study that enrolled 189 consecutive patients who had coronary artery disease. In multiple logistic regression analysis, higher levels of preprocedural small platelet aggregates were independently associated with restenosis after PCI. Measurement of small platelet aggregates may serve as a useful clinical variable for stratifying patients who present for PCI.

Histochemical and electron microscopic studies were performed in an attempt to clarify the muscle pathology in an 18-year-old man with Fabry disease, showing proximal limb muscle atrophy, and his 52-year-old mother, who is a Fabry carrier with hypertrophic cardiomyopathy. Despite the relatively mild myopathic changes revealed by histochemistry, electron microscopy demonstrated the widespread accumulation of abundant lamellated bodies in myofibers, associated with increased glycogen granules and autophagic vacuoles. The cardiac muscle of the proband's mother revealed a mosaic pattern of normal-appearing and hypertrophic myofibers containing a number of ring-like, lamellated bodies. Although further studies are necessary to support our findings, skeletal muscle is apparently involved in patients with Fabry disease, and a mosaic pattern of cardiac muscle involvement possibly reflecting Lyonization, may be one of the characteristic findings of a Fabry disease carrier.

Background and aims: Juvenile haemochromatosis (JH) is an autosomal recessive iron disorder characterized by the early onset of secondary cardiomyopathy. The candidate modifier genes are hemojuvelin (HJV) and hepcidin antimicrobial peptide (HAMP). In the Japanese population, the prevalence of JH is quite low. The influence of HJV mutation on the JH phenotype is still unclear. Methods and results: We searched for possible mutations in a Japanese family with 2 members who were JH patients with severe heart failure. To search for possible variants in the HJV and HAMP genes, we performed direct sequencing in the family members. A homozygous nonsense mutation in exon 4 of HJV (Q312X) was identified in the JH patients and their mother. Three individuals in the family were heterozygous for this mutation. Subsequently, we evaluated the frequency of Q312X mutation in a large population (nw=361) without heart failure, using allele-specific real-time PCR assay. No Q312X mutation was detected in this population. In the patients with the homozygous HJV mutation, iron loading revealed high serum ferritin concentration with accompanying elevated transferrin iron saturation. In contrast, ferritin levels were within the normal range in individuals with the heterozygous mutation. Conclusions: We found a nonsense mutation in the HJV gene. This mutation elevates ferritin levels and leads to JH associated with severe cardiomyopathy.

Department of Cardiovascular Medicine, Kumamoto University School of Medicine, Kumamoto, and *Department of BiologicalResponses, Institute for Virus Research, Kyoto University, Kyoto, JapanSummaryBackground and hypothesis:Thioredoxin is an importantbiomarker for oxidative stress. We investigated whether thiore-doxin levels were elevated in patients with acute myocardialinfarction (AMI) and were associated with the results of coro-nary reperfusion.Methods: The present study determined plasma thioredox-in levels in 51 patients with AMI, 30 patients with stable exer-tional angina (SEA), and 30 patients with chest pain syndrome(CPS). Plasma sampling was performed on admission, at 12 h,1 week, 2 weeks, and 4 weeks in patients with AMI, and afteradmission in patients with SEA and CPS.Results: Plasma thioredoxin levels on admission were high-er in patients with AMI than in those with SEA and CPS. Plas-ma thioredoxin levels in patients with AMI were decreased in12 h without further change thereafter. However, thioredoxinlevels in patients with AMI remained higher than in those withSEA. In multivariate analysis, higher levels of thioredoxin onadmission were a risk factor for failure in emergent reperfusiontherapy in patients with AMI independent of other factors.Conclusion: Plasma thioredoxin levels are elevated in pa-tients with AMI, and higher thioredoxin levels may predictsubsequent failed coronary reperfusion therapy in patientswith AMI.Key words: acute myocardial infarction, reperfusion, oxida-tive stress, thioredoxinIntroductionOxidative stress is believed to play an important role incoronary artery disease.

Endothelial dysfunction precedes the development of clinical atherosclerosis. A decrease in endothelium-derived nitric oxide activity shows impaired vasodilator function and causes arterial intimal hyperplasia or thickening. Others and we have reported the close relation of endothelial function in brachial artery and coronary artery. To compare the flow-mediated endothelium-dependent vasodilation (FMD) in brachial artery and the intima+media area in coronary artery, we measured brachial artery vasodilator response following transient occlusion with high resolution ultrasound transducer and intima+media area in coronary arteries with intravascular ultrasound in 25 patients with normal coronary angiograms (age 61.6+/-8.7 years old, men 14 and women 11). FMD was measured at least 7 days after the cessation of all vasodilators. The mean FMD of 25 patients was 3.83+/-2.38%, the mean intima+media area in coronary arteries of 25 patients was 39.9+/-15.5% of total vessel wall. FMD has a close negative relation with the largest percent intima+media area (r=-0.77, p0.01). Especially, the patients whose FMD was less than 3.83% had larger percent intima+media area than those whose FMD was 3.83% or more (48.7+/-10.7% versus 30.3+/-14.2%, p0.01). There is an intima+media thickening even in the patients who had normal coronary angiograms, and that the percent intima+media area correlated with FMD. The measurement of FMD is useful for screening the coronary artery intima+media thickening noninvasively. The pathogenesis of acute coronary syndrome has been reported to be the plaque rupture even in the patients with normal coronary angiograms. Thus, we must pay much attention in the patients with impaired FMD even in the normal coronary angiograms.

Objective The aim of the present study was to determine the effects of glucose intolerance on oxidative stress in patients with coronary artery disease (CAD).Methods The patients were divided into 3 groups, diabetes mellitus (DM), IGT or normal glucose tolerance (NGT) according to the criteria of the American Diabetes Association.Patients The present study consisted of 178 consecutive patients who underwent diagnostic coronary arteriography and a 75-g glucose tolerance test.Results The level of plasma thioredoxin, a marker of oxidative stress was measured in every patient during the fasting state. The levels of plasma thioredoxin were significantly higher in the DM and IGT groups than the NGT group. Furthermore, we found that there was a positive association between thioredoxin levels and glycosylated hemoglobin (σ=0.225, p=0.018). In multivariate logistic regression analysis, glucose intolerance (DM or IGT) was only independently associated with the high levels of thioredoxin. The levels of plasma thioredoxin were significantly higher in the CAD group compared to the non-CAD group. In multivariate logistic regression analysis, high levels of thioredoxin, male, age and hypertension were independently associated with the presence of CAD.Conclusion Glucose intolerance was associated with the high levels of thioredoxin. High levels of thioredoxin were related to the presence of CAD. The measurement of thioredoxin as the marker of oxidative stress may be useful for monitoring the development of the cardiovascular diseases.

A 79-year-old woman was admitted due to chest pain with T wave inversion and anasarca. Echocardiography demonstrated a mass compressing the heart and computed tomography revealed a giant hiatal hernia within the intrathoracic stomach located just behind the heart. After drainage of the gastric contents, the T wave inversion disappeared, but subsequent ST elevation in leads V1-V6 was noted. After surgical correction of the hiatal hernia, the ST segment elevation returned to a nearly normal level. The changes in the compressed heart induced by hiatal hernia may cause pericarditis resulting in electrocardiographic changes.

We assessed serial changes in oxidative stress in patients with acute myocardial infarction by measuring urinary 8-hydroxy-2'-deoxyguanosine excretion. The urinary 8-hydroxy-2'-deoxyguanosine creatinine levels peaked at 4 hours after reperfusion therapy and the levels were higher in the cardiac event group than in the noncardiac event group before and after reperfusion.

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.

Adiponectin is a new member of adipocyte derived proteins belonging to the soluble defence collagens.1 Plasma adiponectin concentrations in obese subjects are decreased in spite of an adipose specific expression.1 More interestingly, the patients with chronic coronary artery disease exhibited lower plasma adiponectin concentrations compared to body mass index (BMI) matched control subjects.2 On the other hand, adiponectin accumulates in the vascular subendothelial space when the endothelial barrier is damaged.3 In vitro, adiponectin suppresses the expression of adhesion molecules in the vascular endothelial cells and cytokine production from macrophages.2,4 Therefore, the molecule may be involved in the inflammation and tissue repairing processes. Acute coronary syndrome is often precipitated by acute thrombosis.5 It is commonly accepted that the rupture or the erosion of plaques by the inflammatory process leads to coronary thrombosis and acute myocardial infarction (AMI). The C reactive protein (CRP) concentrations in the acute phase are suggested to reflect pre-existing coronary plaque instability associated with the onset of AMI. The significance of adiponectin in acute coronary syndrome has never been investigated. In the present study, we examined the serial change in plasma adiponectin concentrations and its relation to plasma CRP concentration in …

The left ventricular ejection fraction (LVEF) is one of the major prognostic factors after acute myocardial infarction (AMI) and matrix metalloproteinase-1 (MMP-1) is an enzyme responsible for extracellular collagen degradation and remodeling. The present study investigated whether the concentration of serum MMP-1 was associated with the LVEF after AMI. Blood was sampled on admission, and at 24 h, 3 days, 7 days, 2 weeks and 4 weeks in 24 patients with their first AMI. Left ventriculography was performed 4 weeks after the onset of AMI and the LVEF was calculated by center line method. MMP-1 concentrations were higher at 7 days and at 2 weeks than on admission (p