Search

We herein report a case of congenital long QT syndrome (LQTS) in which the QT interval was prolonged by Takotsubo syndrome (TTS), inducing ventricular fibrillation (VF). The patient was a 55-year-old woman who had been diagnosed with LQTS. Cardiopulmonary arrest occurred while coughing during sleep. VF was observed, and her heartbeat returned after two defibrillations. An electrocardiogram showed marked QT prolongation and large negative T waves. Echocardiography demonstrated hyperkinesis at the base of the left ventricle and akinesis at the apex. As there was no significant stenosis in the coronary artery, she was diagnosed with TTS.

Objective Few studies have reported on aortic valve replacement (AVR) in patients aged >80 years who have small aortic annuli. Various surgical techniques have been proposed for treating such patients. We investigated AVR using small-diameter mechanical valves, in patients aged >80 years, to determine its effectiveness. Methods Eighteen consecutive patients (15 women; 3 men) aged >80 (mean: 83.3 ± 2.7) years underwent surgical AVR with a 17-mm prosthesis. The clinical status and results of pre- and post-operative echocardiography were evaluated. Midterm examination was conducted at 12.0 ± 1.0 months after AVR. Results The average preoperative body surface area of the patients was 1.39 ± 0.15 m 2 ; the average New York Heart Association functional class was 3.28 ± 0.75. Echocardiography showed a peak pressure gradient of 99.1 ± 38.4 mm Hg. Operative mortality was absent. A significant decrease in the peak pressure gradient was found on early (22.6 ± 7.2 mm Hg) and midterm (22.2 ± 8.0 mm Hg) postoperative echocardiography, compared with that in the preoperative period. During this follow-up, 16 patients improved to class I, a significant change in each perioperative period compared with the preoperative period. No mortality was observed at 1 year postoperatively. Conclusions In patients aged >80 years who have small aortic annuli, AVR using a 17-mm prosthesis showed satisfactory clinical and hemodynamic results and provided a satisfactory remote prognosis.

We herein describe an adult case of double-chambered right ventricle (DCRV) with symptomatic drug-intolerant paroxysmal atrial fibrillation (PAf). The woman was referred to undergo radiofrequency ablation (RFA), and mapping of the pulmonary veins (PVs) demonstrated that a spontaneous spike potential originating from the left inferior PV (LIPV) induced sustained Af in the second procedure. Accordingly, the LIPV was regarded as the arrhythmogenic PV. Since complete isolation of the PVs, the sinus rhythm has been maintained for at least two years. This is the first report to describe that RFA for drug-intolerant PAf was useful in a patient with DCRV.

Summary Background The Japan Atherosclerosis Society's 2007 Guidelines for Prevention of Atherosclerotic Cardiovascular Diseases (JAS2007GL) advocate reducing LDL cholesterol (LDL-C) to target levels in patients with dyslipidemia, but achievement rates are frequently unsatisfactory even in the presence of lipid-lowering therapy. This multicenter, open-label, randomized, parallel-group study compared the efficacy of rosuvastatin and atorvastatin on JAS2007GL LDL-C goals in Japanese patients not achieving their target goal with atorvastatin treatment. Methods The study involved 20 clinical institutes in Japan (Kishiwada Atherosclerosis Prevention Study [KAPS] Group). Patients with category II or III risk of coronary artery disease (CAD), or those with a history of CAD (secondary prevention), who had not achieved their JAS2007GL LDL-C goals during treatment with atorvastatin for at least 4 weeks were switched either to rosuvastatin 5 mg/day (from atorvastatin 10 mg/day) or rosuvastatin 10 mg/day (from atorvastatin 20 mg/day) (n = 75) or continued to receive atorvastatin (n = 77). The primary endpoint was achievement of LDL-C goals at 3 months. The main secondary endpoint was achievement of LDL-C goal + high-sensitivity C-reactive protein level

Aims We tested the hypothesis that immunoglobulin ameliorated experimental autoimmune myocarditis (EAM) in mice attributing to the suppression of reactive oxygen species (ROS)-mediated myocardial injury. Methods We intraperitoneally administered intact type of human immunoglobulin (Ig) or F(ab′) 2 fragments of human immunoglobulin, 1g/kg/day daily for 3weeks, to male BALB/c mice with heart failure due to EAM. Results The results showed that intact type of Ig, but not F(ab′) 2 type, reduced the severity of myocarditis by comparing the heart weight/body weight and lung weight/body weight ratios, pericardial effusion score, macroscopic and microscopic scores. Tissue superoxide production was marked in untreated mice with EAM, which was suppressed by the treatment of immunoglobulins. The cytotoxic activities of lymphocytes in mice with EAM treated with Ig were reduced compared with untreated controls. The shift from Th 1 toward Th 2 cytokine balance was demonstrated by the treatment of immunoglobulins both in vitro and in vivo. Conclusion ROS may be involved in the development of myocarditis. Intact Ig ameliorates myocardial damage in mice with myocarditis associated with suppression of ROS and cytotoxic activity of lymphocytes.

Hyperinsulinemia and insulin resistance have been proposed as having a causal role in pathogenesis of atherosclerosis; however, the relationship between post-load insulin levels and long-term survival is not clear. We investigated whether post-load insulin response is a predictor of outcome in patients without previously recognized diabetes.Data from 933 Japanese patients who underwent both a 75 g oral glucose tolerance test and coronary angiography with suspected coronary artery disease were analyzed. The determinant factors in association with all-cause death or cardiovascular events, including reinfarction, heart failure or angina requiring re-hospitalization, and coronary revascularization were examined by multivariate Cox regression analysis.The numbers of patients with normal glucose tolerance, impaired glucose regulation and diabetes were 326, 408 and 199, respectively. During the follow-up period (median 1113 days), death occurred in 37 patients including 13 cardiac causes. There were no significant differences in mortality or cardiovascular event incidence between glucose tolerance status. Kaplan-Meier curves indicated that the lower-response group of 2-hour insulin levels (75.3 mU/L; median) was associated with higher mortality rates (Log-rank P=0.006). Multivariate Cox regression analysis revealed that 2-hour insulin level was an independent predictor of all-cause death (P=0.026) after adjustment for age, gender, number of stenosed vessels, ejection fraction, metabolic factors, and treatments.Post-load low insulin response is seen as a predictor of mortality rates for patients with no previous diagnosis of diabetes mellitus.

SummaryA 49-year-old woman was admitted to the hospital because of cardiac tamponade. The hemorrhagic pericardial effusion was cytologically negative for malignant cells. Cardiac magnetic resonance imaging showed two masses in the anterior and lateral right atrium; however, positron emission tomography (PET) image using 18F-fluorodeoxyglucose revealed strong uptake in the anterior right atrium, without other tumors or metastasis. Intraoperatively, the lateral mass was confirmed as a thrombus, whereas the anterior mass was removed surgically and was diagnosed as an angiosarcoma with histopathological examination. However, she was re-admitted to the hospital 1 month after the operation because of cerebral hemorrhage, suspicious of distant metastasis. PET is useful for the detection of cardiac angiosarcoma.

Summary Background and objective Plasma B-type natriuretic peptide (BNP) levels are determined by several factors. The presence of atrial fibrillation (AF) is one of these factors. Meanwhile, plasma BNP levels are well correlated with left ventricular (LV) filling pressure in patients with sinus rhythm. Furthermore, LV filling pressure can be estimated by the ratio of early diastolic transmitral velocity to early diastolic mitral annular velocity ( E / e ′ ratio) in patients with sinus rhythm or with AF. However, it is still unclear if elevated plasma BNP levels reflect increases in LV filling pressure in patients with AF, especially with preserved LV systolic function. This study was designed to examine which factors determine plasma BNP levels in patients with persistent nonvalvular AF and preserved LV systolic function. Methods and results We examined 195 clinically stable outpatients with persistent nonvalvular AF and preserved LV systolic function. They underwent comprehensive 2-dimensional and Doppler echocardiography, plasma BNP and creatinine levels, clinical history, and heart rate were determined. Then we statistically analyzed the correlation between plasma BNP levels and several variables including E / e ′ ratio. On univariate analyses, plasma BNP levels were significantly correlated with age, LV diastolic diameter (LVDd), E / e ′ ratio, and mitral E wave deceleration time. In addition, plasma BNP levels were significantly higher in males and in patients with a history of congestive heart failure and those who had been administered a β-blocker. On multiple linear regression analyses, E / e ′ ratio, age, LVDd, and administration of β-blocker were independent determinant factors of plasma BNP levels. Conclusions Plasma BNP levels in patients with persistent AF and preserved LV systolic function are affected by E / e ′ ratio, age, LVDd, and administration of β-blockers.

Background The cardio-ankle vascular index (CAVI) has been recently reported as a new index of aortic stiffness, which is less influenced by blood pressure than pulse wave velocity (PWV). The present study investigated the relationship between the levels of CAVI and carotid and coronary arteriosclerosis. Methods and Results The 443 consecutive patients who underwent CAVI, carotid sonography, and coronary angiography in hospital were examined. Intima - media thickness (IMT) and carotid plaque were evaluated by ultrasonography. The severity of coronary artery disease (CAD) was evaluated by coronary angiography and the subjects were divided into 4 groups (0, no significant organic stenosis: 1, 1-vessel disease: 2, 2-vessel disease: 3, 3-vessel disease). Univariate analyses showed that both CAVI and brachial-ankle PWV (baPWV) were associated with IMT and the presence of carotid plaque. Multiple stepwise regression analyses revealed that CAVI (p=0.0427), but not baPWV, was associated with the IMT. Both CAVI (p

Oxidative stress has been widely recognized to be involved in the pathogenesis of cardiopulmonary disorders. In ischemic heart diseases, it is involved not only in the development of atherosclerosis but also in ongoing ischemic injury, especially in the reperfusion process. Cardiomyopathy is another cardiac disorder in which oxidative stress is involved. In diabetic cardiomyopathy, homocysteine, a well-known source of oxidative stress, is believed to play major roles in its development. Thioredoxin (TRX) is a redox-acting protein ubiquitously present in the human body. It also is inducible by a wide variety of oxidative stresses. TRX is a multifunctional protein and has anti-inflammatory and antiapoptotic effects, as well as antioxidative effects. It is therefore feasible to think that TRX is a potential therapy for cardiac disease. Moreover, serum TRX is a well-recognized biomarker of various diseases involving oxidative stress, and this is also the case for cardiac disorders. Here we discuss how TRX is useful as a biomarker of and therapeutic agent for cardiopulmonary disorders, especially focusing on ischemic heart disease, myocarditis and oxygen sensing, and acute respiratory distress syndrome.

Background Hypoadiponectinemia has been reported to indicate an increased risk of cardiovascular disease, so the present study investigated the significance of serum adiponectin (APN) levels for predicting clinical outcomes after percutaneous coronary intervention (PCI). Methods and Results The APN levels were evaluated in 184 consecutive patients who underwent PCI. The patients were divided into Group A [the lowest quartile of APN levels (APN ≤4.5 μg/ml), n=46] and Group B [the upper 3 quartiles of APN levels (APN >4.5 μg/ml), n=138]. During a mean follow-up period of 27.3 months, the rate of major adverse cardiac and cerebrovascular events (MACCE: death from any cause, re-infarction, repeat coronary revascularization, hospitalization because of congestive heart failure, and cerebral infarction) was higher in Group A (58.7%) than in Group B (37.0%, p=0.0101). Moreover, when the APN levels were calculated by adjusting for sex, age, body mass index, and triglyceride levels, patients in the lowest quartile of residual APN levels had a higher risk of MACCE (p=0.0405). Multiple logistic analyses showed that hypoadiponectinemia (APN ≤4.5 μg/ml) was independently correlated with MACCE. Kaplan-Meier analysis demonstrated a higher MACCE rate in Group A than in Group B (Log-rank χ2=7.89, p=0.0050). Conclusion The APN level may be helpful for predicting clinical outcomes after PCI. (Circ J 2007; 71: 675 - 680)

Some ANG II receptor type 1 (AT1) antagonists are reported to inhibit proinflammatory cytokine production in vitro and in vivo. However, the effects of the drugs on autoimmune diseases are unknown. We tested the hypothesis that olmesartan, a novel AT1 antagonist, ameliorated experimental autoimmune myocarditis (EAM) in rats attributed to the suppression of inflammatory cytokines as well as to the immunomodulatory action of the heart. We administered olmesartan orally at does of 1, 3, and 10 mg·kg−1·day−1 to rats with EAM for 3 wk. The results showed that olmesartan decreased blood pressure significantly compared with the untreated group and markedly reduced the severity of myocarditis associated with the decrease of myocardial macrophage, CD4+, and CD8+ T-cell expression by comparison of heart wt-to-body wt ratios, pericardial effusion scores, and macroscopic and microscopic scores. Numbers of myocardial interleukin-1β (IL-1β)-positive-staining cells (obtained by immunohistochemistry) and quantities of IL-1β expression (obtained by Western blotting) were significantly lower in rats with EAM given olmesartan treatment compared with rats given vehicle. Cardiac myosin-specific, delayed-type hypersensitivity was significantly lower in olmesartan-treated rats than in control rats. The cytotoxic activities of lymphocytes in rats with EAM treated with olmesartan were reduced compared with untreated control rats. In vitro study showed that both olmesartan and its active metabolite RNH-6270 suppressed IL-1β production in U-937 cells and cultured myocytes. Olmesartan ameliorates acute EAM in rats. The cardioprotection of olmesartan may be due to suppression of inflammatory cytokines as well as to suppressive effects of cytotoxic myocardial injury in addition to hemodynamic modifications.

Recently, a member of the GATA-binding family of transcription factors was shown to be involved in human hypoparathyroidism, sensorineural deafness, and renal abnormality (HDR) syndrome. We report here a Japanese family in which two of the members are affected with HDR syndrome. Sequence analysis of GATA3 showed a heterozygous novel mutation in this family: an unusual mutation at exon 3 (709insC) resulting in a premature stop at codon 302 with a loss of both of the zinc finger domains.

Background Recently, the 5-lipoxygenase activating protein gene (ALOX5AP) was reported to confer a risk of myocardial infarction (MI) and stroke, independent of conventional risk factors. The purpose of the present study was to validate those findings in a Japanese population. Methods and Results The study population consisted of 1,875 subjects (males 871, females 1,004) recruited from the Suita study (control group) and 353 subjects (males 306, females 47) with MI. The promoter, all of the exons, and 3'UTR regions of ALOX5AP were sequenced in 96 subjects, and 8 polymorphisms were found. There were significant differences in the frequencies of the haplotypes constructed from the 2 SNPs (A162C and T8733A) between the control and MI groups. Multiple logistic analysis indicated that the homozygous genotype of the (CA) haplotype was significantly associated with a reduced risk for MI. Conclusion The hypothesis that ALOX5AP contributes to susceptibility for MI was validated in a Japanese population. (Circ J 2005; 69: 1029 - 1034)

Background Recently, a mutation in the human MEF2A gene was reported to be responsible for an autosomal dominant form of coronary artery disease, so the purpose of the present study was to assess the significance of MEF2A mutations in Japanese subjects with myocardial infarction (MI). Methods and Results The study population consisted of 589 control subjects recruited from the Suita study and 379 subjects with MI. The promoter, all the exons, and 3'-UTR regions of MEF2A were sequenced in 190 subjects with myocardial infarction. We found 2 amino acid length polymorphisms, a 7-amino acid deletion polymorphism, and a nonsense mutation (R447X) in exon 12. The length and deletion polymorphisms did not confer susceptibility to MI. Although the nonsense mutation was detected in 1 subject with MI, and in none of the control subjects, the impact of this mutation does not appear to be great; the subject had the MI while in his 70 s, had 2 major risk factors, and no family history of ischemic heart disease. Conclusion MEF2A polymorphism does not contribute appreciably to MI in the Japanese population. (Circ J 2005; 69: 1192 - 1195)

Background—Cardiac myosin–induced myocarditis is an experimental autoimmune myocarditis (EAM) model used to investigate autoimmunological mechanisms in inflammatory heart diseases and resembles fulminant myocarditis in humans. We investigated the therapeutic role of thioredoxin-1 (TRX-1), a redox-regulatory protein with antioxidant and antiinflammatory effects, in murine EAM.Methods and Results—EAM was generated in 5-week-old male BALB/c mice by immunization with porcine cardiac myosin at days 0 and 7. Recombinant human TRX-1 (rhTRX-1), C32S/C35S mutant rhTRX-1, or saline was administered intraperitoneally every second day from day 0 to 20. In addition, rabbit anti-mouse TRX-1 serum or normal rabbit serum was administered intraperitoneally on days −1, 2, and 6. Animals were euthanized on day 21. Histological analysis of the heart showed that TRX-1 significantly reduced the severity of EAM, whereas mutant TRX-1 failed to have such an effect, and anti–TRX-1 antibody enhanced the disease markedly. Immunohistochemical analysis showed that TRX-1 significantly suppressed cardiac macrophage inflammatory protein (MIP)-1α, MIP-2, and 8-hydroxydeoxyguanosine expression and macrophage infiltration into the heart in EAM. Although serum levels of MIP-1α were not suppressed by TRX-1 until day 21, both an in vitro chemotaxis chamber assay and an in vivo air pouch model showed that TRX-1 significantly suppressed MIP-1α– or MIP-2–induced leukocyte chemotaxis. However, real-time reverse transcription–polymerase chain reaction showed that TRX-1 failed to decrease chemokine receptor expression increased in the bone marrow cells of EAM mice.Conclusions—TRX-1 attenuates EAM by suppressing chemokine expressions and leukocyte chemotaxis in mice.

Association studies were performed to confirm the effect of polymorphisms in apolipoprotein A1 ( ApoA1) on the high-density lipoprotein cholesterol (HDL-C) level and the incidence of myocardial infarction (MI). A sequence analysis identified nine polymorphisms in ApoA1. After considering linkage disequilibrium, four polymorphisms in ApoA1 and four polymorphisms in the 5'-flanking regions and 3'-flanking regions from the JSNP database were determined in 1,880 subjects recruited from the Suita study, which represents the general population in Japan. Of the eight polymorphisms tested, the ApoA1 T84C polymorphism had the greatest effect on the levels of HDL-C ( P=0.0005, P(c)=0.0040 corrected by the Bonferroni method) and triglyceride ( P0.0001, P(c)=0.0008). The ApoA1 MspI polymorphism was not associated with HDL-C or triglyceride levels. We confirmed that the ApoA1 T84C polymorphism was associated with the HDL-C level but not the triglyceride level in patients with MI ( n=637). Moreover, this polymorphism was associated with the incidence of MI in male subjects ( P=0.0326). A logistic analysis indicated that the frequency of MI in the CC genotype was lower than that in the CT+TT genotype ( P=0.0145, OR=0.4955, 95% CI: 0.2746-0.8525). The ApoA1 T84C polymorphism is an important marker for the HDL-C level and may be a new risk marker for MI in Japanese.

We performed association studies between 118 single-nucleotide polymorphisms (SNPs) of 22 candidate genes (or gene family) and hypertension in a Japanese population.The study population consisted of 1880 subjects representing the general population in Japan, recruited from the Suita study. The candidate genes were selected based on their functions, including insulin resistance (APM1, CD36, HSD11B1), oxidative stress (CYBA, GPX1, GSTMs), steroid hormone (ESR1, ESR2, HSD11B2), renal functions (PTGS2, KLK1, NPHS1, NPHS2, SGK, SLC12A1, PTGES), and others related to cardiovascular physiology (GJA4, NOS1, NTRK3, P2RX4, SPP1, ALDH2).Multiple logistic analyses, with age and body mass index as covariates, indicated that 13 SNPs (eight genes), six SNPs (four genes) and 11 SNPs (four genes) were associated with hypertension (P0.05) in the total, male, and female populations, respectively. PTGS2 seems to be a promising candidate gene for hypertension in men. GSTM3 and SLC12A1 seem to be promising candidate genes for hypertension in women. Especially, a polymorphism in SLC12A1 was significantly associated with hypertension in women even after correction by the Bonferroni method (corrected P = 0.0236). Multiple logistic analyses, with age and body mass index as covariates, indicated that the prevalence of hypertension in females was significantly higher in subjects with the CC genotype than in those with the TT + TC genotypes (P0.0001, odds ratio = 1.967, 95% confidence interval = 1.430-2.712).Although the present results should be replicated in other study populations for confirmation, the present results suggest that SLC12A1 may contribute to hypertension in Japanese women.

To investigate the effects of polymorphisms in the ATP-binding cassette transporter A1 ( ABCA1) gene on the high-density lipoprotein cholesterol (HDL-C) level and the incidence of myocardial infarction (MI), we performed association studies. Sequence analysis identified 14 polymorphisms in the promoter region of ABCA1. After considering linkage disequilibrium, three polymorphisms in the promoter region and 11 polymorphisms from the JSNP database were determined in 1,880 subjects recruited from the Suita Study, representing the general population in Japan. We evaluated the association between the ABCA1 genotype and HDL-C level adjusted not only for standard factors, but also for genetic factors including ApoA1 and ApoE genotypes. Of the 14 polymorphisms tested, the G(-273)C ( P=0.0074), C(-297)T ( P=0.0195), and IMS-JST071749 ( P=0.0093) polymorphisms were significantly associated with the HDL-C level in the Suita population. We could reconfirm that the G(-273)C genotype was influential in another set of subjects ( P=0.0310, n=743). However, the distribution of the ABCA1 G(-273)C genotype in subjects with MI ( n=598) was not different from that in the control population ( n=801). These results indicate that ABCA1 G(-273)C has a significant effect on the HDL-C level in the general Japanese population, but not on the incidence of MI.

Carvedilol, a new β-blocker with antioxidant properties, has been shown to be cardioprotective in experimental models of myocardial damage. We investigated whether carvedilol protects against experimental autoimmune myocarditis (EAM) because of its suppression of inflammatory cytokines and its antioxidant properties. We orally administered a vehicle, various doses of carvedilol, racemic carvedilol [ R(+)-carvedilol, an enantiomer of carvedilol without β-blocking activity], metoprolol, or propranolol to rats with EAM induced by porcine myosin for 3 wk. Echocardiographic study showed that the three β-blockers, except R(+)-carvedilol, suppressed left ventricular fractional shortening and decreased heart rates to the same extent. Carvedilol and R(+)-carvedilol, but not metoprolol or propranolol, markedly reduced the severity of myocarditis at the two different doses and suppressed thickening of the left ventricular posterior wall in rats with EAM. Only carvedilol suppressed myocardial mRNA expression of inflammatory cytokines and IL-1β protein expression in myocarditis. In addition, carvedilol and R(+)-carvedilol decreased myocardial protein carbonyl contents and myocardial thiobarbituric acid-reactive substance products in rats with EAM. The in vitro study showed that carvedilol and R(+)-carvedilol suppressed IL-1β production in LPS-stimulated U937 cells and that carvedilol and R(+)-carvedilol, but not metoprolol or propranolol, suppressed thiobarbituric acid-reactive substance products in myocardial membrane challenged by oxidative stress. It was also confirmed that probucol, an antioxidant, ameliorated EAM in vivo. Carvedilol protects against acute EAM in rats, and the superior cardioprotective effect of carvedilol compared with metoprolol and propranolol may be due to suppression of inflammatory cytokines associated with the antioxidant properties in addition to the hemodynamic modifications.

Thioredoxin (TRX) is a redox regulatory protein that protects cells from various stresses. Angiotensin-converting enzyme (ACE) inhibitor was reported to enhance endogenous antioxidant enzyme activities. This study was carried out to investigate whether temocapril, a novel non-sulfhydryl containing ACE inhibitor, reduces the severity of myocarditis via redox regulation mechanisms involving TRX. Western blot showed that temocapril enhanced cytosolic redox regulatory protein TRX expression, but neither mitochondrial TRX2 nor antioxidant enzymes, such as copper-zinc superoxide dismutase (Cu/Zn-SOD) or manganese superoxide dismutase (Mn-SOD) expression, was increased by the preconditioning treatment. In rats with experimental autoimmune myocarditis (EAM), the protein carbonyl content, a marker of cellular protein oxidation, was increased accompanied with enhanced TRX expression. An immunohistochemical study showed that TRX stain was enhanced in infiltrating inflammatory cells and in damaged myocytes. The severity of the myocarditis and the protein carbonyl contents were less increased in temocapril treatment (10 mg/kg/day, orally) from day 1 to day 21 in which TRX was up regulated when the inflammation started, but not in temocapril treatment from day 15-21 in which TRX was not up-regulated when the inflammation started. The results suggest that TRX and the redox state modified by TRX may play a crucial role in the pathophysiology of EAM. Temocapril ameliorates myocarditis associated with inducing TRX increase in a preconditioning manner, although the mechanism of TRX induction by temocapril remains to be elucidated.

An important role of redox regulation in myocardial diseases and heart failure has been postulated. Thioredoxin (TRX) is a redox-regulating protein. Recent studies indicated a possible association between plasma TRX concentrations and the severity of heart failure. Accordingly, we investigated the myocardial expression of TRX in patients with myocarditis and cardiomyopathies. Four cases of hypertrophic cardiomyopathy (HCM), 10 of dilated cardiomyopathy (DCM), 6 of myocarditis, and 5 of controls were studied. Right and left ventricular endomyocardial biopsy samples were obtained at the diagnostic cardiac catheterization. The samples were processed for immunohistological staining for TRX, which was done by the indirect immunoperoxidase technique. 8-hydoxy-2′-deoxyguanosine (8-OHdG), one of the major DNA base-modified products, was also detected for an established marker for oxidative stress. TRX immunoreactivity was none or trivial in control specimens. Positive TRX staining was found in 6 cases; 3 in active myocarditis and 3 in DCM. The positive staining was found in infiltrating cells and damaged myocytes in the perinecrotic lesions. Damaged myocytes were also positive for 8-OHdG. All the 3 cases of DCM positive for TRX stain showed severe left ventricular hypertrophy on electrocardiogram and highly elevated left ventricular end-diastolic pressure (> 24 mmHg), suggesting the overload of oxidative stress by hemodynamic impairment. Myocardial TRX was upregulated in myocarditis and cardiomyopathies with active necrotic stage associated with DNA damage, which may reflect the oxidative stress overload in hemodynamically uncontrolled status.

Excessive production of nitric oxide (NO) by inducible NO synthase (iNOS) contributes to the progression of myocardial damage in myocarditis. Some dihydropyridine calcium channel blockers reportedly inhibit NO production and proinflammatory cytokines and the present study sought to clarify if a low dose of benidipine, a novel dihydropyridine calcium channel blocker, would ameliorate experimental autoimmune myocarditis (EAM). Rats with or without myocarditis were administered oral benidipine at a dose of 3 mg · kg-1 · day-1 for 3 weeks. Low-dose benidipine did not decrease blood pressure significantly compared with the untreated group, but markedly reduced the severity of myocarditis. Myocardial interleukin-1β (IL-1β) expression and IL-1β-positive cells were significantly less in rats with EAM that were treated with low-dose benidipine compared with untreated rats. Also, myocardial iNOS expression and iNOS-positive cells were markedly reduced in in the treated rats compared with the untreated group. Furthermore, myocardial NO production and nitrotyrosine expression were suppressed by the treatment in rats with EAM. The cardioprotection of low-dose benidipine may be caused by suppression of inflammatory cytokines and inhibition of NO production. (Circ J 2003; 67: 545 - 550)

Selective blockade of the norepinephrine transporter with reboxetine has been reported to induce a slight but significant increase in blood pressure. This study was designed to examine the relation of genetic variants of the norepinephrine transporter gene (solute carrier family 6, member 2; SLC6A2) with hypertension in a Japanese population. We genotyped five genetic variants of SLC6A2, three in the promoter region and two in the intronic sequence, in 1,950 subjects recruited from the Suita study. One of the variants, an A>G polymorphism in the promoter region (Promoter 3 polymorphism), was found to be associated with hypertension. Multiple logistic analysis indicated that sex (p =0.0223), age (p

We here describe the first example of a cancer of unknown primary (CUP) patient with concomitant idi- opathic pulmonary arterial hypertension who was treated with docetaxel monotherapy. A 43-year-old woman was admitted to our hospital with left chest pain in June 2011. Based on the results of the general physical and other examinations, the patient was diagnosed as having CUP. The patient was treated with total doses of 40 Gy to a painful bone metastasis, followed by docetaxel mono- therapy at 60 mg/m 2 . Nine days after chemotherapy, she developed shortness of breath, and laboratory investiga- tions showed a substantial increase in serum amino-ter- minal pro-brain natriuretic peptide levels of 293.2 pg/ml (normal range, \125 pg/ml). At day 17, the right ventric- ular systolic pressure increased from 93 to 125 mmHg, suggesting right-sided heart failure, and consequently she died on day 21.

A 31-year-old woman suspected to have acute myocarditis was admitted to hospital and was managed with intra-aortic balloon pumping and a percutaneous cardiopulmonary support system because of sustained ventricular tachycardia. After immunoglobulin treatment, cardiac function and systematic inflammation were improved. The left ventricular endomyocardial biopsy revealed massive necrosis and degeneration of myocardial cells, and extensive infiltration of inflammatory cells. The clinicopathology of this patient was thought to be fulminant myocarditis. Serial serum thioredoxin (TRX) analysis showed that the serum level was high during the acute phase, and decreased during the chronic phase. Immunohistochemistry for TRX in the biopsy samples showed that inflammatory cells and cardiomyocytes were positively stained.

—In the present study, the mechanisms and importance of the Fc portion of immunoglobulin in experimental giant cell myocarditis were examined. Giant cell myocarditis was induced in rats by immunization of porcine cardiac myosin. Human intact immunoglobulin (1 g · kg−1· d−1) or F(ab′)2fragments of human immunoglobulin (1 g · kg−1· d−1) were administered intraperitoneally daily on days 1 to 21. Intact immunoglobulin administration significantly ameliorated myocarditis, but F(ab′)2fragments did not. The ribonuclease protection assay revealed that therapy with intact immunoglobulin, but not F(ab′)2fragments, suppressed the mRNA expressions of inflammatory and proinflammatory cytokines. Immunohistochemical analysis showed that therapy with intact immunoglobulin, but not F(ab′)2fragments, suppressed dendritic cell (DC) expression during both the early and the subsequent fulminant phases. Moreover, the early treatment of intact immunoglobulin until the 11th day or 14th day, when the expression of DCs was completely suppressed, ameliorated myocarditis. However, the late treatment of intact immunoglobulin beginning on day 15, when the expression of DCs had already been completed, failed to ameliorate the condition. An in vitro study showed that intact immunoglobulin, but not F(ab′)2fragments, suppressed the lipopolysaccharide-induced interleukin-1β production associated with the downregulation of CD32 antigen (Fcγ receptor II) expression. Thus, intact immunoglobulin therapy markedly suppressed myocarditis as a result of Fc receptor–mediated anti-inflammatory action, and the suppression of the disease was associated with the suppression of DCs, ie, the suppression of the initial antigen-priming process in experimental giant cell myocarditis.

Redox regulating mechanisms may be involved in the pathogenesis of viral myocarditis and thioredoxin (TRX) is a small multifunctional protein that contains a redox active sequence. The present study investigated the histopathology and characteristics of TRX expression in acute coxsackievirus B3 myocarditis in inbred strains of mice (severe myocarditis in DBA/2 mice, moderate myocarditis in BALB/c mice and mild myocarditis in C57BL/6 mice). Thioredoxin was upregulated and its expression correlated with the severity of the disease. In addition, 8-hydroxy-2'-deoxyguanosine, which is an established marker for oxidative stress, was concominantly positive in damaged myocytes. Thus, TRX may be specifically induced by the acute inflammatory stimuli in murine viral myocarditis, and the severity and development of acute viral myocarditis may be regulated by the cellular redox state.

An increase in oxidative stress is thought to be involved in the progression of heart disease, but the serum level of thioredoxin (TRX), which regulates the cellular redox state, has not been investigated in patients with heart diseases. The present study determined serum TRX levels with a sandwich enzyme-linked immunosorbent assay in a total of 39 patients with dilated cardiomyopathy (DCM) (n=5), acute coronary syndrome (ACS) (n=7) or stable angina (n=18), including effort angina (n=7) and vasospastic angina (n=11), and in control subjects (n=7). The serum TRX level in patients with New York Heart Association (NYHA) functional classes III and IV (n=8, 33.3+/-8.6 ng/ml) was significantly higher than in the control subjects (n=7, 14.0+/-4.6 ng/ml). In addition, the serum TRX levels correlated positively with the severity of NYHA class, and negatively with the left ventricular ejection fraction. The serum TRX levels were elevated in patients with ACS and DCM compared with the controls. These results indicate a possible association between TRX concentration and the severity of heart failure.

Immunogenetic mechanisms may be involved in the pathogenesis of myocarditis and dilated cardiomyopathy. The present study investigated the incidence, histopathology and histocompatibility characteristics of experimental giant cell myocarditis in various strains of rats. Experimental giant cell myocarditis was induced by immunization with porcine cardiac myosin in Lewis (RT-1(l)), Dahl (DIR/Eis) (RT-1(l)), Fisher (RT-1(lv 1)) rats, but not in Dahl (DIS/Eis) (RT-1(l)) or Brown Norway (RT-1(n)). Myocarditis was most severe in the Lewis rats and their heart weight/body weight ratio was significantly higher than that of control rats immunized with Freund's complete adjuvant alone. In conclusion, this study provides evidence that the expression and severity of experimental giant cell myocarditis may be determined mainly by genetic factors, including both major histocompatibility complex genes as well as other genes, which may be controlled by an immune mechanism.

To investigate the precise disease progression in myocarditis, Lewis rats were injected with porcine cardiac myosin, and C3H/He mice were inoculated with coxsackievirus B3. Both were killed serially, and the hearts were stained with hematoxylin-eosin to compare their pathological characteristics. In viral myocarditis, viral replication in the myocardium resulted in myocardial necrosis with inflammation, and the lesions were distributed transmurally, as previously reported. On the other hand, in giant cell myocarditis, inflammatory lesions appeared at first around the capillaries in the epicardium, and thereafter spread transmurally. Pericardial effusion was noticed in all the rats with myocarditis in the fulminant stage. Levels of interleukin (IL) -1beta and IL-6 in the pericardial effusion were elevated compared with the serum cytokines at the peak of inflammation. However, interferon-gamma in both the pericardial effusion and serum was not elevated. The cause of the myocardial lesions that developed in rats with giant cell myocarditis may be some active inflammatory process via the pericardial effusion.

In this paper, we suggest the improvement of the optimum bus transportation network system, considering the ‘rapid-service bus’. The particular feature is follows:(1) We organize an effect on bus transportation network, by means of running ‘rapid-service bus’(2) We improve the optimum bus transportation network system (which is included the schedule of buses), considering ‘rapid-service bus’.(3) In this study, the useful results can be obtained through numerical analyses applied with reference to Kanazawa city.

Travel mode which commuters choice is not always decided. For example, they change their travel mode because of weather and other purpose. In this study, we analyzed ‘daily change’ of commuter's travel mode, and examine how to apply its result to public transportation planning.As the result, we understood that a temporary condition (weather and other purpose), commuter's individual attribute, and bus service affects commuter's travel choice.

To investigate whether microvascular lesions are present in the skin of patients with chronic congestive heart failure (CHF), skin biopsies were performed at the time of cardiac catheterization, and the results were compared with control subjects. The diagnosis of CHF was done by cardiac catheterization with reference to the elevation of plasma levels of brain natriuretic peptide (BNP). Although the severity of arteriolar hyalinosis did not correlate with the New York Heart Association functional class, increased hyalinosis was found in skin biopsies from 17 of 20 patients with CHF, but in none of the 6 control subjects. These results indicate that microangiopathic alterations in arterioles may exist in patients with CHF and therapy for peripheral vascular remodeling might be considered for such patients.

Animal models of myocarditis are of great value for studying the pathophysiology of the disease. To clarify the key factors for determining the severity of myocarditis, we analyzed immunohistological surface markers of myocardial infiltrating cells in various animal models, and the relationship between myocardiogenic antigens and abnormal behaviours of infiltrating cells was discussed. Myocarditis was induced in mice and rats by cardiotropic viruses and by porcine cardiac myosin. Animals were sacrificed at the peak of their disease. Pathological examinations were performed, and the severity of the lesions was scored semiquantitatively. There were striking differences in the severity of viral and autoimmune giant cell myocarditis among different animal models. However, the majority of myocardial infiltrating cells were comprised of macrophages and CD4+ T cells. Different immunological behaviours of myocardial infiltrating cells were demonstrated in these models of myocarditis. However, the development of severe myocardial lesions may depend on the macrophage-CD4 cell lineage in these animal models.

A 71-year-old woman was admitted to our department because of acute myocarditis. She was ameliorated with conventional heart failure treatment, however she developed left ventricular dilatation and cardiac troponin T (cTnT) was elevated again to >1.0ng/ml 6 month after the first admission. She was re-admitted because of recurrent decompensated heart failure in spite of conventional treatment. Right ventricular endomyocardial biopsy revealed active myocarditis. Immunosuppressive therapy with prednisolone and azathioprine improved her symptoms and left ventricular function accompanied by a striking decrease of cTnT levels. The decreased cTnT level indicated an effective response to immunosuppression early after the beginning of treatment. These findings suggested that it is possible to evaluate the response to immunosuppressive therapy by serial measurement of cardiac troponin.

Background Recently, a large case-control study (2,851 cases and 2,592 controls) reported that a functional single nuclear polymorphism (SNP) in the proteasome subunit α type 6 gene (PSMA6) conferred a risk of myocardial infarction (MI) in a Japanese population. The SNP (exon 1, -8C/G) is located in the 5' untranslated region of exon 1, and the risk-conferring allele G appears to enhance the transcription of PSMA6, which may exaggerate inflammation through activation of nuclear factor-κ β protein. The frequency of the risk conferring genotype (GG) in cases was reported to be greater than that in controls (12.4% vs 8.9%). The purpose of the present study was to validate this observation in our study population. Methods and Results Subjects with MI (n=433) were recruited from the outpatient clinic of the National Cardiovascular Center. Control subjects (n=2,186) were recruited from the Suita study. The frequencies of the GG genotype did not significantly differ between the control (9.8%) and MI groups (10.6%). Moreover, this genotype was not associated with C reactive protein levels in the Suita study. However, the GG genotype was significantly associated with greater intima-media thickness (n=2,051, p=0.015) after adjusting for blood pressure, sex, body mass index and age in the Suita study. Conclusion The reported genotype in PSMA6 appears not to contribute appreciably to MI, but may contribute slightly to atherosclerosis in the present study population. (Circ J 2007; 71: 495 - 498)

It is important to regulate the oxygen concentration and scavenge oxygen radicals throughout the life of animals. In mammalian embryos, proper oxygen concentration gradually increases in utero and excessive oxygen is rather toxic during early embryonic development. Reactive oxygen species (ROS) are generated as by-products in the respiratory system and increased under inflammatory conditions. In the pathogenesis of a variety of adult human diseases such as cancer and cardiovascular disorders, ROS cause an enhancement of tissue injuries. ROS promote not only the development of atherosclerosis but also tissue injury during the reperfusion process. The thioredoxin (TRX) system is one of the most important mechanisms for regulating the redox balance. TRX is a small redox active protein distributed ubiquitously in various mammalian tissues and cells. TRX acts as not only an antioxidant but also an anti-inflammatory and an antiapoptotic protein. TRX is induced by oxidative stress and released from cells in response to oxidative stress. In various human diseases, the serum/plasma level of TRX is a well-recognized biomarker of oxidative stress. Here we discuss the roles of TRX on oxygen stress and redox regulation from different perspectives, in embryogenesis and in adult diseases focusing on cardiac disorders.

Summary Background:Increased oxidative stress has been implicated in the pathogenesis of coronary vasospasm. Thioredoxin (TRX) is a redox-active protein that is known to be induced by oxidative stress. Hypothesis:The serum TRX level may be high in patients with coronary vasospasm. Methods: The serum TRX level was determined using an enzyme-linked immunosorbent assay in 21 patients with the active stage of coronary spastic angina (CSA), in 18 patients with the inactive stage of CSA (iCSA), in 24 control subjects without coronary artery disease (Control), and in 20 patients with stable effort angina (SEA). Results: Serum TRX levels (mean ± standard deviation ng/ml) were significantly higher in CSA (64 ± 44) than in iCSA (28 ± 26), in Control (34 ± 15), and in SEA (36 ± 16). In contrast, serum � -tocopherol levels (mg/g lipids) were significantly lower in CSA (2.8 ± 0.7) than in Control (4.0 ± 1.2) and in SEA (3.2 ± 0.4). Current smoking was significantly more prevalent in CSA (76%) than in any of the other groups. No significant correlation was found between the serum level of TRX and � -tocopherol in the study subjects. In nine patients with CSA, the serum TRX level decreased (93 ± 41 → 41 ± 35 ng/ml) and the � -tocopherol level increased (2.7 ± 0.6 → 3.2 ± 0.7 mg/g lipids) significantly under medication with calcium entry blockers after an at least 3-month angina-free period. Conclusions:Patients with coronary spastic angina had a higher serum TRX level associated with a lower serum level of antioxidant vitamin E, with redox equilibrium appearing to be related to the disease activity of coronary vasospasm in these patients. Oxidative stress may be related to the genesis of coronary vasospasm.

To the Editor: We read with great interest the article by Mineo and colleagues1 exploring the role of FcγIIB, an inhibitory receptor of FcγIIs, on C-reactive protein (CRP)-mediated endothelial dysfunction. Mineo et al examined the mechanisms of CRP actions on endothelium by testing the hypothesis that CRP attenuates endothelial NO synthase (eNOS) activation in vitro. The investigators found that CRP-induced declines in NO production promote monocyte adhesion to endothelium. They further investigated …

Adiponectin is an adipocyte-derived endocrine factor. Hypoadiponectinemia has been observed in obese patients, and plasma adiponectin levels are reported to increase during weight reduction. Moreover, hypoadiponectinemia has also been observed in patients with coronary artery diseases. The present study investigated the relationships between levels of adiponectin and carotid intimal-medial thickness, a marker of early vascular disease, and carotid artery plaque and the severity of coronary artery disease, a marker of advanced vascular disease.Four hundred thirty-one consecutive patients were enrolled from inpatients without acute coronary syndrome who underwent coronary angiography between August 2001 and August 2003. The residual adiponectin levels were calculated by adjusting for sex, age, and body mass index, and a logarithmic transformation was applied. The severity of coronary artery disease was evaluated by coronary angiography and divided into four groups (Group 0: no significant organic stenosis, Group 1: 1-vessel disease, Group 2: 2-vessel disease, Group 3: 3-vessel disease or left main coronary trunk disease). Carotid plaque was evaluated by ultrasonography and divided into two groups [Group(-) : patients without carotid plaque, Group (+): patients with carotid plaque]. The intimal-medial thickness was measured on a longitudinal scan of the common carotid artery at a point 1 cm proximal from the bifurcation bulb.The logarithmic-transformed levels of residual adiponectin were associated with severity of coronary artery disease (Group 0: 0.18 +/- 0.59 microg/ml, Group 1: -0.02 +/- 0.56 microg/ml, Group 2: - 0.09 +/- 0.58 microg/ml, Group 3: - 0.10 +/- 0.66 microg/ml, p = 0.0013). The logarithmic-transformed levels of residual adiponectin were decreased in patients with carotid plaque [Group (-): 0.08 +/- 0.59 microg/ml, Group (+): - 0.08 +/- 0.59 microg/ml, p = 0.045]. However, the logarithmic-transformed levels of residual adiponectin were not associated with intimal-medial thickness (p = 0.6398).Hypoadiponectinemia adjusted for sex, age, body mass index implies the progression of carotid and coronary sclerosis.

In this study, we tested the hypothesis that MCI-186 (3-methyl-1-phenyl-2-pyrazolin-5-one; edaravone), a novel free radical scavenger, protects against acute experimental autoimmune myocarditis (EAM) in rats by the radical scavenging action associated with the suppression of cytotoxic myocardial injury. Recent evidence suggests that oxidative stress may play a role in myocarditis. We administered MCI-186 intraperitoneally at 1, 3, and 10 mg·kg−1·day−1to rats with EAM for 3 wk. The results were compared with untreated rats with EAM. MCI-186 treatment did not affect hemodynamics. MCI-186 treatment (3 and 10 mg·kg−1·day−1) reduced the severity of myocarditis as assessed by comparing the heart-to-body weight ratio and pathological scores. Myocardial interleukin-1β (IL-1β)-positive cells and myocardial oxidative stress overload with DNA damage in rats with EAM given MCI-186 treatment were significantly less compared with those of the untreated rats with EAM. In addition, MCI-186 treatment decreased not only the myocardial protein carbonyl contents but also the myocardial thiobarbituric acid reactive substance products in rats with EAM. The formation of hydroxyl radicals in MCI-186-treated heart homogenates was decreased compared with untreated heart homogenates. Furthermore, cytotoxic activities of lymphocytes of rats with EAM treated with MCI-186 were significantly lower compared with those of the untreated rats with EAM. Hydroxyl radicals may be involved in the development of myocarditis. MCI-186 protects against acute EAM in rats associated with scavenging hydroxyl free radicals, resulting in the suppression of autoimmune-mediated myocardial damage associated with reduced oxidative stress state.

We investigated the suppressive effects of immunoglobulin (Ig) on effector T cells in autoimmune myocarditis. Treatment with Ig reduced production of the so-called T-helper type 1 (Th1) cytokines stimulated by concanavalin A or cardiac myosin in cultured lymph node (LN) cells from rats with myocarditis. The cytotoxic activities of LN cells from rats immunized with myosin and treated with Ig were reduced against cardiomyocytes and F-2 cells compared with those treated without Ig. The adoptive transfer of myocarditis from LN cells of Lewis rats with myocarditis to severe combined immunodeficient (SCID) recipients was successfully achieved. Treatment with Ig, but not with F(ab′)2fragments of Ig, reduced the mortality and severity of myocarditis in SCID recipient mice. Decreased ability of LN cells of Ig-treated rats, but not rats treated with F(ab′)2fragments, to transfer autoimmune myocarditis was also demonstrated. The findings of the present study suggest that autoimmune myocarditis was successfully transferred to SCID mice and that treatment with Ig ameliorated autoimmune myocarditis by inducing selective myosin unresponsiveness via the Fc portion, resulting in suppression of Th1 cytokine production and cytotoxic activities of LN cells, which operated together in the development of autoimmune myocarditis.

Excess amount of cytokine produced by inflammatory stimuli contributes to the progression of myocardial damage in myocarditis. Some angiotensin II receptor type 1 antagonists are reported to inhibit proinflammatory cytokine production in vitro and in vivo. We tested the hypothesis that olmesartan, a novel angiotensin II receptor type 1 antagonist, ameliorated experimental autoimmune myocarditis (EAM) in rats attributing to the suppression of inflammatory cytokines in the heart. We orally administered olmesartan 1, 3, and 10 mg/kg/day to rats with EAM for 3 weeks. The results showed that olmesartan decreased blood pressure significantly compared with the untreated group, but markedly reduced the severity of myocarditis by comparing the heart weight/body weight ratio, pericardial effusion scores, macroscopic scores and microscopic scores. Myocardial interleukin (IL)- 1beta expression by western blotting and IL-1beta-positive staining cells by immunohistochemistry were significantly lower in rats with EAM given olmesartan treatment compared with those of rats given vehicle. We conclude that Olmesartan ameliorates acute EAM in rats. The cardioprotection of olmesartan may be due to suppression of inflammatory cytokines dependent of the hemodynamic modifications.

We investigated whether carvedilol protects against experimental autoimmune myocarditis (EAM) attributing to antioxidant properties. Acute EAM was induced by porcine cardiac myosin in Lewis rats. We orally administered a vehicle, various dosages of carvedilol, metoprolol, or propranolol to rats with EAM for 3 weeks. Three beta-blockers decreased heart rates to the same extent. Carvedilol, but not metoprolol or propranolol, markedly reduced the severity of myocarditis at the two different dosages. Only carvedilol decreased the myocardial protein carbonyl contents, and also decreased the myocardial thiobarbituric acid reactive substance products in rats with EAM. Accordingly, carvedilol protects against acute EAM in rats, and this superior cardioprotective effect of carvedilol to metoprolol and propranolol may be due to the antioxidant properties in addition to the hemodynamic modifications.

Objective It has been suspected that the mast cell chymase gene (CMA1) is important for the generation of angiotensin II and therefore might be associated with the pathogenesis of hypertension. Methods We sequenced the promoter region, exons, and exon-intron junctions of CMA1 and found 13 single-nucleotide polymorphisms, two of which were loss-of-function mutations. The loss-of-function mutations resulted in: (1 ) a premature stop codon; and (2) atypical splicing which creates a frame-shift and a stop codon. To elucidate the role of CMA1 in blood pressure regulation, we conducted an association study using these polymorphisms, including the loss-of-function mutations. The study population consisted of 1859 subjects, selected consecutively from the Suita study, an epidemiological cohort representing the general population in Japan. Results There was no difference in the genotype distribution of the polymorphisms we studied between hypertensive and normotensive subjects, among either men or women. Moreover, neither of the heterozygous loss-of function mutations had a significant effect on blood pressure values. Conclusion Our data suggest that CMA1 is unlikely to influence blood pressure levels in the Japanese population.

This study focused on 3 genetic polymorphisms that have previously been implicated in hypertension: the α-adducin (ADD1/Gly460Trp), β1-adrenoreceptor (ADRB1/Arg389Gly), and G-protein β3 subunit (GNB3/C825T) gene polymorphisms. We determined genetic variants using the TaqMan system in a large cohort representing the general population in Japan (867 males, 1,013 females). Logistic analysis indicated that the ADD1/ G460W polymorphism was associated with hypertension in female subjects. The odds ratio of the WW genotype for hypertension was 1.53 (95%CI, 1.12-2.08) over the WG+GG genotype (p =0.0070, p corrected (pc) =0.0420 corrected by the Bonferroni method). The ADRB1/R389G polymorphism tended to be associated with hypertensive status in male subjects (p =0.0117, pc =0.0702). The odds ratio of the GG genotype for hypertension was 0.38 (95%CI, 0.167-0.780) over the RR+RG genotype. The GNB3/C825T polymorphism was not associated with hypertensive status in either male or female subjects. The present results do not agree with those in previous reports. Almost all common variants may have only a modest effect on common diseases, and a single study even employing 1,880 subjects may lack the statistical power to detect a real association. Accordingly, it will be necessary to verify the association between these three genes and hypertension using a larger number of subjects from the Suita cohort or another population. (Hypertens Res 2004; 27: 31-37)