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Aims: The utility of carotid intima-media thickness (cIMT) as a marker for coronary heart disease is under heavy debate. This is predominantly due to the lack of a standard definition of cIMT, leading to inconsistent results. We investigated and compared the relationships of five different measures of cIMT with coronary calcium., Methods: Japanese men aged 40-79y ( n=869) from Shiga Epidemiological Study of Subclinical Atherosclerosis were examined. Mean cIMT was measured in three segments of the carotid arteries: common carotid artery (CCA mean ), internal carotid artery (ICA mean ) and bifurcation (Bif mean ). Mean cIMT of average values (Mean cIMT) and mean cIMT of maximum values (Mean-Max cIMT) of all segments combined were assessed. Coronary calcium was assessed as coronary artery calcification (CAC). Ordinal logistic regression was used to determine the odds ratio (OR) of higher CAC per 1 standard deviation higher cIMT measure. Analyses were adjusted for cardiovascular covariates and stratified by age quartiles., Results: All cIMT measures had positive associations with CAC (p＜0.001): [OR, 95% Confidence Interval]: ICA mean [1.23, 1.07-1.42], CCA mean [1.27, 1.08-1.49], Bif mean [1.33, 1.15-1.53], Mean cIMT [1.42, 1.22-1.66], and Mean-Max [1.50, 1.28-1.75]. In age-stratified analyses, only Mean-Max cIMT maintained a significant relationship with CAC in every age quartile (p＜0.05), while CCA mean had some of the weakest associations among age quartiles., Conclusions: Mean-Max cIMT had consistently stronger associations with coronary calcium, independent of important confounders, such as age. The most oft-used measure, CCA mean , was no longer associated with coronary calcium after age-adjustment and stratification.

Background and Aims: The impact of weight changes in middle age on the incidence of cardiovascular disease has not been well elucidated. We investigated whether a 5-year weight change was associated with risk of stroke and coronary heart disease (CHD) in middle-aged individuals., Methods: We analyzed data of 74,928 participants aged 40-69 years who provided responses to the baseline and 5-year follow-up questionnaires in the Japan Public Health Center-based Prospective Study. Weight change was calculated by subtracting self-reported weight at baseline from that at 5-year follow-up. Stroke and CHD events were confirmed by reviewing hospital records., Results: During 997,406 person-years of follow-up, we documented 3,975 stroke and 914 CHD events. The multivariable HRs of stroke for losing ≥5 kg compared to stable weight (change ≤2 kg) was 1.17 (95% CI, 1.01-1.37) in men versus 1.33 (1.13-1.57) for losing ≥5 kg and 1.61 (1.36-1.92) for gaining ≥5 kg in women (U-shaped association). These associations did not change after the exclusion of early events. The multivariable HR of CHD for gaining ≥5 kg was 1.22 (0.95-1.58) in men. After exclusion of early events within another 5 years, that positive association became stronger [multivariable HR 1.34 (1.00-1.82)]., Conclusions: Weight gain during middle age was associated with an increased risk of stroke in women and an increased risk of CHD in men. Weight loss was associated with an increased risk of stroke in both men and women., (Copyright © 2021. Published by Elsevier B.V.)

FOXO3 is a prominent longevity gene. To date, no-one has examined whether longevity-associated FOXO3 genetic variants protect against mortality in all individuals, or only in those with aging-related diseases. We therefore tested longevity-associated FOXO3 single nucleotide polymorphisms in a haplotype block for association with mortality in 3,584 elderly American men of Japanese ancestry, 2,512 with and 1,072 without a cardiometabolic disease (CMD). At baseline (1991-1993), 1,010 CMD subjects had diabetes, 1,919 had hypertension, and 738 had coronary heart disease (CHD). Follow-up until Dec 31, 2019 found that in CMD-affected individuals, longevity-associated alleles of FOXO3 were associated with significantly longer lifespan: haplotype hazard ratio 0.81 (95% CI 0.72-0.91; diabetes 0.77, hypertension 0.82, CHD 0.83). Overall, men with a CMD had higher mortality than men without a CMD ( P =6x10 -7 ). However, those men with a CMD who had the FOXO3 longevity genotype had similar survival as men without a CMD. In men without a CMD there was no association of longevity-associated alleles of FOXO3 with lifespan. Our study provides novel insights into the basis for the long-established role of FOXO3 as a longevity gene. We suggest that the FOXO3 longevity genotype increases lifespan only in at-risk individuals by protection against cardiometabolic stress.

Background and Aim: The association of serum cholesterol levels with the occurrence of coronary heart disease (CHD) mortality during a follow-up of 50 years was rarely investigated previously. Thus, we took advantage of results at hand in 10 pooled cohorts of men aged 40-59 years from the Seven Countries Study (9063 individuals and 2057 CHD fatal events) and we assessed this., Methods and Results: Cox proportional hazards models were run with CHD fatal events (as dependent variable) and cholesterol levels (as independent variables) at years 0, 10, and 25 (in 5 cohorts). Cumulative events during subsequent decades (cumulative approach: CA) and separately in each subsequent decade (partitioned approach: PA) were analyzed. The ecological correlation of average baseline serum cholesterol levels with CHD mortality was very high (R = 0.97). Serum cholesterol and CHD mortality for 50 years were associated at the individual level, and the association estimated by the Cox's coefficients (and related hazards ratios) was initially strong in both CA and PA, but slightly declined during later decades. Hazards ratios (for a difference of 40 mg/dl) ranged from 1.39 to 1.20 for CA and from 1.39 to 0.80 for PA. Coefficients were larger for CA than for PA and the decline was more evident for the latter. Partitioned coefficient became negative and significant in the last decade (from year 40-50). Coefficients derived from cholesterol levels measured at year 10 of follow-up showed similar trends but their magnitude was smaller., Conclusion: Thus, the relationship of serum cholesterol levels with CHD mortality remained relatively stable during at least 40 years after a single cholesterol measurement at baseline in middle-aged men., (Copyright © 2020 The Italian Diabetes Society, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition and the Department of Clinical Medicine and Surgery, Federico II University. Published by Elsevier B.V. All rights reserved.)

Aims: This study aims to investigate the association between serum small dense low-density lipoprotein (sdLDL) cholesterol level and the development of coronary heart disease (CHD) in a Japanese community., Methods: A total of 3,080 participants without prior cardiovascular disease, aged 40 years or older, were followed up for 8 years. The participants were divided into the quartiles of serum sdLDL cholesterol levels. The risk estimates were computed using a Cox proportional hazards model., Results: During the follow-up period, 79 subjects developed CHD. Subjects in the highest quartile had a 5.41- fold (95% confidence interval, 2.12-13.82) higher risk of CHD than those in the lowest quartile after controlling for confounders. In the analysis classifying the participants into four groups according to the levels of serum sdLDL cholesterol and serum low-density lipoprotein (LDL) cholesterol levels, the risk of CHD almost doubled in subjects with sdLDL cholesterol of ≥ 32.9 mg/dL (median), regardless of serum LDL cholesterol levels, as compared with subjects with serum sdLDL cholesterol of ＜32.9 mg/dL and serum LDL cholesterol of ＜120.1 mg/dL (median). When serum sdLDL cholesterol levels were incorporated into a model with known cardiovascular risk factors, c-statistics was significantly increased (from 0.77 to 0.79; p=0.02), and the net reclassification improvement was also significant (0.40; p＜0.001)., Conclusions: The present findings suggest that the serum sdLDL cholesterol level is a relevant biomarker for the future development of CHD that offers benefit beyond the serum LDL cholesterol level and a possible therapeutic target to reduce the burden of CHD in a Japanese community.

We investigated the relationship between time trends in nutrient intake and coronary risk factors/mortality rates in Tanushimaru, a Japanese cohort of the Seven Countries Study. All men between the ages of 40 and 64 were enrolled. Subjects numbered 628 in 1958, 539 in 1977, 602 in 1982, 752 in 1989, 402 in 1999, 329 in 2009, and 160 in 2018. Eating patterns were evaluated by 24-h dietary recall from 1958 through 1989, and by a food frequency questionnaire administered from 1999 through 2018. The total daily energy intake decreased from 2,837 kcal in 1958 to 2,096 kcal in 2018. Carbohydrate intake as a percentage of the total decreased remarkably from 84% (1958) to 53% (2018), whereas there was a large increase in fat intake (from 5 to 24%) during the same period. Age-adjusted mean cholesterol levels rose sharply (from 167.9 to 209.4 mg/dl) and body mass index levels also increased (from 21.7 to 24.4 kg/m 2 ), but smoking rate decreased from 69% (1958) to 30% (2018). The mortality rates from stroke and cancer declined, but mortality from myocardial infarction and sudden death remained stable at low levels. The remarkable changes in dietary patterns over the last 60 years can be related to coronary risk factors, but not currently to the mortality of coronary artery disease; more follow-up is needed.

Objective: Tub bathing is considered to have a preventive effect against cardiovascular disease (CVD) by improving haemodynamic function. However, no prospective studies have investigated the long-term effects of tub bathing with regard to CVD risk., Methods: A total of 30 076 participants aged 40-59 years with no history of CVD or cancer were followed up from 1990 to 2009. Participants were classified by bathing frequency: zero to two times/week, three to four times/week and almost every day. The HRs of incident CVD were estimated using Cox proportional hazards models after adjusting for traditional CVD risk factors and selected dietary factors., Results: During 538 373 person-years of follow-up, we documented a total of 2097 incident cases of CVD, comprising 328 coronary heart diseases (CHDs) (275 myocardial infarctions and 53 sudden cardiac deaths) and 1769 strokes (991 cerebral infarctions, 510 intracerebral haemorrhages, 255 subarachnoid haemorrhages and 13 unclassified strokes). The multivariable HRs (95% CIs) for almost daily or every day versus zero to two times/week were 0.72 (0.62 to 0.84, trend p<0.001) for total CVD; 0.65 (0.45 to 0.94, trend p=0.065) for CHD; 0.74 (0.62 to 0.87, trend p=0.005) for total stroke; 0.77 (0.62 to 0.97, trend p=0.467) for cerebral infarction; and 0.54 (0.40 to 0.73, trend p<0.001) for intracerebral haemorrhage. No associations were observed between tub bathing frequency and risk of sudden cardiac death or subarachnoid haemorrhage., Conclusion: The frequency of tub bathing was inversely associated with the risk of CVD among middle-aged Japanese., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ.)

Aim: A positive association between non-high-density lipoprotein cholesterol (non-HDL-C) and coronary heart disease (CHD) has been established; however, associations between non-HDL-C and stroke subtypes have not been determined., Methods: We conducted a prospective study of 30,554 individuals aged 40-69 yrs with no history of cardiovascular disease (CVD) in Japan. Sex-specific hazard ratios (HRs) and 95% confidence intervals (CIs) for the incidence of stroke subtypes and CHD were estimated according to quintiles of non-HDL-C, using Cox proportional hazard models adjusted for other established risk factors., Results: We identified 1,705 stroke and 296 CHD events over a median 15 yrs of follow-up. The fractional polynomials analysis revealed a U-shaped association between non-HDL-C and stroke risk in men. When analyzed for stroke subtypes, the data revealed an inverse relationship between non-HDL-C and intracerebral hemorrhage (ICH), primarily with lobar ICH, and a positive association between non-HDL-C and large-artery occlusive infarction in men [adjusted HR 0.55 (95% CI, 0.35-0.87) and 2.05 (95% CI, 1.07-3.93) for the highest and lowest quintile of non-HDL-C, respectively]. The lowest risk of ICH in women was observed in the fourth quintile, and the lowest risk of embolic infarction was observed in the third quintile. In contrast, non-HDL-C was positively associated with CHD in both sexes., Conclusions: In Japanese men, lower non-HDL-C levels were associated with a decreased risk of large-artery occlusive infarction and an increased risk of ICH, particularly lobar ICH.

Background: We aimed to quantify contributions of changes in risks and uptake of evidence-based treatment to coronary heart disease (CHD) mortality trends in Japan between 1980 and 2012., Methods: We conducted a modelling study for the general population of Japan aged 35 to 84 years using the validated IMPACT model incorporating data sources like Vital Statistics. The main outcome was difference in the number of observed and expected CHD deaths in 2012., Results: From 1980 to 2012, age-adjusted CHD mortality rates in Japan fell by 61%, resulting in 75,700 fewer CHD deaths in 2012 than if the age and sex-specific mortality rates had remained unchanged. Approximately 56% (95% uncertainty interval [UI]: 54-59%) of the CHD mortality decrease, corresponding to 42,300 (40,900-44,700) fewer CHD deaths, was attributable to medical and surgical treatments. Approximately 35% (28-41%) of the mortality fall corresponding to 26,300 (21,200-31,000) fewer CHD deaths, was attributable to risk factor changes in the population, 24% (20-29%) corresponding to 18,400 (15,100-21,900) fewer and 11% (8-14%) corresponding to 8400 (60,500-10,600) fewer from decreased systolic blood pressure (8.87 mm Hg) and smoking prevalence (14.0%). However, increased levels of cholesterol (0.28 mmol/L), body mass index (BMI) (0.68 kg/m 2 ), and diabetes prevalence (1.6%) attenuated the decrease in mortality by 2% (1-3%), 3% (2-3%), and 4% (1-6%), respectively., Conclusions: Japan should continue their control policies for blood pressure and tobacco, and build a strategy to control BMI, diabetes, and cholesterol levels to prevent further CHD deaths., (Copyright © 2019 The Authors. Published by Elsevier B.V. All rights reserved.)

Background and Aims: Predicting cardiovascular events is of practical benefit for disease prevention. The aim of this study was to develop and evaluate an updated risk prediction model for cardiovascular diseases and its subtypes., Methods: A total of 2462 community residents aged 40-84 years were followed up for 24 years. A Cox proportional hazards regression model was used to develop risk prediction models for cardiovascular diseases, and separately for stroke and coronary heart diseases. The risk assessment ability of the developed model was evaluated, and a bootstrapping method was used for internal validation. The predicted risk was translated into a simplified scoring system. A decision curve analysis was used to evaluate clinical usefulness., Results: The multivariable model for cardiovascular diseases included age, sex, systolic blood pressure, hemoglobin A1c, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, smoking habits, and regular exercise as predictors. The models for stroke and coronary heart diseases incorporated both shared and unique variables. The developed models showed good discrimination with little evidence of overfitting (optimism-corrected Harrell's C statistics 0.726-0.777) and calibrations (Hosmer-Lemeshow test, p = 0.44-0.90). The decision curve analysis revealed that the predicted risk-based decision-making would have higher net benefit than either a CVD intervention strategy for all individuals or no individuals., Conclusions: The developed risk prediction models showed a good performance and satisfactory internal validity, which may help understand individual risk and setting personalized goals, and promote risk stratification in public health strategies for CVD prevention., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Background and Aims: Although a potential benefit of drinking green tea has been suggested to reduce the development of cardiovascular disease, no study has investigated the relationship between plasma tea catechin and risk of cardiovascular disease., Methods: A prospective, nested case-control study was conducted to examine the association between plasma tea catechin and risk of stroke and coronary heart disease (CHD) in a cohort of 29,876 men and women aged 40-69 years without history of heart disease, stroke or cancer. Participants completed a survey and donated blood samples between 1990 and 1994, and were followed-up through 2008. A total of 1132 stroke cases and 209 CHD cases, matched 1:1 to controls (n = 1132) for stroke and 1:2 to controls (n = 418) for CHD, were included in the analysis., Results: We found no significant association between plasma tea catechin and the incidence of stroke or CHD in either men or women. However, we found that high plasma levels of epigallocatechin gallate (EGCG) were associated with reduced risk of stroke in non-smoking men; the adjusted odds ratio (95% CI) for the highest vs. non-detectable levels was 0.53 (0.29-0.98). The respective OR in male smokers was 1.23 (0.75-2.16). A significant interaction by smoking status was found for the highest vs. non-detected plasma EGCG in relation to stroke (p-for-interaction: p = 0.09)., Conclusions: Plasma tea catechin was not associated with reduced risks of either stroke or CHD, while a protective effect of certain tea catechin on stroke risk is suggested for male non-smokers., (Copyright © 2018. Published by Elsevier B.V.)

Background and Aims: Higher intake of fish or n-3 polyunsaturated fatty acids (PUFAs) has been associated with reduced risk of coronary heart disease (CHD). However, it is unclear whether increased blood levels of n-3 PUFAs are associated with reduced risk of CHD in the Japanese population., Methods: The relationship between circulating levels of n-3 PUFAs (eicosapentaenoic acid + docosapentaenoic acid + docosahexaenoic acid) and risk of CHD was examined in a nested case-control study among participants in the Japan Public Health Center (JPHC)-based Study Cohort. Plasma n-3 PUFA phospholipid levels were measured at baseline by gas chromatography in 209 cases with CHD and 418 controls matched for sex, age, date of blood draw, time elapsed since last meal before blood collection, and study location. The CHD cases (n = 209) comprised 168 cases of myocardial infarction and 41 of sudden cardiac death, otherwise classified as 157 non-fatal and 52 fatal coronary events, respectively. Mean duration of follow-up was 13.5 years., Results: Multivariate conditional logistic analysis showed no significant association between n-3 PUFAs and risk of total CHD. The odds ratio (OR) for the highest versus lowest quartiles of plasma n-3 PUFAs was 0.79 (95% confidence interval [95% CI]: 0.41-1.51, p for trend = 0.51). Subtype analysis of CHD revealed that the multivariate ORs for the highest versus lowest quartiles for n-3 PUFAs were 0.91 (95% CI: 0.43-1.89, p for trend = 0.90) for myocardial infarction, 0.08 (95% CI: 0.01-0.88, p for trend = 0.04) for sudden cardiac death, 0.89 (95% CI: 0.42-1.89, p for trend = 0.97) for nonfatal coronary events, and 0.12 (95% CI: 0.02-0.75, p for trend = 0.03) for fatal coronary events., Conclusions: Plasma n-3 PUFA levels were not associated with risk of total CHD but were inversely associated with risks of sudden cardiac death and fatal coronary events among middle-aged Japanese individuals., (Copyright © 2017 Elsevier B.V. All rights reserved.)

We assessed the relationship between day-by-day home blood pressure (BP) variability and incident cardiovascular disease (CVD) in clinical practice. J-HOP study (Japan Morning Surge-Home Blood Pressure) participants underwent home BP monitoring in the morning and evening for a 14-day period, and their BP levels and BP variability independent of the mean (VIM) were assessed. Incident CVD events included coronary heart disease and stroke. Cox models were fitted to assess the home BP variability-CVD risk association. Among 4231 participants (mean±SD age, 64.9±10.9 years; 53.3% women; 79.1% taking antihypertensive medication), mean (SD) home systolic BP (SBP) levels over time and VIM SBP were 134.2 (14.3) and 6.8 (2.5) mm Hg, respectively. During a 4-year follow-up period (16 750.3 person-years), 148 CVD events occurred. VIM SBP was associated with CVD risk (hazard ratio per 1-SD increase, 1.32; 95% confidence interval [CI], 1.15-1.52), independently of mean home SBP levels over time and circulating B-type natriuretic peptide levels or urine albumin-to-creatinine ratio. Adding VIM SBP to the CVD prediction model improved the discrimination (C statistic, 0.785 versus 0.770; C statistic difference, 0.015; 95% CI, 0.003-0.028). Changes in continuous net reclassification improvement (0.259; 95% CI, 0.052-0.537), absolute integrated discrimination improvement (0.010; 95% CI, 0.003-0.016), and relative integrated discrimination improvement (0.104; 95% CI, 0.037-0.166) were also observed with the addition of VIM SBP to the CVD prediction models. In addition to the assessments of mean home SBP levels and cardiovascular end-organ damage, home BP variability measurements may provide a clinically useful distinction between high- and low-risk groups among Japanese outpatients., (© 2017 American Heart Association, Inc.)

The aim of this study is to determine which indicator of chronic kidney disease most closely correlates with 10-year Framingham coronary heart disease (CHD) risk among serum creatinine, serum cystatin C (S-CysC), urine albumin-creatinine ratio (UACR), estimated creatinine-based GFRs (eGFRcre), and estimated CysC-based GFRs (eGFRcys) in patients with obesity and diabetes. Serum creatinine, S-CysC, UACR, and cardio-ankle vascular index (CAVI) were examined in 468 outpatients with obesity and type 2 diabetes, free of severe renal dysfunction or previous history of cardiovascular disease, as a cross-sectional survey using baseline data from the multi-centered Japan Diabetes and Obesity Study. S-CysC and eGFRcys had significantly stronger correlations with the 10-year Framingham CHD risk than serum creatinine, eGFRcre, and UACR (creatinine, ρ = 0.318; S-CysC, ρ = 0.497; UACR, ρ = 0.174; eGFRcre, ρ = -0.291; eGFRcys, ρ = -0.521; P < 0.01 by Fisher's z-test). S-CysC and eGFRcys had significantly stronger correlations with CAVI than serum creatinine, eGFRcre, and UACR (creatinine, ρ = 0.198; S-CysC, ρ = 0.383; UACR, ρ = 0.183; eGFRcre, ρ = -0.302; eGFRcys, ρ = -0.444; P < 0.05 by Fisher's z-test). The receiver operating characteristic curves to distinguish the high-risk patients for CHD revealed significantly larger areas under the curve of S-CysC and eGFRcys than those of serum creatinine, UACR, and eGFRcre (serum creatinine, 0.64; S-CysC, 0.75; UACR, 0.56; eGFRcre, 0.63; eGFRcys, 0.76; P < 0.01). The data suggested that eGFRcys can be more predictive of the 10-year CHD risk than eGFRcre in Japanese patients with obesity and diabetes.

Objective: The impact of statin therapy on cardiovascular outcome in coronary artery disease (CAD) patients with aortic aneurysm or dissection (AD) is still unclear. The aim of this study was to elucidate the effect of statins at discharge to improve outcomes in CAD patients with AD., Methods: Among 14,834 consecutive patients who underwent first coronary revascularization in the CREDO-Kyoto PCI/CABG registry, we identified 699 patients (4.7%) with AD. The primary outcome measure was defined as a composite of all-cause death, myocardial infarction, and stroke. The effect of statin therapy was assessed by a Cox proportional hazards model incorporating clinically relevant factors., Results: The risk for the primary outcome measure was significantly higher in patients with AD (adjusted hazard ratio [HR], 1.43; 95% confidence interval [CI], 1.23-1.66; P < .0001). In patients with AD, 215 patients (31%) had already undergone aneurysm repair, and only 274 patients (39%) were treated with statins at discharge. Patients treated with statins were younger, had higher body mass index, and were more often treated with percutaneous coronary intervention. Heart failure, anemia, and hemodialysis were more prevalent in patients treated without statins. In patients without AD, 7014 patients (50%) were treated with statins. Patients treated with statins were younger and had higher body mass index, and more patients were treated for CAD due to myocardial infarction. Heart failure, prior stroke, hemodialysis, anemia, and malignant disease were more prevalent in patients treated without statins. The use of statins was associated with lower risk for the primary outcome measure in patients with AD (adjusted HR, 0.71; 95% CI, 0.51-0.99; P = .045) as well as in patients without AD (adjusted HR, 0.79; 95% CI, 0.73-0.85; P < .0001). The effect size of statin use was similar between the patients with AD and those without AD (P interaction = .69)., Conclusions: CAD patients with AD had significantly higher long-term risk for cardiovascular events. Statin therapy was associated with lower risk for cardiovascular events in patients with CAD with AD as well as in patients without AD., (Copyright © 2014 Society for Vascular Surgery. Published by Mosby, Inc. All rights reserved.)

Blood stasis syndrome is one of the pathological concepts of Oriental traditional medicine. In Oriental traditional medicine, blood is thought of as not only blood but also as a living component of the body. In fact, blood stasis syndrome is related to not just circulation disorders but dermatological and gynecological and other diseases. In Japan, the concept of blood stasis syndrome is based on the past literature, for instance, Synopsis of Golden Chamber (Jin Kui Yao Lue), etc. There are many signs of this syndrome, such as a dry mouth, fullness of the abdomen and rough skin. However, the levels of importance of these signs had been unclear. Therefore, in order to determine the levels of seriousness, a scoring system of blood stasis syndrome was made based on multivariate analysis by Dr. Terasawa (Terasawa's Blood Stasis Score). Using the scoring system, we have studied blood stasis syndrome mainly related to blood circulation using modern techniques of analysis. From the results, we found that patients with blood stasis syndrome showed hemorheological abnormalities, and an improvement in these abnormalities was shown after administration of removing-blood stasis formulae. Furthermore, we have studied blood stasis syndrome from the point of view of molecular biology. We searched for the specific protein expression in blood stasis syndrome by proteomic analysis, and found no specific protein expression. However, there may be a possibility of developing a diagnostic algorithm for blood stasis by construction of a decision tree. During the past few years, as one of the molecular biological factors affecting blood stasis syndrome, we have been studying hypoxia inducible factor, which is located in the upstream of many genes. Above all, blood stasis syndrome is more than just circulatory deficit but encompasses the pathological concept of constant multilateral change in the living body.

Objectives: To conduct a cost-minimization analysis of landiolol for CT diagnosis of coronary heart diseases in patients with tachycardia in Japan., Methods: A decision-tree model was constructed to analyze costs from the healthcare payer's perspective. Drug costs and diagnosis costs, computer tomography coronary angiography (CTCA), and coronary angiography (CAG), are adopted to the model. Landiolol is administered only to slow the heart rate to take CT images appropriately. Since some trials proved that there was no difference between landiolol and placebo in terms of efficacy and safety, this study conducted cost-minimization analysis. Of those suspected of coronary heart diseases, 22.5% are thought to be taking beta-blockers. The success rates for CT scanning for landiolol and placebo, derived from domestic trial data, were 81.4% (96/118, 77.8-84.9%) and 54.2% (64/118, 49.7-58.8%). Patients who failed to take a CT image were thought to take CAG. The healthcare cost was derived from a Japanese fee schedule. Costs of landiolol, CT imaging, and CAG are JPY2634 (USD1 = JPY100, as of November 20, 2013), JPY38,116, and JPY101,322, respectively. The positive rate for CAG, derived from domestic trial data, was 37.1% (33/89, 32.0-42.2%). Various sensitivity analyses, both univariate and probabilistic ones, were conducted., Results: In the base case analysis, expected costs per patient for landiolol and placebo were JPY78,956 and JPY82,232, respectively. In budget impact analysis, 81,062 patients are eligible for landiolol and it can save JPY266million for whole patients. Sensitivity analyses suggested the robustness of the results., Limitations: This study did not consider any adverse effects in the decision-tree model. This model was developed especially for measuring the cost-saving effect of landiolol, through decreasing the number of patients who require CAG, due to imaging failure., Conclusions: Landiolol for CTCA diagnosis in patients suspected of coronary heart disease with tachycardia is thought to be cost saving.

Aim: The Framingham risk score (FRS) is one of the standard tools used to predict the incidence of coronary heart disease (CHD). No previous study has investigated its efficacy for a Japanese population cohort. The purpose of this study was to develop new coronary prediction algorithms for the Japanese population in the manner of the FRS, and to compare them with the original FRS., Methods: Our coronary prediction algorithms for Japanese were based on a large population-based cohort study (Suita study). The study population comprised 5,521 healthy Japanese. They were followed-up for 11.8 years on average, and 213 cases of CHD were observed. Multiple Cox proportional hazard model by stepwise selection was used to construct the prediction model., Results: Our coronary prediction algorithms for Japanese patients were based on a large populationbased cohort study (the Suita study). A multiple Cox proportional hazard model by stepwise selection was used to construct the prediction model. The C-statistics showed that the new model had better accuracy than the original and recalibrated Framingham scores. The net reclassification improvement (NRI) by the Suita score with the inclusion of CKD was 41.2% (P＜0.001) compared with the original FRS. The recalibration of the FRS slightly improved the efficiency of the prediction, but it was still worse than the Suita score with the CKD model. The calibration analysis suggested that the original FRS and the recalibrated FRS overestimated the risk of CHD in the Japanese population. The Suita score with CKD more accurately predicted the risk of CHD., Conclusion: The FRS and recalibrated FRS overestimated the 10-year risk of CHD for the Japanese population. A predictive score including CKD as a coronary risk factor for the Japanese population was more accurate for predicting CHD than the original Framingham risk scores in terms of the C-statics and NRI.

Aim: Patients with peripheral artery disease (PAD) are at a high risk of cardiovascular disease (CVD) among Western populations. However, evidence for an elevated risk in Asian populations is limited., Methods: This prospective cohort study examined 939 Japanese men 60-74 years of age at the time of the baseline survey. A total of 115 cases of CVD were detected during a median 9.3 years of follow-up, and the ankle brachial blood pressure index (ABI) functioned as a surrogate measurement of PAD., Results: The age-adjusted risks of coronary heart disease, ischemic stroke and ischemic CVD (coronary heart disease and ischemic stroke) were higher among men in the lowest ABI tertile compared with that observed in the men in the highest tertile (<1.08 vs. >1.17). These associations did not change substantially after adjusting for cardiovascular risk factors. The respective multivariable hazard ratios (HRs, 95% CI) for the three conditions were as follows: 2.48 (1.08-5.71), p for trend=0.03; 1.95 (0.94-4.02), p for trend=0.04; and 2.16 (1.25-3.72), p for trend=0.004. These results did not vary based on a comparison of the three ABI categories: ≤0.90, 0.91-1.10 and >1.10. The multivariable HRs (95% CI) for an ABI ≤0.90 versus >1.10 were as follows: 2.04 (0.67-6.20), p for trend=0.14 for coronary heart disease; 3.39 (1.10-10.5), p for trend=0.006 for ischemic stroke; and 2.61 (1.19-5.76), p for trend=0.003 for ischemic CVD. There were no associations between the ABI and the risk of hemorrhagic stroke., Conclusions: A low ABI is associated with the risk of coronary heart disease, ischemic stroke and ischemic CVD in elderly Japanese men.

Objectives: The relationships were explored of some cardiovascular risk factors to typical (TYP) and atypical (ATYP) fatal coronary events (CHD)., Material and Methods: Thirteen cohorts of 40-59 year-old men of the Seven Countries Study were followed-up for 40 years (N = 9704 heart disease free subjects). Fatal TYP-CHD were classified when manifested as myocardial infarction, other acute coronary syndromes, angina pectoris and sudden death; and as ATYP-CHD when manifested only as heart failure or arrhythmia in the absence of other clear etiologies. Death rates were computed for single countries separately for TYP and ATYP and for different lengths of follow-up. Cox models included: age, smoking habits, systolic blood pressure (SBP), serum cholesterol (CHOL), forced expiratory volume in ¾ sec (FEV) and diabetes., Results: TYP-CHD was more common in North American and Northern European countries, while ATYP-CHD were more common in Southern and Eastern Europe. Age at death was 5 years greater for ATYP-CHD than for TYP-CHD. Cox models in the pool of 13 cohorts showed that coefficient for age was significantly larger for ATYP-CHD (hazard ratio, HR: 2.36; confidence intervals CI: 2.18 - 2.26) versus TYP-CHD (HR 1.50, CI 1.43-1.58) while coefficients for CHOL was larger and significant for TYP-CHD (HR 1.29, CI 1.22-1.35) but not for ATYP-CHD (HR 0.93, CI 0.85-1.03). SBP, smoking habits, FEV and diabetes all predicted both conditions almost equally., Conclusion: The different relationships of CHOL and age with the two types of fatal CHD suggest that the two groups of manifestations may belong to different diseases., (© 2013.)

Previous intravascular ultrasound studies have shown that echolucent neointimal hyperplasia occasionally appears after bare-metal stent (BMS) or sirolimus-eluting stent (SES) implantation. Optical coherence tomography (OCT) studies have also demonstrated that paclitaxel-eluting stent (PES) restenosis exhibited similar images showing low signal intensity areas (LSIA) surrounding stent struts and three-layer appearance (TLA). The aim of the present study was to investigate the clinical significance of LSIA on OCT images in various types of stents. Fifty nine consecutive patients who underwent scheduled follow-up coronary angiography and OCT were enrolled. There was no significant difference in the prevalence of LSIA among the 3 stent groups (BMS 30%, SES 19%, PES 28%, P = 0.70). LSIA thickness was larger in the PES group than in the other stent groups (BMS 0.51 ± 0.21 mm, SES 0.35 ± 0.06 mm, PES 0.87 ± 0.19 mm, P < 0.01). The ratio of LSIA thickness to the neointimal thickness was also larger in PES compared with other stents (BMS 53 ± 9 %, SES 57 ± 8 %, PES 77 ± 5 %, P < 0.01). Also, LSIA thickness in patients with in-stent restenosis (ISR) was significantly larger than in those without ISR (0.37 ± 0.37 mm versus 0.12 ± 0.26 mm, P = 0.048). Our results suggest that LSIA might be involved in excessive neointimal formation, and that the healing response after PES implantation might be different from BMS or SES.

Objectives: The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC7) defined blood pressure (BP) levels of 120-139/80-89  mmHg as prehypertension. The objective of the present analysis was to examine the impact of prehypertension and its population-attributable fraction for development of cardiovascular events in a general Japanese population., Methods: Two thousand, six hundred and thirty-four residents of the town of Hisayama aged at least 40 years without cardiovascular disease were followed up for 19 years. BP categories were defined using JNC7, and prehypertension was divided into the lower (120-129/80-84  mmHg) and higher ranges (130-139/85-89  mmHg). During the follow-up period, 449 participants developed cardiovascular disease (305 strokes and 187 coronary heart diseases)., Results: The frequencies of normal BP, prehypertension, and stages 1 and 2 hypertension were 24.9, 37.7, 23.8, and 13.6%, respectively. The age and sex-adjusted incidence of cardiovascular disease rose progressively with elevation of BP levels (P < 0.001 for trend). The risks of cardiovascular disease in lower and higher ranges of prehypertension were 58% [95% confidence interval (CI) 11-126%] and 70% (95% CI 18-144%) higher than normal BP even after controlling for other cardiovascular risk factors. The population-attributable fraction of prehypertension was 13.2%, which was similar to those of stages 1 and 2 hypertension., Conclusions: The risks of cardiovascular disease increased significantly from the lower range of prehypertension in a general Japanese population. Approximately one-third of excess cardiovascular events attributable to elevated BP levels were estimated to occur among individuals with prehypertension.

Background: Although clockwise rotation and counterclockwise rotation are distinct findings of the ECG, their prognostic significance is rarely studied., Methods and Results: We studied prognostic values of clockwise and counterclockwise rotation on total, cardiovascular disease (CVD), and subtype mortality using the National Integrated Project for Prospective Observation of Noncommunicable Disease and Its Trends in the Aged, 1980-2004 (NIPPON DATA80) database with a 24-year follow-up. At baseline in 1980, data were collected on study participants aged ≥30 years from randomly selected areas in Japan. We followed 9067 participants (44% men; mean age, 51 years). During the 24-year follow-up, mortality was as follows: 2581 total, 887 CVD, 179 coronary heart disease, 173 heart failure, and 411 stroke. The multivariate-adjusted hazard ratio (HR) with the use of the Cox model including biochemical and other ECG variables revealed that clockwise rotation was significantly positively associated with heart failure in men and women combined (HR=1.79; 95% confidence interval [CI], 1.13-2.83; P=0.013), CVD in men and in men and women combined (HR=1.49; 95% CI, 1.12-1.98; P=0.007 in men; HR=1.28; 95% CI, 1.02-1.59; P=0.030 in combined), and total mortality in men and in men and women combined (HR=1.19; 95% CI, 1.00-1.49; P=0.0496 in men; HR=1.15; 95% CI, 1.00-1.32; P=0.045 in combined). Counterclockwise rotation was significantly inversely associated stroke in men and women combined (HR=0.77; 95% CI, 0.62-0.96; P=0.017), CVD in men and in men and women combined (HR=0.74; 95% CI, 0.59-0.94; P=0.011 in men; HR=0.81; 95% CI, 0.70-0.94; P=0.006 in combined), and total mortality in women (HR=0.87; 95% CI, 0.77-0.98; P=0.023)., Conclusions: We found a significant positive association of clockwise rotation and a significant inverse association of counterclockwise rotation with CVD mortality in men and in men and women combined, independent of confounding factors including other ECG changes.

Background: A large-scale magnetocardiogram (MCG) database was produced, and standard MCG waveforms of healthy patients were calculated by using this database. It was clarified that the standard MCG waveforms are formed with the same shape and current distribution in healthy patients. A new subtraction method for detecting abnormal ST-T waveforms in coronary heart disease (CHD) patients by using the standard MCG waveform was developed., Methods: We used MCGs of 56 CHD patients (63 ± 3 years old) and 101 age-matched normal control patients (65 ± 5 years old). To construct a subtracted ST-T waveform, we used standard MCG waveforms produced from 464 normal MCGs (male: 268, female: 196). The standard MCG waveforms were subtracted from each subject's measured MCGs, which were shortened or lengthened and normalized to adjust to the data length and magnitude of the standard waveform. We evaluated the maximum amplitude and maximum current-arrow magnitude of the subtracted ST-T waveform., Results: The maximum magnetic field, maximum magnitude of current arrows, and maximum magnitude of total current vector increased according to the number of coronary artery lesions. The sensitivity and specificity of detecting CHD and normal control patients were 74.6% and 84.1%, respectively., Conclusions: The subtraction MCG method can be used to detect CHD with high accuracy, namely, sensitivity of 74.6% and specificity of 84.1% (in the case of maximum amplitude of total current vector). Furthermore, the subtraction MCG magnitude and its current distribution can reflect the expanse of the ischemic lesion area and the progress from ischemia to myocardial infarction., (©2010, Wiley Periodicals, Inc.)

The impact of visceral adiposity on subclinical coronary atherosclerosis is unclear in Japanese patients. We investigated the sex-specific relationship between the amount of visceral fat and coronary artery calcium (CAC) using multislice computed tomography (MSCT). This is a cross-sectional study of 321 consecutive Japanese patients (213 men and 108 women) who underwent MSCT scanning for the examination of coronary heart disease. CAC score, visceral fat area (VFA), subcutaneous fat area (SFA), and waist circumference (WC) were determined by MSCT for all patients. The prevalence of detectable CAC was 73% and 57% in men and women, respectively. Using a multivariable logistic and ordinal regression analyses adjusting for traditional cardiovascular risk factors and adiposity measurements, VFA represented an independent predictor of the presence and extent of CAC (odds ratio (95% confidence interval) per one-unit-standard deviation increase in VFA: 2.48 (1.23-6.05) in logistic regression analysis; 2.05 (1.18-3.98) in ordinal regression analysis). Similar relationships were observed across the gender. We further assessed the sex-specific cut-off levels of VFA and WC to predict the presence of CAC. The results of receiver operator characteristic analysis indicated that the VFA cut-off level in men was 116cm(2); and in women, it was 82cm(2), corresponding to WC values of 87.7cm in men and 82.6cm in women. In conclusion, we found that visceral adiposity measured by MSCT is significantly associated with the presence and extent of CAC as a marker of subclinical atherosclerosis in Japanese patients.

Adiponectin is an adipocyte-specific secretory protein that is highly and specifically expressed in adipose tissue, and low plasma levels of adiponectin are associated with coronary artery disease (CAD). It has been suggested that high molecular weight (HMW) adiponectin is more important for vascular protection than total amount of adiponectin. To establish the clinical relevance of HMW adiponectin, we measured its serum levels in 149 patients with CAD. The levels were lower in vasospastic angina pectoris (3.4 +/- 2.4 microg/ml, p <0.01), stable angina pectoris (3.3 +/- 2.6 microg/ml, p <0.001), and healed myocardial infarction (3.8 +/- 2.9 microg/ml, p <0.01) than chest pain syndrome (controls) (6.6 +/- 5.4 microg/ml). The levels were also lower in multivessel CAD (3.4 +/- 2.4 microg/dl) compared with single vessel CAD (4.2 +/- 2.7 microg/ml, p <0.05) or no organic stenosis (5.1 +/- 3.5 microg/ml, p <0.01). In univariate analysis, diabetes mellitus (p = 0.03), insulin resistance (p = 0.06), high-sensitivity C-reactive protein levels (p = 0.0012), and low HMW adiponectin levels (p = 0.0001) predicted cardiovascular events during 7 years of follow-up. However, multivariate analysis showed that only HMW adiponectin levels were an independent predictor of cardiovascular events (relative risk 2.79, 95% confidence interval 1.49 to 5.24, p = 0.0014). In conclusion, serum HMW adiponectin levels may serve as a predictor of future cardiovascular events in patients with CAD as well as a marker for severity of CAD.

Background: Screening for coronary artery disease (CAD) in asymptomatic diabetic patients with atherogenic risk factors is recommended by the American College of Cardiology/American Diabetes Association. It is not clear whether these guidelines apply to the Japanese population with a different epidemiology of CAD. This study evaluates the applicability of the U.S. guidelines to Japan, taking account of cost-effectiveness., Design: A cost-effectiveness analysis using a Markov model was performed to measure the clinical benefit and cost of CAD screening in asymptomatic patients with diabetes and additional atherogenic risk factors. We evaluated cohorts of patients stratified by age, gender, and atherogenic risks. The incremental cost-effectiveness of not screening, exercise electrocardiography, exercise echocardiography, and exercise single-photon emission-tomography (SPECT) was calculated. The data used were obtained from the literature. Outcomes are expressed as US dollars per quality-adjusted life year (QALY)., Results: Compared with not screening, the incremental cost-effectiveness ratio (ICER) of exercise electrocardiography was $31,400/QALY for 60-year-old asymptomatic diabetic men, and 46,600 for 65-year-old women with hypertension and smoking. The ICER of exercise echocardiography was $31,500/QALY and of SPECT was $326,000/QALY, compared with the next dominant strategy. Sensitivity analyses found that these results varied according to age, gender, the combination of additional atherogenic risk factors, and the frequency of screening., Conclusion: From a societal perspective the U.S. guidelines on screening for CAD in high risk diabetic patients are applicable to the Japanese population. However, the population subjected to screening should be carefully selected to obtain greatest benefit from screening.

Coronary heart disease incidence and mortality remain very low in Japan despite major dietary changes and increases in risk factors that should have resulted in a substantial increase in coronary heart disease rates (Japanese paradox). Primary genetic effects are unlikely, given the substantial increase in coronary heart disease in Japanese migrating to the United States. For men aged 40-49 years, levels of total cholesterol and blood pressure have been similar in Japan and the United States throughout their lifetimes. The authors tested the hypothesis that levels of subclinical atherosclerosis, coronary artery calcification, and intima-media thickness of the carotid artery in men aged 40-49 years are similar in Japan and the United States. They conducted a population-based study of 493 randomly selected men: 250 in Kusatsu City, Shiga, Japan, and 243 White men in Allegheny County, Pennsylvania, in 2002-2005. Compared with the Whites, the Japanese had a less favorable profile regarding many risk factors. The prevalence ratio for the presence of a coronary calcium score of > or =10 for the Japanese compared with the Whites was 0.52 (95% confidence interval: 0.35, 0.76). Mean intima-media thickness was significantly lower in the Japanese (0.616 mm (standard error, 0.005) vs. 0.672 (standard error, 0.005) mm, p < 0.01). Both associations remained significant after adjusting for risk factors. The findings warrant further investigations.

Background and Purpose: Although overweight is an important risk factor for cardiovascular disease in Western countries, the impact of overweight has not been well elucidated in Japan, where its prevalence is low., Methods: A total of 104,928 Japanese (43,889 men and 61,039 women) aged 40 to 79 years, free of stroke, coronary heart disease, and cancer at entry participated in the Japan Collaborative Cohort Study for Evaluation of Cancer Risk Sponsored by Monbusho (JACC Study) between 1988 and 1990. Systematic surveillance was completed until the end of 1999, with 1,042,835 person years of follow-up, and the underlying causes of death were determined based on the International Classification of Diseases., Results: There were 765 total strokes (191 intraparenchymal hemorrhages), 379 coronary heart diseases, and 1707 total cardiovascular diseases for men; and for women, there were 685 (145), 256, and 1432, respectively. Compared with persons with body mass index (BMI) 23.0 to 24.9, those with BMI > or =27.0 kg/m2 had a higher risk of coronary heart disease; for men and women, the respective multivariate relative risk (95% CI) was 2.05 (1.35 to 3.13) and 1.58 (0.95 to 2.62). Persons with BMI <18.5 kg/m2 had higher risk of total stroke and intraparenchymal hemorrhage, for men and women, the respective multivariate relative risk was 1.29 (1.01 to 1.49) and 1.92 (1.49 to 2.47) for total stroke and 1.96 (1.16 to 3.31) and 2.32 (1.36 to 3.97) for intraparenchymal hemorrhage. These excess risks did not alter materially when deaths within 5 years were excluded or when smoking status was taken into account., Conclusions: For Japanese men and women, high BMI was associated with increased risk of coronary heart disease, whereas low BMI was associated with intraparenchymal hemorrhage.

Since there is in sufficient evidence on patients with coronary artery disease in Japan, the Japanese Coronary Artery Disease (JCAD) Study, in which 217 institutions participate, was designed to collect basic data based on evidence-based medicine (EBM). In this study, cardiac catheterization is performed on all cases to select study subjects confirmed as having CAD diagnosed based on the criteria that he or she has stenosis in at least one branch of a coronary artery to the extent of 75% or higher according to the AHA classification. Data including background information, risk factors, clinical management, and medication are to be collected over the web. The follow-up arm of the study consists of following each subject for three years to obtain data on the long-term prognosis of patients with CAD while the other arm is for enrolling new subjects every six months who will be followed for six months only for the purpose of determining the latest trend in patients. The two arms of the study have been ongoing since April 2000. As of September 30, 2003, 15,506 subjects have been enrolled in the follow-up arm and the follow-up data have been entered in the database. The authors plan to report data showing any correlation between incidence rate, focusing mainly on cerebrocardiovascular events, and other factors such as the management of risk factors, and type and dosage of medications obtained in the largest cohort ever studied in Japan of patients with a coronary artery lesion confirmed by cardiac catheterization.

Background: In individuals heterozygous for ABCA1 transporter mutations, defective reverse cholesterol transport (RCT) causes low HDL-cholesterol and premature coronary heart disease (CHD). However, the extent to which impaired RCT underlies premature CHD in others with low HDL-cholesterol is not known. The primary acceptors of cell cholesterol are a minor subclass of lipid-poor pre-beta-HDLs. These are generated during remodeling of alpha-HDLs, which account for almost all HDL-cholesterol. We studied the strength of the association of CHD with pre-beta-HDL concentrations in Japanese men., Methods: Blood was collected from 42 men with clinical CHD and 44 healthy controls 40-70 years of age. Pre-beta-HDL was assayed by crossed immunoelectrophoresis., Results: Cases had lower HDL-cholesterol (-23%), total apolipoprotein A-I (-26%), and pre-beta-HDL (-55%; all P <0.001) concentrations; lower pre-beta-HDL:alpha-HDL ratios (-45%; P <0.001); and higher plasma triglycerides (20%; P <0.03) than the controls. On stepwise logistic regression, CHD was associated most strongly with pre-beta-HDL concentrations. On ROC analysis, pre-beta-HDL concentration discriminated between cases and controls better than any other lipoprotein measurement. When plasma was incubated for 16 h at 37 degrees C, mean (SD) pre-beta-HDL increased by 47 (36)% in controls, but was unchanged in cases (group difference, P <0.001)., Conclusions: Our results suggest that inefficient RCT, secondary to a low pre-beta-HDL concentration and production rate in plasma, contributes to premature CHD in Japanese men with low HDL-cholesterol.

Objective: The purpose of this study was to evaluate the prognostic and clinical significance of newly acquired complete right bundle branch block (CRBBB) in airline pilots., Patients: This study included pilots with acquired CRBBB, identified from a group of over 2,700 Japan Airline pilots. When the pilots applied for employment, a past medical history, physical examination, electrocardiogram, and chest radiograph were obtained. The pilots with ECG abnormality including CRBBB were not included in the study because of hiring requirements., Results: Thirty-six pilots with CRBBB were identified between 1983 and 2002. All pilots with CRBBB were evaluated for the presence of ischemic heart disease by treadmill exercise testing, echocardiogram and exercise thallium scintigraphy. Twelve individuals underwent coronary angiography. The mean age of pilots was 44.4 +/- 5.8 years. The mean observation period was 10.9 +/- 5.7 years. For each of the 36 study subjects, Holter electrocardiogram and echocardiogram were obtained every 6 months after the CRBBB was detected. Exercise stress testing was performed every year. Exercise thallium scintigraphy was performed every 2 years to detect ischemic heart disease. During the observation period, two pilots stopped flying temporarily because of frequent ventricular premature beats and one pilot stopped flying permanentaly because of atrial fibrillation. During the follow-up period, no cardiovascular events were observed in pilots with CRBBB who had no underlying ischemic heart disease., Conclusion: Acquired CRBBB does not confer a poor prognosis, particularly in young men working as a pilot if there is no evidence of ischemia on exercise stress testing, echocardiography and exercise thallium scintigraphy.

Unlabelled: We investigated the possible use of serum hepatocyte growth factor (HGF) and vascular endothelial growth factor (VEGF) levels as a predictive indicator for the occurrence of coronary artery lesions (CAL) in Kawasaki disease (KD). Serum HGF and VEGF levels were measured by enzyme-linked immunosorbent assay in 41 patients with KD and 25 afebrile controls. Serum HGF levels of patients in the acute phase of KD were significantly higher than those of afebrile controls (Pc < 0.05) and decreased to lower levels during recovery (P < 0.0001). Univariate analysis showed significant correlations between occurrence of CAL and five variables: duration of fever (P=0.018), serum C-reactive protein concentration (P = 0.024), albumin concentration (P=0.009). serum VEGF level (P=0.009) and serum HGF level (P=0.035). Furthermore, multivariate analysis revealed that serum HGF and VEGF levels and presence of oedema were major risk factors for the occurrence of CAL. For prediction of the development of CAL, we established a new risk classification system with these three variables, which showed a sensitivity of 100% and a specificity of 94.4%., Conclusion: these data show that hepatocyte growth factor, together with vascular endothelial growth factor, might play an important role in the pathophysiology of Kawasaki disease and their serum levels could be a powerful predictor for the development of coronary artery lesions.

Background: Conflict exists regarding the usefulness of measuring plasma B type natriuretic peptide (BNP) concentrations for identifying impaired left ventricular (LV) systolic function during mass screening. Various cardiac abnormalities, regardless of degree of LV dysfunction, are prone to carry a high risk of cardiovascular events., Objective: To examine the validity of plasma BNP measurement for detection of various cardiac abnormalities in a population with a low prevalence of coronary heart disease and LV systolic dysfunction., Design and Setting: Participants in this cross sectional study attended a health screening programme in Iwate, northern Japan. Plasma BNP concentrations were determined in 1098 consecutive subjects (mean age 56 years) by direct radioimmunoassay. All subjects underwent multiphasic health checkups including physical examination, ECG, chest radiography, and transthoracic echocardiography., Results: Conventional diagnostic methods showed 39 subjects to have a wide range of cardiac abnormalities: lone atrial fibrillation or flutter in 11; previous myocardial infarction in seven; valvar heart disease in seven; hypertensive heart disease in six; cardiomyopathy in six; atrial septal defect in one; and cor pulmonale in one. No subjects had a low LV ejection fraction (< 40%). To assess the utility of plasma BNP measurement for identification of such patients, receiver operating characteristic analysis was performed. The optimal threshold for identification was a BNP concentration of 50 pg/ml with sensitivity of 89.7% and specificity of 95.7%. The area under the receiver operating characteristic curve was 0.970. The positive and negative predictive values at the cutoff level were 44.3% and 99.6%, respectively., Conclusion: Measurement of plasma BNP concentration is a very efficient and cost effective mass screening technique for identifying patients with various cardiac abnormalities regardless of aetiology and degree of LV systolic dysfunction that can potentially develop into obvious heart failure and carry a high risk of a cardiovascular event.

Objectives: To examine whether the Framingham Risk Model can appropriately predict coronary heart disease (CHD) events detected by electrocardiography (ECG) in Japanese men., Methods: Using the annual health examination database of a Japanese company 5611 male workers, between the ages of 30 to 59, who were free of cardiovascular disease, were followed up to observe the occurrence of CHD events detected by ECG over a period of five to seven years. The probability of CHD was calculated for each individual from the equations of the Framingham risk model (with total cholesterol)., Results: The incidence of CHD increased with the estimated CHD risk. The Hosmer-Lemeshow goodness of fit test showed an adequate fit of the risk model to the data of the study subjects. In the receiver operating characteristic analysis, the area under the curve reached 0.67 which indicated an acceptable discriminatory accuracy of the risk model., Conclusions: The Framingham risk model provides useful information on future CHD events in Japanese men.

Background and Methods: The incidence of coronary artery bypass grafting (CABG) in elderly patients has been increasing. We retrospectively analyzed the results of CABG performed at Shin-Tokyo Hospital between January 1, 1991, and December 31, 1998. Preoperative, perioperative, and follow-up data of patients > or = 75 years old (group E, n = 190) were collected, and compared with those of patients < 75 years old (group Y, n = 1,380)., Results: Female gender, emergent CABG, preoperative balloon pumping use, cardiogenic shock, hypertension, and preoperative cerebral vascular accident were significantly more frequent in group E (p < 0.05). CABG was completed without any significant differences, except for less frequent use of the bilateral internal mammary artery (p < 0.01), more frequent use of the saphenous vein (p < 0.005), and a greater incidence of blood transfusion in group E (p < 0.0001). The postoperative course required longer intubation, ICU stay, and postoperative hospital stay in group E (p < 0.001), and was more frequently associated with major complication (p < 0.0001) and in-hospital death (p < 0.05). During the mean follow-up of 2.7 years (maximum 6.9 years), the actuarial 5-year survival of groups E and Y were 84.3% and 92.5% (p < 0.01), respectively, excluding in-hospital mortality. The actuarial 5-year cardiac event-free rates were 79.9% in group E and 79.7% in group Y, showing no significant difference., Conclusions: CABG in the elderly carries certain surgical risks. However, the long-term cardiac event-free rate after CABG in the elderly was almost the same as that of younger patients. Inferior long-term survival in the elderly was most likely due to the biological nature of aging.

Efficient use of cholesterol measurements to screen for coronary heart disease in the elderly is not well defined. The purpose of this report is to examine such screening based on national guidelines in a sample of older men. Since relations between cholesterol and coronary heart disease are better established in those who are younger, screening in the elderly will also consider levels of cholesterol that existed earlier in life. Data are from a prospective study of 1,170 men enrolled in the Honolulu Heart Program who were followed over a 12-year period for coronary heart disease. Follow-up began from 1980 to 1982, when cholesterol levels were determined in men who were aged 61 to 81 years. Past cholesterol levels were measured 10 years earlier (1970-1972). During the course of follow-up, coronary heart disease developed in 117 of the men. Risk of disease rose significantly (P = 0.003) with increases in past cholesterol levels (1970-1972) but not with more recent levels (1980-1982). For men with current cholesterol levels that were desirable (<5.2 mmol/L [200 mg/dl], as defined by guidelines from the National Cholesterol Education Program), disease incidence continued to rise with increasing past cholesterol levels (P<0.001). Accounting for high-density lipoprotein cholesterol and other screening factors did little to alter these findings. We conclude that desirable cholesterol levels in the elderly may not be a marker of a healthy risk profile if past cholesterol levels were high. Screening for coronary heart disease in the elderly could be improved by considering past cholesterol levels, rather than just a single measurement in later life.

Magnetic resonance angiography (MRA) has been expected to provide a useful noninvasive means of assessing coronary artery disease as this disease continues to increase due to westernization of life style. Several Japanese investigators have assessed the diagnostic value of two-dimensional (2D) and 3D coronary MRA in clinical patients evaluated for ischemic heart disease. Almost all reports indicate a high correlation between findings on 2D MRA and findings on conventional coronary angiography (CAG) in patients with severe stenosis of proximal arteries. However, in our study involving 153 patients with ischemic heart disease, 2D MRA tended to underestimate lesions in patients with moderate stenotic lesions. Furthermore, this method could not be applied successfully in approximately 15% of our patients due to difficulty with breath-holding. These findings indicate some of the limitations associated with breath-holding in the 2D method. Recently, several reports have described high diagnostic accuracy using respiratory-gated 3D MRA with navigator echo. Effective use of a suitable contrast agent with better spatial and time resolution and better image reconstruction methods will enable 3D MRA to serve a useful role, even in screening for coronary artery disease. J. Magn. Reson. Imaging 1999;10:709-712., (Copyright 1999 Wiley-Liss, Inc.)

Limited data are available on patterns of change in lipids and lipoproteins as persons age. The purpose of this report is to describe the 10-year change in total and high-density lipoprotein (HDL) cholesterol according to suspected determinants in 898 Japanese-American men enrolled in the Honolulu Heart Program. Data are based on examinations that occurred from 1970 to 1972 and at repeat examinations received 10 and 20 years later. At the last examination, men were aged 71 to 93 years. Mean reductions in total cholesterol in the second 10 years of follow-up (24 mg/dl) were more than double the reductions observed in the first 10 years (9 mg/dl). Levels of total cholesterol declined and levels of HDL cholesterol increased regardless of beginning levels of systolic blood pressure, body mass index, physical activity, cigarette smoking status, or the use of treatment for hypertension or elevated total cholesterol. Men with prevalent coronary heart disease experienced greater reductions (p <0.05) in total cholesterol during the second 10 years of follow-up (32 mg/dl) versus men without coronary heart disease (22 mg/dl). Adjustment for baseline covariates failed to alter these findings appreciably. We conclude that alterations in total and HDL cholesterol with advancing age may be expected to occur regardless of risk factor status, disease prevalence, or pharmacologic intervention. In the presence of such effects, evaluation of treatment programs to alter levels of total and HDL cholesterol in older persons should consider the possibility that even in the absence of intervention, changes could also occur due to aging alone.

In this study, the authors examined relations between coronary and carotid atherosclerosis and between coronary atherosclerosis and silent cerebral infarction. They ascertained the risk factors for carotid atherosclerosis and silent cerebral infarction complicating coronary heart disease (CHD) in 77 Japanese subjects. As coronary atherosclerosis progressed, the carotid ultrasonographic score and the brain computed tomographic score increased. Multivariate analyses showed that the significant and independent risk factors for carotid atherosclerosis in patients with CHD were age (p < 0.01) and apolipoprotein (apo) B (p < 0.05) and the factors for silent cerebral infarction were age (p < 0.05) and hypertension (p < 0.05). Their study confirms a positive relation between coronary atherosclerosis and carotid atherosclerosis and between coronary atherosclerosis and silent cerebral infarction in patients with CHD. Their data suggest that carotid atherosclerosis should be looked for in patients with CHD who are old and have a high value of apo B, and silent cerebral infarction should be looked for in those who are old and have hypertension, to prevent complicating symptomatic cerebral vascular disease (CVD). If severe carotid atherosclerosis or silent cerebral infarction are detected, antithrombotic medication should be given.

In an attempt to assess the influence of coronary artery disease and left ventricular dysfunction on postoperative mortality, 107 patients consisting of 32 AAA resections and 44 aortoiliac and 31 femoropopliteal reconstructions were reviewed. All patients had a preoperative coronary angiograms and underwent cardiac catheterization to prevent cardiac-related deaths. Severe coronary artery disease was angiographically demonstrated in 40.6% of AAA, 31.8% of AI and 3.2% of FP patients. Severe left ventricular dysfunction was found in 21.9% of AAA, 18.2% of AI and 6.5% of FP. Both of the early and 5 (45.5%) of the 11 late deaths were caused by cardiac events. The nine-year survival rate (53.3%) in the patients with a documented combination of coronary artery disease and left ventricular dysfunction was significantly lower than those in patients with normal disease, normal left ventricular function and either documented coronary artery disease or left ventricular dysfunction. It is suggested from this series that left ventricular dysfunction is one of the most important risk factors in patients who undergo AAA resection and AI reconstruction and that severe disease and postoperative mortality are possibly reduced by certain kinds of interventional coronary therapies.

Data from the baseline and follow-up examinations of the Honolulu Heart Program (HHP) cohort of 8006 men of Japanese ancestry were used to examine several questions concerning the predictive role of lipids and lipoproteins for incident CHD. For the question "Do serum cholesterol levels measured in middle age predict incident CHD in elderly men 65 years old or older?" the answer was clearly yes. Multivariate relative risks and attributable risks for early and late onset of CHD were similar and statistically significant. For the question "Do serum cholesterol levels measured in the elderly predict subsequent CHD?" the answer again was clearly yes. Multivariate relative risks for elderly men were similar to those for middle-aged men, and attributable risks were consistently higher for elderly men. For the question "Do other lipid or lipoprotein levels measured in the elderly predict incident CHD better than serum cholesterol level?" the answer was no. Multivariate relative risks for low-density-lipoprotein (LDL) and non-high-density-lipoprotein cholesterol were similar to those for total cholesterol. HDL cholesterol was protective for incident CHD, but the patterns were not significant for the elderly. Serum triglyceride level was not a significant predictor of CHD for the elderly. The conclusion was that no matter at what age serum cholesterol was measured, it predicted subsequent CHD in the elderly men in this cohort.

By use of noninvasive tests (Doppler segmental pressure study, supraorbital Doppler flow analysis, and segmental plethysmography), coexistent carotid (CTD) or lower extremity peripheral vascular disease (PVD) were diagnosed and correlated with subjective symptoms, coronary risk factors (CRFs), coronary arteriograms (CAGs), cardiac hemodynamics, and infarct size in 121 consecutive patients with documented coronary artery disease (CAD). PVD was found in 16.5%, CTD in 33.1%, and both PVD and CTD in 9.9% of the patients studied; 20% of PVD patients and 47.5% of CTD patients were asymptomatic with respect to coexistent PVD or CTD. There were no significant differences between the presence or absence of PVD or CTD as regards number of CRFs, Killip classification, cardiac hemodynamics, or number of stenotic coronary arteries. However, serum creatine kinase (CK) and CKMB release curves in the PVD group showed significantly higher peak CK and peak CKMB values than those in the PVD(-) group (4096 +/- 5408/282 +/- 263 vs 1706 +/- 1715/179 +/- 186, p less than 0.05) because of the higher prevalence (100%) of multivessel disease on CAG. Investigation of the relationship of CRFs to coexistent PVD revealed that the smoking ratio in men (86.7%) and the hypertension ratio in women (80%) were extremely high in PVD patients, and statistically significant differences between PVD(+) patients and PVD(-) groups were found with respect to the obesity ratio (p less than 0.05) in men and the hypercholesterolemia ratio (p less than 0.05) and obesity ratio (60%, p less than 0.05) in women.(ABSTRACT TRUNCATED AT 250 WORDS)

Coronary artery disease is a rare involvement of Takayasu's arteritis. From 1961 to 1989, 63 patients, including our five, have been reported to undergo operations for coronary artery disease resulting from Takayasu's arteritis. Most of the patients were Japanese (86%) and female (86%). The initial clinical manifestation was angina pectoris in 71%. Among 92 lesions, coronary ostia were most frequently involved (73%) followed by nonostial proximal lesions (18.5%). Forty-two of 62 (67.7%) ostial lesions of the left main coronary artery had more than 90%, or complete, stenosis. Aortic regurgitation was associated in 28 patients (44.4%). Myocardial revascularization was performed in 49, and transaortic endarterectomy in 12. Concomitant aortic valve replacement was done in 16 patients. Operative mortality was five (7.9%), and late deaths were reported in three patients. Postoperative steroid therapy was performed in 22. Operation was repeated in two patients because of graft failure. Thus coronary artery disease resulting from Takayasu's arteritis should be suspected in young Asian women with angina pectoris. The timing preferred for surgical intervention is during an inactive phase. Two procedures are commonly chosen for surgical intervention, either transaortic endarterectomy or coronary revascularization with vein grafts. Postoperative steroid therapy is strongly recommended to those patients who are operated on in the clinically or histologically active stage.

The incidence of myocardial infarction and death from coronary heart disease was studied in defined samples of 45 to 68 year old Japanese men in Japan, Hawaii and California. The incidence rate was lowest in Japan where it was half that observed in Hawaii (P less than 0.01). The youngest men in the sample in Japan were at particularly low risk. The incidence among Japanese men in California was nearly 50 percent greater than that of Japanese in Hawaii (P less than 0.05). A striking increase in the incidence of myocardial infarction appears to have occurred in the Japanese who migrated to the United States; this increase is more pronounced in California than in Hawaii.

Data from the Honolulu Heart Study suggest that the examining physician's clinical diagnosis, based on questioning the subject about chest pain, was more sensitive than the Rose questionnaire in detecting angina pectoris in a population of Japanese men. The 2 methods appear equally specific for coronary heart disease.

A total of 2437 Japanese American men living in Hawaii were given the Jenkins Activity Survey (JAS) and classified as either type A or type B. Only 18% of the sample scored in the type A direction, a much lower percentage than usually found among white American males. There was a slightly higher prevalence of CHD among type A Japanese Americans than among their type B counterparts (5.7% vs. 3.6%, respectively). A factor analysis of JAS data produced three new factors for this population: HS (hard-driving and impatient), JH (ability to function successfully in job setting), and HW (hard-working). Those men who were more Westernized had a higher prevalence of CHD, expecially if they were also type A, in terms of both geographical mobility and intergenerational change. The results are discussed in light of the dual role of sociocultural influences and behavioral characteristics (type A/B) which predispose an individual to CHD.

Among men of Japanese ancestry, there is a gradient in the occurrence of coronary heart disease (CHD). It is lowest in Japan, intermediate in Hawaii, and highest in California. This gradient appears not to be completely explained by differences in dietary intake, serum cholesterol, blood pressure or smoking. To test the hypothesis that social and cultural differences may account for the CHD differences between Japan and the United States, 3809 Japanese-Americans in California were classified according to the degree to which they retained a traditional Japanese culture. The most traditional group of Japanese-Americans had a CHD prevalence as low as that observed in Japan. The group that was most acculturated to Western culture had a three- to five-fold excess in CHD prevalence. This difference in CHD rate between most and least acculturated groups could not be accounted for by differences in the major coronary risk factors.