Changes in serum cholesterol levels determine future risk of cardiovascular events in patients with acute coronary syndrome in the Japanese Coronary Artery Disease (JCAD) Study.

BACKGROUND: Although increased attention is given to assess absolute values of serum cholesterol profiles as optimal markers for preventing future cardiovascular (CV) events, changes in cholesterol profiles also have the potential to be associated with CV disease outcome in Japanese patients with acute coronary syndrome (ACS). METHODS: From the database of the Japanese Coronary Artery Disease (JCAD) study, 2664 patients with ACS who had serial measurements of serum cholesterol profile parameters were enrolled. These patients were followed-up for a mean period of 2.7 years. The endpoint was all CV events. Baseline clinical characteristics of patients with and without CV events were adjusted by the propensity score matching analysis. RESULTS: None of the serum absolute cholesterol profiles at baseline and 6 months later was associated with CV events, except for baseline serum total cholesterol level. However, large improvements in cholesterol profiles correlated with better CV disease outcome. CONCLUSIONS: This subanalysis of JCAD demonstrated the importance of serial assessment of serum cholesterol profiles for secondary prevention of CV events in Japanese patients with ACS. Changes in serum cholesterol profiles, rather than their absolute values, correlated with future CV events.

Frequency and impact of lifestyle modification in patients with coronary artery disease: the Japanese Coronary Artery Disease (JCAD) study.

BACKGROUND: Lifestyle modifications such as exercise and diet interventions in patients with coronary artery disease (CAD) are widely regarded as important, but little is known about their frequency in clinical practice and their impact on all-cause mortality. METHODS: The JCAD study is a cohort study of 13,812 patients with CAD (≥75% stenosis in ≥1 of 3 major coronary arteries). Patients were enrolled from April 2000 through March 2001 at 202 institutions throughout Japan. Exercise and diet interventions were defined based on Japanese national guidelines. Cox proportional hazards models were used to calculate hazard ratios (HRs) for all-cause mortality with 95% CIs. RESULTS: We studied 11,893 patients in the JCAD study. Over 3 years of follow-up, there were 474 deaths; 4,237 patients (35.6%) underwent exercise intervention, and 8,642 patients (72.7%) underwent diet intervention from the time of discharge. Mortality was lower in patients who underwent an exercise or diet intervention than in patients who did not: HR 0.68 (95% CI 0.56-0.84) and 0.75 (95% CI 0.62-0.91), respectively. After adjustment for age, sex, institution, hypertension, hyperlipidemia, diabetes, obesity, current drinking, current smoking, and the use of antiplatelet agents, ß-blockers, angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, and statins, the associations with these interventions remain statistically significant: HR 0.73 (95% CI 0.55-0.96) for exercise and 0.74 (95% CI 0.58-0.95) for diet interventions. CONCLUSIONS: Exercise and diet interventions have a beneficial impact on all-cause mortality in patients with CAD, yet these interventions are surprisingly infrequent. Lifestyle interventions should be more actively promoted.

Treatment effects of renin-angiotensin system inhibitor and calcium channel blocker in patients with coronary artery narrowing (from the Japanese Coronary Artery Disease Study).

Low-dose antihypertensive drugs in combination are prescribed frequently in clinical practice. Combination treatment is superior to monotherapy with higher doses of each drug in terms of blood pressure reduction and side effects. However, it is unclear whether combination treatment provides additional prognostic benefit beyond the blood pressure lowering effects. We assessed the usefulness of the combined treatment of a renin-angiotensin system inhibitor (RASI) and a calcium channel blocker (CCB) for all cardiovascular events in the Japanese Coronary Artery Disease (JCAD) Study population. In the JCAD Study, which is an observational and non-randomized trial, 13,812 patients with angiographically shown narrowing >50% in ≥1 of 3 major coronary arteries were followed up for a mean of 2.7 years. The primary endpoint of the study was all cardiovascular events. In the present study, baseline covariates possibly influencing the event rate were adjusted between the different treatment groups. There was no statistically significant difference in the event rate between the RASI monotherapy and combined treatment groups, although Kaplan-Meier analysis showed a 23% (p = 0.0003) relative risk reduction with an RASI monotherapy compared with the control group. In conclusion, there may be no additional benefit beyond blood pressure lowering effects in the combination of an RASI and a CCB in patients with angiographically documented CAD.

Elevated serum uric acid is an independent predictor for cardiovascular events in patients with severe coronary artery stenosis: subanalysis of the Japanese Coronary Artery Disease (JCAD) Study.

BACKGROUND: The association of elevated serum uric acid (UA) with cardiovascular events in patients with severe coronary artery stenosis was examined. METHODS AND RESULTS: Patients with stenosis > or = 75% (n=8,832) were followed for "all events" (cardiovascular events and all-cause mortality) for 3 years. The group was divided into quartiles based on baseline UA level. The incidence rate of all events was significantly different among quartiles (58.3, 56.5, 61.2, 76.3/1,000 patients-year, P<0.001). Cox's proportional hazard regression analysis showed that the hazard ratio (HR) for all events was 1.25 [95% confidence interval (CI): 1.07-1.45, P<0.01] in the highest quartile (UA > or = 6.8 mg/dl). The group in which UA increased > or = 1.0 mg/dl after 6 months had significantly higher cardiovascular events rate than the group in which UA did not change (70.6 vs 58.8/1,000 patients-year, P=0.042). Propensity score matching was performed and 4,206 patients were divided into the highest quartile and the rest. High UA remained an independent predictor of all events (HR 1.25, 95%CI 1.06-1.43). However, no significant difference was observed between the group with increased UA > or = 1.0 mg/dl and the group with unchanged UA level. CONCLUSIONS: Elevated UA is an independent predictor of cardiovascular events and all-cause mortality combined in patients with coronary artery stenosis.

Gender differences in patients with coronary artery disease in Japan: the Japanese Coronary Artery Disease Study (the JCAD study).

BACKGROUND: Gender differences among patients with coronary artery disease vary from study to study. In one of the largest studies, the Japanese Coronary Artery Disease (JCAD) Study, gender differences in patients were investigated. METHODS AND RESULTS: Consecutive patients diagnosed with stenosis 75% or more in at least one branch of the coronary arteries were enrolled in the study. The endpoint is a composite of all-cause death and cardiovascular events. Data were collected over the internet. Out of 15,628 patients screened, 13,812 of them met the inclusion criteria and were followed up for a mean period of 2.7 years. The event rate was 62.8 per 1,000 patients-year, all-cause death 17.3 and total cardiac events 47.4. The incident rate of unstable angina was higher in females (27.1) than males (21.8) (P=0.0363). The incidence of all-cause death was lower in females than males (16.9 and 17.8, respectively; P=0.0148). Other than gender, hypertension and number of vessel disease contribute to the event of unstable angina, and age, family history, obesity, impaired fasting glycemia, hyperlipidemia, congestive heart failure and number of vessel disease contribute to the all-cause death. CONCLUSIONS: Gender is an independent contributing factor of unstable angina and of all-cause death.

Elevated serum C-reactive protein levels predict cardiovascular events in the Japanese coronary artery disease (JCAD) study.

BACKGROUND: Accumulating evidence indicates that C-reactive protein (CRP) is an independent predictive factor for atherosclerotic vascular disease in Caucasians. Accordingly, this study sought to investigate the relationship between the serum level of CRP and cardiovascular events of Japanese patients with coronary artery disease (CAD). METHODS AND RESULTS: The Japanese CAD (JCAD) study enrolled 15,628 patients who had significant diameter stenosis (>or=75%) in at least 1 coronary artery. Of these, 6,802 patients had their baseline serum CRP data available. Patients were followed up for a mean of 2.7 years (follow-up rate 88.3%). The primary endpoint of the JCAD study was all events. Baseline covariates possibly influencing the event rate were adjusted between the 2 groups with and without elevated serum CRP level. Kaplan-Meier analysis demonstrated a 30% higher all-events rate in patients with a serum level of CRP >or=0.1 mg/dl (P=0.0002). Cox proportional hazard analysis also showed that a serum level of CRP >or=0.1 mg/dl was an independent predictor of all events (P=0.0001), and of cardiac events and cardiac death (P=0.0005). CONCLUSIONS: Elevated serum level of CRP is an independent predictor of cardiovascular events in JCAD patients.

Demographics and changes in medical/interventional treatment of coronary artery disease patients over a 3.5-year period in Japan: the Japanese Coronary Artery Disease Study: trend examination.

BACKGROUND: Cardiovascular medicine has undergone rapid changes in recent years, but there are insufficient reports using large cohorts regarding these changes for Japanese coronary artery disease (CAD) patients. Hence, a large-scale prospective observational study was needed. METHODS AND RESULTS: A total of 36,298 patients were registered over 6 periods. Patients with hypertension, hyperlipidemia, obesity, and impaired glucose tolerance increased in number, while those with old myocardial infarction (MI), smoking habit, and family history of CAD decreased. Regarding the trends in interventional procedures, stent use increased in both the whole cohort and the acute MI subgroup, while the use of only medical control decreased. Regarding prescription trends, angiotensin-receptor blockers increased while nitrates decreased. CONCLUSIONS: In a period of 3.5 years, significant changes were observed for both interventional procedures and medication, which might be related to the well-timed compliance of physicians with published evidence. However, these changes were not related to changes in the event rates, at least over the short term. Although careful attention should be paid in interpreting the results, because this is an observational study and the background of patients in each cohort might have been heterogeneous, such investigations should be constantly conducted for evidence-based practice.

A crucial role of a high mobility group protein HMGA2 in cardiogenesis.

The high mobility group (HMG) of nuclear proteins regulates expression of many genes through architectural remodelling of the chromatin structure, and formation of multiprotein complexes on promoter/enhancer regions. This leads to the active transcription of their target genes. Here we show that HMGA2, a member of the HMGA sub-family of HMG proteins, has a critical function in cardiogenesis. Overexpression of HMGA2 enhanced, whereas siRNA-mediated knockdown of HMGA2 blocked, cardiomyocyte differentiation of the embryonal carcinoma cell line P19CL6. Moreover, overexpression of a dominant-negative HMGA2 or morpholino-mediated knockdown of HMGA2 expression blocked normal heart formation in Xenopus laevis embryos, suggesting that HMGA2 has an important role in cardiogenesis both in vitro and in vivo. Mechanistically, HMGA2 associated with Smad1/4 and showed synergistic trans-activation of the gene for a cardiac transcription factor Nkx2.5; a conserved HMGA2 binding site was required for the promoter activity of Nkx2.5 gene, both in P19CL6 cells and in transgenic Xenopus embryos. Thus, HMGA2 is a positive regulator of Nkx2.5 gene expression and is essential for normal cardiac development.

Pleiotropic effects of statins on cardiovascular events in the Japanese Coronary Artery Disease study.

We analyzed 6317 patients with a baseline LDL-cholesterol level of 70 to 130 mg/dL among 13,812 patients of the Japanese Coronary Artery Disease (JCAD) study. We divided the patients into 2 groups according to statin treatment and its lipophilicity. We compared the incidence of all-cause events between 2000 statin-treated patients and 4317 patients without statins during a median follow-up period of 1092 days (range 0 to 1676 days). After propensity score matching (n=1641, for each group), Kaplan-Meier analysis showed 25% reduction in the incidence of all-cause events with statin treatment (p=0.0016). The incidence of all-cause events was also compared between 1139 patients with hydrophilic statin and 861 patients with lipophilic statin. After propensity score matching (n=778, for each group), Kaplan-Meier analysis showed no significant difference in the incidence of all-cause events with respect to lipophilicity. Subgroup analysis of the JCAD study suggested a lipid-independent beneficial treatment effect of statins on all-cause events, and these favorable effects were comparable between the hydrophilic and lipophilic statins.

Automated healthcare data mining based on a personal dynamic healthcare system.

The automated healthcare-data-mining system reported here extracts personally useful information, such as rules and patterns concerning lifestyles and health conditions, from daily time-series personal health and lifestyle data stored on a personal dynamic healthcare system by using mobile phone and Web technologies. This system enables users to input their daily data through a mobile phone and to transfer these data to a Web-application server via the Internet. The Web application server provides a data-mining service and uses mobile phones to inform users of important rules concerning their health and lifestyle data. Automated healthcare-data mining of the stored time-series data of volunteer users generated some useful rules correlating their lifestyles with body-fat index.

The use of a supercooling refrigerator improves the preservation of organ grafts.

Current medical transplantation confronts major problems such as the shortage of donors and geographical restrictions that inhibit efficient utilization of finite donor organs within their storage lives. To overcome these issues, expanding organ preservation time has become a major concern. We investigated whether a strategy which best preserves organ grafts can be achieved by the use of a newly developed refrigerating chamber, which is capable of establishing a supercooled and unfrozen state stably by generating an electrostatic field in its inside. When adult rat organs such as heart, liver, and kidneys were stored in the supercooled conditions, the levels of major biochemical markers leaked from the preserved organs were significantly lower than in the ordinary hypothermic storage. No apparent tissue damages were observed histologically after the supercooled preservation. Our results suggest that the use of this supercooling refrigerator improves organ preservation and may provide an innovative technique for human organ transplantation.

Atrial natriuretic peptide inhibits cardiomyocyte hypertrophy through mitogen-activated protein kinase phosphatase-1.

Cardiac hypertrophy is formed in response to hemodynamic overload. Although a variety of factors such as catecholamines, angiotensin II (AngII), and endothelin-1 (ET-1) have been reported to induce cardiac hypertrophy, little is known regarding the factors that inhibit the development of cardiac hypertrophy. Production of atrial natriuretic peptide (ANP) is increased in the hypertrophied heart and ANP has recently been reported to inhibit the growth of various cell types. We therefore examined whether ANP inhibits the development of cardiac hypertrophy. Pretreatment of cultured cardiomyocytes with ANP inhibited the AngII- or ET-1-induced increase in the cell size and the protein synthesis. ANP also inhibited the AngII- or ET-1-induced hypertrophic responses such as activation of mitogen-activated protein kinase (MAPK) and induction of immediate early response genes and fetal type genes. To determine how ANP inhibits cardiomyocyte hypertrophy, we examined the mechanism of ANP-induced suppression of the MAPK activation. ANP strongly induced expression of MAPK phosphatase-1 (MKP-1) and overexpression of MKP-1 inhibited AngII- or ET-1-induced hypertrophic responses. These growth-inhibitory actions of ANP were mimicked by a cyclic GMP analog 8-bromo-cyclic GMP. Taken together, ANP directly inhibits the growth factor-induced cardiomyocyte hypertrophy at least partly via induction of MKP-1. Our present study suggests that the formation of cardiac hypertrophy is regulated not only by positive but by negative factors in response to hemodynamic load.

Development of a pioneering clinical support system utilizing information technology.

Nowadays, evidence-based medicine has entered the mainstream of clinical judgement and the human genome has been completely decoded. Even the concept of individually designed medicine, that is, tailor-made medicine, is now being discussed. Due to their complexity, however, management methods for clinical information have yet to be established. We have conducted a study on a universal technique which enables one to select or produce by employing information processing technology clinical findings from various clinical information generated in vast quantity in day-to-day clinical practice, and to share such information and/or the results of analysis between two or more institutions. In this study, clinically useful findings have been successfully obtained by systematizing actual clinical information and genomic information obtained by an appropriate collecting and management method of information with due consideration to ethical issues. We report here these medical achievements as well as technological ones which will play a role in propagating such medical achievements.

Design and rationale of the Japanese Coronary Artery Disease (JCAD) Study: a large-scale, multicentered prospective cohort study.

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.

Genetic variations of matrix metalloproteinase-1 and -3 promoter regions and their associations with susceptibility to myocardial infarction in Japanese.

Matrix metalloproteinases (MMPs) are involved in plaque rupture, which is the main pathological cause of myocardial infarction (MI). Recently, several genetic studies have demonstrated that MMP-1 1G/2G polymorphism and MMP-3 5A/6A polymorphism modify each transcriptional activity in allele specific manners. Within this context, we conducted case-control studies to examine whether these genetic polymorphisms are associated with susceptibility to MI. Two groups comprising patients with MI (group-1 164 patients, group-2 302 patients) were compared with control group comprising 335 patients without cardiovascular diseases. The MMP-3 5A allele was more frequent in patients with MI than in the control subjects (P=0.018 MI group-1, P=0.0059 MI group-2), whereas there was no disease association for MMP-1 genotypes. Logistic regression analyses revealed that MMP-3 5A/6A polymorphism was associated with susceptibility to MI [odds ratio(OR) (95% confidential interval) 1.67 (1.02-2.74); P=0.042, MI group-1; 1.61 (1.12-2.23); P=0.0095, MI group-2]. Other important findings were that there was strong linkage disequilibrium between these polymorphisms, which are located closely on chromosome 11q.22, and that the 5A-1G haplotype was a genetic risk factor for MI (OR 1.97 P=0.0082, MI group-1 OR 1.51 P=0.017, MI group-2). Taken together, the present findings suggest that genetic variations in these MMP genes and especially their haplotype may be useful genetic markers for determining susceptibility to MI in Japanese.

A common Ile 823 Met variant of ATP-binding cassette transporter A1 gene (ABCA1) alters high density lipoprotein cholesterol level in Japanese population.

Recently, variants in ATP-binding cassette transporter A1 (ABCA1) were demonstrated to be associated with increased level of high density lipoprotein cholesterol (HDL-C) and decreased risk of coronary artery disease (CAD) in Caucasians. However, this is not universally applicable due to the ethnic or environmental differences. In this context, to clarify the effect of ABCA1 in Japanese, we evaluated the phenotypic effects of I/M 823 and R/K 219 variants on the plasma level of HDL-C in 410 patients recruited in our hospital. Subjects with M 823 allele had significantly higher level of HDL-C than those without M823 allele (49.0+/-15.1 vs. 44.9+/-11.5 mg/dl, respectively, P<0.05). This statistical significance did not change even after multiple regression analysis. In contrast, there was no difference in HDL-C level among the genotypes in R/K 219 polymorphism. Further, in our study population an inverse relationship was shown to exist between HDL-C level and incidence of CAD. However, no positive association was observed between those variants and susceptibility to CAD. In this study, we provide evidence that I/M 823 variant, not R/K 219 variant, in ABCA1 is one of the determinants of HDL-C level, suggesting the importance of this gene on lipid metabolism in Japanese.

Deficiency of protein S-mediated familial venous thrombophilia--a case report.

Deficiency of protein S causes potential problems of thrombosis. Cases of familial venous thrombosis due to deficiency of protein S were presented. First, an 85-year-old woman had pulmonary thromboembolism due to left deep femoral venous thrombosis, which might be triggered by leg fracture and the long-term treatment with a plaster cast. Next, her 29-year-old granddaughter had episodes of recurrent venous thrombosis in her legs and arms, which might be triggered by the treatment with a plaster cast and abortion. In the latter part, the aspects of risks for thromboembolism, potential problems in gestational period, and an advisability of thromboprophylaxis in patients with deficiency of protein S are described.

Dual effects of the homeobox transcription factor Csx/Nkx2-5 on cardiomyocytes.

A homeobox-containing transcription factor Csx/Nkx2-5 is an important regulator of cardiac development. Many different human CSX/NKX2-5 mutations have been reported to cause congenital heart disease. We here examined the effects of three representative CSX/NKX2-5 mutations on cardiomyocyte differentiation and death with the use of the P19CL6 cardiomyogenic cell lines. Stable overexpression of wild-type CSX/NKX2-5 enhanced expression of cardiac-specific genes such as MEF2C and MLC2v, the promoter activity of the atrial natriuretic peptide gene, and the terminal differentiation of P19CL6 into cardiomyocytes, while all CSX/NKX2-5 mutants attenuated them by different degrees. When exposed to H(2)O(2) or cultured without change of the medium, many differentiated P19CL6 cells overexpressing the mutants, especially the mutant which lacks the carboxyl terminal region just after the homeodomain, were dead, while most of the cells overexpressing wild-type CSX/NKX2-5 survived. Overexpression of the carboxyl terminus-deleted mutant down-regulated expression of an anti-apoptotic protein Bcl-x(L) and up-regulated that of a pro-apoptotic protein CAS, while in the cells overexpressing wild-type CSX/NKX2-5, expression of a pro-apoptotic protein RIP was reduced. Furthermore, overexpression of wild-type CSX/NKX2-5 decreased the number of H(2)O(2)-induced TUNEL-positive cultured cardiomyocytes of neonatal rats, whereas overexpression of the mutants enhanced it. These results suggest that Csx/Nkx2-5 not only regulates expression of cardiac-specific genes but protects cardiomyocytes from stresses and that cell death may be another cause for the cardiac defects induced by human CSX/NKX2-5 mutations.

Calcium channel blockers and myocardial infarction: a case--control study in a Japanese hospital.

PURPOSE: To examine the relationship of the use of calcium channel blockers (CCBs) in hypertensive patients to myocardial infarction in Japan, where CCBs are prescribed much more frequently than in Europe and America. DESIGN: We conducted a nested case-control study using a hospital information system in Japan. SUBJECTS: Cases were hypertensive patients who were repeat visitors to Tokyo University Hospital as of April 1996 and had an incidence of fatal or non-fatal myocardial infarction between 1996 and 1999. Controls were hypertensive patients individually matched to cases by sex, age and history of angina pectoris. RESULTS: The study consisted of 16 cases, who were matched to 80 controls. Of the 80 control patients, 54 (68%) received CCBs. On the other hand, all but one of 16 cases received CCBs and the crude odds ratio of myocardial infarction associated with the use of calcium channel blockers was as high as 7.0 (0.9-55.3). The odds ratio was reduced to 4.9 (0.6-42.4) when adjusted by diabetes and diastolic blood pressure. CONCLUSIONS: Although the crude odds ratio of myocardial infarction associated with CCBs was high, the ratio was reduced when adjusted by known confounding factors, suggesting a mechanism of confounding by indication. In addition, the results obtained in this study using records from a single hospital should not be generalized.