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The Japan Circulation Society launched the STOP-MI campaign in 2014, focusing on immediate hospital arrival for acute myocardial infarction (AMI) treatment. This study aimed to determine the factors influencing longer prehospital time among patients with AMI in Japan.Methods and Results:This study analyzed a total of 4,625 AMI patients enrolled in the Osaka Acute Coronary Insufficiency Study registry from 1998 to 2014. The prehospital time delay was defined as the time interval from the onset of initial symptoms to hospital arrival time ≥2 h. Among eligible patients, 2,927 (63.3%) had a prehospital time ≥2 h. In multivariable analyses, age 65-79 years (adjusted odds ratio [AOR] 1.19, 95% confidence interval [CI] 1.02-1.39), age ≥80 years (AOR 1.42, 95% CI 1.13-1.79), diabetes mellitus (AOR 1.33, 95% CI 1.16-1.52), and onset time of 0:00-5:59 h (AOR 1.63, 95% CI 1.37-1.95) were positively associated with prehospital time ≥2 h, whereas smoking (AOR 0.78, 95% CI 0.68-0.90) and ambulance use (AOR 0.37, 95% CI 0.32-0.43) were negatively associated with prehospital time ≥2 h.Older age, diabetes mellitus, and nighttime onset were associated with prehospital time delay for AMI patients, whereas smoking and ambulance use were associated with no prehospital time delay. Healthcare providers and patients could help reduce the time to get to a medical facility by being aware of these findings.

The prognostic significance of combining intra-aortic balloon pumping (IABP) with extracorporeal membrane oxygenation (ECMO) for acute myocardial infarction (AMI) patients is still unclear. We investigated whether combining IABP with veno-arterial (VA)-ECMO is associated with a lower risk of short-term mortality.Among 12,093 AMI cases enrolled in the Osaka Acute Coronary Insufficiency Study (OACIS), we identified 519 who were administered VA-ECMO during hospitalization. Among these, 459 received IABP support (IABP group) and 60 cases did not (no-IABP group). The primary endpoint was 30-day all-cause death; the secondary endpoint was major bleeding. Logistic regression analysis using original data was conducted. We also established weighted logistic regression models with inverse probability of treatment weighting (IPTW).Logistic regression analysis revealed that IABP use was significantly associated with a reduced risk of 30-day death in the original data [odds ratio (OR) 0.504, 95% confidence interval (CI) 0.282-0.901, p = 0.021]. After IPTW-adjustment for clinically relevant covariates with the use of IABP, patients receiving VA-ECMO with IABP had a lower risk of 30-day death (OR 0.816, 95% CI 0.746-0.892, p0.001) compared to those without IABP. The incidence of major bleeding was comparable between the groups (IABP 29.0% vs. non-IABP 21.7%, p=0.302). However, the risk of major bleeding was higher in the IABP group after IPTW-adjustment (OR 1.092, 95% CI 1.008-1.184, p=0.032).IABP support for AMI patients with VA-ECMO was significantly associated with reduced risk of short-term mortality, suggesting that the addition of IABP support might contribute to improved survival in AMI patients requiring VA-ECMO.

To elucidate the genetics of coronary artery disease (CAD) in the Japanese population, we conducted a large-scale genome-wide association study of 168,228 individuals of Japanese ancestry (25,892 cases and 142,336 controls) with genotype imputation using a newly developed reference panel of Japanese haplotypes including 1,781 CAD cases and 2,636 controls. We detected eight new susceptibility loci and Japanese-specific rare variants contributing to disease severity and increased cardiovascular mortality. We then conducted a trans-ancestry meta-analysis and discovered 35 additional new loci. Using the meta-analysis results, we derived a polygenic risk score (PRS) for CAD, which outperformed those derived from either Japanese or European genome-wide association studies. The PRS prioritized risk factors among various clinical parameters and segregated individuals with increased risk of long-term cardiovascular mortality. Our data improve the clinical characterization of CAD genetics and suggest the utility of trans-ancestry meta-analysis for PRS derivation in non-European populations.

Aims: This article aimed to examine the cost-effectiveness of rivaroxaban in comparison to warfarin for stroke prevention in Japanese patients with non-valvular atrial fibrillation (NVAF), from a public healthcare payer's perspective.Materials and methods: Baseline event risks were obtained from the J-ROCKET AF trial and the treatment effect data were taken from a network meta-analysis. The other model inputs were extracted from the literature and official Japanese sources. The outcomes included the number of ischaemic strokes, myocardial infarctions, systemic embolisms and bleedings avoided, life-years, quality-adjusted life-years (QALYs), incremental costs and incremental cost-effectiveness ratio (ICER). The scenario analysis considered treatment effect data from the same network meta-analysis.Results: In comparison with warfarin, rivaroxaban was estimated to avoid 0.284 ischaemic strokes per patient, to increase the number of QALYs by 0.535 per patient and to decrease the total costs by ¥118,892 (€1,011.11) per patient (1 JPY = 0.00850638 EUR; XE.com, 7 October 2019). Consequently, rivaroxaban treatment was found to be dominant compared to warfarin. In the scenario analysis, the ICER of rivaroxaban versus warfarin was ¥2,873,499 (€24,446.42) per QALY.Limitations: The various sources of data used resulted in the heterogeneity of the cost-effectiveness analysis results. Although, rivaroxaban was cost-effective in the majority of cases.Conclusion: Rivaroxaban is cost-effective against warfarin for stroke prevention in Japanese patients with NVAF, giving the payer WTP of 5,000,000 JPY.

Aims It is unknown whether Asian and non-Asian patients with atherosclerotic vascular disease derive similar benefits from long-term antithrombotic therapy. Methods and results In patients with chronic coronary artery disease (CAD) and/or peripheral artery disease (PAD) enrolled in The Cardiovascular Outcomes for People Using Anticoagulation Strategies trial, the effects of rivaroxaban 2.5 mg b.i.d. plus aspirin 100 mg o.d. were compared with those of aspirin 100 mg o.d. in Asian vs. non-Asian patients (race was self-identified). Asians (n = 4269) vs. non-Asians (n = 23 126) had similar rates of major adverse cardiovascular events (MACEs) (4.85% vs. 4.83%, P = 0.30) and modified International Society on Thrombosis and Haemostasis (ISTH) major bleeding (2.72% vs. 2.58%, P = 0.22), but higher rates of intracranial haemorrhage (ICH) (0.63% vs. 0.29%, P = 0.01) and minor bleeding (13.61% vs. 6.49%, P Conclusion Asian compared with non-Asian patients with chronic CAD and/or PAD have higher rates of ICH and minor bleeding. The combination of rivaroxaban and aspirin vs. aspirin alone produces similar effects for MACE, modified ISTH major bleeding, and net clinical outcome but may be associated with higher rates of ICH in Asian patients.

Background The previous large‐scale randomized controlled trial showed that routine thrombus aspiration (TA) during percutaneous coronary intervention (PCI) was associated with an increased risk of stroke. However, real‐world clinical evidence is still limited. Methods and Results We investigated the association between manual TA and stroke risk during primary PCI in the OACIS (Osaka Acute Coronary Insufficiency Study) database (N=12 093). The OACIS is a prospective, multicenter registry of myocardial infarction. The primary end point of the present study is stroke at 7 days. A total of 9147 patients who underwent primary PCI within 24 hours of hospitalization were finally analyzed (TA group, n=4448, versus non‐TA group, n=4699 patients). TA was independently associated with risk of stroke at 7 days (odds ratio [OR], 1.92 [95% CI, 1.19‒3.12]; P =0.008) in the simple logistic regression model, while the multilevel random effects logistic regression model with hospital treated as a random effect showed that manual TA was not associated with incremental risk of stroke at 7 days (OR, 0.91 [95% CI, 0.71‒1.16]; P =0.435). The 7‐day stroke risk of manual TA was significantly heterogeneous in different institutions ( P for interaction =0.007). Conclusions Manual TA during primary PCI for patients with acute myocardial infarction was independently associated with the overall increased risk of periprocedural stroke. However, this result was substantially skewed because of institution specific risk variation, suggesting that the periprocedural stroke may be preventable by prudent PCI procedure or appropriate periprocedural management. Registration URL: https://upload.umin.ac.jp/cgi‐open‐bin/ctr_e/ctr_view.cgi?recptno=R000005464 . Unique identifier: UMIN000004575.

To investigate the difference in the prognostic impact of loop diuretics in patients with acute myocardial infarction (AMI) based on plasma volume status, a total of 3,364 survivors of AMI who were registered in the large database of the Osaka Acute Coronary Insufficiency Study (OACIS) were studied. Plasma volume status was assessed by the estimated plasma volume status (ePVS) that was calculated based on a weight- and hematocrit-based formula at discharge. The endpoint was a composite endpoint of all-cause death and rehospitalization due to heart failure for 5 years. During a median follow-up period of 1.9 years, 90 and 223 patients had events in the groups with low ePVS (median value of 4.07%) and high ePVS (≥4.07%), respectively. Multivariable Cox regression analysis showed that loop diuretics use was independently associated with an increased risk of the composite endpoint in the low ePVS group (hazard ratio [HR], 2.572; 95% confidence interval [CI], 1.386-4.771; p = 0.002), but not in the high ePVS group (HR, 1.028; 95% CI, 0.698-1.512; p = 0.890). These results were unchanged even in the propensity-score matched cohorts. There was no heterogeneity in the increased risk of the primary endpoints between various patient characteristics and loop diuretic use in the matched cohorts. In conclusion, prescription of loop diuretics at discharge was associated with increased risk of poor long-term prognosis in patients with AMI without PV expansion, but not with PV expansion. Therefore, careful observation is needed when loop diuretics are prescribed for AMI patients without PV expansion.

Aims We aimed to establish a practical method for the assessment of tradeoff between thrombotic and bleeding risks. Methods We aimed to investigate the balance between bleeding risk and coronary thrombotic risk according to the number of the Academic Research Consortium for high bleeding risk (ARC-HBR) criteria in the multicenter prospective ST/non-ST elevation myocardial infarction (STEMI/NSTEMI) registry (N=12,093). Patients were divided as follows by the number of ARC-HBR criteria fulfilled: group 0, 0 major with ≤ 1 minor (N=6,792); group 1, 1 major with 0 minor (N=1,705); group 2, 0 major with ≥ 2 minors (N=790); group 3, 1 major with ≥ 1 minor (N=1,709); group 4, 2 majors with ≥ 0 minors (N=861); and group 5, ≥ 3 majors with ≥ 0 minor (N=236). We assessed the acute-phase absolute risk differences between bleeding and coronary thrombotic events in each group. Results At 7-day follow-up, all patients (groups 0-5) had a higher risk of major bleeding than that of any myocardial infarction (MI). Patients at ARC-HBR (groups 1-5) had a balanced risk between fatal MI and fatal bleeding, whereas patients at non-ARC-HBR (group 0) had a higher risk of fatal MI than that of fatal bleeding. Conclusions All STEMI/NSTEMI patients have a relatively high risk of major bleeding as compared with the risk of any MI in the acute phase. The ARC-HBR criteria would be a practical tool for assessing the tradeoff between fatal bleeding and fatal MI risks. This practical assessment would be helpful for the optimal decision-making of appropriate treatment strategy considering the balance between bleeding and coronary thrombotic risks.

The effect of a history of cancer on the prognosis of patients with acute myocardial infarction (AMI) after percutaneous coronary intervention (PCI) is poorly understood.From the Osaka Acute Coronary Insufficiency Study (OACIS) registry in Osaka, Japan, we enrolled the case data of a total of 3499 patients with AMI treated with PCI between 1998 and 2014, of whom 462 had a cancer history (cancer group, 13.2%) and 3037 did not (non-cancer group, 86.8%). All of the cases were followed for up to five years from discharge.The Kaplan-Meier curve and multivariate analysis using Cox proportional hazards models revealed that all-cause mortality was significantly higher in the cancer group than in the non-cancer group (adjusted hazard ratio [HR], 2.43; P0.001). Deaths from cardiac, cancer, and other causes were treated as competing events, and competing analysis using the cumulative incidence function (CIF) and Fine-Gray model revealed that mortality due to cancer was higher in the cancer group than in the non-cancer group, whereas cardiac mortality was similar between the two groups. The incidences of cardiovascular events, including stroke, recurrent infarction, and heart failure requiring readmission, were also similar between the two groups, although the Kaplan-Meier analysis and univariate Cox proportional hazards model revealed that the incidence of stroke was higher in the cancer group than in the non-cancer group.A history of cancer increased all-cause and cancer mortality among patients with AMI treated with PCI, although it was not associated with cardiovascular events.

The Japanese high-bleeding-risk criteria (Japanese-HBR), modified criteria of the Academic Research Consortium (ARC) HBR, has been recently proposed. We aimed to investigate the prevalence of the ARC-HBR and the Japanese-HBR, and to assess their prognostic significance in patients with acute myocardial infarction (AMI).We applied the ARC-HBR and the Japanese-HBR criteria to the OACIS prospective multicenter acute myocardial infarction registry (12,093 patients, 66 ± 12 years, 9,096 males). The primary endpoint was fatal bleeding (BARC-5). Median follow-up duration was 4.84 [inter-quartile range 1.35, 5.01] years. Prevalence of the ARC-HBR was 43.8%, while that of the Japanese-HBR was 61.8%. Cumulative incidence of fatal bleeding was higher in the ARC-HBR group than in the no ARC-HBR group at 1 year (1.3 vs. 0.6%) and at 5 years (2.0 vs. 0.7%). The Kaplan-Meier curves stratified by the Japanese-HBR criteria more prominently diverged (1.3 vs. 0.2% at 1 year; and 1.9 vs. 0.3% at 5 years). The Japanese-HBR criteria showed superior discriminative performance over the ARC-HBR criteria (C-statistics: 0.677 vs. 0.598, P 0.001).In the real-world Japanese AMI registry, nearly half of the patients fulfilled the criteria of ARC-HBR, and two-thirds met the Japanese-HBR. Our findings support the validity of both ARC- and Japanese-HBR criteria in AMI patients but encourage the future application of the Japanese-HBR criteria to the Japanese AMI cohort.UMIN000004575.

BACKGROUND Anemia portends a poor clinical outcome in patients with chronic heart failure (CHF). However, its mechanism remains unknown. We sought to elucidate the effect of anemia on patients with HF with reduced ejection fraction (HFrEF) who receive carvedilol therapy.Methods and Results:J-CHF study was a prospective, randomized, multicenter trial that assigned 360 HFrEF patients to 2.5 mg/5 mg/20 mg carvedilol groups according to the target dose. At baseline 70 patients (19%) had anemia ([A]) defined as hemoglobin level (Hb)

BACKGROUND: Long-term aspirin prevents vascular events but is only modestly effective. Rivaroxaban alone or in combination with aspirin might be more effective than aspirin alone for vascular prevention in patients with stable coronary artery disease (CAD) or peripheral artery disease (PAD). Rivaroxaban as well as aspirin increase upper gastrointestinal (GI) bleeding and this might be prevented by proton pump inhibitor therapy. METHODS: Cardiovascular Outcomes for People Using Anticoagulation Strategies (COMPASS) is a double-blind superiority trial comparing rivaroxaban 2.5 mg twice daily combined with aspirin 100 mg once daily or rivaroxaban 5 mg twice daily vs aspirin 100 mg once daily for prevention of myocardial infarction, stroke, or cardiovascular death in patients with stable CAD or PAD. Patients not taking a proton pump inhibitor were also randomized, using a partial factorial design, to pantoprazole 40 mg once daily or placebo. The trial was designed to have at least 90% power to detect a 20% reduction in each of the rivaroxaban treatment arms compared with aspirin and to detect a 50% reduction in upper GI complications with pantoprazole compared with placebo. RESULTS: Between February 2013 and May 2016, we recruited 27,395 participants from 602 centres in 33 countries; 17,598 participants were included in the pantoprazole vs placebo comparison. At baseline, the mean age was 68.2 years, 22.0% were female, 90.6% had CAD, and 27.3% had PAD. CONCLUSIONS: COMPASS will provide information on the efficacy and safety of rivaroxaban, alone or in combination with aspirin, in the long-term management of patients with stable CAD or PAD, and on the efficacy and safety of pantoprazole in preventing upper GI complications in patients receiving antithrombotic therapy. ispartof: Canadian Journal of Cardiology vol:33 issue:8 pages:1027-1035 ispartof: location:England status: published

Background Results from the J-ROCKET AF study revealed that rivaroxaban was non-inferior to warfarin with respect to the principal safety outcomes in patients with non-valvular atrial fibrillation. This subgroup analysis evaluated whether non-major clinically relevant bleeding (NMCRB) could be a predictive factor for major bleeding (MB). Other predictive factors for MB were also obtained in both rivaroxaban and warfarin treatment groups. Methods The temporal incidence of MB was compared between the rivaroxaban and warfarin treatment groups. Assessment was made whether MB events were often preceded by NMCRB. Univariate and multivariate analyses were carried out to identify any independent predictive factors for MB in both treatment groups. Results The incidences of MB and NMCRB were 18.04% (138/639 patients) in the rivaroxaban arm, and 16.42% in the warfarin arm (124/639 patients). NMCRB preceded MB in only four patients in each treatment group (rivaroxaban: 4/117 and warfarin: 4/98). Multivariate analysis identified predictive factors for bleeding events: anemia with warfarin treatment and concomitant use of antiplatelet agents with rivaroxaban treatment. Conclusions Results from this subgroup analysis, particularly the fact that there was no repeated or sequential pattern between NMCRB and MB occurrences in both treatment groups, suggests that NMCRB might not be a predictive factor for MB. On the contrary, anemia and concomitant use of antiplatelet therapy were likely predictive factors for bleeding with warfarin and rivaroxaban treatment, respectively.

In patients with ST-segment elevation myocardial infarction (STEMI), the association between stress-induced hyperglycemia (SIH) and long-term outcomes, as well as the effects of baseline diabetic status on this association remain elusive. To clarify the association between SIH and long-term outcomes, and the effects of baseline diabetic status on this association, we studied 6,287 STEMI patients who were discharged alive. SIH was estimated using the stress hyperglycemia ratio (SHR), which is defined as [(admission glucose (mg/dl))/(28.7 × HbA1c (%) − 46.7)]. End points were all-cause death and admission for heart failure (HF). We compared prognosis between patients in the highest SHR quartile and those in other quartiles of the nondiabetic and diabetic population. Over a follow-up of 5 years (median 1,522 days), 464 (7.4%) and 401 (6.4%) cases of all-cause death and HF admission were observed. In the nondiabetic population, the highest SHR quartile (Q4) group was significantly associated with worse long-term outcomes (adjusted hazard ratio [HR] (95% confidence interval [CI]), all-cause death; 1.45 (1.06 to 1.98), p = 0.021, HF admission; 1.48 (1.04 to 2.10), p = 0.031). However, in the diabetic population, SHR Q4 group was not significantly associated with worse long-term outcomes (adjusted HR (95% CI), all-cause death; 1.00 (0.68 - 1.48), p = 0.996, HF admission; 1.31 (0.90 to 1.89), p = 0.154). In conclusion, in STEMI patients discharged alive, high SHR was significantly associated with worse long-term prognosis in the nondiabetic population. In contrast, high SHR was not significantly associated with worse long-term prognosis in the diabetic population.

Atrial fibrillation (AF) affects an estimated 1.5 million individuals in Japan, increasing their stroke risk and imposing considerable costs on the Japanese healthcare system. To reduce stroke incidence, guidelines recommend using anticoagulants in moderate-to-high risk non-valvular AF (NVAF) patients; however, many patients receive no treatment, aspirin only, or remain poorly-controlled on vitamin K antagonists (VKAs) due to high VKA discontinuation rates and non-adherence to guidelines. A prevalence-based Markov model was developed to estimate the clinical and budgetary impact of treating these patients with Xarelto(TM) (rivaroxaban, Bayer AG) in Japan.Population, baseline risk of events, and associated management costs were estimated using data from Japanese publications where available. Treatment efficacy and safety were derived from published data and the J-ROCKET AF trial. Drug and physician visit costs were based on data from the Ministry of Health, Labor, and Welfare, the J-ROCKET AF trial, and Japanese clinical guidelines.This model demonstrates that increased use of rivaroxaban in inadequately-managed NVAF patients could avoid 456 081 non-fatal ischemic strokes (IS) and 76 975 cardiovascular deaths over 10 years in Japan. This clinical benefit offsets the increased incidence of myocardial infarctions and anticoagulant-related bleeding. Decreased event costs could lead to a ¥188.4 billion decrease in net spending over the analysis time horizon.Introducing rivaroxaban may decrease the burden of NVAF in Japanese society. From a clinical perspective, the reduction in IS and embolic events outweighs the increased risk of anticoagulant-related bleeding; from an economic perspective, reduced event costs offset drug and physician visit costs, resulting in cost savings.

BACKGROUND: Coronary artery disease is a major cause of morbidity and mortality worldwide, and is a consequence of acute thrombotic events involving activation of platelets and coagulation proteins. Factor Xa inhibitors and aspirin each reduce thrombotic events but have not yet been tested in combination or against each other in patients with stable coronary artery disease.METHODS: In this multicentre, double-blind, randomised, placebo-controlled, outpatient trial, patients with stable coronary artery disease or peripheral artery disease were recruited at 602 hospitals, clinics, or community centres in 33 countries. This paper reports on patients with coronary artery disease. Eligible patients with coronary artery disease had to have had a myocardial infarction in the past 20 years, multi-vessel coronary artery disease, history of stable or unstable angina, previous multi-vessel percutaneous coronary intervention, or previous multi-vessel coronary artery bypass graft surgery. After a 30-day run in period, patients were randomly assigned (1:1:1) to receive rivaroxaban (2·5 mg orally twice a day) plus aspirin (100 mg once a day), rivaroxaban alone (5 mg orally twice a day), or aspirin alone (100 mg orally once a day). Randomisation was computer generated. Each treatment group was double dummy, and the patients, investigators, and central study staff were masked to treatment allocation. The primary outcome of the COMPASS trial was the occurrence of myocardial infarction, stroke, or cardiovascular death. This trial is registered with ClinicalTrials.gov, number NCT01776424, and is closed to new participants.FINDINGS: Between March 12, 2013, and May 10, 2016, 27 395 patients were enrolled to the COMPASS trial, of whom 24 824 patients had stable coronary artery disease from 558 centres. The combination of rivaroxaban plus aspirin reduced the primary outcome more than aspirin alone (347 [4%] of 8313 vs 460 [6%] of 8261; hazard ratio [HR] 0·74, 95% CI 0·65-0·86, pINTERPRETATION: In patients with stable coronary artery disease, addition of rivaroxaban to aspirin lowered major vascular events, but increased major bleeding. There was no significant increase in intracranial bleeding or other critical organ bleeding. There was also a significant net benefit in favour of rivaroxaban plus aspirin and deaths were reduced by 23%. Thus, addition of rivaroxaban to aspirin has the potential to substantially reduce morbidity and mortality from coronary artery disease worldwide.FUNDING: Bayer AG.

Background Autoantibody against β 1 -adrenergic receptors (β 1 -AAb) exerts agonist-like action inducing receptor uncoupling and myocardial damage. We attempted to determine the significance of β 1 -AAb in chronic heart failure (CHF) patients who received carvedilol in a substudy of the Japanese Chronic Heart Failure study. Methods and Results In this prospective, randomized, multicenter trial, 117 patients were assigned to 2.5 mg, 5 mg, and 20 mg (n = 38, 36, and 43) carvedilol groups according to the target dose. β 1 -AAb was positive in 51 patients (44%, P) and negative in 66 (56%, N). The percentage increase of left ventricular ejection fraction over 56 weeks (ΔLVEF) was larger in P than in N ( P = .050) and in the high-titer group (H) than in the low-titer group (L; P = .04). Left ventricular (LV) volume decreased to a greater extent in H than in L over 56 weeks. β 1 -AAb titer was significantly correlated with ΔLVEF and the percentage change of LV volume and was an independent predictor of them. No difference was seen in the composite end point (all-cause mortality and hospitalization for cardiovascular diseases or heart failure). However, in patients with dilated cardiomyopathy, it was more common in the 2.5 mg group than in the other groups in N, and it was similar among the 3 groups in P. Conclusions Our data suggest that the presence of β 1 -AAb is associated with favorable response to carvedilol in CHF.

Cardiovascular complications, including heart failure, hypertension, ischemic syndromes and venous thromboembolism, have been identified in patients treated with anti-cancer drugs. Oxidative stress, mitochondrial dysfunction and DNA synthesis inhibition are considered to be responsible for the cardiotoxicity induced by these agents. Protein quality control (PQC) has 3 major components, including the endoplasmic reticulum (ER), the ubiquitin-proteasome system (UPS) and the autophagy-lysosome system, and participates in protein folding and degradation to maintain protein homeostasis. We have demonstrated that PQC dysfunction is a new causal mechanism for the development of cardiac hypertrophy and failure. Increasing evidence shows that anti-cancer drugs, such as tyrosine kinase inhibitors, proteasome inhibitors, anthracyclines and autophagy inhibitors, cause PQC dysfunction. Here, we provide an overview of the potential role of PQC dysfunction in the development of cardiovascular complications induced by anti-cancer drugs.

Recent advances in laparoscopic surgical technology have made it possible to perform advanced high-level surgery, such as lymph node dissection for malignancy. Grasping the anatomy during such procedures is important for a safe operation. We have developed a new image information system that provides three-dimensional (3D) reconstructed CT images synchronized with the motion of the laparoscope. This study assesses this new navigation system.Enhanced CT using a custom-made software program can provide 3D angiography images reconstructed as a laparoscopic view. A motion sensor mounted on the laparoscope can detect the direction angle of the laparoscope. The real-time rendered 3D CT images are synchronized with the laparoscopic video images according to the motion of the scope. These 3D CT images are projected on another monitor close to the laparoscopic video monitor. Lymph node dissection can be performed with the help of the real-time navigation system that provides a detailed 3D view of the vasculature.Ten laparoscopic gastrectomies were performed using this navigation system. Real-time intraoperative navigation of the vasculature was available, allowing for an excellent surgical outcome. No complications occurred in this series.Our intraoperative navigation system allows for safe laparoscopic gastric lymph node dissection.

BackgroundThe Japanese Diastolic Heart Failure Study (J-DHF) has suggested beneficial effects of the standard-dose prescription of carvedilol in heart failure with preserved ejection fraction (HFPEF). However, it is unclear whether any risk factors modulate the effects of the standard-dose carvedilol.Methods and resultsData from 245 patients with HFPEF in J-DHF were evaluated. Decreased body mass index, diabetes mellitus, and left atrial (LA) dilatation were independent risk factors for both of the primary outcomes (cardiovascular death and unplanned hospitalization for heart failure) and another major composite outcome (cardiovascular death and unplanned hospitalization for any cardiovascular causes) in multivariable analysis. In patients with LA diameter≥the median value (43.2mm), standard-dose carvedilol was associated with unadjusted hazard ratio (HR) 0.263 [95% confidence interval (CI): 0.080–0.859] and covariate adjusted 0.264 (0.080–0.876) for the primary outcome. In those with LA diameter

Introduction Results from the multicenter trial (J-Land study) of landiolol versus digoxin in atrial fibrillation (AF) and atrial flutter (AFL) patients with left ventricular (LV) dysfunction revealed that landiolol was more effective for controlling rapid HR than digoxin. The subgroup analysis for patient characteristics was conducted to evaluate the impact on the efficacy and safety of landiolol compared with digoxin. Methods Two hundred patients with AF/AFL, heart rate (HR) ≥ 120 beats/min, and LV ejection fraction (LVEF) 25–50% were randomized to receive either landiolol (n = 93) or digoxin (n = 107). Successful HR control was defined as ≥20% reduction in HR together with HR

This study sought to evaluate whether genetic variants in the renin-angiotensin-aldosterone system (RAAS) have an impact on long-term mortality after acute myocardial infarction (AMI) in the percutaneous coronary intervention (PCI) era. We investigated the impacts of individual and combinations of 4 major RAAS genetic variants, angiotensinogen (AGT) T1311C, angiotensin-converting enzyme (ACE) insertion/deletion (I/D), angiotensin 2 type 1 receptor A1166C, and aldosterone synthase T4660C on 5-year mortality in 3149 post-AMI patients using multivariate Cox regression analysis. The predictive accuracy of all possible RAAS genetic combinations was evaluated using Cox regression analysis, and the best combination that affected prognosis was determined based on the minimal Akaike Information Criterion. There were 220 deaths during a median follow-up of 4.9 years. Independent analyses of any single RAAS variant did not show signifi cant impacts on 5-year mortality. However, analyses in combination revealed that absence of both AGT CC genotype and ACE D allele was associated with lower 5-year mortality (log-rank P = 0.005). Patients with at least either of the AGT CC or ACE D allele had increased mortality with adjusted hazard ratios of 2.07 (95% confi dence interval 1.18-3.65, P = 0.012), compared with those with neither the AGT CC nor ACE D allele. Among the 4 RAAS genetic variants examined, a combination of AGT and ACE polymorphisms was associated with 5-year mortality after AMI.

BACKGROUND & AIMS: Proton pump inhibitors (PPIs) are effective at treating acid-related disorders. These drugs are well tolerated in the short term, but long-term treatment was associated with adverse events in observational studies. We aimed to confirm these findings in an adequately powered randomized trial.METHODS: We performed a 3 × 2 partial factorial double-blind trial of 17,598 participants with stable cardiovascular disease and peripheral artery disease randomly assigned to groups given pantoprazole (40 mg daily, n = 8791) or placebo (n = 8807). Participants were also randomly assigned to groups that received rivaroxaban (2.5 mg twice daily) with aspirin (100 mg once daily), rivaroxaban (5 mg twice daily), or aspirin (100 mg) alone. We collected data on development of pneumonia, Clostridium difficile infection, other enteric infections, fractures, gastric atrophy, chronic kidney disease, diabetes, chronic obstructive lung disease, dementia, cardiovascular disease, cancer, hospitalizations, and all-cause mortality every 6 months. Patients were followed up for a median of 3.01 years, with 53,152 patient-years of follow-up.RESULTS: There was no statistically significant difference between the pantoprazole and placebo groups in safety events except for enteric infections (1.4% vs 1.0% in the placebo group; odds ratio, 1.33; 95% confidence interval, 1.01-1.75). For all other safety outcomes, proportions were similar between groups except for C difficile infection, which was approximately twice as common in the pantoprazole vs the placebo group, although there were only 13 events, so this difference was not statistically significant.CONCLUSIONS: In a large placebo-controlled randomized trial, we found that pantoprazole is not associated with any adverse event when used for 3 years, with the possible exception of an increased risk of enteric infections. ClinicalTrials.gov Number: NCT01776424.

To evaluate if esomeprazole prevents recurrent peptic ulcer in adult patients with a history of peptic ulcer receiving low-dose acetylsalicylic acid (ASA, aspirin) for cardiovascular protection in East Asia.In this prospective, randomised, double-blind, placebo-controlled trial conducted in Japan, Korea and Taiwan, eligible patients receiving low-dose ASA for cardiovascular protection (81-324 mg/day) were randomised to esomeprazole 20 mg/day or placebo for ≤72 weeks. All patients received concomitant mucosal protection (gefarnate 100 mg/day). The primary endpoint was time to ulcer recurrence (Kaplan-Meier analysis). Efficacy findings are presented up to week 48, as per a planned interim analysis within the study protocol.A total of 364 patients (79.9% men; mean age, 67.1 years) comprised the full analysis set (esomeprazole, n=182; placebo, n=182). There was a statistically significant difference in the time to ulcer recurrence between esomeprazole and placebo (HR 0.09; 96.65% CI 0.02 to 0.41; p0.001). The estimated ulcer-free rate at week 12 was 99.3% (esomeprazole) and 89.0% (placebo). The high estimated ulcer-free rate for esomeprazole was maintained through to week 48 (98.3% vs. 81.2% of placebo-treated patients). No factors, other than female gender, reduced time to ulcer recurrence in addition to the effect of esomeprazole (p0.001). Treatment with esomeprazole was generally well tolerated.Daily esomeprazole 20 mg is efficacious and well tolerated in reducing the recurrence of peptic ulcer in East-Asian patients with a history of ulcers who are taking low-dose ASA for cardiovascular protection.NCT01069939.

Although clinical guidelines recommend long-term β-blocker (BB) therapy to decrease mortality after acute myocardial infarction, these recommendations are based predominantly on evidence from before the reperfusion and thrombolytic eras. To investigate the effects of BB therapy for patients with acute myocardial infarctions on mortality in the percutaneous coronary intervention era, a total of 5,628 consecutive patients who were admitted

Background: In the percutaneous coronary intervention (PCI) era, little evidence exists regarding the incidence, predictors and long-term mortality of recurrent myocardial infarction (Re-MI) following discharge for acute myocardial infarction (AMI). Methods and Results: A total of 7,870 patients who survived AMI were studied with a median follow-up period of 3.9 years: 353 patients (4.5%) experienced Re-MI, with 7 of those dying within 30 days, which was classified as fatal Re-MI. The incidence of Re-MI per year was 2.65% for the first year, and 0.91–1.42% thereafter up to 5 years. Multivariate Cox regression analyses revealed that predictors of Re-MI were diabetes mellitus (hazard ratio (HR): 2.079, P

Aims The therapeutic strategy for heart failure with preserved ejection fraction (HFPEF) has not been established. The Japanese Diastolic Heart Failure Study (J-DHF) is a multicentre, prospective, randomized, open, blinded-endpoint trial, designed to assess the effects of carvedilol in HFPEF patients. Methods and results A total of 245 patients with heart failure and ejection fraction >40% were randomly assigned into those treated with (carvedilol group, n = 120) and without carvedilol (control group, n = 125). The primary outcome is a composite of cardiovascular death and unplanned hospitalization for heart failure. During a median follow-up of 3.2 years, the primary endpoint occurred in 29 patients in the carvedilol group and in 34 patients in the control group [adjusted hazard ratio (HR) 0.902, 95% confidence interval (CI) 0.546–1.488, P = 0.6854]. Another major composite endpoint, cardiovascular death and unplanned hospitalization for any cardiovascular causes, occurred in 38 patients of the carvedilol group and 52 patients of the control group (HR 0.768, 95% CI 0.504–1.169; P = 0.2178). The target dose of carvedilol was 20 mg/day, but the median prescribed dose was 7.5 mg/day. In the patients treated with standard doses (carvedilol >7.5 mg/day, n = 58), this composite outcome was significantly less than in the controls (HR 0.539, 95% CI 0.303–0.959; P = 0.0356), whereas it was comparable with the controls in the patients treated with carvedilol ≤7.5 mg/day (n = 62, HR 1.070, 95% CI 0.650–1.763; P = 0.7893). Conclusions Carvedilol did not improve prognosis of HFPEF patients overall; however, the standard dose, not the low dose, prescription might be effective. This may facilitate further investigation. UMIN number: C000000318.

Background: A rapid heart rate (HR) during atrial fibrillation (AF) and atrial flutter (AFL) in left ventricular (LV) dysfunction often impairs cardiac performance. The J-Land study was conducted to compare the efficacy and safety of landiolol, an ultra-short-acting β-blocker, with those of digoxin for swift control of tachycardia in AF/AFL in patients with LV dysfunction. Methods and Results: The 200 patients with AF/AFL, HR ≥120beats/min, and LV ejection fraction 25–50% were randomized to receive either landiolol (n=93) or digoxin (n=107). Successful HR control was defined as ≥20% reduction in HR together with HR

BACKGROUND Little is known about the prognostic significance of elevated serum heart-type fatty acid-binding protein (H-FABP) in post-acute myocardial infarction (post-AMI) patients. METHODS AND RESULTS A total of 1,283 post-AMI patients with available serum samples collected in the convalescent stage were studied. During a median follow-up period of 1,785 days, 176 patients (14%) had adverse events (all-cause mortality, n=81; non-fatal MI, n=44; readmission for heart failure [HF], n=51). Patients were divided into 2 groups according to a serum H-FABP level of 6.08ng/ml, which was determined to be the optimal cut-off for discriminating all-cause mortality based on the maximum value of the area under the receiver operating characteristic curve. Patients with elevated H-FABP (>6.08ng/ml, n=224) had a significantly higher incidence of death (18.3% vs. 3.8%, P

Background: In the Japanese Rivaroxaban Once-daily oral direct factor Xa inhibition Compared with vitamin K antagonism for prevention of stroke and Embolism Trial in Atrial Fibrillation (J-ROCKET AF) study, rivaroxaban 15mg once daily was given to patients with creatinine clearance (CrCl) ≥50ml/min (preserved renal function), and was reduced to 10mg once daily in patients with CrCl 30–49ml/min (moderate renal impairment). The aim of this subanalysis was to assess the safety and efficacy of the adjusted dose of rivaroxaban compared with warfarin in a cohort with moderate renal impairment. Methods and Results: Compared with patients with preserved renal function, those with moderate renal impairment (22.2% of all randomized patients) had higher rates of bleeding and stroke events irrespective of study treatment. Among those with moderate renal impairment, the principal safety endpoint occurred at 27.76%/year with rivaroxaban vs. 22.85%/year with warfarin (hazard ratio [HR], 1.22; 95% confidence interval [CI]: 0.78–1.91) and the rate of the primary efficacy endpoint was 2.77%/year vs. 3.34%/year (HR, 0.82; 95% CI: 0.25–2.69), respectively. There were no significant interactions between renal function and study treatment in the principal safety and the primary efficacy endpoints (P=0.628, 0.279 for both interactions, respectively). Conclusions: The safety and efficacy of rivaroxaban vs. warfarin were consistent in patients with moderate renal impairment and preserved renal function. (Circ J 2013; 77: 632–638)

Nonvalvular atrial fibrillation (AF) is a risk factor for stroke in elderly patients. Although warfarin has been used to prevent AF‐associated stroke for more than 50 years, non–vitamin K antagonist oral anticoagulants (NOACs) including dabigatran, rivaroxaban, apixaban, and edoxaban recently have been developed to overcome the disadvantages of warfarin. Based on the results of NOAC clinical trials, Savelieva and Camm made recommendations regarding selection of NOACs in patients with nonvalvular AF. Recent accumulating evidence indicates that NOACs work differently in Asian and non‐Asian individuals. In this review, we discuss the results of the large, randomized, phase 3 international clinical trials on NOACs, the subanalyses of Asians, and a Japanese phase 3 clinical trial of rivaroxaban to discriminate Japanese patient–specific characteristics with regard to their responses to NOACs and make recommendations. Our analysis revealed that rivaroxaban decreased the incidence of gastrointestinal (GI) bleeding compared with warfarin in Japanese patients. The efficacy results showed that rivaroxaban significantly decreased the incidence of ischemic stroke (hazard ratio: 0.40, 95% confidence interval: 0.17‐0.96) compared with warfarin. The lower incidence of GI bleeding and ischemic stroke may be specific to Japanese patients. Based on the present and previous results, the following recommendations regarding the selection of NOACs are added in the Camm chart for Japanese patients: edoxaban for patients with a high risk of bleeding and those with a previous stroke; and rivaroxaban for patients with a high risk of ischemic stroke and a low bleeding risk, and those with previous GI bleeding.

To investigate the prognostic impact of circulating microRNAs (miRs) in patients who survived acute myocardial infarction (AMI), we compared the circulating miR signature at the time of survival discharge among samples in the serum bank of the Osaka Acute Coronary Insufficiency Study. Using a high-throughput array consisting of 667 miRs, 11 miRs were found to be differentially expressed in the serum among patients at high-risk for cardiac death. Real-time RT-PCR confirmed that the serum levels of miR-155 and miR-380* were approximately 4- and 3-fold higher, respectively, in patients who experienced cardiac death within 1 year after discharge. Accordingly, a subset of circulating miRs might be predictive for cardiac death in post-AMI patients.

Cardiovascular risk of increased heart rate (HR) was first reported in the Framingham study. Thereafter, the risk of increased HR for mortality has been extensively studied, suggesting the higher risk in clinical outcomes with increased HR in the general population and in patients with coronary artery disease or heart failure (HF). In a long-term follow-up study in Framingham, the general population in this cohort showed an increase in all-cause mortality by 14% at every 10 bpm increase in HR. In patients with heart failure, resting HR of more than 80 bpm could cause myocardial dysfunction which further deteriorates HF. Downregulation of β-adrenoreptor receptors with suppressed signal transductions, impaired intracellular Ca homeostasis, and excitation-contraction coupling may play a role in myocardial dysfunction. These subcellular alterations are mimicked in the pacing-induced HF in large animals; however, exact mechanisms of cardiac deterioration by increased HR are not fully understood. β-Blocker treatment is the most effective therapy for long-term survival of patients with chronic HF. Meta-analysis of HR reduction and improvement in survival in patients with chronic HF indicates that HR reduction is more important than the titrated dose of β-blockers, although the relative importance of HR reduction in improvement of prognosis is not clear. A recent study in which ivabradine decreased the hospitalization from HR deterioration in patients with chronic HF, demonstrated that further HR reduction with optimal treatment for HF is beneficial for clinical outcomes of the patients. These findings strongly suggest that HR reduction should be a pivotal target of the treatment in patients with HF.

Background. Previous studies showed that nicorandil can reduce coronary events in patients with coronary artery disease. However, it is unclear whether oral nicorandil treatment may reduce mortality following acute myocardial infarction (AMI). Methods and Results. We examined the impact of oral nicorandil treatment on cardiovascular events in 1846 AMI patients who were hospitalized within 24 h after AMI onset, treated with emergency percutaneous coronary intervention (PCI), and discharged alive. Patients were divided into those with (Group N, n = 535) and without (Group C, n = 1311) oral nicorandil treatment at discharge. No significant differences in age, gender, body mass index, prevalence of coronary risk factors, or history of myocardial infarction existed between the two groups; however, higher incidences of multi-vessel disease, and a lower rate of successful PCI were observed in Group N. During the median follow-up of 709 (340–1088) days, allcause mortality rate was 43% lower in Group N compared with Group C (2.4% vs. 4.2%, stratified log-rank test: p = 0.0358). Multivariate Cox regression analysis revealed that nicorandil treatment was associated with all-cause death after discharge (Hazard ratio 0.495, 95% CI: 0.254–0.966, p = 0.0393), but not for other cardiovascular events such as re-infarction, admission for heart failure, stroke and arrhythmia. Conclusions. The results suggest that oral administration of nicorandil is associated with reduced incidence of death in the setting of secondary prevention after AMI.

Tolvaptan may reduce the signs of volume overload in heart failure (HF) patients who experience volume overload despite using conventional diuretics. In this study, we evaluated the dose-response effects of tolvaptan on weight loss, urine volume and electrolyte excretion in furosemide-treated Japanese HF patients exhibiting volume overload. In the study, 117 HF patients with volume overload on stable doses of furosemide (≥40 mg/day) were treated with tolvaptan (15, 30 or 45 mg) or placebo once-daily for 7 days. The decrease in body weight from baseline to the day after the final dose with 15, 30 or 45 mg tolvaptan (–1.62 ± 1.55, –1.35 ± 1.54 and –1.85 ± 1.10 kg, respectively), was significantly greater compared with that in the placebo group (–0.53 ± 0.96 kg) (p

Diuretics are recommended to treat volume overload with heart failure (HF), however, they may cause serum electrolyte imbalance, limiting their use. Moreover, patients with advanced HF could poorly respond to these diuretics. In this study, we evaluated the efficacy and safety of Tolvaptan, a competitive vasopressin V2-receptor antagonist developed as a new drug to treat volume overload in HF patients. A phase III, multicenter, randomized, double-blind, placebo-controlled parallel study was performed to assess the efficacy and safety of tolvaptan in treating HF patients with volume overload despite the use of conventional diuretics. One hundred and ten patients were randomly assigned to receive either placebo or 15 mg/day tolvaptan for 7 consecutive days. Compared with placebo, tolvaptan administered for 7 days significantly reduced body weight and improved symptoms associated with volume overload. The safety profile of tolvaptan was considered acceptable for clinical use with minimal adverse effects. Tolvaptan reduced volume overload and improved congestive symptoms associated with HF by a potent water diuresis (aquaresis).

This study aimed to investigate the pharmacokinetics, pharmacodynamics, efficacy and safety of tolvaptan, an orally effective vasopressin V2-receptor antagonist. This was a multicenter, randomized, double-blind, parallel group study. Tolvaptan was administered at 7.5 or 15 mg, in combination with furosemide, for 7 days in Japanese heart failure (HF) patients with volume overload that had not resolved despite receiving furosemide. The blood concentration of tolvaptan was maintained at a higher concentration for a longer time in patients who received 15 mg/day when compared with patients who received 7.5 mg/day. Tolvaptan increased urine volume and increased weight loss dose-dependently when used in combination with furosemide. Importantly, tolvaptan enhanced water diuresis without affecting blood electrolyte levels. Tolvaptan exerts diuretic effects and causes body weight loss at the low dose of 7.5 mg; however, these effects were less than those elicited by 15 mg tolvaptan.

Edema is defined as a state of extracellular fluid accumulation, mostly of intercellular fluid, and clinically as a state where the subcutaneous tissues become enlarged because of the accumulation of interstitial fluid. Edema is often observed in daily clinical practice and the most serious causes include heart failure (HF), hepatic cirrhosis, and nephrotic syndrome. Patients with HF are often in a volume overload state because of the increases in extracellular volume, plasma volume, and blood volume; collectively, these disorders result in lower limb edema, jugular venous distension, hepatomegaly, and pulmonary congestion. In patients with HF, volume overload usually accounts for an increase in body weight of as much as 2–5 kg [1]. Volume overload in patients with heart diseases is generally called “cardiac edema”.

This study was a prospective, randomized, open, blinded endpoint study to assess the effects of angiotensin II type 1 receptor blocker, losartan, compared with calcium channel blocker, amlodipine, on left ventricular (LV) diastolic function and atherosclerosis of the carotid artery in Japanese patients with mild-to-moderate hypertension, LV hypertrophy, diastolic dysfunction and preserved systolic function. Fifty-seven patients were randomly assigned to losartan- or amlodipine-based treatment groups and were followed up for 18 months. Blood pressure was similarly reduced by both regimens. Losartan shortened the transmitral E-wave deceleration time, and amlodipine reduced LV mass index; however, there was no significant difference in the percent changes of these indices between the two groups. Mean carotid intima-media thickness (mean IMT) as well as plaque score significantly increased in the amlodipine-based regimen (pre: 1.05±0.26 mm, follow-up: 1.23±0.33 mm, P=0.0015), but not in the losartan-based regimen (pre: 1.08±0.35 mm, follow-up: 1.16±0.52 mm, P=non-significant). The percent increase in mean IMT in the amlodipine-based regimen tended to be large compared with the losartan-based regimen (amlodipine: 19.8±23.7%, losartan: 6.9±23.3%, P=0.06). Under similar reduction of blood pressure, losartan is likely effective in protecting the progression of atherosclerosis of the carotid artery compared with amlodipine. Losartan may improve LV diastolic function, and amlodipine may attenuate LV hypertrophy; however, this study cannot make consecutive remarks about the superiority of either treatment regimen in the effects on cardiac function and geometry. This study has been registered at http://www.umin.ac.jp/ctr/listj/ (identifier C000000319).

Clinical characteristics were compared between hypertensive patients with and without heart failure in the absence of reduced ejection fraction (EF) to gain insights into the effects of renal insufficiency on the prevalence of diastolic heart failure. Study subjects consisted of 691 hypertensive patients with an EF40%. Patients with serum creatinine2.5 mg/dL were excluded from the study. The Framingham heart failure criteria were met by 198 patients, and competing risks of the prevalence of heart failure were analyzed. The multiple logistic regression analysis revealed that obesity, female gender, creatinine clearance (CCr), and a ratio of transmitral E velocity to early diastolic mitral annular velocity (E/ E')15 were independently associated with the prevalence of heart failure with preserved EF. Patients with 60or =CCr90 mL/min represented higher E/E' ratio and lower E' velocity than the patients with CCror =90 mL/min, although there was no difference in the prevalence of heart failure between the two groups. These indices were not different between the patients with 60or =CCr90 mL/min and CCr60 mL/min, although the prevalence of heart failure was higher in the patients with CCr60 mL/min. The hemoglobin concentration was significantly decreased and the brachial-ankle pulse wave velocity was significantly elevated in patients with CCr60 mL/min. Thus, progressive left ventricular diastolic dysfunction and renal insufficiency are competing risks of the prevalence of diastolic heart failure in hypertensive patients. Renal insufficiency may exert its effects through the modulation of extracardiac factors such as anemia and arterial stiffening rather than through the promotion of diastolic dysfunction.

Stabilization of carotid artery plaques by pharmacologic intervention is a promising strategy for the prevention of ischemic stroke. In this study, we examined the effect of 12 months of statin therapy on carotid plaque echogenicity. This study included 81 hypercholesterolemic patients with carotid atherosclerotic plaques. Echogenicity of the largest plaque in each patient was evaluated by ultrasound with integrated backscatter analysis. All patients underwent dietary modification. Forty patients were treated with simvastatin (10 mg/day, n = 24) or atorvastatin (5 mg/day, n = 16) according to the choice by each attending physician. Carotid plaques were monitored by measuring plaque thickness and echogenicity during a 12-month follow-up period. Levels of serum high-sensitivity CRP (hs-CRP), interleukin (IL)-6 and IL-18 were determined in all patients. Total cholesterol, triglyceride, hs-CRP and IL-18 were significantly decreased after 12 months of statin therapy. The change in IL-6 level was not significant. Significant increases in echogenicity of carotid plaques and decreases in plaque thickness were noted after statin therapy. In the 41 patients without statin therapy, carotid plaque echogenicity, plaque thickness and serum levels of inflammatory markers were not significantly altered. Our results suggest that statin therapy in hypercholesterolemic patients for 12 months increases carotid plaque echogenicity and decreases plaque thickness, in addition to lowering serum levels of lipids and inflammatory markers. (E-mail: kitagawa@medone.med.osaka-u.ac.jp).

Grb2-associated binder 1 (Gab1) coordinates various receptor tyrosine kinase signaling pathways. Although skeletal muscle differentiation is regulated by some growth factors, it remains elusive whether Gab1 coordinates myogenic signals. Here, we examined the molecular mechanism of insulin-like growth factor-I (IGF-I)-mediated myogenic differentiation, focusing on Gab1 and its downstream signaling. Gab1 underwent tyrosine phosphorylation and subsequent complex formation with protein-tyrosine phosphatase SHP2 upon IGF-I stimulation in C2C12 myoblasts. On the other hand, Gab1 constitutively associated with phosphatidylinositol 3-kinase regulatory subunit p85. To delineate the role of Gab1 in IGF-I-dependent signaling, we examined the effect of adenovirus-mediated forced expression of wild-type Gab1 (Gab1(WT)), mutated Gab1 that is unable to bind SHP2 (Gab1(DeltaSHP2)), or mutated Gab1 that is unable to bind p85 (Gab1(Deltap85)), on the differentiation of C2C12 myoblasts. IGF-I-induced myogenic differentiation was enhanced in myoblasts overexpressing Gab1(DeltaSHP2), but inhibited in those overexpressing either Gab1(WT) or Gab1(Deltap85). Conversely, IGF-I-induced extracellular signal-regulated kinase 1/2 (ERK1/2) activation was significantly repressed in myoblasts overexpressing Gab1(DeltaSHP2) but enhanced in those overexpressing either Gab1(WT) or Gab1(Deltap85). Furthermore, small interference RNA-mediated Gab1 knockdown enhanced myogenic differentiation. Overexpression of catalytic-inactive SHP2 modulated IGF-I-induced myogenic differentiation and ERK1/2 activation similarly to that of Gab1(DeltaSHP2), suggesting that Gab1-SHP2 complex inhibits IGF-I-dependent myogenesis through ERK1/2. Consistently, the blockade of ERK1/2 pathway reversed the inhibitory effect of Gab1(WT) overexpression on myogenic differentiation, and constitutive activation of the ERK1/2 pathway suppressed the enhanced myogenic differentiation by overexpression of Gab1(DeltaSHP2). Collectively, these data suggest that the Gab1-SHP2-ERK1/2 signaling pathway comprises an inhibitory axis for IGF-I-dependent myogenic differentiation.

BACKGROUND AND PURPOSE: Chronic middle cerebral artery (MCA) occlusion is more common than generally thought. It is important to assess the cerebral hemodynamic status in patients with this chronic condition. We investigated the cerebral hemodynamic and metabolic disturbances in these patients in relation to the development of the collateral vasculature. MATERIALS AND METHODS: We studied 13 patients with chronic unilateral MCA occlusion who had a minor or no stroke by using positron-emission tomography (PET). PET was performed by the oxygen 15 ( 15 O) gas steady-state inhalation method. The intracranial arteries were evaluated by digital subtraction angiography. We divided the patients into 2 subgroups according to whether they had a normal or increased oxygen extraction fraction (OEF) in the occluded MCA territory and compared the 2 groups. RESULTS: Of the 13 patients, 9 were classified into the normal OEF and 4 were classified into the increased OEF group. In the increased OEF group, the mean OEF values were also increased in the territories of the ipsilateral anterior cerebral artery, ipsilateral posterior cerebral artery, and contralateral MCA. The patients in the increased OEF group had more than 1 steno-occlusive lesion in the major intracranial arteries ( P = .008). Three of the 4 patients in the increased OEF group also had vascular lesions in the collateral pathways to the MCA territory. CONCLUSION: Most patients with chronic MCA occlusion did not show severe hemodynamic impairment. Those with increased OEF tended to have other areas of severe hemodynamic impairment and other vascular lesions, especially in the collateral pathways.

Background Because plasma levels of adenosine are increased in patients with chronic heart failure (CHF), we examined adenosine concentrations in the plasma and heart and assessed the activity of ecto-5′-nucleotidase in the plasma and ventricular myocardium in patients with CHF. Methods and Results We studied 36 patients with CHF (New York Heart Association Class I/II/III/IV, 9/8/12/7). Twenty-five subjects without CHF were used as controls. Both plasma adenosine levels and ecto-5′-nucleotidase activity were significantly higher in patients with CHF (219 ± 28 nmol/L and 0.72 ± 0.03 nmoL/mg protein/min, respectively) than in control subjects (71 ± 8 nmol/L and 0.54 ± 0.02 nmoL/mg protein/min, respectively). Plasma adenosine levels sampled from the coronary sinus were significantly higher than from the aorta in patients with CHF, but these differences were not observed in control subjects. Ecto-5′-nucleotidase protein levels were markedly increased in the ventricular myocardium in patients with CHF. Conclusions These increases in ecto-5′-nucleotidase in the plasma and myocardium may contribute to increased plasma and cardiac adenosine levels. The increased ecto-5′-nucleotidase activity and adenosine levels in blood may become an index of the presence or severity of CHF.

Chemotherapeutic agents to induce DNA damage have been limited to use due to severe side effects of cardiotoxicity. ATM (Ataxia-telangiectasia mutated) is an essential protein kinase in triggering DNA damage responses. However, it is unclear how the ATM-mediated DNA damage responses are involved in the cardiac cell damage. To elucidate these functions in heart, we searched for specific substrates of ATM from mouse heart homogenate. Combining an in vitro phosphorylation following anion-exchange chromatography with purification by reverse-phase high-performance liquid chromatography (HPLC), we successfully identified p32, an ASF/SF2-associated protein, as a novel substrate for ATM. An in vitro kinase assay using recombinant p32 revealed that ATM directly phosphorylated p32. Furthermore, we determined Ser 148 of p32 as an ATM phosphorylation site. Since p32 is known to regulate mRNA splicing and transcription, p32 phosphorylation by ATM might be a new transcriptional regulatory pathway for specific DNA damage responses in heart.

Background It has been reported that stent deployment results in acute inflammation and platelet deposition as an acute phase reaction and smooth muscle cell (SMC) proliferation as a chronic phase reaction. Other studies have shown that statin therapy can reduce thrombosis as a pleiotropic effect. The present study was undertaken to examine whether preprocedural statin therapy can reduce the thrombotic reaction after stent implantation by using in-stent restenosis (ISR) tissue. Methods and Results The study group consisted of 45 consecutive patients (stable angina) with ISR who underwent directional coronary atherectomy (DCA). According to the histological findings, the patients were divided into 2 groups: those whose ISR tissue included thrombus and SMC (T group), and those whose ISR tissue included only SMC (S group). Just before DCA, serum markers were evaluated, including high-sensitivity C-reactive protein (hs-CRP), lipoprotein (a), plasminogen activator inhibitor-1 (PAI-1), fibrinogen, total cholesterol, triglyceride, high-density lipoprotein cholesterol, fasting blood glucose, and hemoglobin A1c. Preprocedural medications, including statins, were also evaluated. The values for hs-CRP and PAI-1 in the T group were significantly higher than those in the S group, and the rate of statin use in the T group was significantly lower than that in the S group. There were no significant differences in any of the other factors. Multivariate analysis revealed that preprocedural statin use and the PAI-1 level were significant independent variables affecting the histological findings. Conclusion Preprocedural statins, associated with the involvement of PAI-1, can reduce the thrombotic reaction after stent implantation. (Circ J 2008; 72: 232 - 237)

New-onset diabetes after renal transplantation (NODAT) is known to be a potent risk factor for cardiovascular events. We therefore investigated the incidence and risk factors for NODAT, and evaluated surrogate endpoints of atherosclerosis in Japanese patients with stable renal function after renal transplantation. Seventy-nine patients were enrolled in the study, and a 75 g oral glucose tolerance test (OGTT) was performed in subjects excluding patients with known NODAT. We evaluated the risk factors for NODAT and the degree of atherosclerosis, determined by brachial-ankle pulse wave velocity (baPWV), ankle-brachial blood pressure index (ABPI) and intima-media thickness (IMT) of the carotid artery. Eleven patients diagnosed as NODAT had significantly higher fasting plasma glucose before transplantation, blood pressure, and incidence of hepatitis C virus (HCV) infection than patients without NODAT. Multivariate regression analysis revealed that the independent determinant of NODAT was fasting plasma glucose pre-transplantation, HCV infection and systolic blood pressure. The baPWV in patients with NODAT was significantly higher compared to that in patients without NODAT. In addition, the independent determinant of baPWV evaluated by multivariate regression analysis was an increase in systolic blood pressure and age, and a decrease of adiponectin levels. In conclusion, we found that high fasting plasma glucose prior to transplantation, HCV infection and high blood pressure are risk factors for NODAT in Japanese patients after renal transplantation. Since NODAT patients have advanced arterial stiffness probably due to high blood pressure, strict control of blood pressure will be important for preventing the development of cardiovascular disease in NODAT.

Background: Patients with major cerebral artery steno-occlusion and the formation of the moyamoya-like vessels associated with some other disorders have been distinguished from moyamoya disease and classified as moyamoya syndrome. The hemodynamic and metabolic backgrounds of the moyamoya syndrome associated with atherosclerosis have not yet been investigated. We aimed to elucidate the hemodynamic and metabolic characteristics associated with the development of basal moyamoya-like vessels in moyamoya syndrome with atherosclerosis. Methods: Twenty-one patients with chronic unilateral atherosclerotic steno-occlusive lesions of the internal carotid artery or middle cerebral artery (MCA) were enrolled in the study. Based on the angiographic findings, the patients were classified into 2 groups: the moyamoya syndrome group (n = 7) and the non-moyamoya-syndrome group (n = 14). We conducted angiographic evaluations of the extent of the development of basal moyamoya-like vessels in the moyamoya syndrome group. The cerebral blood flow, cerebral metabolic rate of oxygen, oxygen extraction fraction (OEF) and cerebral blood volume were measured using PET in the ipsilateral MCA area in the patients and in normal controls (n = 6). Results: The OEF in the ipsilateral MCA area, except in the basal ganglia, was significantly higher in the moyamoya syndrome group than in the non-moyamoya-syndrome group (p < 0.001). The extent of the development of basal moyamoya-like vessels was closely correlated with the elevation of the OEF (r > 0.999, p < 0.001). Conclusion: The basal moyamoya-like vessels are evidence of misery perfusion in patients with unilateral chronic atherosclerotic steno-occlusive lesions of major cerebral artery trunks.

Insulin transcription factor MafA is unique in being exclusively expressed at the secondary and principal phase of insulin-expressing cell production during pancreas organogenesis and is the only transcriptional activator present exclusively in islet β-cells. Here we show that ectopic expression of MafA is sufficient to induce a small amount of endogenous insulin expression in a variety of non-β-cell lines. Insulin mRNA and protein expression was induced to a much higher level when MafA was provided with two other key insulin activators, pancreatic and duodenal homeobox (PDX-1) and BETA2. Potentiation by PDX-1 and BETA2 was entirely dependent upon MafA, and MafA binding to the insulin enhancer region was increased by PDX-1 and BETA2. Treatment with activin A and hepatocyte growth factor induced even larger amounts of insulin in AR42J pancreatic acinar cells, compared with other non-β endodermal cells. The combination of PDX-1, BETA2, and MafA also induced the expression of other important regulators of islet β-cell activity. These results support a critical role of MafA in islet β-cell function.