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Abstract Background Few simple risk models, without echocardiography have been developed for patients with heart failure (HF) and preserved left ventricular ejection fraction (LVEF) (HFpEF). Methods To develop a risk score to predict all-cause death for HFpEF patients, we examined 1277 HF patients with LVEF ≥50% and BNP ≥100 pg/ml in the CHART-2 Study, a large-scale prospective cohort study for HF in Japan. We selected the optimal subset of covariates for the score with Cox proportional hazard models and random survival forests (RSF). Results During the median 5.7-year follow-up, 576 deaths occurred. Cox models and RSF analyses consistently indicated age ≥75 years, albumin <3.7 g/dl, anemia, BMI <22 kg/m2, BNP ≥300 pg/ml (or NT-proBNP ≥1400 pg/ml), and BUN ≥25 mg/dl, as the important 6 prognostic variables. Incorporating these 6 variables, we developed a scoring system (3A3B score, with 2 points given to age ≥75 years and 1 point to the others based on the hazard ratios. The discrimination ability of the risk score was excellent (c-index 0.708). Regarding model goodness-of-fit, the overall gradient in 5-year risk was well captured by the score. The predictive accuracy of the 3A3B score was confirmed in the external validation cohorts from the TOPCAT trial (N = 835, c-index 0.652) and the ASIAN-HF registry (N = 170, c-index 0.741). Conclusions We developed a simple risk score to predict long-term prognosis of HFpEF patients. The 3A3B score, comprising 6 commonly available parameters in daily practice, has potential utility in the risk stratification and management of HFpEF patients. Highlights • We developed the 3A3B risk score to predict long-term prognosis of HFpEF patients. • The 3A3B score consists only 6 items (age, albumin, anemia, BMI, BNP/NT-proBNP, and BUN). • The discrimination ability of the risk score is excellent in both the derivation and the validation cohorts. • The overall gradient in 5-year risk is well captured by the score. [ABSTRACT FROM AUTHOR]

Despite considerable progress in preventive and therapeutic strategies, myocardial infarction (MI) is one of the leading causes of death throughout the world. A total of 55 susceptibility genes have been identified mostly in European genome-wide association studies (GWAS). Nevertheless, large-scale GWAS from other population could possibly find additional susceptibility loci. To identify as many MI susceptibility loci as possible, we performed a large-scale genomic analysis in Japanese population. To identify MI susceptibility loci in Japanese, we conducted a GWAS using 1666 cases and 3198 controls using the Illumina Human610-Quad BeadChip and HumanHap550v3 Genotyping BeadChip. We performed replication studies using a total of 11 412 cases and 28 397 controls in the Japanese population. Our study identified two novel susceptibility loci for MI: PLCL2 on chromosome 3p24.3 (rs4618210:A>G, P=2.60 × 10−9, odds ratio (OR)=0.91) and AP3D1-DOT1L-SF3A2 on chromosome 19p13.3 (rs3803915:A>C, P=3.84 × 10−9, OR=0.89). Besides, a total of 14 previously reported MI susceptibility loci were replicated in our study. In particular, we validated a strong association on chromosome 12q24 (rs3782886:A>G: P=1.14 × 10−14, OR=1.46). Following pathway analysis using 265 genes related to MI or coronary artery disease, we found that these loci might be involved in the pathogenesis of MI via the promotion of atherosclerosis. In the present large-scale genomic analysis, we identified PLCL2 and AP3D1-DOT1L-SF3A2 as new susceptibility loci for MI in the Japanese population. Our findings will add novel findings for MI susceptibility loci. [ABSTRACT FROM AUTHOR]

Compares myocardial contrast echocardiography and coronary angiography which assess coronary collaterals in patients at Osaka Police Hospital, Japan. Changes in recruitable myocardial perfusion and collateral vessel filling; Development of myocardial ischemia during coronary occlusion; Cardioprotective effect of collateral flow during coronary occlusion.

Background: To date, several prediction models for patients with heart failure (HF) have been developed. However, they are not necessarily used in daily clinical practice because of complicated calculation processes with various variables. Moreover, few risk models have been developed for patients with HF with preserved left ventricular ejection fraction (HFpEF), employing simple items available in daily practice (e.g. without echocardiography or stress test data). Methods and Results: The Chronic Heart Failure Analysis and Registry in The Tohoku District (CHART)-2 Study is the largest multicenter prospective observational cohort study for Stage A/B/C/D HF in Japan (N=10,219). In this study, we examined 3,193 consecutive Stage C/D patients with LVEF>50% in the CHART-2 Study (mean 69.5 years, male 64.8%) to develop a simple risk model for all-cause mortality for HFpEF patients. Continuous variables were transformed into binary categorical variables for usefulness in daily practice. To select the optimal subset of covariates for our risk model, we used Cox proportional hazard models and random survival forests (RSF). During the median 6.4-year follow-up, 976 died. Both Cox model and RSF analysis independently showed that age>75 years, anemia, albumin<3.7 mg/dl, BUN>25 mg/dl, and BNP>100 pg/ml, which was equivalent to NT-proBNP>440 pg/ml, were the top 5 prognostic variables. Then, we developed a scoring system incorporating these 5 items, with 2 points given to age>75 years and 1 point to other items based on the beta coefficients. The Kaplan-Meir curves showed that the score clearly stratified the risk (Figure) with excellent discrimination ability mortality (c-index of 0.769). Conclusion: We were able to develop a useful risk model to predict long-term prognosis of HFpEF patients in the CHART-2 Study. This model consists of only 5 simple items, providing us with a useful tool to stratify the risk of HFpEF patients in daily practice. [ABSTRACT FROM AUTHOR]

Background: Olanzapine 10 mg added to standard antiemetic therapy including aprepitant, palonosetron, and dexamethasone has been recommended for the prevention of chemotherapy-induced nausea and vomiting. Guidelines suggest that a dose reduction to 5 mg should be considered to prevent sedation. In several phase 2 studies, olanzapine 5 mg has shown equivalent activity to olanzapine 10 mg and a favourable safety profile in relation to somnolence. We evaluated the efficacy of olanzapine 5 mg combined with standard antiemetic therapy for the prevention of chemotherapy-induced nausea and vomiting caused by cisplatin-based chemotherapy.Methods: This was a randomised, double-blind, placebo-controlled, phase 3 study to evaluate the efficacy of olanzapine 5 mg with triplet-combination antiemetic therapy done in 26 hospitals in Japan. Key inclusion criteria were patients with a malignant tumour (excluding those with a haemopoietic malignancy) who were scheduled to be treated with cisplatin (≥50 mg/m2) for the first time, age between 20 and 75 years, and with Eastern Cooperative Oncology Group performance status of 0-2. Eligible patients were randomly assigned (1:1) to receive either oral olanzapine 5 mg or placebo once daily on days 1-4 combined with aprepitant, palonosetron, and dexamethasone (dosage based on the standard antiemetic therapy against highly emetogenic chemotherapy). Patients were randomly assigned to interventions by use of a web entry system and the minimisation method with a random component, with sex, dose of cisplatin, and age as factors of allocation adjustment. Patients, medical staff, investigators, and individuals handling data were all masked to treatment assignment. The primary endpoint was the proportion of patients who achieved a complete response, defined as absence of vomiting and no use of rescue medications in the delayed phase (24-120 h). All randomly assigned patients who satisfied eligibility criteria received a dose of cisplatin 50 mg/m2 or more, and at least one study treatment, were included in efficacy analysis. All patients who received any treatment in this study were assessed for safety. This study is registered at UMIN Clinical Trials Registry, number UMIN000024676.Findings: Between Feb 9, 2017, and July 13, 2018, 710 patients were enrolled; 356 were randomly assigned to receive olanzapine and 354 were assigned to receive placebo. All eligible patients were observed 120 h after cisplatin initiation. One patient in the olanzapine group and three in the placebo group did not receive treatment and were excluded from all analyses. One patient in the olanzapine group discontinued treatment on day 1 and was excluded from the efficacy analysis. In the delayed phase, the proportion of patients who achieved a complete response was 280 (79% [95% CI 75-83] of 354 patients in the olanzapine group and 231 (66% [61-71] of 351 patients in the placebo group (p<0·0001). One patient had grade 3 constipation and one patient had grade 3 somnolence related to treatment in the olanzapine group.Interpretation: Olanzapine 5 mg combined with aprepitant, palonosetron, and dexamethasone could be a new standard antiemetic therapy for patients undergoing cisplatin-based chemotherapy.Funding: Japan Agency for Medical Research and Development. [ABSTRACT FROM AUTHOR]

Background: The comparative efficacy and safety of adjusted- and standard-dose prasugrel in East Asian patients with acute myocardial infarction (AMI) undergoing percutaneous coronary intervention (PCI) remain unclear. This study aimed to comparatively assess the ischaemic and bleeding outcomes of adjusted-dose (maintenance dose: 3.75 mg) and standard-dose (maintenance dose: 10 mg) prasugrel in East Asian patients with AMI undergoing PCI., Methods: From a combined dataset sourced from nationwide AMI registries in Japan and South Korea (n = 17,118), patients treated with either adjusted- or standard-dose prasugrel were identified. Patients who did not undergo emergent PCI, those on oral anticoagulants, and those meeting the criteria of contraindication of prasugrel in South Korea (age ≥ 75 years, body weight < 60 kg, or history of stroke) were excluded. Major adverse cardiovascular events (MACE) and Thrombolysis in Myocardial Infarction (TIMI) major bleeding events were compared between the adjusted-dose (n = 1160) and standard-dose (n = 1086) prasugrel groups., Results: Within the propensity-matched cohort (n = 702 in each group), no significant difference was observed in the in-hospital MACE between the adjusted- and standard-dose prasugrel groups (1.85% vs. 2.71%, odds ratio [OR] 0.68, 95% confidence interval [CI] 0.33-1.38, p = 0.286). However, the incidence of in-hospital major bleeding was significantly lower in the adjusted-dose prasugrel group than in the standard-dose group (0.43% vs. 1.71%, OR 0.25, 95% CI 0.07-0.88, p = 0.031). The cumulative 12-month incidence of MACE was equivalent in both groups (4.70% vs. 4.70%, OR 1.00, 95% CI 0.61-1.64, p = 1.000)., Conclusions: Among East Asian patients with AMI undergoing PCI, those administered adjusted-dose prasugrel exhibited a lower risk of in-hospital bleeding events than those administered standard-dose prasugrel, while maintaining a comparable 1-year incidence of MACE., Competing Interests: Declaration of competing interest Dr. Yasuda reports remuneration for lectures from Takeda, Daiichi Sankyo, and Bristol-Myers Squibb and trust research/joint research funds from Takeda and Daiichi Sankyo; Dr. Takayama reports lecture fees from Daiichi Sankyo; and Dr. Ogawa reports lecture fees and research grants from Abbot Medical Japan, Bayer, Daiichi Sankyo, Eisai, Kowa, Takeda Pharmaceutical, and Teijin. Other authors have no conflict of interest., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Aims: The incidence and prognosis of symptomatic heart failure following acute myocardial infarction (AMI) in the primary percutaneous coronary intervention era have rarely been reported in the literature. This study aimed to (i) determine the incidence of heart failure admission among AMI survivors, (ii) compare 1 year outcomes between patients with heart failure admission and those without, and (iii) identify the independent risk factors associated with heart failure admission., Methods and Results: The Japan Acute Myocardial Infarction Registry is a prospective multicentre registry from which data on consecutively enrolled patients with AMI from 50 institutions between 2015 and 2017 were obtained. Among the 3411 patients enrolled, 3226 who survived until discharge were included in this study. The primary endpoint was all-cause mortality. The secondary endpoints were major adverse cardiovascular events (defined as cardiovascular mortality, non-fatal myocardial infarction, or non-fatal cerebral infarction) and major bleeding events corresponding to Bleeding Academic Research Consortium Type 3 or 5. Clinical outcomes were compared between the patients who were and were not admitted for heart failure. Over a median follow-up of 12 months, 124 patients (3.8%) were admitted due to heart failure. Independent risk factors for heart failure admission included older age, female sex, Killip class ≥2 on admission, left ventricular ejection fraction <40%, estimated glomerular filtration rate ≤30 mL/min/1.73 m 2 , a history of malignancy, and non-use of angiotensin-converting enzyme inhibitors at discharge. The cumulative incidence of all-cause mortality was significantly higher in the heart failure admission group than in the no heart failure admission group (11.3% vs. 2.5%, P < 0.001). The rates of major adverse cardiovascular events (16.9% vs. 2.7%, P < 0.001) and major bleeding (6.5% vs. 1.6%, P < 0.001) were significantly higher in the heart failure admission group. Heart failure admission was associated with a higher risk of all-cause mortality, even after adjusting for potential confounders (adjusted hazard ratio: 2.41, 95% confidence interval: 1.33-4.39, P = 0.004)., Conclusions: Utilizing real-world data of the contemporary percutaneous coronary intervention era from the Japan Acute Myocardial Infarction Registry database, this study demonstrates that the heart failure admission of AMI survivors was significantly associated with higher all-cause mortality rates., (© 2024 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Background: This post hoc subanalysis aimed to investigate the impact of polyvascular disease (PolyVD) in patients with acute myocardial infarction (AMI) in the contemporary era of percutaneous coronary intervention (PCI)., Methods and results: The Japan Acute Myocardial Infarction Registry (JAMIR), a multicenter prospective registry, enrolled 3,411 patients with AMI between December 2015 and May 2017. Patients were classified according to complications of a prior stroke and/or peripheral artery disease into an AMI-only group (involvement of 1 vascular bed [1-bed group]; n=2,980), PolyVD with one of the complications (2-bed group; n=383), and PolyVD with both complications (3-bed group; n=48). The primary endpoint was all-cause death. Secondary endpoints were major adverse cardiovascular events (MACE), including cardiovascular death, non-fatal myocardial infarction, non-fatal stroke, and major bleeding. In the 1-, 2-, and 3-bed groups, the cumulative incidence of all-cause death was 6.8%, 17.5%, and 23.7%, respectively (P<0.001); that of MACE was 7.4%, 16.4%, and 33.8% (P<0.001), respectively; and that of major bleeding was 4.8%, 10.0%, and 13.9% (P<0.001), respectively. PolyVD was independently associated with all-cause death (hazard ratio [HR] 2.21; 95% confidence interval [CI], 1.48-3.29), MACE (HR 2.07; 95% CI 1.40-3.07), and major bleeding (HR 1.68; 95% CI 1.04-2.71)., Conclusions: PolyVD was significantly associated with worse outcomes, including thrombotic and bleeding events, in the contemporary era of PCI in AMI patients.

Background: Little is known about clinical or sociodemographic factors that influence health-related quality of life (HRQoL) in patients with adult congenital heart disease (ACHD)., Methods and results: We conducted a nationwide prospective cross-sectional multicenter study at 4 large ACHD centers in Japan. From November 2016 to June 2018, we enrolled 1,223 ACHD patients; 1,025 patients had an HRQoL score. Patients completed a questionnaire survey, including sociodemographic characteristics, and the 36-Item Short-Form Health Survey (SF-36). To determine factors associated with HRQoL, correlations between 2 SF-36 summary scores (i.e., physical component score [PCS] and mental component score [MCS]) and other clinical or sociodemographic variables were examined using linear regression analysis. In multivariable analysis, poorer PCS was significantly associated with 11 variables, including older age, higher New York Heart Association class, previous cerebral infarction, being unemployed, and limited participation in physical education classes and sports clubs. Poorer MCS was associated with congenital heart disease of great complexity, being part of a non-sports club, current smoking, and social drinking. Student status and a higher number of family members were positively correlated with MCS., Conclusions: This study demonstrates that HRQoL in ACHD patients is associated with various clinical and sociodemographic factors. Further studies are needed to clarify whether some of these factors could be targets for future intervention programs to improve HRQoL outcomes.

Background: Although a door-to-balloon (D2B) time ≤90 min is recognized as a key indicator of timely reperfusion for patients with ST-segment elevation myocardial infarction (STEMI), it is unclear whether regional disparities in the prognostic value of D2B remain in contemporary Japan., Methods and results: We retrospectively analyzed 17,167 STEMI patients (mean [±SD] age 68±13 years, 77.6% male) undergoing primary percutaneous coronary intervention. With reference to the Japanese median population density of 1,147 people/km 2 , patients were divided into 2 groups: rural (n=6,908) and urban (n=10,259). Compared with the urban group, median D2B time was longer (70 vs. 62 min; P<0.001) and the rate of achieving a D2B time ≤90 min was lower (70.7% vs. 75.4%; P<0.001) in the rural group. In-hospital mortality was lower for patients with a D2B time ≤90 min than >90 min, regardless of residential area, whereas multivariable analysis identified prolonged D2B time as a predictor of in-hospital death only in the rural group (adjusted odds ratio 1.57; 95% confidence interval 1.18-2.09; P=0.002). Importantly, the rural-urban disparity in in-hospital mortality emerged most distinctively among patients with Killip Class IV and a D2B time >90 min., Conclusions: These data suggest that there is a substantial rural-urban gap in the prognostic significance of D2B time among STEMI patients, especially those with cardiogenic shock and a prolonged D2B time.

Background: Previous studies have reported that acute myocardial infarction (AMI) related to left anterior descending (LAD) lesion is associated with worse outcomes than left circumflex artery (LCX) or right coronary artery (RCA) lesions. However, it is unknown whether those relationships are still present in the contemporary era of primary percutaneous coronary intervention (PCI), using newer generation drug-eluting stents and potent antiplatelet agents.Methods and Results:This study is a sub-analysis of the Japan AMI Registry (JAMIR), a multicenter, prospective registry enrolling 3,411 AMI patients between December 2015 and May 2017. Among them, 2,780 patients undergoing primary PCI for only a culprit vessel were included and stratified based on infarction-related artery type (LAD, LCX, and RCA). The primary outcome was 1-year cardiovascular death. The overall incidence of cardiovascular death was 3.4%. Patients with LAD infarction had highest incidence of cardiovascular death compared to patients with LCX and RCA infarction (4.8%, 1.3%, and 2.4%, respectively); however, landmark analysis showed that culprit vessel had no significant effect on cardiovascular death if a patient survived 30 days after primary PCI. LAD lesion infarction was an independent risk factor for cardiovascular death in adjusted Cox regression analysis., Conclusions: The present sub-analysis of the JAMIR demonstrated that LAD infarction is still associated with worse outcomes, especially during the first 30 days, even in the contemporary era of PCI.

Background: 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., Conclusions: 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.

Background: Acute myocardial infarction (AMI) patients with low body mass index (BMI) exhibit worse clinical outcomes than obese patients; however, to our knowledge, no prospective, nationwide study has assessed the effect of BMI on the clinical outcomes of AMI patients.Methods and Results:In this multi-center, prospective, nationwide Japanese trial, 2,373 AMI patients who underwent emergent percutaneous coronary intervention within 12 h of onset from the Japanese AMI Registry (JAMIR) were identified. Patients were divided into the following 4 groups based on their BMI at admission: Q1 group (BMI <18.5 kg/m 2 , n=133), Q2 group (18.5≤BMI<25.0 kg/m 2 , n=1,424), Q3 group (25.0≤BMI<30.0 kg/m 2 , n=672), and Q4 group (30.0 kg/m 2 ≤BMI, n=144). The primary endpoint was all-cause death, and the secondary endpoint was a composite of cardiovascular death, non-fatal myocardial infarction (MI), and non-fatal stroke. The median follow-up period was 358 days. Q1 patients were older and had lower prevalence of coronary risk factors. Q1 patients also had higher all-cause mortality and higher incidence of secondary endpoints than normal-weight or obese AMI patients. Multivariate analysis showed that low BMI (Q1 group) was an independent predictor for primary endpoint., Conclusions: AMI patients with low BMI had fewer coronary risk factors but worse clinical outcomes than normal-weight or obese patients.

Background: 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)., Methods and Results: 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)., Conclusions: 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., Trial Registration Number: UMIN000004575., (© 2021. Springer Japan KK, part of Springer Nature.)

Background: De-escalation of P2Y12 inhibitor may occur for various clinical reasons in patients with acute myocardial infarction (AMI). We aimed to assess the characteristics and outcomes of patients who underwent a de-escalation strategy in real-world clinical practice., Methods and Results: We studied 2604 AMI patients initially treated with prasugrel using the Japan Acute Myocardial Infarction Registry (JAMIR) database. Of these, 110 (4%) were discharged on clopidogrel [de-escalation group; switching 4 days after admission (median)] and the remaining 2494 continued prasugrel at discharge (continuation group). The de-escalation group had higher incidence of heart failure or history of cerebrovascular disease, and were more likely to receive mechanical circulatory support, and oral anticoagulation than the continuation group. During mean follow-up of 309±133 days post-discharge, no significant differences were observed in ischemic events (2.2% vs. 2.8%, p = 0.74) or major bleeding (1.1% vs. 1.6%, p = 0.72) between the de-escalation and continuation groups., Conclusions: Although, patients with de-escalation from prasugrel to clopidogrel had higher bleeding risk profile than those continued on prasugrel, post discharge ischemic and bleeding events were similar between patients with and without de-escalation. De-escalation strategy may be an option for AMI patients with high risk for bleeding., Competing Interests: Declaration of Competing Interest Dr Yasuda reports remuneration for lectures from Takeda, Daiichi Sankyo, and Bristol-Myers Squibb, and trust research/joint research funds from Takeda and Daiichi Sankyo; Dr Takayama reports lecture fees from Daiichi Sankyo; Dr Ogawa reports lecture fees and research grants from AstraZeneca, Bayer, Boehringer Ingelheim, Daiichi Sankyo, Pfizer, and Sanofi. None of the other authors have any conflicts of interest to declare., (Copyright © 2021. Published by Elsevier Ltd.)

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; P < 0.001). 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.

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.

The overwhelming majority of participants in current genetic studies are of European ancestry. To elucidate disease biology in the East Asian population, we conducted a genome-wide association study (GWAS) with 212,453 Japanese individuals across 42 diseases. We detected 320 independent signals in 276 loci for 27 diseases, with 25 novel loci (P < 9.58 × 10 -9 ). East Asian-specific missense variants were identified as candidate causal variants for three novel loci, and we successfully replicated two of them by analyzing independent Japanese cohorts; p.R220W of ATG16L2 (associated with coronary artery disease) and p.V326A of POT1 (associated with lung cancer). We further investigated enrichment of heritability within 2,868 annotations of genome-wide transcription factor occupancy, and identified 378 significant enrichments across nine diseases (false discovery rate < 0.05) (for example, NKX3-1 for prostate cancer). This large-scale GWAS in a Japanese population provides insights into the etiology of complex diseases and highlights the importance of performing GWAS in non-European populations.

Background: Genome-wide association studies provided many biological insights into coronary artery disease (CAD), but these studies were mainly performed in Europeans. Genome-wide association studies in diverse populations have the potential to advance our understanding of CAD., Methods: We conducted 2 genome-wide association studies for CAD in the Japanese population, which included 12 494 cases and 28 879 controls and 2808 cases and 7261 controls, respectively. Then, we performed transethnic meta-analysis using the results of the coronary artery disease genome-wide replication and meta-analysis plus the coronary artery disease 1000 Genomes meta-analysis with UK Biobank. We then explored the pathophysiological significance of these novel loci and examined the differences in CAD-susceptibility loci between Japanese and Europeans., Results: We identified 3 new loci on chromosome 1q21 ( CTSS ), 10q26 ( WDR11-FGFR2 ), and 11q22 ( RDX - FDX1 ). Quantitative trait locus analyses suggested the association of CTSS and RDX - FDX1 with atherosclerotic immune cells. Tissue/cell type enrichment analysis showed the involvement of arteries, adrenal glands, and fat tissues in the development of CAD. We next compared the odds ratios of lead variants for myocardial infarction at 76 genome-wide significant loci in the transethnic meta-analysis and a moderate correlation between Japanese and Europeans, where 8 loci showed a difference. Finally, we performed tissue/cell type enrichment analysis using East Asian-frequent and European-frequent variants according to the risk allele frequencies and identified significant enrichment of adrenal glands in the East Asian-frequent group while the enrichment of arteries and fat tissues was found in the European-frequent group. These findings indicate biological differences in CAD susceptibility between Japanese and Europeans., Conclusions: We identified 3 new loci for CAD and highlighted the genetic differences between the Japanese and European populations. Moreover, our transethnic analyses showed both shared and unique genetic architectures between the Japanese and Europeans. While most of the underlying genetic bases for CAD are shared, further analyses in diverse populations will be needed to elucidate variations fully.

Background: Along with the global aging, the number of geriatric patients with acute myocardial infarction (AMI) has been increasing. However, temporal trends in the prevalence and outcomes of geriatric patients with AMI, with a special reference to heart failure (HF) on admission, remain to be elucidated., Methods: The Miyagi AMI Registry is a prospective, multicenter, and observational study. This registry was established in 1979 and has been continued for 40 years. We examined a total of 6,596 AMI patients aged ≥70 years (male/female 4,141/2,455) registered in this registry from 2005 to 2016 and divided them into 3 groups according to age [70-79 (n = 3,485), 80-89 (n = 2,601), and ≥90 years (n = 510)]., Results: Of those, 17.6% had HF (Killip class ≥ II) on admission, for which age, female sex, diabetes, and previous MI were identified as independent predictors. Importantly, the prevalence of HF on admission significantly increased in all ages during the study period (all p for trend <0.01). Despite the presence of HF on admission, primary percutaneous coronary intervention (PCI) was performed in about 70% of patients aged in their 80 s and about half of those aged ≥90 years. In each group, performance rate of primary PCI also progressively increased (all p < 0.05) irrespective of concomitant HF. However, in-hospital mortality remained unchanged. Multivariable analysis demonstrated that, even for patients with HF on admission, primary PCI was associated with improved in-hospital mortality in the younger 2 groups [adjusted odds ratios (ORs), 95% confidence intervals (CI) 0.58 (0.36-0.93) for 70s, 0.64 (0.43-0.95) for 80s, and 0.99 (0.44-2.21) for ≥90s], whereas PCI was ineffective to reduce long-term hospitalization ≥30 days in all groups [adjusted ORs (95%CI) 0.90 (0.52-1.54), 0.66 (0.38-1.14), and 0.38 (0.07-2.10)]., Conclusions: These results demonstrate that increasing prevalence of HF on admission and increasing performance of primary PCI counteract each other with resultant unchanged in-hospital outcomes in geriatric AMI patients in Japan., (Copyright © 2019. Published by Elsevier Ltd.)

Physical activity (PA) in the daily life is strongly related to prognosis in patients with or at high risk of heart failure (HF). However, factors limiting habitual exercise and their prognostic impacts remain unknown in HF patients. We sent questionnaires asking factors limiting habitual exercise in the daily life to 8370 patients with Stage A/B/C/D HF in our nationwide registry and received valid responses from 4935 patients (mean age 71.8 years, 71.0% male). Among the 5 components consisting of "busyness", "weak will", "dislike, "socioeconomic reasons" and "diseases" in the questionnaires, "busyness" (34.5%) and "diseases" (34.7%) were the most frequently reported factors limiting habitual exercise, while "socioeconomic reasons" were the least (15.3%). Multiple Cox proportional hazard models indicated that "busyness"and "diseases" were associated with better (hazard ratio (HR) 0.53, 95% confidence interval (CI) 0.39-0.72, P < 0.001) and worse prognosis (HR 1.57, 95% CI 1.21-1.98, P < 0.001), respectively, while other components were not. Furthermore, it was noted that, while prognostic relevance of "busyness" limiting exercise did not differ by age or sex, negative impact of "diseases" was particularly evident in patients with age < 75 years (P for interaction < 0.01). Factors limiting habitual exercise were associated with "busyness" and "diseases", but not with "weak will", "dislike, or "socioeconomic reasons". While "busyness" was associated with better prognosis regardless of age and sex, "diseases" was associated with worse prognosis in younger populations. Thus, physicians may pay more attentions to the reasons that limit exercise in the daily lives of HF patients rather than the low amount of exercise itself.

Background: Several studies have reported that C-reactive protein (CRP), an inflammatory biomarker, predicts cardiovascular events independently of low-density lipoprotein cholesterol levels. However, no study examined whether temporal changes in CRP levels are associated with clinical events in patients with previous myocardial infarction (MI)., Methods and Results: We examined 2184 consecutive patients with previous MI and CRP data at baseline in the Chronic Heart Failure Registry and Analysis in the Tohoku district-2 (CHART-2) Study. During the median 6.4 years follow-up, 592 all-cause, 245 cardiovascular, and 273 non-cardiovascular deaths occurred. Patients with CRP ≥ 2.0 mg/L at baseline had significantly increased incidence of all-cause (hazard ratio (HR) 1.68, P < 0.001) and non-cardiovascular death (HR 1.86, P < 0.001), compared with those with CRP < 2.0 mg/L. Temporal changes in CRP levels were associated with prognosis; among patients with CRP ≥ 2.0 mg/L at baseline, those with CRP ≥ 2.0 mg/L at 1-year had significantly increased incidence of all-cause (HR 2.12, P < 0.001), cardiovascular (HR 2.31, P < 0.001), and non-cardiovascular death (HR 2.29, P < 0.001). Among patients with CRP < 2.0 mg/L at baseline, those with CRP ≥ 2.0 mg/L at 1-year had significantly increased incidence of all-cause (HR 1.76, P < 0.001) and cardiovascular death (HR 2.10, P = 0.001). These results remained significant after adjusted with the inverse probability of treatment weighted models using propensity sore. Furthermore, as compared with patients with CRP < 2.0 mg/L at both baseline and 1-year, those with CRP ≥ 2.0 mg/L at both baseline and 1-year had increased incidence of all-cause, cardiovascular, and non-cardiovascular death., Conclusions: These results provide the evidence that temporal increases in CRP levels are associated with increased clinical events in patients with previous MI., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Background: Although several factors, including heart failure (HF) and inflammation, are known to increase the incidence of cancer, it remains unknown whether HF may increase cancer mortality, especially with a reference to inflammation., Methods and Results: We examined 8843 consecutive cardiovascular patients without a prior history of cancer in our CHART-2 Study (mean 68 yrs., female 30.9%). As compared with patients without HF (Stage A/B, N = 4622), those with HF (Stage C/D, N = 4221) were characterized by higher prevalence of diabetes, previous myocardial infarction, atrial fibrillation, and stroke. During the median 6.5-year follow-up (52,675 person-years), 282 cancer deaths occurred. HF patients had significantly higher cancer mortality than those without HF in both the overall (3.7 vs, 2.8%, hazard ratio (HR) 1.42, 95% confidence interval (CI) 1.12-1.79, P = 0.004) and the propensity score-matched cohorts (HR 1.46, 95%CI 1.10-1.93, P = 0.008), which was confirmed in the competing risk models. The multivariable Cox proportional hazard model in the matched cohort showed that HF was associated with increased cancer mortality in patients with C-reactive protein (CRP) ≥ 2.0 mg/L (HR 1.87, 95%CI 1.18-2.96, P = 0.008) at baseline, but not in those with CRP < 2.0 mg/L (HR 0.89, 95%CI 0.54-1.45, P = 0.64) (P for interaction = 0.03). Furthermore, temporal changes in CRP levels were associated with cancer death in the overall cohort; HF patients with CRP ≥ 2.0 mg/L at both baseline and 1-year had significantly increased cancer death, while those with CRP ≥ 2.0 mg/L at baseline and < 2.0 mg/L at 1-year not., Conclusions: These results provide the first evidence that HF is associated with increased cancer death, especially when associated with prolonged inflammation., (Copyright © 2019. Published by Elsevier B.V.)

Background: Antiplatelet therapy is the corner stone of treatment following acute myocardial infarction (AMI). Prasugrel, a new and potent antiplatelet agent, was recently introduced to clinical practice. We compared the clinical outcomes of patients with AMI treated with prasugrel with those treated with clopidogrel in real-world clinical practice in Japan.Methods and Results:The Japan AMI Registry (JAMIR) is a multicenter, nationwide, prospective registry enrolling patients with AMI from 50 institutes. Between December 2015 and May 2017, a total of 3,411 patients were enrolled. Among them, 3,069 patients were treated with either prasugrel (n=2,607) or clopidogrel (n=462) during hospitalization. Median follow-up period was 12 months. Prasugrel-treated patients were predominantly male, younger, more often showed ST-elevation AMI, and had fewer comorbidities. After adjustment using inverse probability of treatment weighting, the primary endpoint, defined as a composite of cardiovascular death, non-fatal MI and non-fatal stroke, was comparable between the prasugrel and clopidogrel groups (adjusted hazard ratio [HR] 1.07, 95% confidence interval [CI] 0.67-1.72), whereas the risk of major bleeding (BARC type 3 or 5 bleeding) was significantly lower in the prasugrel group (adjusted HR 0.62, 95% CI 0.39-0.99)., Conclusions: The present real-world database of the JAMIR demonstrated that the potent P2Y12-inhibitor prasugrel showed comparable rates of 1-year ischemic events to clopidogrel, but the risk of bleeding was lower with prasugrel than with clopidogrel.

Objective- Secondary prevention for recurrent myocardial infarction (MI) is one of the most important therapeutic goals in patients with old MI (OMI). Although statins are widely used for this purpose, there remains considerable residual risk even after LDL (low-density lipoprotein cholesterol) is well controlled by statins. Approach and Results- We examined clinical impacts of nHDL (nonhigh-density lipoprotein cholesterol) and its major components triglyceride and LDL as residual risks for acute MI recurrence, using the database of our CHART (Chronic Heart Failure Analysis and Registry in the Tohoku District)-2 Study, the largest-scale cohort study of cardiovascular patients in Japan. We enrolled 1843 consecutive old MI patients treated with statins (mean age 67.3 years, male 19.2%) in the CHART-2 Study. The incidence of recurrent acute MI during the median 8.6-year follow-up was compared among the groups divided by the levels of nHDL (<100, 100-129, and ≥130 mg/dL), LDL (<70, 70-99, and ≥100 mg/dL), triglyceride (<84, 84-149, and ≥150 mg/dL), and combination of LDL and triglyceride. Kaplan-Meier curves and multiple Cox proportional hazards models showed that higher levels of nHDL, but not LDL or triglyceride alone, were associated with higher incidence of recurrent acute MI. Furthermore, higher triglyceride levels were associated with higher incidence of recurrent MI in patients with LDL <100 mg/dL but not in those with LDL ≥100 mg/dL. Conclusions- These results indicate that management of residual risks for acute MI recurrence should include nHDL management considering both LDL and triglyceride in old MI patients under statin treatment. Clinical Trial Registration- URL: http://www.clinicaltrials.gov . Unique identifier: NCT00418041.

Background: Antiplatelet therapy is a cornerstone of treatment following acute myocardial infarction (AMI). Recently, prasugrel, a new and potent antiplatelet agent, has been introduced in clinical practice. To date, however, real-world in-hospital and follow-up data in Japanese patients with AMI remain limited., Objectives: To examine ischemic and bleeding events in Japanese patients with AMI and the association between these events and antiplatelet therapy., Methods: The Japan AMI Registry (JAMIR) is a multicenter, nationwide, prospective registry enrolling patients with AMI from 50 institutions. The inclusion criterion is spontaneous onset of AMI diagnosed based on either the universal definition or Monitoring Trends and Determinants in Cardiovascular disease (MONICA) criteria. The major exclusion criteria are hospital admission ≥ 24 h after onset, no return of spontaneous circulation on admission following out-of-hospital cardiopulmonary arrest, and AMI as a complication of percutaneous coronary intervention or coronary artery bypass grafting. The primary end point of the study is the composite of cardiovascular death, non-fatal myocardial infarction, and non-fatal stroke. Major safety end points include major bleeding based on Thrombolysis in Myocardial Infarction (TIMI) criteria and type 3 or type 5 bleeding based on Bleeding Academic Research Consortium (BARC) criteria. Between December 2015 and May 2017, a total of 3411 patients (mean age 68.1 ± 13.2 years, 23.4% female) were enrolled in the study. Patients will be followed for 1 year., Conclusions: JAMIR will provide important information regarding contemporary practice patterns in the management of Japanese patients with AMI, their demographic and clinical characteristics, in-hospital and post-discharge outcomes, and how they are related to antiplatelet therapy.

Background: The beneficial prognostic impact of statins has been established in patients with ischemic heart disease but not in those with heart failure (HF). In addition, it is still unclear whether patients benefit from statins regardless of low-density lipoprotein cholesterol levels., Methods and Results: We examined 2444 consecutive stage C or D HF patients with ischemic heart disease registered in CHART-2 (Chronic Heart Failure Registry and Analysis in the Tohoku District 2), a multicenter, prospective, observational cohort study in Japan. Patients were divided into 3 groups according to the Japanese standard doses of statins and statin-intensity categories defined by the 2013 American College of Cardiology and American Heart Association guidelines: higher (moderate-high)-intensity (n=868), lower (low)-intensity (n=526), and no statin (n=1050). The median follow-up period was 6.4 years (13929 person-years). Analysis with the inverse probability of treatment weighted using a propensity score for multiple treatment revealed that both the higher-intesity group (hazard ratio [HR]: 0.68; P <0.001) and the lower-intensity group (HR: 0.82; P <0.001) had significantly lower incidence of the primary end point-a composite of all-cause death and HF admission-compared with the no statin group. The higher-intensity statin group had significantly lower incidence of the primary end point (HR: 0.82; P <0.001), all-cause death (HR: 0.83; P <0.001), and HF admission (HR: 0.78; P <0.001) than the lower-intensity statin group. Moreover, the use of statins, either higher- or lower-intensity, was associated with reduced incidence of the primary end point, regardless of low-density lipoprotein cholesterol levels., Conclusions: These results suggest that statin use, particularly the use of higher-intensity statins, has a beneficial prognostic impact in HF patients with ischemic heart disease, regardless of low-density lipoprotein cholesterol levels., Clinical Trial Registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00418041., (© 2018 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley.)

Background: The effectiveness of statins remains to be examined in patients with heart failure (HF) with preserved ejection fraction (EF). METHODS AND RESULTS: Among 4,544 consecutive HF patients registered in the Chronic Heart Failure Registry and Analysis in the Tohoku district-2 (CHART-2) between 2006 and 2010, 3,124 had EF ≥50% (HFpEF; mean age 69 years; male 65%) and 1,420 had EF <50% (HF with reduced EF (HFrEF); mean age 67 years; male 75%). The median follow-up was 3.4 years. The 3-year mortality in HFpEF patients was lower in patients receiving statins [8.7% vs. 14.5%, adjusted hazard ratio (HR) 0.74; 95% confidence interval (CI), 0.58-0.94; P<0.001], which was confirmed in the propensity score-matched cohort (HR, 0.72; 95% CI, 0.49-0.99; P=0.044). The inverse probability of treatment weighted further confirmed that statin use was associated with reduced incidence of all-cause death (HR, 0.71; 95% CI, 0.62-0.82, P<0.001) and noncardiovascular death (HR, 0.53; 95% CI, 0.43-0.66, P<0.001), specifically reduction of sudden death (HR, 0.59; 95% CI, 0.36-0.98, P=0.041) and infection death (HR, 0.53; 95% CI, 0.35-0.77, P=0.001) in HFpEF. In the HFrEF cohort, statin use was not associated with mortality (HR, 0.87; 95% CI, 0.73-1.04, P=0.12), suggesting a lack of statin benefit in HFrEF patients., Conclusions: These results suggest that statin use is associated with improved mortality rates in HFpEF patients, mainly attributable to reductions in sudden death and noncardiovascular death.

Background: Recent trends in the clinical characteristics, management and prognosis of dilated cardiomyopathy (DCM) remain to be examined in Japan., Methods and Results: We compared 306 and 710 DCM patients in the Chronic Heart Failure Analysis and Registry in the Tohoku District (CHART)-1 (2000-2005, n=1,278) and the CHART-2 (2006-present, n=10,219) Studies, respectively. Between the 2 groups of DCM patients, there were no significant differences in baseline characteristics. The prevalence of hypertension, dyslipidemia and diabetes mellitus were all significantly increased from the CHART-1 to the CHART-2 Study. The use of β-blockers and aldosterone antagonists was significantly increased, while that of loop diuretics and digitalis was significantly decreased in the CHART-2 Study. The 3-year mortality rate was significantly improved from 14% in the CHART-1 to 9% in the CHART-2 Study (adjusted HR, 0.60; 95% CI: 0.49-0.81; P=0.001). In particular, 3-year incidence of cardiovascular death was significantly decreased (adjusted HR, 0.26; 95% CI: 0.14-0.50, P<0.001), while that of HF admission was not (adjusted HR, 0.90; 95% CI: 0.59-1.37, P=0.632). The prognostic improvement was noted in patients with BNP <220 pg/ml, LVEF>40%, β-blocker use and aldosterone antagonist use., Conclusions: Long-term prognosis of DCM patients has been improved, along with the implementation of evidence-based medication in Japan.

Background: We examined the prevalence, predictors and prognostic impact of post-traumatic stress disorder (PTSD) after the Great East Japan Earthquake in patients with cardiovascular disease (CVD) in the CHART-2 study. METHODS AND RESULTS: The prevalence of PTSD was 14.7% at 6 months after the Earthquake. Female sex, experiencing the Tsunami, property loss, poverty, and insomnia medication use were associated with PTSD. The patients with PTSD more frequently experienced a composite of death, acute myocardial infarction, stroke and heart failure (18.5% vs. 15.0%, P=0.035)., Conclusions: PTSD was frequent in CVD patients after the Earthquake and had an adverse prognostic impact.

Background: Temporal trends in clinical characteristics, management and prognosis of patients with symptomatic heart failure (HF) remain to be elucidated in Japan., Methods and results: From the Chronic Heart Failure Analysis and Registry in the Tohoku District-1 (CHART-1; 2000-2005, n=1,278) and CHART-2 (2006-present, n=10,219) Studies, we enrolled 1,006 and 3,676 consecutive symptomatic stage C/D HF patients, respectively. As compared with the patients in the CHART-1 Study, those in the CHART-2 Study had similar age and sex prevalence, and were characterized by lower brain natriuretic peptide, higher prevalence of preserved left ventricular ejection fraction (LVEF) and higher prevalence of hypertension, diabetes mellitus and ischemic heart disease (IHD), particularly IHD with LVEF ≥50%. From CHART-1 to CHART-2, use of renin-angiotensin system inhibitors, β-blockers and aldosterone antagonists was significantly increased, while that of loop diuretics and digitalis was decreased. Three-year incidences of all-cause death (24 vs. 15%; adjusted hazard ratio [adjHR], 0.73; P<0.001), cardiovascular death (17 vs. 7%; adjHR, 0.38; P<0.001) and hospitalization for HF (30 vs. 17%; adjHR, 0.51; P<0.001) were all significantly decreased from CHART-1 to CHART-2. In the CHART-2 Study, use of β-blockers was associated with improved prognosis in patients with LVEF <50%, while that of statins was associated with improved prognosis in those with LVEF ≥50%., Conclusions: Along with implementation of evidence-based medications, the prognosis of HF patients has been improved in Japan. (, Trial Registration: clinicaltrials.gov identifier: NCT00418041)

Background: The risk of patients with aortic stenosis (AS) should be stratified not only by AS severity but also by comorbidities., Methods and Results: We aimed to develop a risk score for mortality in 412 patients with AS (pressure gradient ≥30 mmHg, mean age 74.9 years, male 52.4%) in the CHART-2 Study (n=10,219). During a 3-year follow-up, 73 (17.7%) patients died. Crude 3-year mortality of patients in New York Heart Association (NYHA) classes I, II, and III/IV was 9.5%, 16.5%, and 49.7%, respectively (P<0.001). Stepwise Cox regression analysis showed that the combination of 7 factors was the best model to predict the mortality of AS patients, who were scored according to their hazard ratios, including NYHA class III-IV (score 6), male sex (3), serum albumin level ≤4 g/dl (2), aortic peak flow ≥4.5 m/s (2), age ≥75 years (2), chronic kidney disease (2), and anemia (1). Receiver-operating characteristic analysis showed excellent association between the sum of the scores and 3-year mortality (area under the curve, 0.78). The multivariate Cox proportional hazard model demonstrated that the present risk score also well stratified the mortality risk., Conclusions: The present study demonstrates that, in addition to the classical prognostic factors related to symptoms and AS severity, various comorbidities are associated with mortality. Thus, the present comprehensive risk score may be useful for risk stratification of AS patients.

Few studies have investigated whether angiotensin II receptor blocker (ARB) is a practical alternative to angiotensin-converting enzyme inhibitor (ACEI) for long-term use after acute myocardial infarction (AMI) in real-world practice in the percutaneous coronary intervention era. We compared 5-year survival benefits of ACEI and ARB in patients with AMI registered in the Osaka Acute Coronary Insufficiency Study. Study subjects were divided into 3 groups: ACEI (n = 4,425), ARB (n = 2,158), or patients without either drug (n = 2,442). A total of 661 deaths were recorded. Cox regression analysis revealed that treatment with either ACEI or ARB was associated with reduced 5-year mortality (adjusted hazard ratio [HR] 0.70, 95% confidence interval [CI] 0.58 to 0.83, p <0.001 and HR 0.79, 95% CI 0.64 to 0.98, p = 0.03, respectively). However, Kaplan-Meier estimates and Cox regression analyses based on propensity score revealed that ACEI was associated with better survival than ARB from 2 to 5 years after survival discharge (adjusted HR 0.53, 95% CI 0.38 to 0.74, p <0.001). These findings were confirmed in a propensity score-matched population. In conclusion, treatment with ACEI was associated with better 5-year survival after AMI., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Objective: The onset of acute myocardial infarction (AMI) shows characteristic circadian variations involving a definite morning peak and a less-defined night-time peak. However, the factors influencing the circadian patterns of AMI onset and their influence on morning and night-time peaks have not been fully elucidated., Design, Setting and Participants: An analysis of patients registered between 1998 and 2008 in the Osaka Acute Coronary Insufficiency Study, which is a prospective, multicentre observational study of patients with AMI in the Osaka region of Japan. The present study included 7755 consecutive patients with a known time of AMI onset., Main Outcomes and Measures: A mixture of two von Mises distributions was used to examine whether a circadian pattern of AMI had uniform, unimodal or bimodal distribution, and the likelihood ratio test was then used to select the best circadian pattern among them. The hierarchical likelihood ratio test was used to identify factors affecting the circadian patterns of AMI onset. The Kaplan-Meier method was used to estimate survival curves of 1-year mortality according to AMI onset time., Results: The overall population had a bimodal circadian pattern of AMI onset characterised by a high and sharp morning peak and a lower and less-defined night-time peak (bimodal p<0.001). Although several lifestyle-related factors had a statistically significant association with the circadian patterns of AMI onset, serum triglyceride levels had the most prominent association with the circadian patterns of AMI onset. Patients with triglyceride ≥150 mg/dL on admission had only one morning peak in the circadian pattern of AMI onset during weekdays, with no peaks detected on weekends, whereas all other subgroups had two peaks throughout the week., Conclusions: The circadian pattern of AMI onset was characterised by bimodality. Notably, several lifestyle-related factors, particularly serum triglyceride levels, had a strong relation with the circadian pattern of AMI onset., Trial Registration Number: UMIN000004575., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)

Aims: It is still controversial whether elevated baseline heart rate (HR) is associated with higher mortality in patients with heart failure (HF) with preserved ejection fraction (HFpEF). We compared the impacts of baseline HR on mortality in patients with HFpEF and those with HF with reduced ejection fraction (HFrEF)., Methods and Results: We enrolled consecutive 2688 patients in Stage C or D HF with sinus rhythm from our Chronic Heart Failure Analysis and Registry in the Tohoku District 2 (CHART-2) Study (n = 10 219). The prognostic impact of HR increase was compared between the two groups, defined as left ventricular ejection fraction of < 50% (HFrEF) and > 50% (HFpEF). Cox regression analysis revealed that elevated baseline HR was associated with increased all-cause mortality in both groups [hazard ratio for the highest tertile (HH) 1.77 in HFrEF, P = 0.008; HH1.82 in HFpEF, P = 0.001]. However, as for mode of death, elevated HR was associated with cardiovascular (CV) death in HFpEF (HH 2.17, P = 0.012), but the association was modest in HFrEF (HH1.49, P = 0.14): in particular, impact on HF death was different between HFpEF (HH 3.79, P = 0.020) and HFrEF (HH 1.07, P = 0.864). In contrast, the prognostic impact of baseline HR on non-CV death was noted only in patients with HFrEF. β-Blocker therapy was associated with reduced HF mortality in HFrEF (hazard ratio 0.49, P = 0.038) but not in HFpEF (hazard ratio 0.64, P = 0.321)., Conclusions: Elevated HR was associated with increased CV death in HFpEF compared with HFrEF, although its impact on all-cause mortality was comparable between the two groups., (© 2013 The Authors. European Journal of Heart Failure © 2013 European Society of Cardiology.)

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 significant 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% confidence 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: Although emergency care of acute myocardial infarction (AMI) could theoretically be improved through improved patient delay, this notion remains to be confirmed. Additionally, the influence of large earthquakes on the emergency care of AMI cases remains to be elucidated. The Great East Japan Earthquake (March 11, 2011) has enabled us to address these issues., Methods and Results:  We analyzed the data from 2008 to 2011 (n=3,937) in the Miyagi AMI Registry Study. In-hospital mortality was significantly lower in 2011 as compared with the previous 3 years (7.3% vs. 10.5%, P<0.05). This improvement was noted especially during the first 2 months after the Earthquake, associated with shorter elapsing time from onset to admission (120 vs. 240min, P<0.001) and higher performance rate of primary percutaneous coronary intervention (PCI) (86.8% vs. 76.2%, P<0.01). Importantly, after the Earthquake, patients with early admission (≤3h from onset) was significantly increased (59.1% vs. 47.0%, P<0.05) and their prognosis became better (7.9% vs. 11.4%, P=0.02), associated with a lower prevalence of heart failure on admission (6.9% vs. 16.2%, P=0.02) and higher performance rate of primary PCI (89.1% vs. 76.4%, P<0.01)., Conclusions:  Emergency care of AMI improved soon after the Great East Japan Earthquake compared with ordinary times by the contribution of earlier admission from onset and higher performance rate of primary PCI.  (Circ J 2014; 78: 634-643).

Background: Microalbuminuria, traditionally defined as urinary albumin/creatinine ratio (UACR) ≥30 mg/g, is a risk factor for mortality even in patients with preserved glomerular filtration rate (GFR). The prognostic impact of subclinical microalbuminuria, however, remains unknown in patients with chronic heart failure (CHF). METHODS AND RESULTS: In the Chronic Heart Failure Analysis and Registry in the Tohoku District 2 Study, we enrolled 2,039 consecutive symptomatic CHF patients (median age, 67.4 years; 68.9% male) after excluding those on hemodialysis. On classification and regression tree analysis, UACR=10.2 mg/g and 27.4 mg/g were identified as the first and second discriminating points to stratify the risk for composite of death, acute myocardial infarction, HF admission and stroke, therefore subclinical microalbuminuria was defined as UACR ≥10.2 and <27.4 mg/g. There were 506 composite endpoints (24.8%) during the median follow-up of 2.69 years. On Kaplan-Meier analysis and multivariate Cox modeling, subclinical microalbuminuria was significantly associated with increased composite endpoints with hazard ratios of 1.90 (P<0.001) and 2.29 (P<0.001) in patients with preserved (>60 ml·min(-1)·1.73 m(-2), n=1,129) or mildly reduced eGFR (30-59.9 ml·min(-1)·1.73 m(-2), n=789), respectively. In patients with severely reduced GFR (eGFR <30 ml·min(-1)·1.73 m(-2), n=121), >80% had microalbuminuria or macroalbuminuria, and only 9.1% were free from any composite endpoints., Conclusions: Subclinical microalbuminuria was associated with increased risk of cardiovascular events in CHF patients with mildly reduced or preserved renal function.

Background: Although the need for nursing care (NC) in heart failure (HF) patients is recognized, detailed information on the current status in Japan is lacking. METHODS AND RESULTS: In the CHART-2 Study, we obtained information on daily life, physical ability, nutrition and mental status for 4,174 patients (mean age, 67.1±10.8 years; 73.3% male) out of 10,219 patients. We examined the prevalence, baseline characteristics and clinical outcomes of stage B and C/D HF patients requiring NC. The prevalence of HF requiring NC was significantly higher in stage C/D (38.6%) than in stage B (30.4%; P<0.001). Among the reasons for requiring NC, physical dysfunction was most prevalent in both stage B (20.6%) and C/D (29.0%). Compared with the non-NC group, the NC group was characterized by higher age, higher prevalence of female gender and cerebrovascular disease, and increased plasma brain natriuretic peptide regardless of HF stage. During a median follow-up of 12.7 months after the survey, the NC group had a significantly higher mortality compared with the non-NC group (9.6% vs. 3.6%, P<0.001). On multivariate logistic analysis depressive mental status (hazard ratio [HR], 3.61; P<0.001) and dementia (HR, 2.70; P<0.001) were significantly associated with NC need., Conclusions: In HF patients, NC need is considerably high and is associated with increased mortality regardless of HF stage in Japan.

Objectives: Chromosome 9p21 single nucleotide polymorphism (SNP) is a susceptibility variant for acute myocardial infarction (AMI) in the primary prevention setting. However, it is controversial whether this SNP is also associated with recurrent myocardial infarction (ReMI) in the secondary prevention setting. The purpose of this study is to evaluate the impact of chromosome 9p21 SNP on ReMI in patients receiving secondary prevention programmes after AMI., Design: A prospective observational study., Setting: Osaka Acute Coronary Insufficiency Study (OACIS) in Japan., Participants: 2022 patients from the OACIS database., Interventions: Genotyping of the 9p21 rs1333049 variant., Primary Outcome Measures: ReMI event after survival discharge for 1 year., Results: A total of 43 ReMI occurred during the 1 year follow-up period. Although the rs1333049 C allele had an increased susceptibility to their first AMI in an additive model when compared with 1373 healthy controls (OR 1.20, 95% CI 1.09 to 1.33, p=2.3*10(−4)), patients with the CC genotype had a lower incidence of ReMI at 1 year after discharge of AMI (log-rank p=0.005). The adjusted HR of the CC genotype as compared with the CG/GG genotypes was 0.20 (0.06 to 0.65, p=0.007). Subgroup analysis demonstrated that the association between the rs1333049 CC genotype and a lower incidence of 1 year ReMI was common to all subgroups., Conclusions: Homozygous carriers of the rs1333049 C allele on chromosome 9p21 showed a reduced risk of 1 year ReMI in the contemporary percutaneous coronary intervention era, although the C allele had conferred susceptibility to their first AMI.

Background: The gender differences in patients with chronic heart failure (CHF) remain to be fully elucidated in the Japanese population., Methods and Results: We examined gender differences in clinical characteristics, treatment and long-term outcome in 4,736 consecutive CHF patients in stage C/D (mean age, 69 years) out of 10,219 patients registered in the CHF Registry, named CHART-2 Study (NCT 00418041). Compared with male patients (68%, n=3,234), female patients (32%, n=1,502) were 3.8 years older and had lower prevalence of ischemic heart disease, diabetes, smoking, myocardial infarction and cancer. At baseline, women had higher prevalence of preserved left ventricular function but had higher NYHA functional class and increased brain natriuretic peptide level. In women, aspirin, β-blockers and statins were less frequently used and diuretics were more frequently used. Crude mortality rate was similar between the genders during the median 3.1-year follow-up (52.4/1,000 and 47.3/1,000 person-years for women and men, respectively, P=0.225). On multivariate Cox regression analysis, women had a reduced risk of mortality (adjusted HR, 0.791; 95% CI: 0.640-0.979, P=0.031)., Conclusions: Substantial gender differences exist in stage C/D CHF patients in real-world practice in Japan. Although female CHF patients had better survival than male patients after adjustment for baseline differences, crude mortality rate was similar between the genders, possibly reflecting relatively severer clinical manifestations in women.

Background: Little is known about the long-term risk of cardiovascular events after discharge among acute myocardial infarction (AMI) survivors living alone in Japan., Methods and Results: A large-scale prospective, observational study in the Osaka region involved consecutive patients with AMI from January 2002 through December 2010. We evaluated the association between living alone and longitudinal risk of cardiovascular events following discharge after AMI. A Cox proportional-hazards model was used to assess the association between living alone and the primary composite endpoint consisting of major adverse cardiovascular events and total deaths. During the study period, 5845 patients (4415 male patients, 1430 female patients) were registered. Living alone was found to be independently associated with a higher risk of composite endpoint consisting of major adverse cardiovascular events and total deaths [adjusted hazard ratio (HR) 1.32; 95% confidence interval (CI): 1.11-1.58]. Multivariate-adjusted HRs of composite endpoint were 1.34 (95% CI: 1.08-1.68) among male patients and 1.31 (95% CI: 0.95-1.81) in the female patients. AMI survivors living alone tend to have a higher adjusted HR of composite endpoint than those not living alone irrespective of age and gender groups., Conclusions: From this large AMI registry in Osaka, AMI survivors living alone after discharge had a higher risk of cardiovascular events and total deaths than those not living alone., (Copyright © 2013 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.)

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 <24 hours after the onset of ST-segment elevation myocardial infarction, treated with emergent percutaneous coronary intervention, and discharged alive were studied. During a median follow-up period of 1,430 days, mortality rates did not differ between patients with and without BB therapy (5.2% vs 6.2%, p = 0.786). Multivariate analysis revealed that BB treatment was not associated with a reduced risk for mortality (hazard ratio 0.935, 95% confidence interval 0.711 to 1.230, p = 0.534). The results of propensity score matching also indicated that the mortality rates did not differ between the 2 groups. However, subgroup analyses among matched populations revealed that BB treatment was associated with a significantly lower mortality risk for high-risk patients, who were defined as those with Global Registry of Acute Coronary Events (GRACE) risk scores ≥121 (hazard ratio 0.596, 95% confidence interval 0.416 to 0.854, p = 0.005) or those administered diuretics (hazard ratio 0.602, 95% confidence interval 0.398 to 0.910, p = 0.016), but not for lower risk patients. In conclusion, BB treatment was associated with reduced long-term mortality in patients after ST-segment elevation myocardial infarction at higher risk, but not in those at lower risk. Although randomized controlled studies are warranted to confirm these results, the implementation of BB therapy for discharged patients with ST-segment elevation myocardial infarction may need to be assessed on the basis of individual mortality risk in the percutaneous coronary intervention era., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Background: Accumulating evidence has demonstrated the gender differences in the clinical characteristics and outcomes of patients with ischemic heart disease. However, it remains to be elucidated whether it is also the case for vasospastic angina (VSA)., Methods and Results: We enrolled a total of 1,429 VSA patients (male/female, 1090/339; median age 66 years) in our nationwide multicenter registry by the Japanese Coronary Spasm Association. As compared with male patients, female patients were characterized by older age (median 69 vs. 66 years), lower incidence of smoking (20% vs. 72%) and less significant organic stenosis (9% vs. 16%) (all P=0.001). Multivariate analysis demonstrated that the predictors of major adverse cardiac events (MACE) were considerably different by genders; women were more associated with age and electrical abnormalities, whereas men with structural abnormalities. Overall 5-year MACE-free survival was comparable between both genders. However, when the patients were divided into 3 groups by age [young (<50 years), middle-aged (50-64 years) and elderly (≥65 years)], the survival was significantly lower in the young female group (young 82%, middle-aged 92%, elderly 96%, P<0.01), where a significant interaction was noted between age and smoking. In contrast, the survival was comparable among the 3 age groups of male patients., Conclusions: These results indicate that there are gender differences in the characteristics and outcomes of VSA patients, suggesting the importance of gender-specific management of the disorder.

Background: Elevated blood urea nitrogen (BUN) observed in patients hospitalized for acute heart failure syndrome (AHFS) may represent increased neurohumoral activation. The purpose of this study was to examine the prognostic impact of BUN changes during hospitalization on the long-term prognosis of AHFS patients., Methods and Results: The Tohoku Acute Heart Failure Registry (n=497) is a multicenter retrospective cohort study enrolling AHFS patients who were admitted in 2007. The 337 survivors (mean age, 76 years; 52% male) were divided into 3 groups according to tertiles of BUN change during hospitalization: Decreased (D-BUN, ΔBUN (BUN level at discharge-BUN level at hospitalization)≤-1.63 mg/dl, n=112); Unchanged (U-BUN, ΔBUN-1.64 to 5.73 mg/dl, n=113); Increased (I-BUN, ΔBUN>5.73 mg/dl, n=112). The D-BUN group had higher prevalence of lowest glomerular filtration rate during hospitalization, whereas the I-BUN group had higher systolic blood pressure. During a median follow-up period of 2.3 years after discharge, the Kaplan-Meier curve showed that D-BUN and I-BUN had worse prognosis compared with U-BUN. Multivariable logistic model showed that all-cause death was more frequent in I-BUN (hazard ratio, 2.94; 95% confidence interval, 1.51-5.73; P<0.001). Subgroup analysis revealed that BUN increase during hospitalization was associated with all-cause death, regardless of renal function., Conclusions: AHFS patients with a BUN increase during hospitalization have worse long-term prognosis, independent of renal function.

Background: We have previously demonstrated that the prevalence of metabolic syndrome in chronic heart failure (CHF) is more than double compared with the general population in Japan. However, the impact of physical activity on cardiovascular events in CHF patients remains to be fully elucidated., Methods and Results: We performed a prospective, nationwide large-scale multicenter study of 9,178 patients with stage A/B/C/D CHF in Japan. We obtained the baseline physical activity data for 7,292 and yearly changes in physical activity data during a 3-year follow-up period for 4,353 patients. We divided the patients into high- and low-exercise groups by using the median value of physical activity in the stage A/B and C/D groups. In both groups, patients who exercised more were characterized by younger age and less advanced stage of CHF. Importantly, the baseline physical activity levels were significantly associated with all-cause death, heart failure (HF) hospitalization and other cardiovascular events (except acute myocardial infarction, stroke, HF hospitalization). Furthermore, the yearly change in physical activity level was also significantly associated with HF hospitalization and other cardiovascular events in both groups., Conclusions: The baseline level of physical activity and its yearly changes are significantly associated with all-cause death and major cardiovascular events in both stage A/B and C/D patients, suggesting that physical activity could be an important therapeutic target to improve the long-term prognosis of CHF patients.

Aims: While previous studies reported a short-term increase in individual cardiovascular disease (CVD) after great earthquakes, mid-term occurrences of all types of CVDs after great earthquakes are unknown. We addressed this important issue in our experience with the Great East Japan Earthquake (11 March 2011)., Methods and Results: We retrospectively examined the impact of the Earthquake on the occurrences of CVDs and pneumonia by comparing the ambulance records made by doctors in our Miyagi Prefecture, the centre of the disaster area, during the periods of 2008-11 (n = 124,152). The weekly occurrences of CVDs, including heart failure (HF), acute coronary syndrome (ACS), stroke, cardiopulmonary arrest (CPA), and pneumonia were all significantly increased after the Earthquake compared with the previous 3 years. The occurrences of ACS and CPA showed the rapid increase followed by a sharp decline, whereas those of HF and pneumonia showed a prolonged increase for more than 6 weeks and those of stroke and CPA showed a second peak after the largest aftershock (7 April 2011). Furthermore, the occurrence of CPA was increased in the first 24 h after the Earthquake, followed by other diseases later on. These increases were independent of age, sex, or residence area (seacoast vs. inland)., Conclusion: These results indicate that the occurrences of all types of CVDs and pneumonia were increased in somewhat different time courses after the Earthquake, including the first observation of the marked and prolonged increase in HF, emphasizing the importance of intensive medical management of all types of CVDs after great earthquakes.

Background: Patients with chronic kidney disease (CKD) still frequently experience cardiovascular events despite recent progress in treatment. We examined whether nicorandil, a hybrid nitrate and adenosine triphosphate-sensitive potassium channel opener, could improve a biomarker and physiological markers of cardiovascular events., Methods: Patients with advanced stage CKD (stage III-V with or without peritoneal dialysis) were included in this trial if they were considered at high risk for cardiovascular events [past history of cardiovascular diseases, past history of coronary angiography, presence of endothelial dysfunction measured by reactive hyperemia peripheral arterial tonometry, and presence of high brain natriuretic peptide (BNP) values]. Patients were randomly assigned to be treated with or without oral nicorandil, 15 mg/day. BNP values and endothelial function (augmentation index, pulse wave velocity, and reactive hyperemia peripheral arterial tonometry) before and 1 month after the initiation of the trial were assessed., Results: Nineteen patients (15 men, 4 women) with a mean age of 61 ± 10 (SD) years were included. The median baseline BNP value was 75.3 (interquartile range, 32.1-138.8) pg/ml, and the BNP level was significantly reduced in the nicorandil group (P < 0.05). Regression analysis demonstrated that only the use of nicorandil is related to a decrease of BNP levels [standardized β coefficient, -75.1 (95% CI, -19.7 to -130.6), P = 0.01]. There were no significant changes in the rest of the parameters in the nicorandil group in comparison to the control group. The change in BNP levels was correlated with changes in the augmentation index (P < 0.01) and central pulse pressure (P = 0.03)., Conclusions: Nicorandil treatment may reduce the level of BNP by reducing the central blood pressure in CKD patients.