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Introduction Neither the pathophysiology nor an effective treatment for heart failure with preserved ejection fraction (HFpEF) has been elucidated to date. The purpose of this ongoing study is to elucidate the pathophysiology and prognostic factors for patients with HFpEF admitted to participating institutes. We also aim to obtain insights into the development of new diagnostic and treatment methods by analysing patient background factors, clinical data and follow-up information.Methods and analysis This study is a prospective, multicentre, observational study of patients aged ≥20 years admitted due to acute decompensated heart failure with preserved left ventricular ejection fraction (≥50%) and elevated N-terminal-pro brain natriuretic peptide (NT-proBNP) (≥400 pg/mL). The study began in June 2016, with the participation of Osaka University Hospital and 31 affiliated facilities. We will collect data on history in detail, accompanying diseases, quality of life, frailty score, medication history, and laboratory and echocardiographic data. We will follow-up each patient for 5 years, and collect outcome data on mortality, cause of death, and the number and cause of hospitalisation. The target number of registered cases is 1500 cases in 5 years.Ethics and dissemination The protocol was approved by the Institutional Review Board (IRB) of Osaka University Hospital on 24 February 2016 (ID: 15471), and by the IRBs of the all participating facilities. The findings will be disseminated through peer-reviewed publications and conference presentations.

Background: The effectiveness of β-blocker in patients with heart failure with preserved ejection fraction (HFpEF) remains to be determined. We aimed to clarify the association between the use of β-blocker and prognosis according to the status of frailty., Methods: We compared prognosis between HFpEF patients with and without β-blockers stratified with the Clinical Frailty Scale (CFS), using data from the PURSUIT-HFpEF registry (UMIN000021831)., Results: Among 1159 patients enrolled in the analysis (median age, 81.4 years; male, 44.7%), 580 patients were CFS ≤ 3, while 579 were CFS ≥ 4. Use of β-blockers was associated with a worse composite endpoint of all-cause death and heart failure readmission in patients with CFS ≥ 4 (adjusted hazard ratio (HR) 1.43, 95% CI 1.10-1.85, p = 0.007), but was not significantly associated with this endpoint in those with CFS ≤ 3 (adjusted HR 0.95, 95% CI 0.71-1.26, p = 0.719) in multivariable Cox proportional hazard models. These results were confirmed in a propensity-matched analysis (HR in those with CFS ≥ 4: 1.42, 95% CI 1.05-1.90, p = 0.020; that in those with CFS ≤ 3: 0.83, 95% CI 0.60-1.14, p = 0.249), and in an analysis in which patients were divided into CFS ≤ 4 and CFS ≥ 5., Conclusions: Use of β-blockers was significantly associated with worse prognosis specifically in patients with HFpEF and high CFS, but not in those with low CFS. Use of β-blockers in HFpEF patients with frailty may need careful attention., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany.)

Aim: Both recurrent myocardial infarction (ReMI) and bleeding events after acute myocardial infarction (AMI) were reportedly associated with increased mortality. To date, the prognostic impact of these events on subsequent outcomes in East Asians is still unclear. In this study, we aimed to investigate the impact of bleeding or thrombotic events during acute phase on subsequent mortality and time-dependent change of the impact in patients with AMI undergoing percutaneous coronary intervention (PCI)., Method: We conducted a prospective, multicenter, observational study of patients with AMI (n=12,093). The patients who did not undergo emergent PCI were excluded. In addition, the patients registered before 2003 were excluded because the data of bleeding severity was not obtained. Eligible patients were divided into two groups based on the occurrence of major bleeding within 7 days of PCI, and the same approach was performed for ReMI within 7 days of PCI. The endpoint of this study was all-cause death. We assessed the impact of major bleeding and ReMI, which occurred within 7 days of index PCI, on the subsequent clinical outcomes up to 5 years., Results: A total of 6,769 patients were found to be eligible. All-cause death occurred in 898 (13.3%) patients during a median follow-up period of 1,726 [511-1,840] days. After adjustment for multiple confounders, major bleeding in 7 days from index PCI was independently associated with higher 30-day and 30-day to 1-year mortality (odds ratio [OR]: 2.06 [1.45-2.92] p＜0.001, OR: 2.03 [1.28-3.15] p=0.002), whereas ReMI was not (OR: 1.93 [0.92-3.80] p=0.07, OR: 0.81 [0.24-2.03] p=0.68). Major bleeding and ReMI did not affect mortality between 1 and 5 years (hazard ratio [HR]: 1.32 [0.77-2.26] p=0.31, HR: 0.48 [0.12-1.94] p=0.30)., Conclusion: Major bleeding in 7 days from admission was independently associated with higher 30-day and 1-year mortality but not during 1-5 years. ReMI did not affect mortality in all phases. We should be more concerned about bleeding event during acute phase after PCI.

It is unclear whether adaptive servo-ventilation (ASV) therapy for heart failure with preserved ejection fraction (HFpEF) is effective. The aim of this study was to investigate the details of ASV use, and to evaluate the effectiveness and safety of ASV in real-world HFpEF patients. We retrospectively enrolled 36 HFpEF patients at nine cardiovascular centers who initiated ASV therapy during hospitalization or on outpatient basis and were able to continue using it at home from 2012 to 2017 and survived for at least one year thereafter. The number of hospitalizations for heart failure (HF) during the 12 months before and 12 months after introduction of ASV at home was compared. The median number of HF hospitalizations for each patient was significantly reduced from 1 [interquartile range: 1-2] in the 12 months before introduction of ASV to 0 [0-0] in the 12 months after introduction of ASV (p < 0.001). In subgroup analysis, reduction in heart failure hospitalization was significantly greater in female patients, patients with a body mass index < 25, and those with moderate or severe tricuspid valve regurgitation. In patients with HFpEF, the number of HF hospitalizations was significantly decreased after the introduction of ASV. HFpEF patients with female sex, BMI < 25, or moderate to severe tricuspid valve regurgitation are potential candidates who might benefit from ASV therapy., (© 2023. Springer Nature Japan KK, part of Springer Nature.)

It remains unknown whether the recent trend of short dual antiplatelet therapy (DAPT) followed by P2Y12 inhibitor monotherapy can simply be applied to patients undergoing complex percutaneous coronary intervention (PCI). We performed a systematic review and meta-analysis to evaluate P2Y12 inhibitor monotherapy vs. conventional DAPT in patients undergoing complex PCI and non-complex PCI (PROSPERO: CRD42022335723). Primary endpoint was the 1-year Net Adverse Clinical Event (NACE). Among 5,323 screened studies, six randomized trials fulfilled the eligibility criteria. A total of 10,588 complex PCI patients (5,269 vs. 5,319 patients) and 25,618 non-complex PCI patients (12,820 vs 12,798 patients) were randomly assigned to P2Y12 inhibitor monotherapy vs. conventional DAPT. In complex PCI patients, P2Y12 inhibitor monotherapy was associated with a lower risk of NACE than conventional DAPT [Odds ratio (OR) 0.76, 95% confidence interval (CI) 0.63-0.91, P = 0.003], whereas in non-complex PCI patients, P2Y12 inhibitor monotherapy was associated with a trend toward lowering the risk of NACE (OR 0.86, 95% CI 0.72-1.02, P = 0.09). This meta-analysis across randomized trials demonstrated that a strategy of short DAPT followed by P2Y12 inhibitor monotherapy reduces the risk of 1-year NACE in patients undergoing complex PCI., (© 2023. Springer Nature Limited.)

Background: Individualized treatment approach based on pre-procedural precise risk balance assessment between bleeding and thrombosis would be desirable for patients with myocardial infarction (MI) undergoing emergent percutaneous coronary intervention (PCI) in this ultra-short dual antiplatelet therapy era. We aimed to develop and validate a quick thrombosis/bleeding risk-balance assessment tool., Methods: We developed and validated a novel thrombosis/bleeding risk-balance assessment tool using individual patient data from the prospective multicenter MI registry. Individual risks of thrombosis and bleeding within 7 days of the index PCI were estimated using a multinomial logistic regression model. The model was developed in the derivation cohort (4554 patients enrolled during 2003-2009) and validated in the validation cohort (2215 patients during 2010-2014)., Results: A total of 6769 patients (66 ± 12 years, 5175 men) were eligible in this analysis. Predictive performance of the multinomial logistic regression models for bleeding and thrombosis assessed by calibration plots was good both in the derivation and validation cohorts. The net predicted probability (NPP) was defined as predicted probability of bleeding event (%) - predicted probability of thrombotic event (%). The NPP successfully stratified patients into those with a higher risk of bleeding than thrombosis and those with a higher risk of thrombosis than bleeding. This finding was consistent between the derivation and validation cohorts., Conclusions: We have established the risk balance assessment model for bleeding and thrombosis. Pre-procedural quick and precise assessment of the risk balance may help a decision making of procedural strategy and antithrombotic regimens in STEMI/non-STEMI patients undergoing PCI., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Y. Sotomi received research grants from Abbott Medical Japan and TOA EIYO, and speaker honoraria from Abbott Medical Japan, Boston Scientific Japan, TERUMO, Japan Lifeline, Biosensors, Medtronic, Daiichi-Sankyo, Bayer, Boehringer Ingelheim, and Bristol Myers Squibb, and is an endowed chair funded by TOA EIYO. H. Mizuno is an endowed chair funded by TERUMO, Asahi Intecc, NIPRO, and Shimadzu Corporation, and received personal fees from Medtronic Japan, Japan Lifeline, and Abbott Medical Japan. Y. Sakata received grants form Abbott Medical Japan and Biotronik. The other authors have nothing to disclose., (© 2023 The Authors.)

Background: We recently reported that nearly half of patients with heart failure with preserved ejection fraction (HFpEF) did not show echocardiographic diastolic dysfunction (DD), but had normal diastolic function (ND) or indeterminate diastolic function (ID). However, the clinical course and outcomes of patients with HFpEF with ND or ID (ND/ID) remain unknown., Methods: From the PURSUIT-HFpEF registry, we extracted 289 patients with HFpEF with ND/ID at discharge who had echocardiographic data at 1-year follow-up. Patients were classified according to the status of progression from ND/ID to DD at 1 year. Primary endpoint was a composite of all-cause death or HF rehospitalization., Results: Median age was 81 years, and 138 (47.8%) patients were female. At 1 year, 107 (37%) patients had progressed to DD. The composite endpoint occurred in 90 (31.1%) patients. Compared to patients without progression to DD, those with progression had a significantly higher cumulative rate of the composite endpoint (P < 0.001) and HF rehospitalization (P < 0.001) after discharge and at the 1-year landmark (P = 0.030 and P = 0.001, respectively). Progression to DD was independently associated with the composite endpoint (hazard ratio (HR): 2.014, 95%CI 1.239-3.273, P = 0.005) and HF rehospitalization (HR: 2.362, 95%CI 1.402-3.978) after discharge. Age (odds ratio (OR): 1.043, 95%CI 1.004-1.083, P = 0.031), body mass index (BMI) (OR: 1.110, 95%CI 1.031-1.195, P = 0.006), and albumin (OR: 0.452, 95%CI 0.211-0.969, P = 0.041) were independently associated with progression from ND/ID to DD., Conclusions: More than one-third of HFpEF patients with ND/ID progressed to DD at 1 year and had poor outcomes. Age, BMI and albumin were independently associated with this progression., Umin-Ctr Id: UMIN000021831., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany.)

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 (

The impact of changes in nutritional status during hospitalization on prognosis in patients with heart failure with preserved ejection fraction (HFpEF) remains unknown. We examined the association between changes in the Geriatric Nutritional Risk Index (GNRI) and prognosis during hospitalization in patients with HFpEF stratified by nutritional status on admission. Nutritional status did and did not worsen in 348 and 349 of 697 patients with high GNRI on admission, and in 142 and 143 of 285 patients with low GNRI on admission, respectively. Kaplan-Meier analysis revealed no difference in risk of the composite endpoint, all-cause death, or heart failure admission between patients with high GNRI on admission whose nutritional status did and did not worsen. In contrast, patients with low GNRI on admission whose nutritional status did not worsen had a significantly lower risk of the composite endpoint and all-cause death than those who did. Multivariable analysis revealed that worsening nutritional status was independently associated with a higher risk of the composite endpoint and all-cause mortality in patients with low GNRI on admission. Changes in nutritional status during hospitalization were thus associated with prognosis in patients with malnutrition on admission, but not in patients without malnutrition among those with HFpEF.

Objective: The pathophysiological heterogeneity of heart failure with preserved ejection fraction (HFpEF) makes the conventional 'one-size-fits-all' treatment approach difficult. We aimed to develop a stratification methodology to identify distinct subphenotypes of acute HFpEF using the latent class analysis., Methods: We established a prospective, multicentre registry of acute decompensated HFpEF. Primary candidates for latent class analysis were patient data on hospital admission (160 features). The patient subset was categorised based on enrolment period into a derivation cohort (2016-2018; n=623) and a validation cohort (2019-2020; n=472). After excluding features with significant missingness and high degree of correlation, 83 features were finally included in the analysis., Results: The analysis subclassified patients (derivation cohort) into 4 groups: group 1 (n=215, 34.5%), characterised by arrythmia triggering (especially atrial fibrillation) and a lower comorbidity burden; group 2 (n=77, 12.4%), with substantially elevated blood pressure and worse classical HFpEF echocardiographic features; group 3 (n=149, 23.9%), with the highest level of GGT and total bilirubin and frequent previous hospitalisation for HF and group 4 (n=182, 29.2%), with infection-triggered HF hospitalisation, high C reactive protein and worse nutritional status. The primary end point-a composite of all-cause death and HF readmission-significantly differed between the groups (log-rank p<0.001). These findings were consistent in the validation cohort., Conclusions: This study indicated the feasibility of clinical application of the latent class analysis in a highly heterogeneous cohort of patients with acute HFpEF. Patients can be divided into 4 phenotypes with distinct patient characteristics and clinical outcomes., Trial Registration Number: UMIN000021831., Competing Interests: Competing interests: YSo has received personal fees from Daiichi-Sankyo, Bayer, Boehringer Ingelheim and Bristol-Myers Squibb. SH has received grants from Roche Diagnostics, FUJIFILM Toyama Chemical, Actelion Pharmaceuticals; and personal fees from Daiichi-Sankyo, Astellas Pharma, Bayer, Pfizer Pharmaceuticals, Boehringer Ingelheim Japan, Kowa Company and Ono Pharmaceutical. DN has received personal fees from Roche Diagnostics. HM is an endowed chair lecturer supported by Asahi Intecc, Terumo Corporation, Nipro Corporation and Shimadzu Corporation, and has received personal fees from Medtronic Japan, Japan Tobacco, Pfizer Japan, Bayer Yakuhin, Japan Lifeline, Abbott Japan, Nippon Boehringer Ingelheim, Toa Eiyo, Daiichi-Sankyo and Kowa. KO has received personal fees from Bayer. YSa has received personal fees from Otsuka Pharmaceutical, Ono Pharmaceutical, Daiichi-Sankyo, Mitsubishi Tanabe Pharma, AstraZeneca and Actelion Pharmaceuticals, and grants from Roche Diagnostic, FUJIFILM Toyama Chemical, Bristol-Myers Squibb, Biosense Webster, Abbott Medical Japan, Otsuka Pharmaceutical, Daiichi-Sankyo, Mitsubishi Tanabe Pharma, Astellas Pharma, Kowa Company, Boehringer Ingelheim Japan and Biotronik., (© Author(s) (or their employer(s)) 2022. No commercial re-use. See rights and permissions. Published by BMJ.)

Background Modification of arrhythmogenic substrates with extensive ablation comprising linear and/or complex fractional atrial electrogram ablation in addition to pulmonary vein isolation (PVI-plus) can theoretically reduce the recurrence of atrial fibrillation. The DR-FLASH score (score based on diabetes mellitus, renal dysfunction, persistent form of atrial fibrillation, left atrialdiameter >45 mm, age >65 years, female sex, and hypertension) is reportedly useful for identifying patients with arrhythmogenic substrates. We hypothesized that, in patients with persistent atrial fibrillation, the DR-FLASH score can be used to classify patients into those who require PVI-plus and those for whom a PVI-only strategy is sufficient. Methods and Results This study is a post hoc subanalysis of the a multicenter, randomized controlled, noninferiority trial investigating efficacy and safety of pulmonary vein isolation alone for recurrence prevention compared with extensive ablation in patients with persistent atrial fibrillation (EARNEST-PVI trial). This analysis focuses on the relationship between DR-FLASH score and the efficacy of different ablation strategies. We divided the population into 2 groups based on a DR-FLASH score of 3 points. A total of 469 patients were analyzed. Among those with a DR-FLASH score >3 (N=279), the event rate of atrial arrhythmia recurrence was significantly lower in the PVI-plus arm than in the PVI-only arm (hazard ratio [HR], 0.45 [95% CI, 0.28-0.72]; P <0.001). In contrast, among patients with a DR-FLASH score ≤3 (N=217), no differences were observed in the event rate of atrial arrhythmia recurrence between the PVI-only arm and the PVI-plus arm (HR, 1.08 [95% CI, 0.61-1.89]; P =0.795). There was significant interaction between patients with a DR-FLASH score >3 and DR-FLASH score ≤3 ( P value for interaction=0.020). Conclusions The DR-FLASH score is a useful tool for deciding the catheter ablation strategy for patients with persistent atrial fibrillation. Registration URL: https://clinicaltrials.gov; Unique identifier: NCT03514693.

Aims: Application of the latent class analysis to acute heart failure with preserved ejection fraction (HFpEF) showed that the heterogeneous acute HFpEF patients can be classified into four distinct phenotypes with different clinical outcomes. This model-based clustering required a total of 32 variables to be included. However, this large number of variables will impair the clinical application of this classification algorithm. This study aimed to identify the minimal number of variables for the development of optimal subphenotyping model., Methods and Results: This study is a post hoc analysis of the PURSUIT-HFpEF study (N = 1095), a prospective, multi-referral centre, observational study of acute HFpEF [UMIN000021831]. We previously applied the latent class analysis to the PURSUIT-HFpEF dataset and established the full 32-variable model for subphenotyping. In this study, we used the Cohen's kappa statistic to investigate the minimal number of discriminatory variables needed to accurately classify the phenogroups in comparison with the full 32-variable model. Cohen's kappa statistic of the top-X number of discriminatory variables compared with the full 32-variable derivation model showed that the models with ≥16 discriminatory variables showed kappa value of >0.8, suggesting that the minimal number of discriminatory variables for the optimal phenotyping model was 16. The 16-variable model consists of C-reactive protein, creatinine, gamma-glutamyl transferase, brain natriuretic peptide, white blood cells, systolic blood pressure, fasting blood sugar, triglyceride, clinical scenario classification, infection-triggered acute decompensated HF, estimated glomerular filtration rate, platelets, neutrophils, GWTG-HF (Get With The Guidelines-Heart Failure) risk score, chronic kidney disease, and CONUT (Controlling Nutritional Status) score. Characteristics and clinical outcomes of the four phenotypes subclassified by the minimal 16-variable model were consistent with those by the full 32-variable model. The four phenotypes were labelled based on their characteristics as 'rhythm trouble', 'ventricular-arterial uncoupling', 'low output and systemic congestion', and 'systemic failure', respectively., Conclusions: The phenotyping model with top 16 variables showed almost perfect agreement with the full 32-variable model. The minimal model may enhance the future clinical application of this clustering algorithm., (© 2022 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

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.

Background: Women experience more severe arrhythmogenic substrates. This study hypothesized that an extensive ablation strategy, such as linear ablation and/or complex fractionated atrial electrogram (CFAE) ablation in addition to pulmonary vein isolation (PVI-plus), might be effective for women, whereas the PVI alone strategy (PVI-alone) might be sufficient for men to maintain sinus rhythm. The aim of this study was to test this hypothesis., Methods and results: This study is a post-hoc subanalysis of the EARNEST-PVI trial focusing on sex differences in the efficacies of different ablation strategies. The EARNEST-PVI trial was a prospective, multicenter, randomized, and open-label non-inferiority trial in patients with persistent AF. The primary endpoint was recurrence of AF, atrial flutter, or atrial tachycardia. The EARNEST-PVI trial randomized 376 (76%) men (PVI-alone 186, PVI-plus 190) and 121 (24%) women (PVI-alone 63, PVI-plus 58). The event rate was significantly lower for men and numerically lower for women in the PVI-plus than the PVI-alone group, and there was no interaction between men and women (hazard ratio, 0.641; 95% confidence interval, 0.417-0.985; P value, 0.043 for men vs. hazard ratio, 0.661; 95% confidence interval, 0.352-1.240; P value, 0.197 for women; P value for interaction, 0.989)., Conclusions: The superiority of the extensive ablation strategy vs. the PVI-alone strategy for persistent AF was consistent across both sexes.

Aims: As part of efforts to identify candidates for patient education aimed at decreasing mortality from acute myocardial infarction, we investigated the prevalence of pre-infarction angina and its predictors among comorbidities in patients who were hospitalized with acute myocardial infarction (MI)., Methods: We conducted a prospective multicenter observational registry of MI patients from 1998 to 2014 ( N = 12,093). The present study investigated the prevalence of pre-infarction angina and its predictors among comorbidities with a logistic regression model. Pre-infarction angina was defined as chest pain/oppression observed within 1 month before the onset of MI but which lasted <30 min., Results: After excluding 976 (8.1%) patients with missing data on pre-infarction angina, 11,117 patients [66.4 ± 12.0 years, 9,096 (75.2%) male] were analyzed. Of these, 5,428 patients (48.8%) experienced pre-infarction angina before the onset of MI, while 5,689 (51.2%) experienced sudden onset of acute MI. Most patients experienced the first episode of angina >6 h before the onset of MI, while 15% did so ≤6 h before. Patients with hypertension, diabetes, dyslipidemia, or a family history of MI had a higher probability of pre-infarction angina than those without. Elderly patients and those with a history of cerebrovascular disease were less likely to experience pre-infarction angina., Conclusions: Almost half of MI patients in our registry experienced pre-infarction angina before MI onset. Patients with hypertension, diabetes, dyslipidemia, or a family history of MI had a higher probability of experiencing pre-infarction angina than those without., Competing Interests: YSo received research grants from Abbott Medical Japan, and speaker honoraria from Abbott Medical Japan, Boston Scientific Japan, TERUMO, Japan Lifeline, Biosensors, and Medtronic, and is an endowed chair funded by TOA EIYO. YU received research grants from Abbott Medical Japan and Medtronic, and lecture fees from NIPRO. HM is an endowed chair funded by TERUMO, Asahi Intecc, NIPRO, and Shimadzu Corporation, and received personal fees from Medtronic Japan, Japan Lifeline, and Abbott Medical Japan. YasushiS received grants from Abbott Medical Japan and Biotronik. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Sotomi, Ueda, Hikoso, Okada, Dohi, Kida, Oeun, Sunaga, Sato, Kitamura, Mizuno, Nakatani, Sakata, Sato, Hori, Komuro and Sakata.)

Background: Few data are available regarding the impact of atrial fibrillation (AF) at diagnosis and type of AF during the follow-up period on long-term outcomes in patients with heart failure with preserved ejection fraction (HFpEF). Methods and Results: In all, 1,697 patients diagnosed as HFpEF between March 2010 and December 2017 were included in this study. At enrollment, 698 (41.1%) patients had AF. Over a median follow-up of 1,017 days, there were no significant differences between patients with and without AF in the adjusted hazard ratio (HR) for all-cause death or admission for heart failure. However, those with AF had a higher risk of stroke (HR 1.831; P=0.003). Of 998 patients with sinus rhythm at enrollment, 139 (13.9%) developed new-onset AF. Predictors of new-onset AF were pulse, hemoglobin, left ventricular end-diastolic dimension, and B-type natriuretic peptide. Compared with sinus rhythm, paroxysmal AF had a similar risk for all-cause death, admission for HF, and stroke; persistent AF had a lower risk of all-cause death (HR 0.701; P=0.015), but a higher risk for admission for HF (HR 1.608; P=0.002); and new-onset AF had a lower risk for all-cause death (HR 0.654; P=0.040), but a higher risk of admission for HF (HR 2.475; P<0.001). Conclusions: In patients with HFpEF, long-term outcome may differ by type of AF. Physicians need to consider individual risk with regard to AF type., Competing Interests: D.N. has received honoraria from Roche Diagnostics and grants from Bristol-Myers Squibb KK. Y. Sotomi has received honoraria from Daiichi-Sankyo, Bayer, Boehringer Ingelheim, and Bristol-Myers Squibb. H.M. has received personal fees from Daiichi Sankyo, Kowa, Bayer and Pfizer Pharmaceuticals, and grant from Terumo. S.H. has received personal fees from Daiichi Sankyo, Bayer, Bristol-Myers Squibb KK, and Boehringer Ingelheim Japan, and grants from Roche Diagnostics, FUJIFILM Toyama Chemical, and Actelion Pharmaceuticals. Y. Sakata has received personal fees from Otsuka Pharmaceutical, Ono Pharmaceutical, Daiichi Sankyo, Mitsubishi Tanabe Pharma, and Actelion Pharmaceuticals, and grants from Roche Diagnostic, FUJIFILM Toyama Chemical, Abbott Medical Japan, Otsuka Pharmaceutical, Daiichi Sankyo, Mitsubishi Tanabe Pharma, and Biotronik. The remaining authors have no conflicts of interest to disclose., (Copyright © 2022, THE JAPANESE CIRCULATION SOCIETY.)

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: 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., Methods: 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)., Results: 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, p < 0.001) 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)., Conclusions: 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., Competing Interests: Conflicts of interest All authors declare no conflicts of interest associated with this manuscript., (Copyright © 2021. Published by Elsevier Ltd.)

Background: The relationship between general obesity or abdominal obesity (abdominal circumference of ≥85 cm in men and ≥ 90 cm in women) and the heart-to-mediastinum ratio (HMR), a measure of cardiac sympathetic innervation, on cardiac iodine-123-metaiodobenzylguanidine scintigraphy (MIBG) in patients with heart failure with preserved ejection fraction (HFpEF) has not been clarified., Methods: A total of 239 HFpEF patients with both MIBG and abdominal circumference data were examined. We divided these patients into those with abdominal obesity and those without it. In the cardiac MIBG study, early phase image was acquired 15-20 min after injection, and late phase image was acquired 3 h after the early phase. A HMR obtained from a low-energy type collimator was converted to that obtained by a medium-energy type collimator., Results: Early and late HMRs were significantly lower in those with abdominal obesity, although washout rates were not significantly different. The incidence of patients with early and late HMRs <2.2 was significantly higher in those with abdominal obesity. Multivariate linear regression analysis revealed that abdominal obesity was independently associated with early HMR (standardized β = -0.253, P = 0.003) and late HMR (standardized β = -0.222, P = 0.010). Multivariate logistic regression analysis revealed that abdominal obesity was independently associated with early (odds ratio [OR] [95% confidence interval {CI}] = 4.25 [2.13, 8.47], P < 0.001) and late HMR < 2.2 (OR [95% CI] = 2.06 [1.11, 3.83], P = 0.022). Elevated BMI was not significantly associated with low early and late HMR. The presence of abdominal obesity was significantly associated with low early and late HMR even in patients without elevated BMI values., Conclusion: Abdominal obesity, but not general obesity, in HFpEF patients was independently associated with low HMR, suggesting that visceral fat may contribute to decreased cardiac sympathetic activity in patients with HFpEF., Trial Registration: UMIN000021831., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Although diastolic dysfunction is important pathophysiology in heart failure with preserved ejection fraction (HFpEF), its prognostic impact in HFpEF patients, including those with atrial fibrillation (AF), remains to be elucidated., Methods and results: We included the data for 863 patients (321 patients with AF) registered in a prospective multicenter observational study of patients with HFpEF. Patients were divided into 3 groups according to the 2016 ASE/EACVI recommendations. The primary endpoint was a composite of all-cause death or HF rehospitalization. Median age was 83 years, and 55.5% were female. 196 (22.7%) were classified with normal diastolic function (ND), 253 (29.3%) with indeterminate (ID) and 414 (48.0%) with diastolic dysfunction (DD). The primary endpoint occurred more frequently in patients with DD than in those with ND or ID (log-rank P<0.001 for DD vs. ND, and log-rank P=0.007 for DD vs. ID, respectively). Taking ND as the reference, multivariable Cox regression analysis revealed that DD (hazard ratio (HR): 1.57, 95% confidence interval (CI):1.06-2.32, P=0.024) was independently associated with the composite endpoint, whereas ID (HR: 1.28, 95% CI: 0.84-1.95, P=0.255) was not. DD was associated with the composite endpoint in both patients with and without AF., Conclusions: HFpEF patients classified with DD using the 2016 ASE/EACVI recommendations had worse clinical outcomes than those with ND or ID. DD may be considered a prognostic marker in patients with HFpEF regardless of AF.

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&#95;e/ctr&#95;view.cgi?recptno=R000005464. Unique identifier: UMIN000004575.

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.)

Objective: The semiquantitative urine dipstick test is a simple and convenient method that is available in the smallest community-based healthcare clinics. We sought to clarify the prognostic significance of dipstick proteinuria in patients with heart failure (HF) with preserved ejection fraction (HFpEF)., Design: A P rospective m U lticente R ob S ervational st U dy of pat I en T s with H eart F ailure with p reserved E jection F raction (PURSUIT-HFpEF) registry., Participants and Setting: We assessed 851 discharged-alive patients in the PURSUIT-HFpEF registry who were initially hospitalised due to an acute decompensated HFpEF (EF≥50%) and elevated N-terminal-pro-brain natriuretic peptide (≥400 ng/L) at Osaka University Hospital and other 30 affiliated hospitals in the Kansai region of Japan. Patients received a urine dipstick test, and were divided into two groups according to the absence or presence of proteinuria. A trace or more of dipstick proteinuria was defined as the presence of proteinuria., Main Outcome Measures: A composite of cardiac death or HF rehospitalisation., Results: Median age was 83 years and 473 patients (55.6%) were female. Five hundred and two patients (59%) were proteinuria (-) and 349 patients (41%) were proteinuria (+). The composite endpoint and HF rehospitalisation occurred more often in proteinuria (+) individuals than proteinuria (-) individuals (log-rank p=0.006 and p=0.007, respectively); but cardiac death did not (log-rank p=0.139). Multivariable Cox regression analysis showed that the presence of proteinuria was associated with the composite endpoint (HR: 1.47, 95% CI 1.07 to 2.01, p=0.016), and HF rehospitalisation (HR: 1.48, 95% CI 1.07 to 2.05, p=0.020), but not with cardiac death (HR: 1.52, 95% CI 0.83 to 2.76, p=0.172)., Conclusions: Dipstick proteinuria may be a prognostic marker in patients with HFpEF. Evaluation of proteinuria by a urine dipstick test may be a simple but useful method for risk stratification in HFpEF., Umin-Ctr Id: UMIN000021831., Competing Interests: Competing interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: SH reports a relationship with Daiichi Sankyo Company, Bayer, Astellas Pharma, Pfizer Pharmaceuticals and Boehringer Ingelheim Japan that includes: speaking and lecture fees. SH reports a relationship with Roche Diagnostics, FUJIFILM Toyama Chemical and Actelion Pharmaceuticals that includes: funding grants. ND reports a relationship with Roche Diagnostics that includes: speaking and lecture fees. HM reports a relationship with Daiichi Sankyo Company, Kowa Company, Bayer and Pfizer Pharmaceuticals that includes: speaking and lecture fees. HM reports a relationship with Terumo that includes: funding grants. YS reports a relationship with Abbott Vascular Japan, Boston Scientific Japan, TERUMO, Japan Lifeline, Biosensors, Medtronic, Daiichi-Sankyo, Bayer, Boehringer Ingelheim, and Bristol-Myers Squibb that includes: funding grants and speaking and lecture fees. YS reports a relationship with TERUMO, Asahi Intecc, NIPRO, and Shimadzu Corporation that includes: consulting or advisory. YS reports a relationship with Otsuka Pharmaceutical, Ono Pharmaceutical, Daiichi Sankyo Company, Mitsubishi Tanabe Pharma Corporation and Actelion Pharmaceuticals that includes: speaking and lecture fees. YS reports a relationship with Roche Diagnostic, FUJIFILM Toyama Chemical, Abbott Medical Japan, Otsuka Pharmaceutical, Daiichi Sankyo Company, Mitsubishi Tanabe Pharma Corporation and Biotronik that includes: funding grants. YS reports financial support was provided by Japan Society for the Promotion of Science. YS reports financial support was provided by Japan Agency for Medical Research and Development., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Recurrence rates of atrial fibrillation (AF) after pulmonary vein isolation (PVI) are higher in patients with a left atrial low-voltage area (LVA) than those without. However, the efficacy of LVA guided ablation is still unknown. The purpose of this study-the Efficacy and Safety of Left Atrial Low-voltage Area Guided Ablation for Recurrence Prevention Compared to Pulmonary Vein Isolation Alone in Patients with Persistent Atrial Fibrillation trial (SUPPRESS-AF trial)-is to elucidate whether LVA guided ablation in addition to PVI is superior to PVI alone in patients with persistent AF. The Osaka Cardiovascular Conference will conduct a multicenter, randomized, open-label trial aiming to examine whether LVA guided ablation in addition to PVI is superior to PVI alone in patients with persistent AF and LVAs. The primary outcome is the recurrence of AF documented by scheduled or symptom-driven electrocardiography (ECG) during the 1 year follow-up period after the index ablation. The key secondary endpoints include all-cause death, symptomatic stroke, bleeding events, and other complications related to the procedure. A total of 340 patients with an LVA will be enrolled and followed up to 1 year. The SUPPRESS-AF trial is a randomized controlled trial designed to assess whether LVA guided ablation in addition to PVI is superior to PVI alone for patients with persistent AF and LVAs detected while undergoing their first catheter ablation., (© 2021 The Authors. Clinical Cardiology published by Wiley Periodicals LLC.)

Aims: Frailty is associated with prognosis of cardiovascular diseases. However, the significance of frailty in patients with heart failure with preserved ejection fraction (HFpEF) remains to be elucidated. The purpose of this study was to examine the prognostic significance of the Clinical Frailty Scale (CFS) in real-world patients with HFpEF using data from a prospective multicentre observational study of patients with HFpEF (PURSUIT-HFpEF study)., Method and Results: We classified 842 patients with HFpEF enrolled in the PURSUIT-HFpEF study into two groups using CFS. The registry enrolled patients hospitalized with a diagnosis of decompensated heart failure. Median age was 82 [interquartile range: 77, 87], and 45% of the patients were male. Of 842 patients, 406 were classified as high CFS (CFS ≥ 4, 48%) and 436 as low CFS (CFS ≤ 3, 52%). The primary endpoint was the composite of all-cause mortality and heart failure admission. Secondary endpoints were all-cause mortality and heart failure admission. Patients with high CFS were older (85 vs. 79 years, P < 0.001), predominantly female (65% vs. 46%, P < 0.001) and more likely to have New York Heart Association (NYHA) ≥ 2 (75% vs. 53%, P < 0.001) and a higher level of NT-proBNP (1360 vs 838 pg/mL, P < 0.001) than those with low CFS. Patients with high CFS had a significantly greater risk of composite endpoint (Kaplan-Meier estimated 1-year event rate 39% vs. 23%, log-rank P < 0.001), all-cause mortality (Kaplan-Meier estimated 1-year event rate 17% vs. 7%, log-rank P < 0.001) and heart failure admission (Kaplan-Meier estimated 1-year event rate 28% vs. 19%, log-rank P = 0.002) than those with low CFS. Multivariable Cox regression analysis revealed that high CFS was significantly associated with composite endpoint (adjusted HR 1.92, 95% CI 1.35-2.73, P < 0.001), all-cause mortality (adjusted HR 2.54, 95% CI 1.39-4.66, P = 0.003) and heart failure admission (adjusted HR 1.55, 95% CI 1.03-2.32, P = 0.035) even after adjustment for covariates. Moreover, change in CFS grade was also significantly associated with composite endpoint (adjusted HR 1.23, 95% CI 1.11-1.36, P < 0.001), all-cause mortality (adjusted HR 1.32, 95% CI 1.13-1.55, P = 0.001) and heart failure admission (adjusted HR 1.15, 95% CI 1.02-1.30, P = 0.021)., Conclusions: Frailty assessed by the CFS was associated with poor prognosis in patients with HFpEF., (© 2021 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Differences in guiding catheters (GCs) manipulations and selections among different access sites are currently unclear. We examined the differences in the routes of GCs for the left coronary artery (LCA) among the right radial, left radial, and femoral approaches. We used a combined angiography-computed tomography (CT) system that enabled to perform CT scans during percutaneous coronary intervention (PCI). We enrolled 88 patients who underwent CT scans during LCA PCI or percutaneous transluminal septal myocardial ablation. To evaluate the route of GCs, we analyzed the positions of the catheter's contact point on the contralateral aortic wall to the LCA ostium, which were expressed by the angle formed by the vertical line and the diagonal line from the GC shaft to the center of the aorta. The procedures were performed via the right radial in 47 cases, left radial in 20, and femoral approach in 21. The positions of the catheter's contact point were significantly different depending on the approaches (interquartile range - 3.7 [- 14.3 to 7.8], - 46.5 [- 76.9 to - 9.3], and - 30.7 [- 39.4 to - 22.4] degrees, respectively; p < 0.001). Multivariate analysis demonstrated that access sites and LCA ostium locations had significant impacts on the positions of the catheter's contact point. The routes of LCA GCs were different among the right radial, left radial, and femoral approaches.

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.

Background: Estimated plasma volume status (ePVS) is a well-validated prognostic indicator in heart failure. However, it remains unclear whether ePVS has prognostic significance in patients with acute myocardial infarction (AMI). Moreover, there is no available information on its additive effect with the Global Registry of Acute Coronary Events (GRACE) risk score in AMI patients., Methods: Data were obtained from the Osaka Acute Coronary Insufficiency Study (OACIS) registry database. Patients whose data were available for ePVS derived from Hakim's formula and the GRACE risk score were studied. The primary endpoints were in-hospital and 5-year mortality., Results: Of 3930 patients, 206 and 200 patients died during hospitalization and 5 years after discharge, respectively. After adjustment, ePVS remained an independent predictor of in-hospital death (OR:1.02, 95% CI: 1.00-1.04, p = 0.036), and 5-year mortality(HR:1.03, 95% CI: 1.01-1.04, p < 0.001). An additive effect of ePVS with the GRACE risk score was observed in predicting the 5-year mortality with an area under the receiver operating characteristic curve (AUC) from 0.744 to 0.763 (p = 0.026), but not in-hospital mortality (the AUC changed from 0.875 to 0.875, p = 0.529). The incremental predictive value of combining ePVS and the GRACE risk score for 5-year mortality was significantly improved, as shown by the net reclassification improvement (NRI:0.378, p < 0.001) and integrated discrimination improvement (IDI:0.014, p < 0.001)., Conclusions: In patients with AMI, ePVS independently predicted in-hospital and long-term mortality. In addition, ePVS had an additive effect with the GRACE risk score on long-term mortality. Therefore, ePVS may be useful for identifying high-risk subjects for intensive treatment., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2021 Published by Elsevier B.V.)

Background The female preponderance in heart failure with preserved ejection fraction (HFpEF) is a distinguishing feature of this disorder, but the association of sex with degree of diastolic dysfunction and clinical outcomes among individuals with HFpEF remains unclear. Methods and Results We conducted a prospective, multicenter, observational study of patients with HFpEF (PURSUIT-HFpEF [Prospective Multicenter Observational Study of Patients with Heart Failure with Preserved Ejection Fraction]: UMIN000021831). Between 2016 and 2019, 871 patients were enrolled from 26 hospitals (follow-up: 399±349 days). We investigated sex-related differences in diastolic dysfunction and postdischarge clinical outcomes in patients with HFpEF. The echocardiographic end point was diastolic dysfunction according to American Society of Echocardiography/European Association of Cardiovascular Imaging criteria. The clinical end point was a composite of all-cause death and heart failure readmission. Women accounted for 55.2% (481 patients) of the overall cohort. Compared with men, women were older and had lower prevalence rates of hypertension, coronary artery disease, and chronic kidney disease. Women had diastolic dysfunction more frequently than men (52.8% versus 32.0%, P <0.001). The incidence of the clinical end point did not differ between women and men (women 36.1/100 person-years versus men 30.5/100 person-years, P =0.336). Female sex was independently associated with the echocardiographic end point (adjusted odds ratio, 2.839; 95% CI, 1.884-4.278; P <0.001) and the clinical end point (adjusted hazard ratio, 1.538; 95% CI, 1.143-2.070; P =0.004). Conclusions Female sex was independently associated with the presence of diastolic dysfunction and worse clinical outcomes in a cohort of elderly patients with HFpEF. Our results suggest that a sex-specific approach is key to investigating the pathophysiology of HFpEF. Registration URL: https://upload.umin.ac.jp; Unique identifier: UMIN000021831.

Introduction: Neither the pathophysiology nor an effective treatment for heart failure with preserved ejection fraction (HFpEF) has been elucidated to date. The purpose of this ongoing study is to elucidate the pathophysiology and prognostic factors for patients with HFpEF admitted to participating institutes. We also aim to obtain insights into the development of new diagnostic and treatment methods by analysing patient background factors, clinical data and follow-up information., Methods and Analysis: This study is a prospective, multicentre, observational study of patients aged ≥20 years admitted due to acute decompensated heart failure with preserved left ventricular ejection fraction (≥50%) and elevated N-terminal-pro brain natriuretic peptide (NT-proBNP) (≥400 pg/mL). The study began in June 2016, with the participation of Osaka University Hospital and 31 affiliated facilities. We will collect data on history in detail, accompanying diseases, quality of life, frailty score, medication history, and laboratory and echocardiographic data. We will follow-up each patient for 5 years, and collect outcome data on mortality, cause of death, and the number and cause of hospitalisation. The target number of registered cases is 1500 cases in 5 years., Ethics and Dissemination: The protocol was approved by the Institutional Review Board (IRB) of Osaka University Hospital on 24 February 2016 (ID: 15471), and by the IRBs of the all participating facilities. The findings will be disseminated through peer-reviewed publications and conference presentations., Competing Interests: Competing interests: SS has received personal fees from Nihon Medi-Physics and FUJIFILM Toyama Chemical. SH has received personal fees from Daiichi Sankyo Company, Bayer, Astellas Pharma, Pfizer Pharmaceuticals and Boehringer Ingelheim Japan, and grants from Roche Diagnostics, FUJIFILM Toyama Chemical and Actelion Pharmaceuticals. AN has received personal fees from AstraZeneca and Otsuka Pharmaceutical. YM has a leadership position and stock of MKS, and has received a grant from MKS. HM has received personal fees from Daiichi Sankyo Company, Kowa Company, Bayer and Pfizer Pharmaceuticals, and a grant from Terumo. DN has received a personal fee from Daiichi Sankyo Company. YS has received personal fees from Otsuka Pharmaceutical, Ono Pharmaceutical, Daiichi Sankyo Company, Mitsubishi Tanabe Pharma Corporation and Actelion Pharmaceuticals, and grants from Roche Diagnostic, FUJIFILM Toyama Chemical, Abbott Medical Japan, Otsuka Pharmaceutical, Daiichi Sankyo Company, Mitsubishi Tanabe Pharma Corporation and Biotronik., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Anticoagulation for patients with atrial fibrillation (AF) complicated by left atrial thrombi (LAT) is a frequent cause of bleeding complications, but risk factors remain unknown. Methods and Results: Of 3,139 AF patients who underwent transesophageal echocardiography, 82 with LAT under anticoagulation were included in this study. Patients treated with combination antiplatelet and anticoagulant therapy (n=31) were compared with those receiving anticoagulant monotherapy (n=51) to investigate the effects of antiplatelet agents during anticoagulation on bleeding complications. Over a mean (±SD) follow-up of 878±486 days, bleeding events occurred more frequently in the combination therapy than monotherapy group (58% vs. 20%; P<0.001), but there was no significant difference in embolic events (6.5% vs. 3.9%; P=0.606). Kaplan-Meier analysis also showed a significantly higher rate of bleeding events in the combination therapy group, but no significant difference in the rate of embolic events. Inverse probability of treatment weighting revealed that combination therapy was independently associated with an increased risk of bleeding (hazard ratio [HR] 2.98, 95% confidence interval [CI] 1.14-7.89, P=0.026), but not with the risk of embolic events (HR 0.30, 95% CI 0.04-2.59, P=0.275). Net clinical benefit analysis was almost negative for combination therapy vs. monotherapy. Conclusions: In patients with AF and LAT, combination therapy was significantly associated with an increased risk of bleeding events, but not with a reduced risk of embolic events., Competing Interests: S.H., K.I., A.H., M.M., Y.F., T.W., and H. Minamiguchi have received remuneration from Boehringer Ingelheim and Bayer. D.N. has received remuneration from Boehringer Ingelheim and Sanofi. Y.O. has received remuneration from Boehringer Ingelheim. K.K. has received remuneration from Boehringer Ingelheim, Bayer, and Sanofi. H. Mizuno has received remuneration from Boehringer-Ingelheim and Bayer, as well as research funding from Boehringer-Ingelheim. T. Kitamura has received remuneration from Bayer. Y.S. has received remuneration from Eizai, Boehringer-Ingelheim, Bayer, and Sanofi, served as a consultant to Boehringer-Ingelheim, Bayer, and Sanofi, holds patents with Eizai, Boehringer-Ingelheim, Bayer, and Sanofi, and has received research funding from Eizai, Bayer, and Sanofi. K.I. is a member of Circulation Reports ’ Editorial Team. The remaining authors have no conflicts of interest to report., (Copyright © 2020, THE JAPANESE CIRCULATION SOCIETY.)

Background: Little is known about factors associated with elevated N-terminal pro B-type natriuretic peptide (NT-proBNP) at the convalescent stage and their effects on 1-year outcomes in patients with heart failure with preserved ejection fraction (HFpEF). Methods and Results: This study included 469 patients with HFpEF. Elevated NT-proBNP was defined as the highest quartile. The first 3 quartiles (Q1-Q3) were combined together for comparison with the fourth quartile (Q4). Median NT-proBNP concentrations in Q1-Q3 and Q4 were 669 and 3,504 pg/mL, respectively. Multivariate logistic regression analysis revealed that low albumin (odds ratio [OR] 2.44; 95% confidence interval [CI] 1.35-4.39; P=0.003), low estimated glomerular filtration rate (OR 5.83; 95% CI 3.46-9.83; P<0.001), high C-reactive protein (OR 2.09; 95% CI 1.21-3.63; P=0.009), and atrial fibrillation at discharge (OR 2.33; 95% CI 1.40-3.89; P=0.001) were associated with elevated NT-proBNP. Cumulative rates of all-cause mortality and heart failure rehospitalization were significantly higher in Q4 than in Q1-Q3 (P=0.001 and P<0.001, respectively). Incidence and hazard ratios of these adverse events increased when the number of associated factors for elevated NT-proBNP clustered together (P<0.001 and P=0.002, respectively). Conclusions: In addition to atrial fibrillation, extracardiac factors (malnutrition, renal impairment and inflammation) were associated with elevated NT-proBNP at the convalescent stage, and led to poor prognosis in patients with HFpEF., Competing Interests: D.N. has received honoraria from Roche Diagnostics K.K.; S.H. and Y.S. have received grant support from Roche Diagnostics K.K. and Fuji Film Toyama Chemical. The other authors have no conflicts of interest to declare., (Copyright © 2020, THE JAPANESE CIRCULATION SOCIETY.)

Background: Studies comparing the cardiac consequences of hydrophilic and lipophilic statins in experimental and clinical practice settings have produced inconsistent results. In particular, evidence focusing on diabetic patients after acute myocardial infarction (AMI) is lacking. Methods and Results: From the Osaka Acute Coronary Insufficiency Study (OACIS) registry database, 1,752 diabetic patients with AMI who were discharged with a prescription for statins were studied. Long-term outcomes were compared between hydrophilic and lipophilic statins, including all-cause death, recurrent myocardial infarction (re-MI) and admission for heart failure (HF) and a composite of these (major adverse cardiac events; MACE). During a median follow-up period of 1,059 days, all-cause death, non-fatal re-MI, admission for HF, and MACE occurred in 95, 89, 112 and 249 patients, respectively. Although there was no significant difference between statins in the risk of all-cause death, re-MI and MACE, the risk of HF admission was significantly lower in patients with hydrophilic than lipophilic statins before (adjusted hazard ratio [aHR], 0.560; 95% CI: 0.345-0.911, P=0.019) and after (aHR, 0.584; 95% CI: 0.389-0.876, P=0.009) propensity score matching. Hydrophilic statin use was consistently associated with lower risk for HF admission than lipophilic statins across the subgroup categories. Conclusions: In the present diabetic patients with AMI, hydrophilic statins were associated with a lower risk of admission for HF than lipophilic statins., Competing Interests: Yasuhiko S. has received honoraria from Kowa. S.H. has received honoraria from Kowa and Daiichi-Sankyo. H.M. has received honoraria from Daiichi-Sankyo. T. Kitamura has received honoraria from AstraZeneca and Bristol-Myers Squibb. A.S. has received honoraria from Daiichi-Sankyo. M.H. has received honoraria from Boehringer-Ingelheim, Bayer, and Tanabe-Mitsubishi Pharma. I.K. has received honoraria from Pfizer, Daiichi-Sankyo, and MSD, and research grants from Kowa, Astellas, Daiichi-Sankyo and Mitsubishi Tanabe Pharma. Yasushi S. has received honoraria from Pfizer, Daiichi-Sankyo, Bristol-Myers Squibb, Kowa, Mitsubishi Tanabe Pharma, Astellas, MSD, Shionogi, AstraZeneca, and Novartis. Yasuhiko S., I.K. are members of Circulation Reports’ Editorial Team. The other authors declare no conflicts of interest., (Copyright © 2020, THE JAPANESE CIRCULATION SOCIETY.)

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., (Copyright © 2019 Elsevier Inc. All rights reserved.)