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

Objectives : Coronary microvascular dysfunction (CMD) is associated with many heart diseases, including heart failure (HF) with preserved ejection fraction (HFpEF). Invasive examinations for CMD detection are difficult in older patients with HFpEF, and the decision criteria for noninvasive CMD measurements are unclear. We aimed to identify alternative factors in the possible involvement of CMD in the progression and prognosis of HFpEF. Methods : We analyzed 607 patients with HFpEF who were hospitalized for acute decompensated HF without a history of coronary artery disease (CAD). Blood tests and transthoracic echocardiography were performed. We focused on left ventricular hypertrophy (LVH) and coronary perfusion pressure (diastolic blood pressure, dBP). Results : The patients with LVH showed reduced diastolic function (E/e') and a lower incidence of atrial fibrillation (AF) compared with those without LVH, with no differences in age or dBP. No differences were observed in all-cause mortality between patients with low and high dBP without LVH. In the patients with LVH, the incidence of all-cause mortality was significantly higher, with a lower incidence of AF, reduced renal function, and higher C-reactive protein levels in those with low dBP than in those with high dBP. The comprehensive diastolic functional index, diastolic elastance/arterial elastance, was markedly higher in the patients with LVH, especially in those with all-cause mortality. This index, but not E/e', was a significant prognostic index in the multivariate Cox hazard analysis when adjusting for age, sex and N-terminal pro-brain natriuretic peptide levels. Conclusions : LVH and dBP were clinically important factors in elderly HFpEF patients without a history of CAD.

Aims: Anaemia has been reported as poor predictor in heart failure with preserved ejection fraction (HFpEF). The aim of this study was to evaluate the impact of changes in haemoglobin (Hb) from discharge to 1 year after discharge on the prognosis using a lower cut-off value of Hb than the World Health Organization (WHO) criteria., Methods and Results: First, 547 HFpEF cases were divided into two groups, Hb < 11.0 g/dL (n = 218) and Hb ≥ 11.0 g/dL (n = 329), according to Hb at discharge, and further were divided according to Hb 1 year after discharge into Hb < 11.0 g/dL (G1, n = 113), Hb ≥ 11.0 g/dL (G2, n = 105), Hb < 11.0 g/dL (G3, n = 66), and Hb ≥ 11.0 g/dL (G4, n = 263), respectively. Major adverse cardiovascular events (MACE) was defined as composite of all-cause death and heart failure readmission after a visit 1 year after discharge. The cut-off value of Hb was analysed by the receiver operating characteristics curve that predicts MACE. We examined the incidence rate of MACE between G4 and other subgroups and verified predictors of improving or worsening anaemia and covarying factors with change in Hb. In multivariate Cox proportional hazard model, MACE was significantly higher in G3 with worsening anaemia from Hb ≥ 11.0 g/dL to <11.0 g/dL than G4 with persistently Hb ≥ 11 g/dL (adjusted hazard ratio (HR): 3.14 [95% confidence interval (CI), 1.76-5.60], P < 0.001). MACE was not significantly different between G2 with improving anaemia from Hb < 11.0 g/dL to ≥ 11.0 g/dL and G4 (adjusted HR: 1.37 [95% CI, 0.68-2.75], P = 0.38). In multivariate logistic regression analysis, independent predictors of improving anaemia were male [odds ratio (OR): 0.45], chronic obstructive pulmonary disease (OR: 10.3), prior heart failure hospitalization (OR: 0.38), and estimated glomerular filtration rate (OR: 1.04). Independent predictors of worsening anaemia were age (OR: 1.07), body mass index (BMI) (OR: 0.86), clinical frailty scale score (OR: 1.29), Hb at discharge (OR: 0.63), and use of angiotensin-converting-enzyme inhibitor or angiotensin II receptor blocker (OR: 2.76). In multivariate linear regression analysis, covarying factors with change in Hb were BMI (β = -0.098), serum albumin (β = 0.411), and total cholesterol (β = 0.179)., Conclusions: Change in haemoglobin after discharge using a lower cut-off value than WHO criteria has prognostic impact in patients with HFpEF., (© 2024 The Author(s). ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Background: In patients with persistent atrial fibrillation (AF), extensive ablation for substrate modification, such as linear ablation or complex fractionated atrial electrogram ablation in addition to pulmonary vein isolation (PVI) remains controversial. Previous studies investigating extensive ablation have demonstrated its varying efficacy, suggesting the possible heterogeneity of its efficacy. Aging is a major risk factor for AF and is associated with atrial remodeling. We aimed to compare the efficacy and safety of the extensive ablation strategy compared with PVI alone strategy between young and elderly patients., Methods: This study is a post-hoc analysis of the multicenter, randomized controlled, noninferiority trial investigating the efficacy and safety of PVI-only (PVI-alone arm) compared with extensive ablation (PVI-plus arm) in patients with persistent AF (EARNEST-PVI trial). We divided the overall population into 2 groups based on age and assessed treatment effects., Results: In the young group (age <65 years, N = 206), there was no significant difference in the recurrence rate between the PVI-alone group and PVI-plus group [hazard ratio (HR): 1.00, 95 % CI: 0.57-1.73, p = 0.987], whereas the recurrence rate was significantly lower in the PVI-plus group compared to the PVI-alone group in the elderly group (age ≥65 years, N = 291) (HR: 0.47, 95 % CI: 0.29-0.76, p = 0.0021) (p for interaction = 0.0446). There were no fatal procedural complications., Conclusion: In patients with persistent AF, the extensive ablation strategy was more effective than the PVI-alone strategy in elderly patients, while the effectiveness of both approaches was comparable in young patients., Trial Registration: URL: https://clinicaltrials.gov; Unique identifier: NCT03514693. URL: https://center6.umin.ac.jp/cgi-open-bin/ctr&#95;e/ctr&#95;view.cgi?recptno=R000022454 Unique ID issued by UMIN: UMIN000019449., Competing Interests: Declaration of competing interest Y. Sotomi has received grants from Roche Diagnostics, FUJIFILM Toyama Chemical, TOA EIYO, Bristol-Myers Squibb, Biosense Webster, Abbott Medical Japan, and NIPRO, and personal fees from Abiomed, Abbott Medical Japan, AstraZeneca, Amgen Astellas BioPharma, Biosensors, Boehringer Ingelheim, Bristol-Myers Squibb, Boston Scientific Japan, Bayer, Daiichi Sankyo, Eli Lilly, Novartis, TERUMO, Medtronic, and Pfizer Pharmaceuticals. S. Hikoso has received grants from Roche Diagnostics, FUJIFILM Toyama Chemical, Actelion Pharmaceuticals; and personal fees from AstraZeneca, Daiichi Sankyo, Astellas Pharma, Bayer, Pfizer Pharmaceuticals, Boehringer Ingelheim Japan, Kowa Company, and Ono Pharmaceutical. D. Nakatani has received personal fees from Roche Diagnostics. T. Dohi has received grants from Medtronic, Johnson & Johnson, and Abbott, during the conduct of the study. A. Sunaga has received grants from Medtronic, Johnson & Johnson, and Abbott, during the conduct of the study and personal fees from Bayer, Daiichi Sankyo, and Medtronic, outside the submitted work. M. Masuda has received personal fees from Bayer, Bristol-Myers Squibb, Boehringer Ingelheim, Daiichi Sankyo, Johnson & Johnson, Boston Scientific, Abbott, Nihon Kohden, Otsuka Pharmaceutical, AstraZeneca, and Medtronic, outside the submitted work. T. Watanabe has received personal fees from Biosense Webster, Abbott, Bristol-Myers Squibb, Pfizer, Boehringer Ingelheim, Bayer, Daiichi Sankyo, Nihon Kohden, and Fukuda Denshi, outside the submitted work. H. Minamiguchi has received grants from Medtronic, Johnson & Johnson, and Abbott, during the conduct of the study, and personal fees from Medtronic, Abbott, Johnson & Johnson, Nihon Kohden, Biotronik, Japan Lifeline, Daiichi Sankyo, Bayer, Pfizer, Squibb, Boehringer Ingelheim, Kowa, Ono Pharmaceutical, and Otsuka Pharmaceutical, outside the submitted work. Y. Egami has received personal fees from Japan Lifeline and Medtronic, and non-financial support from Johnson & Johnson, Abbott, and Medtronic, outside the submitted work; T. Oka has received personal fees from Medtronic, Biotronik, Abbott, Daiichi Sankyo, Beyer, Bristol-Myers Squibb, Boehringer Ingelheim, MSD, and AstraZeneca, outside the submitted work. Y. Matsuda has received personal fees from Daiichi Sankyo, Boehringer Ingelheim, Bayer, Medtronic, and Biotronik, outside the submitted work. M. Kawasaki has received personal fees from Medtronic, Bayer, Boehringer Ingelheim, Daiichi Sankyo, Bristol-Myers Squibb, and Abbott, and grants from Osaka Heart Club, outside the submitted work. K. Inoue has received personal fees from Bayer, Bristol-Myers Squibb, Boehringer Ingelheim, Daiichi Sankyo, Johnson & Johnson, and Medtronic, outside the submitted work. Y. Sakata has received personal fees from Otsuka Pharmaceutical, Ono Pharmaceutical, Daiichi Sankyo, Mitsubishi Tanabe Pharma Corporation, AstraZeneca K.K. and Actelion Pharmaceuticals, and grants from Roche Diagnostic, FUJIFILM Toyama Chemical, Bristol-Myers Squibb, Co, Biosense Webster, Inc., Abbott Medical Japan, Otsuka Pharmaceutical, Daiichi Sankyo Company, Mitsubishi Tanabe Pharma Corporation, Astellas Pharma, Kowa Company, Boehringer Ingelheim Japan, and Biotronik. Other authors have nothing to disclose., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: The relationship between baseline yellow plaque (YP) and vascular response after stent implantation has not been fully investigated., Methods: This was a sub-analysis of the Collaboration-1 study (multicenter, retrospective, observational study). A total of 88 lesions from 80 patients with chronic coronary syndrome who underwent percutaneous coronary intervention were analyzed. Optical coherence tomography (OCT) and coronary angioscopy (CAS) were serially performed immediately and 11 months after stent implantation. YP was defined as the stented segment with yellow or intensive yellow color assessed by CAS. Neoatherosclerosis was defined as a lipid or calcified neointima assessed by OCT. OCT and CAS findings at 11 months were compared between lesions with baseline YP (YP group) and lesions without baseline YP (Non-YP group)., Results: Baseline YP was detected in 37 lesions (42 %). OCT findings at 11 months showed that the incidence of neoatherosclerosis was significantly higher in the YP group (11 % versus 0 %, p = 0.028) and mean neointimal thickness tended to be lower (104 ± 43 μm versus 120 ± 48 μm, p = 0.098). CAS findings at 11 months demonstrated that the dominant and minimum neointimal coverage grades were significantly lower (p = 0.049 and P = 0.026) and maximum yellow color grade was significantly higher (p < 0.001) in the YP group., Conclusions: Baseline YP affected the incidence of neoatherosclerosis as well as poor neointimal coverage at 11 months after stent implantation., Competing Interests: Declaration of competing interest Isamu Mizote has received a scholarship fund from Abbott Medical Japan. Toshiaki Mano has received a research grant from Abbott Medical Japan and Biosensors Japan. Yasushi Sakata has received a scholarship fund from Abbott Medical Japan. The remaining authors have no conflicts of interest to declare., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Extensive ablation in addition to pulmonary vein isolation (PVI) in patients with persistent atrial fibrillation (AF) has not yielded consistent results, indicating diversity in their efficacy. Mitral regurgitation (MR) associated with AF may indicate a higher prevalence of arrhythmogenic substrate, suggesting potential benefits of extensive ablation for these patients., Methods: This post-hoc analysis of the EARNEST-PVI trial compared PVI alone versus an extensive ablation strategy (PVI-plus) in persistent AF patients, stratified by MR presence. The primary endpoint of the study was the recurrence of AF. The secondary endpoints included death, cerebral infarction, and procedure-related complications., Results: The trial included 495 eligible patients divided into MR and non-MR groups. The MR group consisted of 192 patients (89 in the PVI-alone arm and 103 in the PVI-plus arm), while the non-MR group had 303 patients (158 in the PVI-alone arm and 145 in the PVI-plus arm). In the non-MR group, recurrence rates were similar between PVI-alone and PVI-plus arms (Log-rank P = 0.47, Hazard ratio = 0.85 [95%CI: 0.54-1.33], P = 0.472). However, in the MR group, PVI-plus was significantly more effective in preventing AF recurrence (Log-rank P = 0.0014, Hazard ratio = 0.40 [95%CI: 0.22-0.72], P = 0.0021). No significant differences were observed in secondary endpoints between the two arms., Conclusions: For persistent AF patients with mild or greater MR, receiving PVI-plus was superior to PVI-alone in preventing AF recurrence. Conversely, for patients without MR, the effectiveness of extensive ablation was not demonstrated. These findings suggest tailoring ablation strategies based on MR presence can lead to better outcomes in AF management., Competing Interests: Declaration of competing interest Y. Sotomi has received grants from Roche Diagnostics, FUJIFILM Toyama Chemical, TOA EIYO, Bristol-Myers Squibb, Biosense Webster, Abbott Medical Japan, and NIPRO, and personal fees from Abiomed, Abbott Medical Japan, AstraZeneca, Amgen Astellas BioPharma, Biosensors, Boehringer Ingelheim, Bristol-Myers Squibb, Boston Scientific Japan, Bayer, Daiichi Sankyo, Eli Lilly, Novartis, TERUMO, Medtronic, and Pfizer Pharmaceuticals. S. Hikoso has received grants from Roche Diagnostics, FUJIFILM Toyama Chemical, Actelion Pharmaceuticals; and personal fees from AstraZeneca, Daiichi Sankyo, Astellas Pharma, Bayer, Pfizer Pharmaceuticals, Boehringer Ingelheim Japan, Kowa Company, and Ono Pharmaceutical. D. Nakatani has received personal fees from Roche Diagnostics. T. Dohi has received grants from Medtronic, Johnson & Johnson, and Abbott, during the conduct of the study. A. Sunaga has received grants from Medtronic, Johnson & Johnson, and Abbott, during the conduct of the study and personal fees from Bayer, Daiichi Sankyo, and Medtronic, outside the submitted work. M. Masuda has received personal fees from Bayer, Bristol-Myers Squibb, Boehringer Ingelheim, Daiichi Sankyo, Johnson & Johnson, Boston Scientific, Abbott, Nihon Kohden, Otsuka Pharmaceutical, AstraZeneca, and Medtronic, outside the submitted work. T. Watanabe has received personal fees from Biosense Webster, Abbott, Bristol-Myers Squibb, Pfizer, Boehringer Ingelheim, Bayer, Daiichi Sankyo, Nihon Kohden, and Fukuda Denshi, outside the submitted work. H. Minamiguchi has received grants from Medtronic, Johnson & Johnson, and Abbott, during the conduct of the study, and personal fees from Medtronic, Abbott, Johnson & Johnson, Nihon Kohden, Biotronik, Japan Lifeline, Daiichi Sankyo, Bayer, Pfizer, Squibb, Boehringer Ingelheim, Kowa, Ono Pharmaceutical, and Otsuka Pharmaceutical, outside the submitted work. Y. Egami has received personal fees from Japan Lifeline and Medtronic, and non-financial support from Johnson & Johnson, Abbott, and Medtronic, outside the submitted work; T. Oka has received personal fees from Medtronic, Biotronik, Abbott, Daiichi Sankyo, Beyer, Bristol-Myers Squibb, Boehringer Ingelheim, MSD, and AstraZeneca, outside the submitted work. Y. Matsuda has received personal fees from Daiichi Sankyo, Boehringer Ingelheim, Bayer, Medtronic, Boston Scientific Japan, Japan Lifeline, Asahi Kasei ZOLL Medical, Synaptic Medical Japan and Biotronik, outside the submitted work. M. Kawasaki has received personal fees from Medtronic, Bayer, Boehringer Ingelheim, Daiichi Sankyo, Bristol-Myers Squibb, and Abbott, and grants from Osaka Heart Club, outside the submitted work. K. Inoue has received personal fees from Bayer, Bristol-Myers Squibb, Boehringer Ingelheim, Daiichi Sankyo, Johnson & Johnson, and Medtronic, outside the submitted work. Y. Sakata has received personal fees from Otsuka Pharmaceutical, Ono Pharmaceutical, Daiichi Sankyo, Mitsubishi Tanabe Pharma Corporation, AstraZeneca K.K. and Actelion Pharmaceuticals, and grants from Roche Diagnostic, FUJIFILM Toyama Chemical, Bristol-Myers Squibb, Co, Biosense Webster, Inc., Abbott Medical Japan, Otsuka Pharmaceutical, Daiichi Sankyo Company, Mitsubishi Tanabe Pharma Corporation, Astellas Pharma, Kowa Company, Boehringer Ingelheim Japan, and Biotronik. Other authors have nothing to disclose., (Copyright © 2023. Published by Elsevier B.V.)

Background: The transmission of carbapenemase-producing Enterobacterales (CPE) in the external environment, especially through food, presents a significant public health risk., Objectives: To investigate the prevalence and genetic characteristics of CPE in food markets of Dhaka, Bangladesh, using WGS., Methods: CPE isolates were obtained from different food and water samples collected from food markets in the southern part of Dhaka, Bangladesh. The isolates subsequently underwent molecular typing, WGS employing both short- and long-read sequencers, and plasmid analysis., Results: This study unveiled an extensive spread of CPE, with no significant difference in contamination rates observed in samples ( N  = 136), including meat ( n  = 8), fish ( n  = 5), vegetables ( n  = 36) or various food-washed water ( n  = 65) from markets near hospitals or residential areas. Thirty-eight Enterobacterales from 33 samples carried carbapenemase genes ( bla NDM-1, -4, -7 , bla KPC-2 , bla OXA-181 or bla IMI-1 ). Among these, the high-risk Escherichia coli ST410 clone was the most prevalent and distributed across various locations. Furthermore, the identification of IncHI2 plasmids co-harbouring resistance genes like bla NDM-5 and mcr-1.1 , without discernible epidemiological connections, is a unique finding, suggesting their widespread dissemination., Conclusions: The analysis unveils a dynamic landscape of CPE dissemination in food markets, underscored by the proliferation of novel IncHI2 hybrid plasmids carrying both colistin- and carbapenem-resistance genes. This illuminates the ever-evolving landscape of antimicrobial resistance in Dhaka, urging us to confront its emergent challenges., (© The Author(s) 2024. Published by Oxford University Press on behalf of British Society for Antimicrobial Chemotherapy.)

Aims: Interleukin-16 (IL-16) has been reported to mediate left ventricular myocardial fibrosis and stiffening in patients with heart failure with preserved ejection fraction (HFpEF). We sought to elucidate whether IL-16 has a distinct impact on pathophysiology and prognosis across different subphenotypes of acute HFpEF., Methods and Results: We analysed 211 patients enrolled in a prospective multicentre registry of acute decompensated HFpEF for whom serum IL-16 levels after stabilization were available (53% female, median age 81 [interquartile range 75-85] years). We divided this sub-cohort into four phenogroups using our established clustering algorithm. The study endpoint was all-cause death. Patients were subclassified into phenogroup 1 ('rhythm trouble' [n = 69]), phenogroup 2 ('ventricular-arterial uncoupling' [n = 49]), phenogroup 3 ('low output and systemic congestion' [n = 41]), and phenogroup 4 ('systemic failure' [n = 52]). After a median follow-up of 640 days, 38 patients had died. Among the four phenogroups, phenogroup 2 had the highest IL-16 level. The IL-16 level showed significant associations with indices of cardiac hypertrophy, diastolic dysfunction, and congestion only in phenogroup 2. Furthermore, the IL-16 level had a significant predictive value for all-cause death only in phenogroup 2 (C-statistic 0.750, 95% confidence interval 0.606-0.863, P = 0.017), while there was no association between the IL-16 level and the endpoint in the other phenogroups., Conclusions: Our results indicated that the serum IL-16 level had a significant association with indices that reflect the pathophysiology and prognosis of HFpEF in a specific phenogroup in acute HFpEF., (© 2024 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Background: Coronary angioscopy (CAS) has 2 unique abilities: direct visualization of thrombi and plaque color. However, in the recent drug-eluting stent (DES) era, serial CAS findings after DES implantation have not been fully elucidated. We investigated the impact of CAS findings after implantation of a polymer-free biolimus A9-coated stent (PF-BCS) or durable polymer everolimus-eluting stent (DP-EES).Methods and Results: We investigated serial CAS and optical coherence tomography (OCT) findings at 1 and 12 months in 99 patients who underwent PF-BCS or DP-EES implantation. We evaluated factors correlated with angioscopic thrombi and yellow plaque, and the clinical impact of both thrombi and yellow plaque at 12 months (BTY). The BTY group included 17 (22%) patients. The incidence and grade of thrombi and yellow plaque decreased from 1 to 12 months. Although no patients had newly appearing thrombi at 12 months, 2 DP-EES patients had newly appearing yellow plaque at 12 months. Multivariable analysis revealed HbA1c, minimum stent area, and adequate strut coverage were significant factors correlated with 12-month angioscopic thrombi, and DP-EESs were significantly correlated with 12-month yellow plaque. However, BTY was not correlated with clinical events., Conclusions: The management of diabetes, stent area, and adequate stent coverage are important for intrastent thrombogenicity and polymer-free stents are useful for stabilizing plaque vulnerability.

Background: It has not been fully elucidated which patients with persistent atrial fibrillation (PerAF) should undergo substrate ablation plus pulmonary vein isolation (PVI). This study aimed to identify PerAF patients who required substrate ablation using intraprocedural assessment of the baseline rhythm and the origin of atrial fibrillation (AF) triggers., Methods and results: This was a post hoc subanalysis using extended data of the EARNEST-PVI trial, a prospective multicenter randomized trial comparing PVI-alone and PVI-plus (i.e., PVI with added catheter ablation) arms. We divided 492 patients into 4 groups according to baseline rhythm and the location of AF triggers before PVI: Group A (n=22), sinus rhythm with pulmonary vein (PV)-specific AF triggers (defined as reproducible AF initiation from PVs only); Group B (n=211), AF with PV-specific AF triggers; Group C (n=94), sinus rhythm with no PV-specific AF trigger; Group D (n=165), AF with no PV-specific AF trigger. Among the 4 groups, only in Group D (AF at baseline and no PV-specific AF triggers) was arrhythmia-free survival significantly lower in the PVI-alone than PVI-plus arm (P=0.032; hazard ratio 1.68; 95% confidence interval 1.04-2.70)., Conclusions: Patients with sinus rhythm or PV-specific AF triggers did not receive any benefit from substrate ablation, whereas patients with AF and no PV-specific AF trigger benefited from substrate ablation.

Background: The optimal duration of atrial fibrillation (AF) persistence for predicting poor outcomes after catheter ablation of long-standing AF (LsAF) and the best ablation strategy for these patients remain unclear., Objective: We aimed to assess the impact of the duration of AF persistence on outcomes after catheter ablation of AF., Methods: We analyzed the Efficacy of Pulmonary Vein Isolation Alone in Patients with Persistent Atrial Fibrillation (EARNEST-PVI) trial data comparing pulmonary vein isolation (PVI) alone (PVI-alone) with additional linear ablation or defragmentation (PVI-plus) in persistent AF (PerAF). Patients who received catheter ablation by contact force-sensing catheter were enrolled in the study. In patients with LsAF, the optimal cutoff duration of AF persistence was evaluated. With use of the threshold, patients with LsAF were divided into 2 groups and compared with PerAF <1 year for arrhythmia-free survival after a 3-month blanking period., Results: The optimal cutoff duration was 2.4 years. Of 458 patients, arrhythmia-free survival rates for LsAF 1-2.4 years were comparable to those of PerAF (hazard ratio [HR], 1.01; 95% CI, 0.67-1.52). However, LsAF >2.4 years had a higher recurrence risk than PerAF (HR, 2.22; 95% CI, 1.42-3.47). In LsAF >2.4 years, the PVI-plus strategy showed advantages over the PVI-alone strategy (HR, 0.36; 95% CI, 0.14-0.89). However, the interaction effect between LsAF 1-2.4 years and LsAF >2.4 years did not reach statistical significance (P = .116)., Conclusion: Whereas LsAF 1-2.4 years has similar outcomes to those of PerAF, LsAF >2.4 years was linked to higher arrhythmia recurrence risks. For LsAF >2.4 years, the PVI-plus strategy showed a potential to be superior to the PVI-alone strategy., Competing Interests: Disclosures Drs Minamiguchi, Dohi, Nakatani, Hikoso, and Sakata have received grants from Medtronic, Johnson & Johnson, and Abbott during the conduct of the study. Other authors have nothing to disclose related to the submitted work. Conflict of interest outside the submitted work is found in a supplemental file., (Copyright © 2024 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

Aims: Low-density lipoprotein cholesterol (LDL-C), anaemia and low platelets have been associated with worse clinical outcomes in heart failure patients. We investigated the relationship between the combination of these three components and clinical outcome in patients with heart failure with preserved ejection fraction (HFpEF)., Methods and Results: We examined the data of 1021 patients with HFpEF hospitalized with acute decompensated heart failure (HF) from the PURSUIT-HFpEF registry, a prospective, multicenter observational study. The enrolled patients were classified into four groups by an LEP (LDL-C, Erythrocyte, and Platelet) score of 0 to 3 points, with 1 point each for LDL-C, erythrocyte and platelet values less than the cut-off values as calculated by receiver operating characteristic curve analysis. The endpoint, a composite of all-cause death and HF readmission, was evaluated among the four groups. Median follow-up duration was 579 [300, 978] days. Risk of the composite endpoint significantly differed among the four groups (P < 0.001). Kaplan-Meier analysis showed that the groups with an LEP score of 2 had higher risk of the composite endpoint than those with an LEP score of 0 or 1 (P < 0.001, and P = 0.013, respectively), while those with an LEP score of 3 had higher risk than those with an LEP score of 0, 1 or 2 (P < 0.001, P < 0.001 and P = 0.020, respectively). Cox proportional hazards analysis showed that an LEP score of 3 was significantly associated with the composite endpoint (P = 0.030). Kaplan-Meier analysis showed that risk of the composite of all-cause death and HF readmission was significantly higher in low LDL values (less than the cut-off values as calculated by receiver operating characteristic curve analysis) patients with statin use than in those without statin use (log rank P = 0.002)., Conclusions: LEP score, which comprehensively reflects extra-cardiac co-morbidities, is significantly associated with clinical outcomes in HFpEF patients., (© 2024 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

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.)

Aims: Blood stasis is crucial in developing left atrial (LA) thrombi. LA appendage peak flow velocity (LAAFV) is a quantitative parameter for estimating thromboembolic risk. However, its impact on LA thrombus resolution and clinical outcomes remains unclear., Methods and Results: The LAT study was a multicentre observational study investigating patients with atrial fibrillation (AF) and silent LA thrombi detected by transoesophageal echocardiography (TEE). Among 17 436 TEE procedures for patients with AF, 297 patients (1.7%) had silent LA thrombi. Excluding patients without follow-up examinations, we enrolled 169 whose baseline LAAFV was available. Oral anticoagulation use increased from 85.7% at baseline to 97.0% at the final follow-up (P < 0.001). During 1 year, LA thrombus resolution was confirmed in 130 (76.9%) patients within 76 (34-138) days. Conversely, 26 had residual LA thrombi, 8 had thromboembolisms, and 5 required surgical removal. These patients with failed thrombus resolution had lower baseline LAAFV than those with successful resolution (18.0 [15.8-22.0] vs. 22.2 [17.0-35.0], P = 0.003). Despite limited predictive power (area under the curve, 0.659; P = 0.001), LAAFV ≤ 20.0 cm/s (best cut-off) significantly predicted failed LA thrombus resolution, even after adjusting for potential confounders (odds ratio, 2.72; 95% confidence interval, 1.22-6.09; P = 0.015). The incidence of adverse outcomes including ischaemic stroke/systemic embolism, major bleeding, or all-cause death was significantly higher in patients with reduced LAAFV than in those with preserved LAAFV (28.4% vs. 11.6%, log-rank P = 0.005)., Conclusion: Failed LA thrombus resolution was not rare in patients with AF and silent LA thrombi. Reduced LAAFV was associated with failed LA thrombus resolution and adverse clinical outcomes., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Objective: The heterogeneous pathophysiology of the diverse heart failure with preserved ejection fraction (HFpEF) phenotypes needs to be examined. We aim to assess differences in the biomarkers among the phenotypes of HFpEF and investigate its multifactorial pathophysiology., Methods: This study is a retrospective analysis of the PURSUIT-HFpEF Study (N=1231), an ongoing, prospective, multicentre observational study of acute decompensated HFpEF. In this registry, there is a predefined subcohort in which we perform multibiomarker tests (N=212). We applied the previously established machine learning-based clustering model to the subcohort with biomarker measurements to classify them into four phenotypes: phenotype 1 (n=69), phenotype 2 (n=49), phenotype 3 (n=41) and phenotype 4 (n=53). Biomarker characteristics in each phenotype were evaluated., Results: Phenotype 1 presented the lowest value of N-terminal pro-brain natriuretic peptide (NT-proBNP), high-sensitive C reactive protein, tumour necrosis factor-α, growth differentiation factor (GDF)-15, troponin T and cystatin C, whereas phenotype 2, which is characterised by hypertension and cardiac hypertrophy, showed the highest value of these markers. Phenotype 3 showed the second highest value of GDF-15 and cystatin C. Phenotype 4 presented a low NT-proBNP value and a relatively high GDF-15., Conclusions: Distinctive characteristics of biomarkers in HFpEF phenotypes would indicate differential underlying mechanisms to be elucidated. The contribution of inflammation to the pathogenesis varied considerably among different HFpEF phenotypes. Systemic inflammation substantially contributes to the pathophysiology of the classic HFpEF phenotype with cardiac hypertrophy., Trial Registration Number: UMIN-CTR ID: UMIN000021831., Competing Interests: Competing interests: YSo has received grants from Roche Diagnostics, FUJIFILM Toyama Chemical, TOA EIYO, Bristol-Myers Squibb, Biosense Webster, Abbott Medical Japan and NIPRO; and personal fees from Abiomed, AstraZeneca, Amgen Astellas BioPharma, Biosensors, Boehringer Ingelheim, Bristol-Myers Squibb, Abbott Medical Japan, Boston Scientific Japan, Bayer, Daiichi Sankyo, Novartis, TERUMO, Medtronic and Pfizer Pharmaceuticals. SH has received grants from Roche Diagnostics, FUJIFILM Toyama Chemical and 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. YSa has received personal fees from Otsuka Pharmaceutical, Ono Pharmaceutical, Daiichi Sankyo, Mitsubishi Tanabe Pharma Corporation, AstraZeneca and Actelion Pharmaceuticals; and grants from Roche Diagnostic, FUJIFILM Toyama Chemical, Bristol-Myers Squibb Co, Biosense Webster, Abbott Medical Japan, Otsuka Pharmaceutical, Daiichi Sankyo Company, Mitsubishi Tanabe Pharma Corporation, Astellas Pharma, Kowa Company, Boehringer Ingelheim Japan and Biotronik., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Identifying patients who would benefit from extensive catheter ablation along with pulmonary vein isolation (PVI) among those with persistent atrial fibrillation (AF) has been a subject of controversy. The objective of this study was to apply uplift modeling, a machine learning method for analyzing individual causal effect, to identify such patients in the EARNEST-PVI trial, a randomized trial in patients with persistent AF. We developed 16 uplift models using different machine learning algorithms, and determined that the best performing model was adaptive boosting using Qini coefficients. The optimal uplift score threshold was 0.0124. Among patients with an uplift score ≥ 0.0124, those who underwent extensive catheter ablation (PVI-plus) showed a significantly lower recurrence rate of AF compared to those who received only PVI (PVI-alone) (HR 0.40; 95% CI 0.19-0.84; P-value = 0.015). In contrast, among patients with an uplift score < 0.0124, recurrence of AF did not significantly differ between PVI-plus and PVI-alone (HR 1.17; 95% CI 0.57-2.39; P-value = 0.661). By employing uplift modeling, we could effectively identify a subset of patients with persistent AF who would benefit from PVI-plus. This model could be valuable in stratifying patients with persistent AF who need extensive catheter ablation before the procedure., (© 2024. The Author(s).)

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.

The coexistence of heart failure is frequent and associated with higher mortality in patients with type 2 diabetes (T2DM), and its management is a critical issue. The WATCH-DM risk score is a tool to predict heart failure in patients with type 2 diabetes mellitus (T2DM). We investigated whether it could estimate outcomes in T2DM patients with heart failure with preserved ejection fraction (HFpEF). The WATCH-DM risk score was calculated in 418 patients with T2DM hospitalized for HFpEF (male 49.5%, age 80 ± 9 years, HbA1c 6.8 ± 1.0%), and they were divided into the "average or lower" (≤ 10 points), "high" (11-13 points) and "very high" (≥ 14 points) risk groups. We followed patients to observe all-cause death for 386 days (median). We compared the area under the curve (AUC) of the WATCH-DM score for predicting 1-year mortality with that of the Meta-Analysis Global Group in Chronic Heart Failure (MAGGIC) score and of the Barcelona Bio-Heart Failure Risk (BCN Bio-HF). Among the study patients, 108 patients (25.8%) had average or lower risk scores, 147 patients (35.2%) had high risk scores, and 163 patients (39.0%) had very high risk scores. The Cox proportional hazard model selected the WATCH-DM score as an independent predictor of all-cause death (HR per unit 1.10, 95% CI 1.03 to 1.19), and the "average or lower" risk group had lower mortality than the other groups (p = 0.047 by log-rank test). The AUC of the WATCH-DM for 1-year mortality was 0.64 (95% CI 0.45 to 0.74), which was not different from that of the MAGGIC score (0.72, 95% CI 0.63 to 0.80, p = 0.08) or that of BCN Bio-HF (0.70, 0.61 to 0.80, p = 0.25). The WATCH-DM risk score can estimate prognosis in T2DM patients with HFpEF and can identify patients at higher risk of mortality., (© 2024. The Author(s).)

Background: After issuing the "Global action plan on antimicrobial resistance" in 2015, the World Health Organization (WHO) established a priority pathogens list for supporting research and development of novel antimicrobials. We conducted a comprehensive analysis of the WHO priority organisms in a Japanese tertiary hospital to apprehend the local AMR epidemiology., Methods: Data were obtained from electrical medical records in Osaka University Hospital between January 2010 and March 2021. The critical, high, and medium "priority pathogens list" categories of the WHO were used to compare results between the early (2010-2015) and late (2016-2021) phases., Results: Out of 52,130 culture-positive specimens, a total of 9,872 (18.9%) contained WHO priority isolates. In comparison to early phases, late phases were likely to have higher rates of carbapenem resistance in Pseudomonas aeruginosa (15.7% vs 25.0%, P<0.001), 3rd generation cephalosporin resistance in Escherichia coli (11.5% vs 17.8%, P<0.001) as well as Klebsiella pneumoniae (1.6% vs 4.4%, P<0.001), and ampicillin resistance in Haemophilus influenzae (2.4% vs 3.9%, P<0.001). After 2015, however, the proportion of methicillin-resistant and vancomycin-intermediate Staphylococcus aureus was low. In this study, in-hospital mortality was comparable among patients with resistance to the three WHO priority pathogen types: critical (5.9%), high (3.9%), and medium (3.8%), and no significant change was observed between two phases in each category. However, significant interactions for in-hospital mortality were observed in subgroup analyses between "critical priority" AMR and the presence of comorbid conditions, such as chronic kidney disease or diabetes mellitus., Conclusions: To implement better antimicrobial stewardship policies and practices, local priority pathogens and "high-risk" patients for in-hospital death need to be acknowledged and evaluated periodically., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Nisa et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: Myotonic dystrophy type 1 (DM1) is a devastating multisystemic disorder caused by a CTG repeat expansion in the DMPK gene, which subsequently triggers toxic RNA expression and dysregulated splicing. In a preclinical study, we demonstrated that erythromycin reduces the toxicity of abnormal RNA and ameliorates the aberrant splicing and motor phenotype in DM1 model mice., Methods: This multicentre, randomised, double-blind, placebo-controlled, phase 2 trial was conducted at three centres in Japan to translate preclinical findings into practical applications in patients with DM1 by evaluating the safety and efficacy of erythromycin. Between Nov 29, 2019, and Jan 20, 2022, a total of 30 adult patients with DM1 were enrolled and randomly assigned in a 1:2:2 ratio to receive either placebo or erythromycin at two daily doses (500 mg or 800 mg) for 24 weeks. The primary outcome included the safety and tolerability of erythromycin. The secondary efficacy measures included splicing biomarkers, 6-min walk test results, muscle strength, and serum creatinine kinase (CK) values. This trial is registered with the Japan Registry of Clinical Trials, jRCT2051190069., Findings: Treatment-related gastrointestinal symptoms occurred more frequently in the erythromycin group, but all adverse events were mild to moderate and resolved spontaneously. No serious safety concerns were identified. The CK levels from baseline to week 24 decreased in the overall erythromycin group compared with the placebo group (mean change of -6.4 U/L [SD 149] vs +182.8 [SD 228]), although this difference was not statistically significant (p = 0.070). Statistically significant improvements in the overall erythromycin treated groups compared to placebo were seen for two of the eleven splicing biomarkers that were each evaluated in half of the trial sample. These were MBNL1 (p = 0.048) and CACNA1S (p = 0.042)., Interpretation: Erythromycin demonstrated favourable safety and tolerability profiles in patients with DM1. A well-powered phase 3 trial is needed to evaluate efficacy, building on the preliminary findings from this study., Funding: Japan Agency for Medical Research and Development., Competing Interests: M.N. and H.M. are coinventors on a patent (no. JP6460552B2, US10500223B2, EP3323419B1) for MYD-0124 owned by Osaka University. EH belongs to a joint research chair with Shionogi Pharma Co., Ltd., (© 2023 The Author(s).)

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.)

Background An optimal strategy for left atrial ablation in addition to pulmonary vein isolation (PVI) in patients with persistent atrial fibrillation (AF) has not been determined. Methods and Results We conducted an extended follow-up of the multicenter randomized controlled EARNEST-PVI (Efficacy of Pulmonary Vein Isolation Alone in Patients With Persistent Atrial Fibrillation) trial, which compared 12-month rhythm outcomes in patients with persistent AF between patients randomized to a PVI-alone strategy (n=248) or PVI-plus strategy (n=248; PVI followed by left atrial additional ablation, including linear ablation or ablation targeting areas with complex fractionated electrograms). The present study extended the follow-up period to 3 years after enrollment. Outcomes were compared not only between randomly allocated groups but also between on-treatment groups categorized by actually created ablation lesions. Recurrence rate of AF or atrial tachycardia (AT) was lower in the randomly allocated to PVI-plus group than the PVI-alone group (29.0% versus 37.5%, P =0.036). On-treatment analysis revealed that patients with PVI+linear ablation (n=205) demonstrated a lower AF/AT recurrence rate than those with PVI only (26.3% versus 37.8%, P =0.007). In contrast, patients with PVI+complex fractionated electrograms ablation (n=37) had an AF/AT recurrence rate comparable to that of patients with PVI only (40.5% versus 37.8%, P =0.76). At second ablation in 126 patients with AF/AT recurrence, ATs excluding common atrial flutter were more frequent in patients with PVI+linear ablation than in those with PVI only (32.6% versus 5.7%, P <0.0001). Conclusions Left atrial ablation in addition to PVI was efficacious during 3-year follow-up. Linear ablation was superior to other ablation strategies but may increase iatrogenic ATs. Registration URL: http://www.umin.ac.jp/ctr/index-j.htm; Unique identifier: UMIN000019449.

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.)

Objective: Our previously established machine learning-based clustering model classified heart failure with preserved ejection fraction (HFpEF) into four distinct phenotypes. Given the heterogeneous pathophysiology of HFpEF, specific medications may have favourable effects in specific phenotypes of HFpEF. We aimed to assess effectiveness of medications on clinical outcomes of the four phenotypes using a real-world HFpEF registry dataset., Methods: This study is a posthoc analysis of the PURSUIT-HFpEF registry, a prospective, multicentre, observational study. We evaluated the clinical effectiveness of the following four types of postdischarge medication in the four different phenotypes: angiotensin-converting enzyme inhibitors (ACEi) or angiotensin-receptor blockers (ARB), beta blockers, mineralocorticoid-receptor antagonists (MRA) and statins. The primary endpoint of this study was a composite of all-cause death and heart failure hospitalisation., Results: Of 1231 patients, 1100 (83 (IQR 77, 87) years, 604 females) were eligible for analysis. Median follow-up duration was 734 (398, 1108) days. The primary endpoint occurred in 528 patients (48.0%). Cox proportional hazard models with inverse-probability-of-treatment weighting showed the following significant effectiveness of medication on the primary endpoint: MRA for phenotype 2 (weighted HR (wHR) 0.40, 95% CI 0.21 to 0.75, p=0.005); ACEi or ARB for phenotype 3 (wHR 0.66 0.48 to 0.92, p=0.014) and statin therapy for phenotype 3 (wHR 0.43 (0.21 to 0.88), p=0.020). No other medications had significant treatment effects in the four phenotypes., Conclusions: Machine learning-based clustering may have the potential to identify populations in which specific medications may be effective. This study suggests the effectiveness of MRA, ACEi or ARB and statin for specific phenotypes of HFpEF., Trial Registration Number: UMIN000021831., Competing Interests: Competing interests: SH has received grants from Roche Diagnostics, FUJIFILM Toyama Chemical and 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. TK has received honoraria from AstraZeneca. YS has received personal fees from Otsuka Pharmaceutical, Ono Pharmaceutical, Daiichi Sankyo, Mitsubishi Tanabe Pharma Corporation, AstraZeneca K.K. and Actelion Pharmaceuticals, and grants from Roche Diagnostic, FUJIFILM Toyama Chemical, Bristol-Myers Squibb, Co, Biosense Webster, Inc., Abbott Medical Japan, Otsuka Pharmaceutical, Daiichi Sankyo Company, Mitsubishi Tanabe Pharma Corporation, Astellas Pharma, Kowa Company, Boehringer Ingelheim Japan, and Biotronik. The other authors have nothing to disclose., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Abstract: There were few clinical studies on the relationship between sodium glucose cotransporter 2 inhibitors (SGLT2i) and hematopoiesis in patients with diabetes (DM) and heart failure (HF) with consideration of systemic volume status. A total of 226 DM patients with HF enrolled in the CANDLE trial, a multicenter, prospective, randomized open-label blinded-endpoint trial, were studied. Estimated plasma volume status (ePVS) was calculated based on a weight- and hematocrit-based formula. At baseline, there was no significant difference in hematocrit and hemoglobin between the canagliflozin (n = 109) and glimepiride (n = 116) groups. Hematocrit and hemoglobin at 24 weeks, changes in hematocrit and hemoglobin difference (24 weeks-baseline), and hematocrit and hemoglobin ratio (24 weeks/baseline) were significantly higher in the canagliflozin than in the glimepiride group, respectively. There was no significant difference in ePVS at baseline and 24 weeks between the 2 groups. After adjustment for baseline parameters, canagliflozin correlated positively with changes in hematocrit and hemoglobin difference, and hematocrit and hemoglobin ratio by multivariate linear regression analyses. The difference in hematocrit and hemoglobin between the 2 groups became statistically significant at 3 and 6 months after randomization. There was no heterogeneity between canagliflozin and the characteristics of the patients for hematocrit and hemoglobin difference and ratio. A correlation of the changes in hematocrit and hemoglobin with cardiac and renal improvement was not observed. In conclusion, canagliflozin was associated with an increased hematocrit and hemoglobin in patients with diabetes and HF regardless of their volume status and characteristics., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Backgrounds: Drug treatments of heart failure with preserved ejection fraction (HFpEF) have a little clinical benefit, but cardiovascular polypharmacy (CP) trend is observed in elderly HFpEF. We investigated the impact of CP on octogenarian with HFpEF., Methods: We examined 783 consecutive octogenarians (≥80 years) enrolled in the PURSUIT-HFpEF registry. We defined medications for hypertension, dyslipidemia, heart failure (HF), coronary artery disease, stroke, peripheral artery disease, and atrial fibrillation as cardiovascular medications (CM). In this study, we defined CP as ≥5 CM. We investigated whether CP was correlated with the composite end point (CE) of all-cause mortality and HF rehospitalization., Results: The proportion with CP was 51.9% (n = 406). Background characteristics correlated with CP were frailty, history of coronary artery disease, atrial fibrillation and left atrial dimension. Multivariable Cox proportional hazards analysis showed CP was significantly and independently correlated with CE (hazard ratio (HR): 1.31; 95% confidence Interval (CI): 1.01-1.70) in addition to age, clinical frailty scale, history of HF admission and N-terminal pro brain natriuretic peptide. Kaplan-Meier curve analysis showed that, compared with the non-CP group, the CP group had significantly higher risk of CE and HF (HR: 1.27; 95%CI: 1.04-1.56; P = 0.02 and HR: 1.46; 95%CI: 1.13-1.88; P < 0.01, respectively), but not any-cause death. In addition, diuretics were correlated with CE (HR: 1.61; 95%CI: 1.17-2.22; P < 0.01), but antithrombotic drugs and HFpEF medications were not., Conclusions: CP at discharge is a prognostic factor driven by HF rehospitalization in octogenarians with HFpEF. In these patients, diuretics may be correlated with the prognosis., Competing Interests: Declaration of Competing Interest Daisaku Nakatani has received honoraria from Roche Diagnostics. Shungo Hikoso 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. Yasushi Sakata 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. The other authors have no conflicts of interest to disclose., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Aims: Patient reported outcomes (PROs) are gradually being incorporated into daily practice to assess individual health-related quality of life (QOL). However, despite accumulating evidence of the prognostic utility of heart failure (HF)-specific QOL indices, evidence on the generic QOL score is scarce, especially in patients with HF with preserved ejection fraction (HFpEF)., Methods and Results: Patient data were extracted from the Prospective mUlticenteR obServational stUdy of patIenTs with Heart Failure with Preserved Ejection Fraction (PURSUIT HFpEF) study. EuroQol 5 dimensions 5-level (EQ-5D-5L) data were obtained at discharge to evaluate patients' health-related QOL. The study population (n = 864) was divided into tertiles based on their EQ-5D-5L index as follows: low EQ-5D-5L 0.038-0.664 (n = 287), middle EQ-5D-5L 0.665-0.867 (n = 293), and high EQ-5D-5L 0.871-1.000 (n = 284). A total of 206 patients died over a mean follow-up period of 2.0 ± 1.2 years. Kaplan-Meier analysis revealed that the risk of mortality increased with the tertile of the EQ-5D-5L index (34% vs. 23% vs. 14%, P < 0.001). Cox multivariable analysis revealed that patients with EQ-5D-5L index in the low and middle tertiles had a significantly greater risk of mortality than those with EQ-5D-5L index in the high tertile [low EQ-5D-5L: adjusted hazard ratio (HR): 1.81 (1.12-2.92), P = 0.002, middle EQ-5D-5L: adjusted HR 1.91 (1.21-3.03), P = 0.006]. Among the dimensions of EQ-5D-5L, mobility (P = 0.014), self-care (P = 0.023) and usual activities (P = 0.008) were significant factors associated with all-cause mortality after multivariable adjustment., Conclusions: EQ-5D-5L is useful tool for risk stratification in patients with HFpEF., (© 2022 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Objectives: Heart failure with preserved ejection fraction (HFpEF) is often complicated by pulmonary hypertension (PH), which is mainly characterised by postcapillary PH and occasionally accompanied by a precapillary component of PH. Haemodynamic changes in worsening heart failure (HF) can modify the characteristics of PH. However, the clinical features of PH after HF treatment in HFpEF remain unclear. We investigated the prevalence and clinical significance of the precapillary component of PH after HF treatment in HFpEF, using data from the Prospective Multicentre Observational Study of Patients with HFpEF (PURSUIT-HFpEF)., Methods: From the PURSUIT-HFpEF registry, 219 patients hospitalised with acute HF who underwent right heart catheterisation after initial HF treatment were divided into four groups according to the 2015 and 2018 PH definitions: non-PH, isolated postcapillary pulmonary hypertension (Ipc-PH), precapillary PH and combined postcapillary and precapillary pulmonary hypertension (Cpc-PH). The latter two were combined as PH with the precapillary component., Results: Using the 2015 definition, we found that the prevalence of PH after HF treatment was 27% (Ipc-PH: 20%, precapillary PH: 3%, Cpc-PH: 4%). Applying the 2018 definition resulted in a doubled frequency of precapillary PH (6%). PH with a precapillary component according to the 2015 definition was associated with poor clinical outcomes and characterised by small left ventricular dimension and high early diastolic mitral inflow velocity/early diastolic mitral annular tissue velocity., Conclusion: After initial HF treatment, 7% of hospitalised patients with HFpEF had precapillary component of PH according to the 2015 definition. Echocardiographic parameters of the left ventricle can contribute to the risk stratification of patients with HFpEF with a precapillary component of PH., Competing Interests: Competing interests: FS received modest lecture fees from Actelion Pharmaceuticals, Pfizer and Nippon Boehringer Ingelheim. TO received modest lecture fees from Bristol-Myers Squibb, Daiichi Sankyo Company, Nippon Boehringer Ingelheim and Otsuka Pharmaceutical, as well as significant medical advisory fees from Takeda Pharmaceutical. SH received modest personal fees from Daiichi Sankyo Company, Bayer and Astellas Pharma, as well as a modest grant from Actelion Pharmaceuticals. KY-T received a modest lecture fee from Actelion Pharmaceuticals. YS received significant personal fees from Otsuka Pharmaceutical and Daiichi Sankyo Company, and modest personal fees from Actelion Pharmaceuticals, Ono Pharmaceutical, Astellas Pharma, AstraZeneca, Novartis Pharma, Bayer, Pfizer and TOA EIYO. The other authors have no conflicts of interest to disclose., (© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

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 Neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) are novel inflammation markers. Their combined usefulness for estimating the prognosis of patients with heart failure with preserved ejection fraction (HFpEF) admitted for acute decompensated heart failure remains elusive. Methods and Results We investigated 1026 patients registered in the Prospective Multicenter Observational Study of Patients with Heart Failure with Preserved Ejection Fraction. Both NLR and PLR values were measured at the time of admission. Comorbidity burden was defined as the number of occurrences of 8 common comorbidities of HFpEF. The primary end point was cardiac death. The patients were stratified into 3 groups based on the optimal cut-off values of NLR and PLR on the receiver operating characteristic curve analysis for predicting cardiac death (low NLR and PLR, either high NLR or PLR, and both high NLR and PLR). After a median follow-up of 429 days, 195 patients died, with 85 of these deaths attributed to cardiac causes. An increased comorbidity burden was significantly associated with a higher proportion of patients with high NLR (>4.5) or PLR (>193), or both. High NLR and PLR values were independently associated with cardiac death, and a combination of both values was the strongest predictor (hazard ratio, 2.66 [95% CI, 1.51%-4.70%], P =0.0008). A significant difference was found in the rate of cardiac death among the 3 groups stratified by NLR and PLR values. Conclusions The combination of NLR and PLR is useful for the prediction of postdischarge cardiac death in patients with acute HFpEF. Registration URL: ClinicalTrials.gov; Unique identifier: UMIN000021831.

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.)

Two key echocardiographic parameters, left ventricular mass index (LVMI) and left atrial volume index (LAVI), are important in assessing structural myocardial changes in heart failure (HF) with preserved ejection fraction (HFpEF). However, the differences in clinical characteristics and outcomes among groups classified by LVMI and LAVI values are unclear.We examined the data of 960 patients with HFpEF hospitalized due to acute decompensated HF from the PURSUIT-HFpEF registry, a prospective, multicenter observational study. Four groups were classified according to the cut-off values of LVMI and LAVI [LVMI = 95 g/m 2 (female), 115 g/m 2 (male) and LAVI = 34 mL/m 2 ]. Clinical endpoints were the composite of HF readmission and all-cause death. Study endpoints among the 4 groups were evaluated. The composite endpoint occurred in 364 patients (37.9%). Median follow-up duration was 445 days. Kaplan-Meier analysis revealed significant differences in the composite endpoint among the 4 groups (P < 0.001). Cox proportional hazards analysis demonstrated that patients with increased LAVI alone were at significantly higher risk of HF readmission and the composite endpoints than those with increased LVMI alone (P = 0.030 and P = 0.024, respectively). Age, male gender, systolic blood pressure at discharge, atrial fibrillation (AF) hemoglobin, renal function, and LAVI were significant determinants of LVMI and female gender, AF, hemoglobin, and LVMI were significant determinants of LAVI.In HFpEF patients, increased LAVI alone was more strongly associated with HF readmission and the composite of HF readmission and all-cause death than those with increased LVMI alone.

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: We aim to clarify the differences in the association between re-admission for heart failure (HF) and left atrial (LA) overload indices by sex in heart failure and a preserved ejection fraction (HFpEF)., Methods: We analyzed 898 HFpEF patients hospitalized for acute decompensated HF. Blood tests and transthoracic echocardiography were performed before discharge. The primary endpoint was re-admission for HF during the first year., Results: The ratio of diastolic elastance to arterial elastance ( p = 0.014), a relative index of LA pressure overload, in men and LA volume index (LAVI, p = 0.020) in women were significant for re-admission for HF during the first year in the multivariable Fine-Gray analysis. Stroke volume (SV)/LA volume (LAV), another index for LAV overload, was not a significant prognostic factor of re-admission for HF during this time., Conclusion: LA overload was an important prognostic factor for HF re-readmission during the first year after enrolment in patients with HFpEF, but the indices relating to LA overload differed by sex.

Background An association between uric acid (UA) and cardiovascular diseases, including heart failure (HF), has been reported. However, whether UA is a causal risk factor for HF is controversial. In particular, the prognostic value of lowering UA in patients with HF with preserved ejection fraction (HFpEF) is unclear. Methods and Results We enrolled patients with HFpEF from the PURSUIT-HFpEF (Prospective Multicenter Observational Study of Patients With Heart Failure With Preserved Ejection Fraction) registry. We investigated whether UA was correlated with the composite events, including all-cause mortality and HF rehospitalization, in patients with hyperuricemia and HFpEF (UA >7.0 mg/dL). Additionally, we evaluated whether lowering UA for 1 year (≥1.0 mg/dL) in them reduced mortality or HF rehospitalization. We finally analyzed 464 patients with hyperuricemia. In multivariable Cox regression analysis, UA was an independent determinant of composite death and rehospitalization (hazard ratio [HR], 1.15 [95% CI, 1.03-1.27], P =0.015). We divided them into groups with severe and mild hyperuricemia according to median estimated value of serum UA (8.3 mg/dL). Cox proportional hazards models revealed the incidence of all-cause mortality was significantly higher in the group with severe hyperuricemia than in the group with mild hyperuricemia (HR, 1.73 [95% CI, 1.19-2.25], P =0.004). The incidence of all-cause mortality was significantly decreased in the group with lowering UA compared with the group with nonlowering UA (HR, 1.71 [95% CI, 1.02-2.86], P =0.041). The incidence of urate-lowering therapy tended to be higher in the group with lowering UA than in the group with nonlowering UA (34.9% versus 24.6%, P =0.06). Conclusions UA is a predictor for the composite of all-cause death and HF rehospitalization in patients with hyperuricemia and HFpEF. In these patients, lowering UA, including the use of urate-lowering therapy, may improve prognosis.

Background: Blood urea nitrogen (BUN) reflects decreased glomerular filtration rate (GFR). The effect of BUN on clinical outcomes, excluding the impact of GFR, in heart failure with preserved ejection fraction (HFpEF) patients remains unknown., Methods: We enrolled HFpEF (left ventricular ejection fraction ≥50%) patients hospitalized due to acute decompensated heart failure (HF) from PURSUIT-HFpEF registry which was prospective, multicenter and observational study. For excluding the effect of renal function on BUN value, propensity score-matching was performed using the variables which were associated with GFR. The incidence of composite of all-cause death and HF readmission among the patients stratified by BUN and the association between BUN and echocardiographic parameters in HFpEF patients were evaluated., Results: We finally analyzed 1029 patients. In the present study, BUN cut-off value was defined as 24.4 mg/dL, which was the median value in overall population. The high and low BUN groups consisted of 193 patients after 1:1 propensity score-matching, respectively. The median follow-up duration was 401 days and the composite endpoint occurred in 129 patients (33.4%). Kaplan-Meier analysis showed the high BUN group had a significantly greater risk of the composite endpoint than the low group in the propensity score-matched pairs (p = 0.032). BUN value significantly correlated with left atrial volume index by multiple regression analysis using echocardiographic parameters (standardized beta-coefficient = 0.139, p = 0.043)., Conclusion: BUN was a useful marker for the composite of all-cause death and HF readmission, regardless of the baseline renal function and correlated with left atrial function in HFpEF patients., Clinical Trial Registration: UMIN000021831 ; PURSUIT-HFpEF., (Copyright © 2022 Elsevier B.V. All rights reserved.)

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: A polymer-free biolimus A9-coated stent (PF-BCS) may achieve better arterial healing than a durable polymer drug-eluting stent owing to its polymer-free feature., Methods and results: This multicenter, prospective, observational study enrolled 105 patients (132 lesions) who underwent PF-BCS (51 patients, 71 lesions) or durable polymer everolimus-eluting stent (DP-EES, 54 patients, 61 lesions) implantation. Serial coronary angioscopy (CAS) and optical coherence tomography (OCT) examinations were performed at 1 and 12 months, and the serial vessel responses were compared between PF-BCS and DP-EES. The primary outcome measure was the incidence of subclinical intrastent thrombus on CAS. The secondary outcome measures were: adequate strut coverage (≥40 μm) on OCT and maximum yellow color grade on CAS. The incidence of thrombus was high at 1 month (100% vs. 93%, P=0.091), but decreased at 12 months (18% vs. 25%, P=0.56), without a significant difference between PF-BCS and DP-EES. The adequate strut coverage rate was significantly higher (84±14% vs. 69±22%, P<0.001) and yellow color was significantly less intense (P=0.012) at 12 months in PF-BCS than in DP-EES; however, they were not significantly different at 1 month (adequate strut coverage: 47±21% vs. 50±17%, P=0.40; yellow color: P=0.99)., Conclusions: Although the thrombogenicity of PF-BCS was similar to that of DP-EES, the adequate coverage and plaque stabilization rates of PF-BCS were superior to those of DP-EES at 12 months.

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.

Objectives: The prognostic significance of an afterload-integrated diastolic index, the ratio of diastolic elastance (Ed) to arterial elastance (Ea) (Ed/Ea=[E/e']/[0.9×systolic blood pressure]), is valid for 1 year after discharge in older patients with heart failure with preserved ejection fraction (HFpEF). We aimed to clarify the association with changes in Ed/Ea from enrolment to 1 year and prognosis thereafter in patients with HFpEF., Setting: A prospective, multicentre observational registry of collaborating hospitals in Osaka, Japan., Participants: We enrolled 659 patients with HFpEF hospitalised for acute decompensated heart failure (men/women: 296/363). Blood tests and transthoracic echocardiography were performed before discharge and at 1 year after., Primary Outcome Measures: All-cause mortality and/or re-admission for heart failure were evaluated after discharge., Results: High Ed/Ea assessed before discharge was a significant prognostic factor during the first, but not the second, year after discharge in all-cause mortality or all-cause mortality and/or re-admission for heart failure. When re-analysis was performed using the value of Ed/Ea at 1 year after discharge, high Ed/Ea was significant for the prognosis during the second year for both end points (p=0.012 and p=0.033, respectively). The poorest mortality during 1‒2 years after enrolment was observed in those who showed a worsening Ed/Ea during the first year associated with larger left ventricular mass index and reduced left ventricular ejection fraction. In all-cause mortality and/or re-admission for heart failure, the event rate during 1‒2 years was highest in those with persistently high Ed/Ea even after 1 year., Conclusions: Time-sensitive prognostic performance of Ed/Ea, an afterload-integrated diastolic index, was observed in older patients with HFpEF., Trial Registration Number: UMIN000021831., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Right ventricular (RV) to pulmonary artery (PA) uncoupling is known to be important for the prognosis of not only heart failure (HF) with reduced ejection fraction but also HF with preserved ejection fraction (HFpEF). We further investigated key factors in the poor prognosis for HFpEF patients with RV-PA uncoupling., Methods: We studied 817 patients with HFpEF who were discharged alive in a multicentred cohort using post hoc analyses, with a primary endpoint of cardiac mortality or HF readmission. A total of 288 RV-PA uncoupled patients were observed, namely those with a tricuspid annular plane systolic excursion (TAPSE)/PA systolic pressure (PASP) ratio < 0.46 mm/mm Hg., Results: Among the RV-PA uncoupled patients, 101 adverse outcomes occurred over a median of 340 days. Echocardiographic RV dimension (RVD) was significantly important for prognosis in both univariable and multivariable Cox regression testing (hazard ratio 1.044, 95% confidence interval 1.014-1.074, P = 0.0042, and hazard ratio 1.036, 95% confidence interval 1.001-1.072, P = 0.0438, respectively) considered with the covariates of age, atrial fibrillation, renal function, N-terminal pro-brain natriuretic peptide, and other echocardiographic parameters. We further divided the patients into 4 groups, first into 2 groups with a TAPSE/PASP either ≥ or < 0.46 mm/mm Hg, and then into 4 groups by RVD medians of 31.9 mm and 33.3 mm, respectively. Kaplan-Meier curve analysis showed that outcomes were worst in patients with a low TAPSE/PASP ratio and larger RVD (log-rank P < 0.0001)., Conclusions: This multicentre observational study highlighted the further prognostic importance of larger RVD among HFpEF patients with RV-PA uncoupling., (© 2022 The Authors.)

Background Although potential therapeutic candidates for heart failure with preserved ejection fraction (HFpEF) are emerging, it is still unclear whether they will be effective in patients with left ventricular ejection fraction (LVEF) of 60% or higher. Our aim was to identify the clinical characteristics of these patients with HFpEF by comparing them to patients with LVEF below 60%. Methods and Results From a multicenter, prospective, observational cohort (PURSUIT-HFpEF [Prospective Multicenter Obsevational Study of Patients with Heart Failure with Preserved Ejection Fraction]), we investigated 812 consecutive patients (median age, 83 years; 57% women), including 316 with 50% ≤ LVEF <60% and 496 with 60% ≤ LVEF, and compared the clinical backgrounds of the 2 groups and their prognoses for cardiac mortality or HF readmission. Two hundred four adverse outcomes occurred at a median of 366 days. Multivariable Cox regression tests adjusted for age, sex, heart rate, atrial fibrillation, estimated glomerular filtration rate, N-terminal pro-B-type natriuretic peptide, and prior heart failure hospitalization revealed that systolic blood pressure (hazard ratio [HR], 0.925 [95% CI, 0.862-0.992]; P =0.028), high-density lipoprotein to C-reactive protein ratio (HR, 0.975 [95% CI, 0.944-0.995]; P =0.007), and left ventricular end-diastolic volume index (HR, 0.870 [95% CI, 0.759-0.997]; P =0.037) were uniquely associated with outcomes among patients with 50% ≤ LVEF <60%, whereas only the ratio of peak early mitral inflow velocity to velocity of mitral annulus early diastolic motion e'(HR, 1.034 [95% CI, 1.003-1.062]; P =0.034) was associated with outcomes among patients with 60% ≤ LVEF. Conclusions Prognostic factors show distinct differences between patients with HFpEF with 50% ≤ LVEF <60% and with 60% ≤ LVEF. These findings suggest that the 2 groups have different inherent pathophysiology. Registration URL: https://upload.umin.ac.jp/cgi-open-bin/ctr&#95;e/ctr&#95;view.cgi?recptno=R000024414; Unique identifier: UMIN000021831 PURSUIT-HFpEF.

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.)