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Naoyuki Akashi,1 Tomio Umemoto,1 Hodaka Yamada,2 Takayuki Fujiwara,3 Kei Yamamoto,1 Yousuke Taniguchi,1 Kenichi Sakakura,1 Hiroshi Wada,1 Shin-ichi Momomura,1 Hideo Fujita1 1Division of Cardiovascular Medicine, Jichi Medical University Saitama Medical Center, Saitama, Japan; 2Division of Endocrinology and Metabolism, Jichi Medical University Saitama Medical Center, Saitama, Japan; 3Department of Cardiovascular Medicine, The University of Tokyo Hospital, Tokyo, JapanCorrespondence: Tomio Umemoto, Division of Cardiovascular Medicine, Jichi Medical University Saitama Medical Center, 1-847 Amanuma-cho, Omiya-ku, Saitama, 330-8503, Japan, Tel +81-48-647-2111, Fax +81-48-648-5188, Email to-ume@omiya.jichi.ac.jpPurpose: Dipeptidyl peptidase-4 (DPP-4) inhibitors increase endothelial progenitor cells (EPCs) in peripheral blood circulation. However, the underlying mechanisms and effects on vascular endothelial function remain unclear. We evaluated whether the DPP-4 inhibitor teneligliptin increases circulating EPCs by inhibiting stromal-derived factor-1α (SDF-1α) and improves flow-mediated vascular dilatation (FMD) in type 2 diabetes mellitus patients with acute coronary syndrome (ACS) or its risk factors.Patients and Methods: This single-center, open-label, prospective, randomized controlled trial evaluated 17 patients (hemoglobin A1c ≤ 7.5% and peak creatinine phosphokinase < 2000 IU/mL) with ACS or a history of ACS or multiple cardiovascular risk factors. Metabolic variables of glucose and lipids, circulating EPCs, plasma DPP-4 activity, and SDF-1α levels, and FMD were evaluated at baseline and 28 ± 4 weeks after enrollment. Patients were randomly assigned to either the teneligliptin (n = 8) or control (n = 9) groups.Results: The DPP-4 activity (∆− 509.5 ± 105.7 vs ∆32.8 ± 53.4 μU/mL) and SDF-1α levels (∆− 695.6 ± 443.2 vs ∆11.1 ± 193.7 pg/mL) were significantly decreased after 28 weeks in the teneligliptin group than those in the control group. The number of EPCs showed an increasing trend in the teneligliptin treated group; albeit this did not reach statistical significance. Glucose and lipid levels were not significantly different between the groups before and after 28 weeks. However, FMD was significantly improved in the teneligliptin group when compared to the control group (∆3.8% ± 2.1% vs ∆− 0.3% ± 2.9%, P=0.006).Conclusion: Teneligliptin improved FMD through a mechanism other than increasing the number of circulating EPCs.Keywords: endothelial progenitor cell, teneligliptin, DPP-4 inhibitor, flow-mediated dilation, type 2 diabetes mellitus

Background: The Asian Working Group for Cachexia (AWGC) proposed a new definition of cachexia; however, its impact on cachexia prevalence and overlaps with other conditions, such as sarcopenia and malnutrition, are unclear. We investigated these aspects and the prognostic value of cachexia based on the AWGC on mortality in older patients with heart failure (HF)., Methods: This study was a secondary analysis of a prospective multicentre cohort, namely, the FRAGILE-HF cohort study. Older (≥ 65 years) patients who had been hospitalized due to decompensated HF were enrolled. We assessed the presence/absence of cachexia based on the AWGC and Evans' criteria. Sarcopenia and malnutrition based on the Asian Working Group for Sarcopenia 2014 and the Global Leadership Initiative on Malnutrition criteria were also assessed to compare their prevalence and the overlaps between them. Patients were stratified in relation to the presence/absence of cachexia based on the AWGC criteria, and their mortality rates were compared., Results: Of the 861 enrolled patients (median [interquartile range] age, 80 years [73-85 years]; male, 58.9%), cachexia, as evaluated based on the AWGC and Evans' criteria, sarcopenia and malnutrition, was present in 74.1%, 36.2%, 20.6% and 55.2% of patients, respectively. AWGC-defined cachexia was most common in the four conditions. All-cause death events occurred in 153 (18.1%) patients in 2 years. AWGC-defined cachexia (adjusted hazard ratio [aHRs], 1.442; 95% confidence interval [95% CI], 0.931-2.233; p = 0.101) was not associated with all-cause mortality in older patients with HF after adjusting for other HF prognosis factors, such as the B-type natriuretic peptide and the Meta-Analysis Global Group in Chronic risk score, whereas cachexia evaluated based on Evans's criteria (aHRs, 1.547; 95% CI, 1.118-2.141; p = 0.009), sarcopenia (aHRs, 1.737; 95% CI, 1.214-2.485; p = 0.003), and malnutrition (aHRs, 1.581; 95% CI, 1.094-2.284; p = 0.015) was associated with all-cause mortality., Conclusions: Three-quarters of older patients with HF had cachexia as evaluated by the AWGC criteria, and this was not associated with a worse prognosis. As the new AWGC cachexia criteria will result in a significantly larger proportion of patients being diagnosed with cachexia, the implementation of the criteria in clinical practice requires further consideration., Trial Registration: UMIN-CTR unique identifier: UMIN000023929., (© 2024 The Author(s). Journal of Cachexia, Sarcopenia and Muscle published by Wiley Periodicals LLC.)

Background: Physical frailty and malnutrition coexist in older patients with heart failure (HF) and form a vicious cycle exacerbating each other and can cause poor clinical outcomes. We aimed to clarify the association of prevalence of physical frailty and malnutrition and clinical outcomes in hospitalized patients with HF., Methods: A total of 862 hospitalized patients aged ≥65 years with HF decompensation were included in this FRAGILE-HF post-hoc sub-analysis. Patients were categorized into Neither, Either, or Both groups based on the prevalence of physical frailty and malnutrition. The primary outcome was all-cause mortality within 1 year after discharge. Prognoses among the groups were compared in the entire cohort and in subgroups with preserved ejection fraction (pEF) and reduced/mildly reduced left ventricular ejection fractions (rEF/mrEF)., Results: The Neither, Either, and Both groups comprised 32 %, 40 %, and 28 % respectively. During a 1-year follow-up period, 101 (12 %) patients died. Kaplan-Meier analysis showed significant differences in the primary outcomes among the groups ( P  < 0.001). The Both group had a higher risk of mortality (HR: 2.47, 95 % CI: 1.38-4.42) than the Neither group, while the Either group showed insignificant risk increase (HR: 1.58, 95 % CI: 0.86-2.90). Similar trends were observed in the pEF and rEF/mrEF subgroups ( P  = 0.60)., Conclusions: Physical frailty and malnutrition coexist in approximately one-quarter of hospitalized older patients with HF and are associated with an increased risk of mortality. Assessing both conditions is crucial for risk stratification and interventions to mitigate their interplay., Competing Interests: Y.M. received an honorarium from Otsuka Pharmaceutical Co., Novartis Pharma K.K., Bayer Inc., and AstraZeneca and research grants from Pfizer Japan Inc., Otsuka Pharmaceutical Co, EN Otsuka Pharmaceutical Co., Ltd., and Nippon Boehringer Ingelheim Co., Ltd. T.K. is affiliated with a department endowed by Philips Respironics, ResMed, Teijin Home Healthcare, and Fukuda Denshi. All other authors have nothing to disclose. NK receives an honoarium from Novartis Pharma, Otsuka Pharma, Boehringer Ingelheim, and Eli Lilly, and research grants from AMI Inc. and EchoNous Inc., and is affiliated with a department funded by Philips Japan, InterReha, Fukuda Denshi, KYOCERA, and AMI based on the collaborative research agreement., (© 2024 The Authors.)

The clinical ramifications of adaptive servo-ventilation (ASV) therapy have stirred debate within the medical community. Given the potential detrimental effect of elevated expiratory positive airway pressure (EPAP) on cardiac output, we hypothesized that relatively lower EPAP may be recommended for successful ASV therapy. In-hospital patients with congestive heart failure refractory to medical therapy were included in the prospective cohort study of ASV therapy on prognosis in repeatedly hospitalized patients with chronic heart failure: longitudinal observational study of effects on readmission and mortality (SAVIOR-L) study. Assignment to either the ASV treatment group or the medical management group was at the discretion of the attending physicians. For the purposes of this retrospective study, our focus remained solely on the ASV cohort. We conducted an extensive analysis to elucidate the influence of lower EPAP settings on midterm mortality. A total of 108 patients were included. The median age was 74 years, and 83 (77%) patients were male. The median EPAP setting employed was 4 cmH 2 O, with 60 patients subjected to EPAP levels below 5 cmH 2 O. There were no significant differences in the baseline characteristics between the lower and higher EPAP groups, which were divided at the EPAP cutoff of 4.5 cmH 2 O (p > 0.05 for all). A trend toward reduced mortality emerged among patients with EPAP settings below 5 cmH 2 O, exhibiting a hazard ratio of 0.48 (95% confidence interval 0.22-1.07, p = 0.072) after adjusting for potential confounding factors: 2-year mortality 26% vs. 38%; p = 0.095. Heart failure readmission rates were not significantly different between the two groups (p = 0.61). The adoption of relatively lower EPAP settings during ASV therapy may be advisable. Such an approach has the potential to ameliorate mortality rates while concurrently maintaining heart failure recurrence rates at levels commensurate with those with default EPAP settings., (© 2024. Springer Nature Japan KK, part of Springer Nature.)

Background: The PARALLEL-HF trial showed that treatment with sacubitril/valsartan resulted in more symptomatic hypotension versus enalapril in Japanese patients with heart failure (HF) and reduced ejection fraction, similar to PARADIGM-HF. Use of sacubitril/valsartan in these patients may be limited by concerns regarding hypotension., Methods: This post-hoc analysis characterized hypotension-related adverse events (AEs) and their effects on efficacy using data from PARALLEL-HF, in which patients received sacubitril/valsartan 200 mg twice daily or enalapril 10 mg twice daily., Results: Of 223 patients, 28.2 % experienced hypotension-related AEs and incidence was higher with sacubitril/valsartan versus enalapril (hazard ratio, 2.2; 95 % CI, 1.3-3.8; p = 0.0027). However, reduction in mean systolic blood pressure from baseline to study end did not significantly differ (sacubitril/valsartan: -2.2 mmHg vs enalapril: -1.3 mmHg; p = 0.6895). Patients who experienced hypotension-related AEs had lower mean body mass index, higher median N-terminal pro-brain natriuretic peptide at randomization, and more frequent history of stroke. Hypotension-related AEs leading to treatment discontinuation were not significantly different for sacubitril/valsartan versus enalapril (3.4 % vs 6.9 %, p = 0.5957). Reduction in risk of cardiovascular death or HF hospitalization was similar with sacubitril/valsartan versus enalapril in patients with or without hypotension-related AEs., Conclusions: Incidence of hypotension-related AEs was higher in the sacubitril/valsartan versus enalapril group but did not affect risk of cardiovascular death or HF hospitalization, which was similar between treatment groups., Competing Interests: Declaration of competing interest H.T. was an Executive Committee Chair of PARALLEL-HF and has received consultation fees from Novartis Pharma K.K., Nippon Boehringer Ingelheim, Bayer Yakuhin, and Ono Pharmaceutical; remuneration from MSD, Astellas Pharma, Pfizer, Bristol-Myers Squibb, Otsuka Pharmaceutical, Daiichi Sankyo, Mitsubishi Tanabe Pharma, Nippon Boehringer Ingelheim, Takeda Pharmaceutical, Bayer Yakuhin, Novartis Pharma K.K., Kowa Pharmaceutical, and Teijin Pharma; research funding from Actelion Pharmaceuticals, Mitsubishi Tanabe Pharma, Nippon Boehringer Ingelheim, Daiichi Sankyo, IQVIA Services, and Omron Healthcare; and scholarship funds from Astellas Pharma, Novartis Pharma K.K., Daiichi Sankyo, Takeda Pharmaceutical, Mitsubishi Tanabe Pharma, Teijin Pharma, and MSD. S.M. was an Executive Committee member of PARALLEL-HF and has received speakers bureau/honoraria from Ono Pharmaceutical, MSD, and Nippon Boehringer Ingelheim. Y. Saito was an Executive Committee member of PARALLEL-HF and has received research funds from Otsuka Pharmaceutical, Mitsubishi Tanabe Pharma, Daiichi Sankyo, Takeda Pharmaceutical Co., Ltd., Nihon Medi-Physics Co. Ltd., and LSI Medience Corporation; research expenses from Novartis Pharma K.K., and Roche Diagnostics; speakers bureau/honorarium from Otsuka Pharmaceutical, Daiichi Sankyo, Nippon Boehringer Ingelheim, and Novartis Pharma K.K.; and consultation fees from Novartis Pharma K.K. H.I. was an Executive Committee member of PARALLEL-HF and has received speakers bureau/honorarium from Takeda Pharmaceutical, Daiichi-Sankyo, MSD, Mochida Pharmaceutical, Mitsubishi Tanabe Pharma, Kowa Pharmaceutical, Toa Eiyo, Otsuka Pharmaceutical, Medtronic Japan, Astellas Pharma, Bayer Yakuhin, and Ono Pharmaceutical; research funds from Takeda Pharmaceutical, Daiichi-Sankyo, MSD, Mochida Pharmaceutical, Mitsubishi Tanabe Pharma, Kowa Pharmaceutical, Toa Eiyo, Otsuka Pharmaceutical, Medtronic Japan, Astellas Pharma, Bayer Yakuhin, Shionogi, Sumitomo Dainippon Pharma, and Ono Pharmaceutical; honorarium for writing promotional material for Daiichi-Sankyo; consultation fees from Novartis Pharma K.K.; and is affiliated with an endowed department sponsored by Medtronic Japan. K.Y. was a Medical Advisor for PARALLEL-HF and has received speakers bureau/honorarium and research funds from Otsuka Pharmaceutical and Novartis Pharma K.K.; and consultation fees from Novartis Pharma K.K. Y. Sakata was a Data Monitoring Committee member for PARALLEL-HF and reports no conflicts of interest. T.O., T.I., and T.K. were employees of Novartis at the time of the study., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Aims: The six-minute walk test (6MWT) is a widely accepted tool for evaluating exercise tolerance and physical capacity, and the six-minute walk distance (6MWD) is an established prognostic factor in patients with heart failure (HF). However, the prognostic implications of post-6MWT dyspnoea remain unknown. We aimed to investigate the prognostic value of Borg scores after the 6MWT in patients with HF., Methods: Patients hospitalized for HF who underwent the 6MWT before discharge were included. Post-test dyspnoea was assessed using the Borg scale. Patients were stratified into low and high Borg score groups based on the median Borg score. The primary outcome was 2-year mortality., Results: Among 1,185 patients analysed, the median Borg score was 12. The 6MWD was significantly shorter in the high Borg score group than in the low Borg score group. The 2-year mortality rate was 20.2%. In the Kaplan-Meier analysis, the high Borg score group demonstrated an association with 2-year mortality, which remained significant even after adjustment for conventional risk factors, including the 6MWD. Furthermore, Borg scale provided significant net reclassification improvement to the conventional risk model incorporating 6MWD., Conclusion: In hospitalized patients with HF, post-6MWT Borg scores were associated with 2-year mortality independent of the 6MWD, providing incremental prognostic value to the 6MWD. Even if patients are able to walk long distances for 6 minutes, it is essential to closely observe dyspnoea immediately thereafter., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Background: Influenza is associated with an increased risk for cardiovascular events in patients with heart failure (HF). This study aimed to investigate the prevalence of influenza vaccination among Japanese patients with HF enrolled in the PARALLEL-HF (Prospective comparison of ARNI with ACEi to determine the noveL beneficiaL trEatment vaLue in Japanese Heart Failure patients) trial and the association between receiving influenza vaccination and cardiovascular events including death or HF hospitalization., Methods and Results: In PARALLEL-HF, in which 223 patients with HF and reduced ejection fraction (HFrEF) were randomized to the angiotensin-receptor neprilysin inhibitor (sacubitril/valsartan) or enalapril, 97 (43%) received influenza vaccination. Influenza vaccination tended to be associated, though statistically not significant, with a lower risk for all-cause death (adjusted hazard ratio [HR]: 0.67; 95% confidence interval [CI]: 0.32-1.39) and cardiopulmonary or influenza-related hospitalization or death (adjusted HR: 0.72; 95% CI: 0.46-1.11) in propensity score-adjusted models., Conclusions: The influenza vaccination rate in Japanese patients with HFrEF who were well managed on guideline-directed medical therapy was suboptimal despite recommendations from clinical practice guidelines. However, importantly, it could be associated with better clinical benefits., Competing Interests: H.T. was an Executive Committee Chair of PARALLEL-HF and has received consultation fees from Novartis Pharma K.K., Nippon Boehringer Ingelheim, Bayer Yakuhin, and Ono Pharmaceutical; remuneration from MSD, Astellas Pharma, Pfizer, Bristol-Myers Squibb, Otsuka Pharmaceutical, Daiichi Sankyo, Mitsubishi Tanabe Pharma, Nippon Boehringer Ingelheim, Takeda Pharmaceutical, Bayer Yakuhin, Novartis Pharma K.K., Kowa Pharmaceutical, and Teijin Pharma; research funding from Actelion Pharmaceuticals, Mitsubishi Tanabe Pharma, Nippon Boehringer Ingelheim, Daiichi Sankyo, IQVIA Services, and Omron Healthcare; and scholarship funds from Astellas Pharma, Novartis Pharma K.K., Daiichi Sankyo, Takeda Pharmaceutical, Mitsubishi Tanabe Pharma, Teijin Pharma, and MSD. S.M. was an Executive Committee member of PARALLEL-HF and has received speakers bureau/honoraria from Ono Pharmaceutical, MSD, and Nippon Boehringer Ingelheim. Y. Saito was an Executive Committee member of PARALLEL-HF and has received research funds from Otsuka Pharmaceutical, Mitsubishi Tanabe Pharma, Daiichi Sankyo, Takeda Pharmaceutical Co., Ltd., Nihon Medi-Physics Co. Ltd., and LSI Medience Corporation; research expenses from Novartis Pharma K.K., and Roche Diagnostics; speakers bureau/honorarium from Otsuka Pharmaceutical, Daiichi Sankyo, Nippon Boehringer Ingelheim, and Novartis Pharma K.K.; and consultation fees from Novartis Pharma K.K. H.I. was an Executive Committee member of PARALLEL-HF and has received speakers bureau/honorarium from Takeda Pharmaceutical, Daiichi-Sankyo, MSD, Mochida Pharmaceutical, Mitsubishi Tanabe Pharma, Kowa Pharmaceutical, Toa Eiyo, Otsuka Pharmaceutical, Medtronic Japan, Astellas Pharma, Bayer Yakuhin, and Ono Pharmaceutical; research funds from Takeda Pharmaceutical, Daiichi-Sankyo, MSD, Mochida Pharmaceutical, Mitsubishi Tanabe Pharma, Kowa Pharmaceutical, Toa Eiyo, Otsuka Pharmaceutical, Medtronic Japan, Astellas Pharma, Bayer Yakuhin, Shionogi, Sumitomo Dainippon Pharma, and Ono Pharmaceutical; honorarium for writing promotional material for Daiichi-Sankyo; consultation fees from Novartis Pharma K.K., and is affiliated with an endowed department sponsored by Medtronic Japan. K.Y. was a Medical Advisor for PARALLEL-HF and has received speakers bureau/honorarium and research funds from Otsuka Pharmaceutical, and Novartis Pharma K.K.; and consultation fees from Novartis Pharma K.K. Y. Sakata was a Data Monitoring Committee member for PARALLEL-HF and reports no conflicts of interest. T.O. and C.I. were employees of Novartis. H.I. is a member of Circulation Reports’ Editorial Team., (Copyright © 2024, THE JAPANESE CIRCULATION SOCIETY.)

Aims: This study aimed to investigate the prevalence, clinical characteristics, and prognostic value of bendopnea in older patients hospitalized for heart failure., Methods and Results: This post hoc analysis was performed using two prospective, multicentre, observational studies: the FRAGILE-HF (main cohort) and SONIC-HF (validation cohort) cohorts. Patients were categorized based on the presence of bendopnea, which was evaluated before discharge. The primary endpoint was 2-year all-cause mortality after discharge. Among the 1243 patients (median age, 81 years; 57.2% male) in the FRAGILE-HF cohort and 225 (median age, 79 years; 58.2% men) in the SONIC-HF cohort, bendopnea was observed in 31 (2.5%) and 10 (4.4%) patients, respectively. Over a 2-year follow-up period, all-cause death occurred in 20.8 and 21.9% of the patients in the FRAGILE-HF and SONIC-HF cohorts, respectively. Kaplan-Meier survival curves demonstrated significantly higher mortality rates in patients with bendopnea than in those without bendopnea in the FRAGILE-HF (log-rank P = 0.006) and SONIC-HF cohorts (log-rank P = 0.014). Cox proportional hazard analysis identified bendopnea as an independent prognostic factor for all-cause mortality in both the FRAGILE-HF [hazard ratio (HR) 2.11, 95% confidence interval (CI) 1.18-3.78, P = 0.012] and SONIC-HF cohorts (HR 4.20, 95% CI 1.63-10.79, P = 0.003), even after adjusting for conventional risk factors., Conclusion: Bendopnea was observed in a relatively small proportion of older patients hospitalized for heart failure before discharge. However, its presence was significantly associated with an increased risk of all-cause mortality., Competing Interests: Conflict of interest: Y.M. received an honorarium from Otsuka Pharmaceutical Co., Novartis Pharma K.K., Bayer Inc., and AstraZeneca and research grants from Pfizer Japan Inc., Otsuka Pharmaceutical Co., EN Otsuka Pharmaceutical Co., Ltd, and Nippon Boehringer Ingelheim Co., Ltd. T.K. (Takatoshi Kasai) was affiliated with a department sponsored by Philips Respironics, ResMed, Teijin Home Healthcare, and Fukuda Denshi. N.K. is affiliated with a department funded by Paramount Bed Ltd., and receives research grants from EchoNous Inc. and AMI Inc. and honorarium from Novartis Pharama, Otsuka Pharma, Boehringer Ingelheim, and Elli Lilly. K.K. received funding outside the submitted work from Eiken Chemical Co., Ltd and SoftBank Corp., Ltd. The other authors have no conflicts of interest to declare., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Background: Sarcopenia is a substantial therapeutic target, yet the validity of risk stratification values per the latest Asian Working Group for Sarcopenia in 2019 (AWGS 2019) remains unconfirmed in patients with heart failure. We hypothesized that using the 6-minute walk test (6MWT) to assess physical performance improves risk stratification., Methods: The study included 832 hospitalized patients with heart failure who could walk at discharge. Sarcopenia was diagnosed using both the original AWGS 2019 criteria (AWGS 2019 model) and an alternative method in which physical performance components were replaced with the 6MWT (modified model). An < 300 m 6MWT indicated low physical performance in the modified model. The primary outcome was 2-year mortality., Results: Sarcopenia and severe sarcopenia were identified in 45 and 150 patients with the AWGS 2019 model and in 75 and 108 patients with the modified model, respectively. Over the 2-year follow-up period, 145 (17.4%) deaths occurred. Adjusted Cox proportional hazard analysis showed both sarcopenia and severe sarcopenia were significantly associated with 2-year mortality in the modified model. In the AWGS 2019 model, only severe sarcopenia was significantly related to 2-year mortality. The modified model demonstrated significant net reclassification improvement (NRI) over the AWGS 2019 model (NRI, 0.396; 95% CI, 0.214-0.578; P < 0.001)., Conclusions: In patients with heart failure who were ambulatory at discharge, sarcopenia assessment with the modified AWGS 2019 model using the 6MWT as a physical performance component improved risk stratification compared with the original AWGS 2019 model. Reconsidering the current criteria to improve risk stratification is necessary to ensure timely, appropriate treatment., Clinical Trial Registration: UMIN000023929., (Copyright © 2024 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.)

Background: Weight loss is a poor prognostic factor in patients with chronic heart failure (HF). However, whether the same is true for hospitalized patients with HF is unknown, even though hospitalization is the first opportunity for many patients to be diagnosed with HF. This study aimed to investigate the prognostic value of weight loss in patients hospitalized for HF., Methods: This was a post-hoc analysis of the FRAGILE-HF study, a prospective multi-center, observational study including 1,332 hospitalized older (≥65 years) patients with HF. The primary outcome was all-cause death within two years of discharge., Results: Self-reported body weight data one year prior to hospital admission were available for 1,106 patients (83.0%) and were compared with their weight after decongestion therapy. The median weight change was -6.9% [-2.4 - -11.9] and 86.8% of the overall cohort experienced some weight loss. Whereas patients with weight loss ≥ 5%, which is a well-validated cut-off in chronic HF, had comparable mortality to those with less weight loss (p = 0.96 by log-rank test), patients with weight loss > 12%, the lowest quartile value, had higher mortality than those with less weight loss (p = 0.024 for all-cause mortality, p = 0.028 for non-cardiovascular mortality, and p = 0.28 for cardiovascular mortality, respectively). In a Cox proportional hazard model, > 12% weight loss was associated with high mortality after adjusting for known prognostic factors and history of malignancy (adjusted hazard ratio: 1.485 [1.070-2.062], p=0.018)., Conclusion: Weight loss derived from patient-reported body weight one year before hospitalization was significantly associated with increased mortality after discharge, mainly due to non-cardiovascular etiology, in elderly patients hospitalized for HF., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Aims: In heart failure (HF), inflammation is linked to malnutrition and impaired physical function. In this study, we aimed to assess how novel nutritional-inflammatory markers and lymphocyte-to-C-reactive protein ratio (LCR) and score (LCS) are associated with the nutritional status, physical function, and prognosis of patients with HF., Methods and Results: This study was a secondary analysis of the FRAGILE-HF study, a prospective observational study conducted across 15 hospitals in Japan. We included 1212 patients (mean age, 80.2 ± 7.8 years; 513 women) hospitalized with HF, who were classified into three groups according to their LCS score: 0 (n = 498), 1 (n = 533), and 2 (n = 181). Baseline data on physical examination, echocardiography, blood test results (including lymphocyte counts and CRP levels), and oral medication usage were collected in a clinically compensated state before discharge. Nutritional status and physical function were evaluated using several indices and tests. The primary outcome of this study was all-cause death within 2 years. Univariate and multivariate linear regression analyses were performed to evaluate the associations among the nutritional status, physical function, and LCR/LCS. Patients with an LCS score of 2 were older and had a lower body mass index than those in the other two groups. Multivariate linear regression analysis revealed that lower LCR and higher LCS were independently associated with worse nutritional status, lower handgrip strength, shorter physical performance battery score, and shorter 6-min walk distance. At 2 years, all-cause death occurred in 254 patients: 86 (17.6%), 113 (21.5%), and 55 (30.9%) with LCS scores of 0, 1, and 2, respectively (P = 0.001). Cox proportional hazards analysis revealed that LCR and LCS were significantly associated with 2-year mortality even after adjusting for the conventional risk model (LCS score, 0 vs. 2: hazard ratio, 1.64; 95% confidence interval [CI]; 1.14-2.35; P = 0.007; log-transformed LCR: hazard ratio, 0.88; 95% CI, 0.81-0.95; P = 0.002). LCR yielded additional prognostic predictability compared with the conventional risk model (continuous net reclassification improvement, 0.153; 95% CI, 0.007-0.299; P = 0.041)., Conclusions: LCR and LCS emerge as potential predictors of nutritional status, physical function, and prognosis in older patients with HF., (© 2024 The Author(s). ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Background: Omecamtiv mecarbil improves outcomes in patients with heart failure and reduced ejection fraction (HFrEF). We examined the relationship between baseline troponin levels, change in troponin levels over time and the treatment effect of omecamtiv mecarbil in patients enrolled in the Global Approach to Lowering Adverse Cardiac Outcomes through Improving Contractility in Heart Failure (GALACTIC-HF) trial (NCT02929329)., Methods: GALACTIC-HF was a double-blind, placebo-controlled trial that randomized 8256 patients with symptomatic HFrEF to omecamtiv mecarbil or placebo. High-sensitivity troponin I (cTnI) was measured serially at a core laboratory. We analyzed the relationship between both baseline cTnI and change in cTnI concentrations with clinical outcomes and the treatment effect of omecamtiv mecarbil., Results: Higher baseline cTnI concentrations were associated with a risk of adverse outcomes (hazard ratio for the primary endpoint of time to first HF event or CV death = 1.30; 95% CI 1.28, 1.33; P < 0.001 per doubling of baseline cTnI). Although the incidence of safety outcomes was higher in patients with higher baseline cTnI, there was no difference between treatment groups. Treatment with omecamtiv mecarbil led to a modest increase in cTnI that was related to plasma concentrations of omecamtiv mecarbil, and it peaked at 6 weeks. An increase in troponin from baseline to week 6 was associated with an increased risk of the primary endpoint (P < 0.001), which was similar, regardless of treatment assignment (P value for interaction = 0.2)., Conclusions: In a cohort of patients with HFrEF, baseline cTnI concentrations were strongly associated with adverse clinical outcomes. Although cTnI concentrations were higher in patients treated with omecamtiv mecarbil, we did not find a differential effect of omecamtiv mecarbil on either safety or efficacy based on baseline cTnI status or change in cTnI., Competing Interests: DISCLOSURES GMF has received research grants from NHLBI, American Heart Association, Amgen, Bayer, BMS, Merck, Cytokinetics, and CSL-Behring; he has acted as a consultant to Novartis, Amgen, BMS, Cytokinetics, Medtronic, Cardionomic, Boehringer-Ingelheim, American Regent, Abbott, Astra-Zeneca, Reprieve, Myovant, Sequana, Windtree Therapuetics, and Whiteswell and has served on clinical endpoint committees/data safety monitoring boards for Amgen, Merck, Medtronic, EBR Systems, V-Wave, LivaNova, Siemens, and Rocket Pharma. SDS reports receiving grants (via Brigham and Women's Hospital) from Amgen and Cytokinetics during the conduct of the study; grants (via Brigham and Women's Hospital) from Actelion, Alnylam Pharmaceuticals, Amgen, AstraZeneca, Bellerophon Therapeutics, Bayer, Bristol Myers Squibb, Celladon, Cytokinetics, Eidos Therapeutics, Eli Lilly, Gilead Sciences,GlaxoSmithKline, Ionis Pharmaceuticals, Mesoblast,Myocardium, the National Heart, Lung, and Blood Institute, NeuroTronik, Novartis, Novo Nordisk, Respicardia, Sanofi Pasteur, and Theracos; and consulting fees from Abbott Laboratories, Action Pharma, Akros Pharma, Alnylam Pharmaceuticals, American Regent, Amgen, Arena Pharmaceuticals, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Cardiac Dimensions, Cardior Pharmaceuticals, Cardurion Pharmaceuticals, CellProthera, Corvia Medical, Cytokinetics, Daiichi Sankyo, Dinaqor, Eli Lilly and Company, GlaxoSmithKline, Janssen Pharmaceuticals, Merck & Co, Moderna, Myokardia, Novartis, Quantum Genomics, Roche, Sanofi Pasteur, Sarepta Therapeutics, Tenaya Therapeutics, Theracos, and Tremeau Pharmaceuticals. MM reports receiving personal fees from Amgen and Servier Laboratories during the conduct of the study and personal fees from Abbott Laboratories, Actelion, AstraZeneca, Edwards Lifesciences, LivaNova, Vifor Pharma, and Windtree Therapeutics. JJVM reports receiving travel fees and nonfinancial support (via the University of Glasgow) from Amgen during the conduct of the study; travel fees and nonfinancial support (via the University of Glasgow) from Alnylam Pharmaceuticals, AstraZeneca, Bayer, Bristol Myers Squibb, Cyclerion Therapeutics, Cytokinetics, DalCor Pharmaceuticals, GlaxoSmithKline, Novartis, Pfizer, Servier Laboratories, and Theracos; and personal fees from Abbott Laboratories, Hikma Pharmaceuticals, Servier Laboratories, and Sun Pharmaceutical Industries. RD reports receiving grants from Amgen during the conduct of the study. BC reports receiving grants (via Brigham and Women's Hospital) from Amgen and Cytokinetics during the conduct of the study and consulting fees from Amgen, Boehringer Ingelheim, Corvia Medical, Myokardia, and Novartis. DEL is supported in part by grants from the National Institutes of Health (P50MD017351, R01HL132154), has received research funding or support from Amgen, Astra Zeneca, Janssen, Eli Lilly, and Somalogic, and has acted as consultant to ACI Clinical (Abbott Laboratories), AstraZeneca, Cytokinetics, Duke Clinical Research Institute (CONNECT-HF), Illumina, Janssen, Martin Pharmaceuticals, Ortho Clinical Diagnostics, and Otsuka. HV reports being a national leader of GALACTIC-HF and has received lecture fees and consultation fees from Amgen. RDL reports research grants or contracts from Amgen, Bristol-Myers Squibb, GlaxoSmithKline, Medtronic, Pfizer, Sanofi-Aventis and funding for educational activities or lectures from Pfizer and Daiichi Sankyo and funding for consulting or other services from Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, and Novo Nordisk. S-IM reports being a national leader of GALACTIC-HF and has received lecture and consultation fees from Amgen. TB-S reports being a steering committee member of the Amgen-financed GALACTIC-HF trial, chief investigator and steering committee chair of the Sanofi Pasteur-financed NUDGE-FLU trial; chief investigator and steering committee chair of the Sanofi Pasteur-financed DANFLU-1 trial; steering committee member of LUX-Dx TRENDS Evaluates Diagnostics Sensors in Heart Failure Patients Receiving Boston Scientific's Investigational ICM System trial; is on the advisory boards of Sanofi Pasteur, Amgen and GSK; receives speaker honoraria from Bayer, Novartis, Sanofi Pasteur, and GSK and research grants from GE Healthcare and Sanofi Pasteur. SBH, PHD, SK, and FIM are employees of Cytokinetics. JRT reports receiving grants from Amgen and Cytokinetics, personal fees from Amgen, Cytokinetics and Servier Laboratories, and nonfinancial support from Amgen and Cytokinetics during the conduct of the study; grants from Abbott Laboratories, Bayer, Boerhinger Ingelheim, Bristol Myers Squibb, EBR Systems, LivaNova, Medtronic, Novartis, and Windtree Therapeutics; and personal fees from Amgen, AstraZeneca, Cytokinetics, Merck & Co, and Servier Laboratories. All other authors report no relevant disclosures., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Social factors encompass a broad spectrum of nonmedical factors, including objective (social isolation [SI]) and perceived (loneliness) conditions. Although social factors have attracted considerable research attention, information regarding their impact on patients with heart failure is scarce. We aimed to investigate the prognostic impact of objective SI and loneliness in older patients with heart failure., Methods and Results: This study was conducted using the FRAGILE-HF (Prevalence and Prognostic Value of Physical and Social Frailty in Geriatric Patients Hospitalized for Heart Failure; derivation cohort) and Kitasato cohorts (validation cohort), which included hospitalized patients with heart failure aged ≥65 years. Objective SI and loneliness were defined using the Japanese version of Lubben Social Network Scale-6 and diagnosed when the total score for objective and perceived questions on the Lubben Social Network Scale-6 was below the median in the FRAGILE-HF. The primary outcome was 1-year death. Overall, 1232 and 405 patients in the FRAGILE-HF and Kitasato cohorts, respectively, were analyzed. Objective SI and loneliness were observed in 57.8% and 51.4% of patients in the FRAGILE-HF and 55.4% and 46.2% of those in the Kitasato cohort, respectively. During the 1-year follow-up, 149 and 31 patients died in the FRAGILE-HF and Kitasato cohorts, respectively. Cox proportional hazard analysis revealed that objective SI, but not loneliness, was significantly associated with 1-year death after adjustment for conventional risk factors in the FRAGILE-HF. These findings were consistent with the validation cohort., Conclusions: Objective SI assessed using the Lubben Social Network Scale-6 may be a prognostic indicator in older patients with heart failure. Given the lack of established SI assessment methods in this population, further research is required to refine such methods.

Background: Although frailty is strongly associated with mortality in patients with heart failure (HF), the risk of which specific cause of death is associated with being complicated with frailty is unclear. We aimed to clarify the association between multidomain frailty and the causes of death in elderly patients hospitalized with HF., Methods: We analyzed data from the FRAGILE-HF cohort, where patients aged 65 years and older, hospitalized with HF, were prospectively registered between 2016 and 2018 in 15 Japanese hospitals before discharge and followed up for 2 years. All patients were assessed for physical, social, and cognitive dysfunction, and categorized into 3 groups based on their number of frailty domains (FDs, 0-1, 2, and 3). Kaplan-Meier survival analysis was used to evaluate the association between the number of FDs and all-cause mortality, whereas Fine-Gray competing risk regression analysis was used for assessing the impact on cause-specific mortality., Results: We analyzed 1181 patients with HF (81 years old in median, 57.4% were male), 530 (44.9%), 437 (37.0%), and 214 (18.1%) of whom were categorized into the FD 0 to 1, FD 2, and FD 3 groups, respectively. During the 2-year follow-up, 240 deaths were observed (99 HF deaths, 34 cardiovascular deaths, and 107 noncardiovascular deaths), and an increase in the number of FD was significantly associated with mortality (Log-rank: P <0.001). The Fine-Gray competing risk analysis adjusted for age and sex showed that FDs 2 (subdistribution hazard ratio, 1.77 [95% CI, 1.11-2.81]) and 3 (2.78, [95% CI, 1.69-4.59]) groups were associated with higher incidence of noncardiovascular death but not with HF and other cardiovascular deaths., Conclusions: Although multidomain frailty is strongly associated with mortality in older patients with HF, it is mostly attributable to noncardiovascular death and not cardiovascular death, including HF death., Registration: URL: https://www.clinicaltrials.gov; Unique identifier: UMIN000023929., Competing Interests: Disclosures Dr Matsue received an honorarium from Otsuka Pharmaceutical Co., Novartis Pharma K.K., Bayer Inc., and AstraZeneca and research grants from Pfizer Japan, Inc, Otsuka Pharmaceutical Co, EN Otsuka Pharmaceutical Co., Ltd., and Nippon Boehringer Ingelheim Co., Ltd. Nobuyuki Kagiyama received grants from Philips, Asahi KASEI Corporation, Toho Holdings Co. Ltd, Inter Reha Co. Ltd, EchoNous, Inc., and AMI, Inc. Outside of the submitted work. Dr Kamiya received grants and honorarium from Eiken Chemical Co., Ltd. and a research grant from SoftBnk Corp. Dr Kasai is affiliated with a department sponsored by Philips Respironics, ResMed, Teijin Home Healthcare, and Fukuda Denshi. The other authors declare no conflicts.

Background: This study investigated whether the chronic use of adaptive servo-ventilation (ASV) reduces all-cause mortality and the rate of urgent rehospitalization in patients with heart failure (HF)., Methods and results: This multicenter prospective observational study enrolled patients hospitalized for HF in Japan between 2019 and 2020 who were treated either with or without ASV therapy. Of 845 patients, 110 (13%) received chronic ASV at hospital discharge. The primary outcome was a composite of all-cause death and urgent rehospitalization for HF, and was observed in 272 patients over a 1-year follow-up. Following 1:3 sequential propensity score matching, 384 patients were included in the subsequent analysis. The median time to the primary outcome was significantly shorter in the ASV than in non-ASV group (19.7 vs. 34.4 weeks; P=0.013). In contrast, there was no significant difference in the all-cause mortality event-free rate between the 2 groups., Conclusions: Chronic use of ASV did not impact all-cause mortality in patients experiencing recurrent admissions for HF.

Aims: MitraScore is a novel, simple, and manually calculatable risk score developed as a prognostic model for patients undergoing transcatheter edge-to-edge repair (TEER) for mitral regurgitation. As its components are considered prognostic in heart failure (HF), we aimed to investigate the usefulness of the MitraScore in HF patients., Methods and Results: We calculated MitraScore for 1100 elderly patients (>65 years old) hospitalized for HF in the prospective multicentre FRAGILE-HF study and compared its prognostic ability with other simple risk scores. The primary endpoint was all-cause deaths, and the secondary endpoints were the composite of all-cause deaths and HF rehospitalization and cardiovascular deaths. Overall, the mean age of 1100 patients was 80 ± 8 years, and 58% were men. The mean MitraScore was 3.2 ± 1.4, with a median of 3 (interquartile range: 2-4). A total of 326 (29.6%), 571 (51.9%), and 203 (18.5%) patients were classified into low-, moderate-, and high-risk groups based on the MitraScore, respectively. During a follow-up of 2 years, 226 all-cause deaths, 478 composite endpoints, and 183 cardiovascular deaths were observed. MitraScore successfully stratified patients for all endpoints in the Kaplan-Meier analysis (P < 0.001 for all). In multivariate analyses, MitraScore was significantly associated with all endpoints after covariate adjustments [adjusted hazard ratio (HR) (95% confidence interval): 1.22 (1.10-1.36), P < 0.001 for all-cause deaths; adjusted HR 1.17 (1.09-1.26), P < 0.001 for combined endpoints; and adjusted HR 1.24 (1.10-1.39), P < 0.001 for cardiovascular deaths]. The Hosmer-Lemeshow plot showed good calibration for all endpoints. The net reclassification improvement (NRI) analyses revealed that the MitraScore performed significantly better than other manually calculatable risk scores of HF: the GWTG-HF risk score, the BIOSTAT compact model, the AHEAD score, the AHEAD-U score, and the HANBAH score for all-cause and cardiovascular deaths, with respective continuous NRIs of 0.20, 0.22, 0.39, 0.39, and 0.29 for all-cause mortality (all P-values < 0.01) and 0.20, 0.22, 0.42, 0.40, and 0.29 for cardiovascular mortality (all P-values < 0.02)., Conclusions: MitraScore developed for patients undergoing TEER also showed strong discriminative power in HF patients. MitraScore was superior to other manually calculable simple risk scores and might be a good choice for risk assessment in clinical practice for patients receiving TEER and those with HF., (© 2024 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Background: Frailty is associated with a poor prognosis in older patients with heart failure (HF). However, multidomain frailty assessment tools have not been established in patients with HF, and the association between the frailty phenotype and the deficit-accumulation frailty index in these patients is unclear. We aimed to understand this relationship and evaluate the prognostic value of the deficit-accumulation frailty index in older patients with HF., Methods: We retrospectively analyzed FRAGILE-HF cohort, which consisted of prospectively registered hospitalized patients with HF aged ≥ 65 years. The frailty index was calculated using 34 health-related items. The physical, social, and cognitive domains of frailty were evaluated using a phenotypic approach. The primary endpoint was all-cause mortality., Results: Among 1027 patients with HF (median age, 81 years; male, 58.1%; median frailty index, 0.44), a higher frailty index was associated with a higher prevalence in all domains of cognitive, physical, and social frailty defined by the phenotype model. During the 2-year follow-up period, a higher frailty index was independently associated with all-cause death even after adjustment for Meta-Analysis Global Group in Chronic Heart Failure (MAGGIC) score plus log B-type natriuretic peptide (per 0.1 increase: hazard ratio, 1.21; 95% confidence interval, 1.07-1.37; P = 0.002). The addition of the frailty index to the baseline model yielded statistically significant incremental prognostic value (net reclassification improvement, 0.165; 95% confidence interval, 0.012-0.318; P = 0.034)., Conclusions: A higher frailty index was associated with a higher prevalence of all domains of frailty defined by the phenotype model and provided incremental prognostic information with pre-existing risk factors in older patients with HF., (Copyright © 2023 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.)

Aims: Empagliflozin, a sodium-glucose co-transporter 2 inhibitor, was shown to be effective in patients with heart failure with preserved ejection fraction (HFpEF) in the EMPEROR-Preserved trial. The present study aims to evaluate the cost-effectiveness of empagliflozin among Japanese patients with HFpEF., Methods and Results: A Markov cohort model was developed to evaluate the cost-effectiveness of empagliflozin added to standard of care (SoC) compared with SoC alone in patients with HFpEF from the perspective of the Japanese healthcare system and with a lifetime horizon. In addition to clinical events, the progression of disease severity was modelled based on the migration of Kansas City Cardiomyopathy Questionnaire-Clinical Summary Scores (KCCQ-CSS). Model inputs, including risk of clinical events, costs, and utilities/disutilities, were derived from EMPEROR-Preserved trial data, a claims database and published literature. The generalizability of model results was investigated by applying various subgroups including age, body mass index (BMI), and region Asia, based on the subgroup analysis of EMPEROR-Preserved data. In the base-case analysis, empagliflozin yielded additional quality-adjusted life years (QALYs; 0.11) with an incremental cost of $1408 per patient for Japanese patients with HFpEF. Incremental cost, mainly derived from drug acquisition cost ($1963 per patient), was largely offset by reduced cost in hospitalization for heart failure (HHF) and cardiovascular death (-$537 per patient and -$166 per patient, respectively). Treatment of empagliflozin provided incremental 0.11 QALYs and 0.08 life years compared with SoC alone. The incremental cost-effectiveness ratio (ICER) was $12 772 (¥1 662 689)/QALY, which was below the Japanese willingness-to-pay (WTP) threshold of $38 408 (¥5 000 000)/QALY. The results were consistent across all the subgroups considered, and empagliflozin was dominant over SoC alone in the region Asia and BMI < 25 kg/m 2 subgroups. ICERs for the remaining subgroups ranged from $7520/QALY (¥978 972/QALY, patients with baseline age ≥ 75 years) to $31 049/QALY (¥4 041 896/QALY, patients with baseline New York Heart Association class III/IV). Deterministic sensitivity analysis result showed that the treatment effect on HHF is the biggest driver of the cost-effectiveness analysis, while the ICER will be still under the threshold even if no effect of empagliflozin on HHF was assumed. The probabilistic sensitivity analysis result showed that 64% of simulations were cost-effective based on the Japanese WTP threshold., Conclusions: Empagliflozin was demonstrated to be cost-effective for patients with HFpEF in Japan based on EMPEROR-Preserved trial data., (© 2023 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Aims: Although sarcopenia is common and associated with poor outcomes in patients with heart failure, its simple screening methods remain unclear. We aimed to investigate the predictive value of the Ishii score, which includes age, grip strength, and calf circumference, for sarcopenia and its prognostic predictability in patients with heart failure., Methods: This was a subanalysis of the FRAGILE-HF study. Receiver operating characteristic curves were used to evaluate the predictive value for sarcopenia. Patients were stratified into the high and low Ishii score groups based on the cutoff values of the Ishii score determined by the Youden index for sarcopenia, and the 1-year mortality rates were compared., Results: Of the 1262 study participants, 936 were evaluated with sarcopenia, and 184 (55 women, 129 men) were diagnosed with sarcopenia. The areas under the receiver operating characteristic curves for sarcopenia were 0.73 and 0.87 for women and men, respectively. The optimal cutoff values for predicting sarcopenia were 165 and 141 for women and men, respectively. Using these cutoff values, the sensitivity and specificity for sarcopenia were 70.9% and 68.5% for women and 88.4% and 69.7% for men, respectively. At 1 year, 151 (low Ishii score group, 98; high Ishii score group, 53) deaths were observed. Adjusted Cox proportional hazards analysis showed that the high Ishii score group was significantly associated with 1-year mortality., Conclusion: Among older patients hospitalized for heart failure, the Ishii score is useful for predicting sarcopenia and 1-year mortality. Geriatr Gerontol Int 2024; 24: 147-153., (© 2023 Japan Geriatrics Society.)

Background: Lower systolic blood pressure (SBP) is known to be associated with poor prognosis in heart failure (HF). We evaluated the efficacy and safety of sacubitril/valsartan according to baseline SBP tertiles in Japanese patients from the PARALLEL-HF study., Methods and results: In all, 223 patients were stratified into tertiles according to baseline SBP (≤114 mmHg: n=75; >114 and ≤130 mmHg: n=76; and >130 mmHg: n=72). Patients with lower SBP (≤114 mmHg) had the highest median N-terminal pro B-type natriuretic peptide (NT-proBNP) concentrations at baseline (P=0.0184). No significant difference was observed between sacubitril/valsartan and enalapril for the composite outcome of cardiovascular death and HF hospitalization across SBP tertiles (P-interaction=0.2682). Although the P-interaction value was not significant (0.2106), a greater reduction in NT-proBNP with sacubitril/valsartan compared with enalapril was observed in patients with SBP >130 mmHg (P=0.0076). The incidence of hypotension-related events and reduction or discontinuation of treatment due to hypotension-related events was higher in the lower SBP subgroup, and these events were more frequent in the sacubitril/valsartan than enalapril group., Conclusions: The efficacy of sacubitril/valsartan compared with enalapril was consistent across baseline SBP tertiles in Japanese patients from the PARALLEL-HF study. Hypotension-related events were more common in patients treated with sacubitril/valsartan with lower SBP.

Background: The PARALLEL-HF study assessed the efficacy and safety of sacubitril/valsartan vs. enalapril in Japanese patients with chronic heart failure with reduced ejection fraction (HFrEF). This open-label extension (OLE) assessed long-term safety with sacubitril/valsartan., Methods and results: This study enrolled 150 patients who received sacubitril/valsartan 50 or 100 mg, b.i.d., in addition to optimal background heart failure (HF) therapy. A dose level of sacubitril/valsartan 200 mg, b.i.d., was targeted by Week 8. At OLE baseline, higher concentrations of B-type natriuretic peptide (BNP) and urine cGMP, and lower concentrations of N-terminal pro B-type natriuretic peptide (NT-proBNP), were observed in the sacubitril/valsartan core group (patients who received sacubitril/valsartan in both the core and extension study) than in the enalapril core group (patients who received enalapril in the core study and were then transitioned to sacubitril/valsartan). The mean exposure to study drug was 98.9%. There was no trend of worsening of HF at Month 12. No obvious changes in cardiac biomarkers were observed, whereas BNP and urine cGMP increased and NT-proBNP decreased in the enalapril core group, which was evident at Weeks 2-4 and sustained to Month 12., Conclusions: Long-term sacubitril/valsartan at doses up to 200 mg, b.i.d., has a positive risk-benefit profile; it was safe and well tolerated in Japanese patients with chronic HFrEF.

Background: Cachexia substantially impacts the prognosis of patients with heart failure (HF); however, there is no standard method for cachexia diagnosis. This study aimed to investigate the association of Evans's criteria, consisting of multiple assessments, with the prognosis of HF in older adults., Methods: This study is a secondary analysis of the data from the FRAGILE-HF study, a prospective multicentre cohort study that enrolled consecutive hospitalized patients aged ≥65 years with HF. Patients were divided into two groups: the cachexia and non-cachexia groups. Cachexia was defined according to Evans's criteria by assessing weight loss, muscle weakness, fatigue, anorexia, a decreased fat-free mass index and an abnormal biochemical profile. The primary outcome was all-cause mortality, as assessed in the survival analysis., Results: Cachexia was present in 35.5% of the 1306 enrolled patients (median age [inter-quartile range], 81 [74-86] years; 57.0% male); 59.6%, 73.2%, 15.6%, 71.0%, 44.9% and 64.6% had weight loss, decreased muscle strength, a low fat-free mass index, abnormal biochemistry, anorexia and fatigue, respectively. All-cause mortality occurred in 270 patients (21.0%) over 2 years. The cachexia group (hazard ratio [HR], 1.494; 95% confidence interval [CI], 1.173-1.903; P = 0.001) had a higher mortality risk than the non-cachexia group after adjusting for the severity of HF. Cardiovascular and non-cardiovascular deaths occurred in 148 (11.3%) and 122 patients (9.3%), respectively. The adjusted HRs for cachexia in cardiovascular mortality and non-cardiovascular mortality were 1.456 (95% CI, 1.048-2.023; P = 0.025) and 1.561 (95% CI, 1.086-2.243; P = 0.017), respectively. Among the cachexia diagnostic criteria, decreased muscle strength (HR, 1.514; 95% CI, 1.095-2.093; P = 0.012) and low fat-free mass index (HR, 1.424; 95% CI, 1.052-1.926; P = 0.022) were significantly associated with high all-cause mortality, but there was no significant association between weight loss alone (HR, 1.147; 95% CI, 0.895-1.471; P = 0.277) and all-cause mortality., Conclusions: Cachexia evaluated by multi-assessment was present in one third of older adults with HF and was associated with a worse prognosis. A multimodal assessment of cachexia may be helpful for risk stratification in older patients with HF., (© 2023 The Authors. Journal of Cachexia, Sarcopenia and Muscle published by John Wiley & Sons Ltd on behalf of Society on Sarcopenia, Cachexia and Wasting Disorders.)

Background: For patients with advanced heart failure, palliative care, including opioids, is needed as a treatment for refractory dyspnea. However, little evidence has been reported on the efficacy and safety of opioids, and their use is not well established. Methods and Results: We have introduced a protocol for the use of opioids for dyspnea in patients with advanced heart failure admitted to Saitama Citizens Medical Center. Following this protocol, differences in clinical variables and outcome were investigated between patients in whom opioids were initiated intravenously or subcutaneously (i.v./s.c. group; n=13) and patients in whom they were initiated orally (oral group; n=18). In a comparison of baseline characteristics, significantly more patients in the oral group had a history of hospitalization for heart failure within the past year, and significantly more patients were treated with dobutamine and tolvaptan. After initiation of opioid treatment, both groups showed improvement in dyspnea; however, serial changes in vital signs were significantly greater in the i.v./s.c. group. The survival rate was significantly higher in the oral group (P<0.0001), with 33% of patients discharged alive. Conclusions: The clinical use of oral opioids using a single-center protocol is reported, suggesting that oral opioids may be practical and effective for dyspnea in patients with advanced heart failure., Competing Interests: The authors declare that they do not have any conflicts of interest to disclose., (Copyright © 2023, THE JAPANESE CIRCULATION SOCIETY.)

Introduction: Heart failure (HF) is an advanced stage of cardiac disease and is associated with a high rate of mortality. Previous studies have shown that sleep apnea (SA) is associated with a poor prognosis in HF patients. Beneficial effects of PAP therapy that is effective on reducing SA on cardiovascular events, were not yet established. However, a large-scale clinical trial reported that patients with central SA (CSA) which was not effectively suppressed by continuous positive airway pressure (CPAP) revealed poor prognosis. We hypothesize that unsuppressed SA by CPAP is associated with negative consequences in patients with HF and SA, including either obstructive SA (OSA) or CSA., Methods: This was a retrospective observational study. Patients with stable HF, defined as left ventricular ejection fraction of ≤50%; New York Heart Association class ≥ II; and SA [apnea-hypopnea index (AHI) of ≥15/h on overnight polysomnography], treated with CPAP therapy for 1 month and performed sleep study with CPAP were enrolled. The patients were classified into two groups according to AHI on CPAP (suppressed group: residual AHI ≥ 15/h; and unsuppressed group: residual AHI < 15/h). The primary endpoint was a composite of all-cause death and hospitalization for HF., Results: Overall, data of 111 patients including 27 patients with unsuppressed SA, were analyzed. The cumulative event-free survival rates were lower in the unsuppressed group during a period of 36.6 months. A multivariate Cox proportional hazard model showed that the unsuppressed group was associated with an increased risk for clinical outcomes (hazard ratio 2.30, 95% confidence interval 1.21-4.38, p  = 0.011)., Conclusion: Our study suggested that in patients with HF and SA including either OSA or CSA, presence of unsuppressed SA even on CPAP was associated with worse prognosis as compared to those with suppressed SA by CPAP., Competing Interests: RN and TK are affiliated with a department endowed by Philips Respironics, ResMed, and Fukuda Denshi. 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, (© 2023 Naito, Kasai, Tomita, Kasagi, Narui and Momomura.)

Background: No study with an adequate patients' number has examined the relationship/overlap between sarcopenia and cachexia. We examined the prevalence of the overlap and prognostic implications of sarcopenia and cachexia in older patients with heart failure using well-accepted definitions., Methods: This was a post-hoc sub-analysis of the FRAGILE-HF study, a prospective, multicenter, observational study conducted at 15 hospitals in Japan. In total, 905 hospitalized older patients were classified into four groups based on the presence or absence of cachexia and/or sarcopenia, which were defined according to the Evans and Asian Working Group for Sarcopenia criteria revised in 2019, respectively. The primary endpoint was 2-year all-cause mortality., Results: Cachexia and sarcopenia prevalence rates were 32.7% and 22.7%, respectively. Patients were classified into the non-cachexia/non-sarcopenia (55.7%), cachexia/non-sarcopenia (21.7%), non-cachexia/sarcopenia (11.6%), and cachexia/sarcopenia (11.0%) groups. During the 2-year follow-up period after discharge, 158 (17.5%) all-cause deaths (124 cardiovascular deaths [CVD] and 34 non-CVD) were observed. The cachexia/sarcopenia group had the lowest body fat mass and exhibited significantly higher mortality rates (log-rank P < 0.001). Cox proportional hazard analysis revealed that cachexia/sarcopenia was an independent prognostic factor after adjusting for known prognostic factors (versus non-cachexia/non-sarcopenia: hazard ratio, 2.78; 95% confidence interval, 1.80-4.29; P < 0.001). Neither cachexia/non-sarcopenia nor non-cachexia/sarcopenia were significantly associated with all-cause mortality compared with non-cachexia/non-sarcopenia., Conclusions: Cachexia and sarcopenia are prevalent among older hospitalized patients with heart failure; nonetheless, the overlap is not as prominent as previously expected. The presence of cachexia and sarcopenia is a risk factor for all-cause mortality., Competing Interests: Declaration of Competing Interest Yuya Matsue and Takatoshi Kasai are affiliated with a department-sponsored by Philips Respironics, ResMed, Teijin Home Healthcare, and Fukuda Denshi. Yuya Matsue received an honorarium from Otsuka Pharmaceutical Co. and Novartis Japan. Nobuyuki Kagiyama received grants from Philips, Asahi KASEI Corporation, Toho Holdings Co. Ltd., Inter Reha Co. Ltd., and EchoNous. Inc., as well as research grants from AMI Inc. outside of the submitted work. Kentaro Kamiya received research funding from Eiken Chemical Co. Ltd. The other authors declare no conflicts of interest., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Aims: Frailty is highly prevalent and associated with poor prognoses in elderly patients with heart failure (HF). However, the potential effects of physical frailty on the benefits of HF medications in elderly patients with HF are unclear. We aimed to determine the influence of physical frailty on the prognosis of HF medications in elderly patients with HF with reduced and mildly reduced ejection fraction (HFr/mrEF)., Methods and Results: From the combined HF database of the FRAGILE-HF and Kitasato cohorts, hospitalized HF patients with a left ventricular ejection fraction < 50% and age ≥ 65 years were analysed. Patients treated with or without renin-angiotensin-aldosterone system inhibitors (RAASi) and beta-blockers at discharge were compared. Physical frailty was defined by the presence of ≥3 items on the Japanese version of the Cardiovascular Health Study criteria. The primary endpoint was all-cause mortality rate. Among the 1021 enrolled patients, 604 patients (59%) received both RAASi and beta-blockers, and 604 patients (59%) were diagnosed as physically frail. Patients receiving both RAASi and beta-blockers showed a significantly lower 1 year mortality than those not receiving either, even after adjusting for covariates (hazard ratio: 0.50, 95% confidence interval: 0.34-0.75). This beneficial effect of both medications on 1 year mortality was comparable between patients with and without physical frailty (hazard ratio: 0.53 and 0.51, respectively; P for interaction = 0.77)., Conclusions: The presence of physical frailty did not interact with the beneficial prognostic impact of RAASi and beta-blocker combination therapy in elderly patients with HFr/mrEF., (© 2022 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Background: Several studies have reported the cost-effectiveness of sodium-glucose co-transporter 2 inhibitors in heart failure patients; however, their economic implications have not been sufficiently elucidated in Japan., Methods: A Markov cohort model was developed to evaluate the cost-effectiveness of empagliflozin plus standard of care (SoC) vs. SoC for patients with heart failure with reduced ejection fraction (HFrEF) in Japan. Model inputs, including risk of clinical events, costs, and utilities based on Kansas City Cardiomyopathy Questionnaire Clinical Summary Scores were derived from EMPEROR-Reduced trial data, published literature, and a claims database., Results: The model predicted lower lifetime hospitalizations for heart failure (HHFs) and additional quality-adjusted life-years (QALYs; 0.21) for empagliflozin plus SoC vs. SoC in the overall population. Increased costs of ¥100,495/patient ($772/patient), primarily driven by higher drug costs of ¥239,558/patient ($1,840/patient), were largely offset by reduced HHF management costs of -¥166,160/patient (-$1,276/patient), yielding an incremental cost-effectiveness ratio (ICER) of ¥469,672/QALY ($3,608/QALY). Results were consistent among subgroups and sensitivity analyses. In probabilistic sensitivity analysis, 82.5 % of runs were below the Japanese ICER reference value of ¥5,000,000/QALY ($38,408/QALY)., Conclusions: Empagliflozin was demonstrated to be cost-effective for HFrEF patients in Japan based on the EMPEROR-Reduced trial data., Competing Interests: Declaration of competing interest Hiroyuki Tsutsui received remuneration for attending meetings from Kowa Company, Limited, TEIJIN PHARMA, Nippon Boehringer Ingelheim Co., Ltd., Mitsubishi Tanabe Pharma Corporation, Pfizer Japan Inc., Ono Pharmaceutical CO., LTD, Daiichi Sankyo Company, Novartis Pharma K.K, Bayer Yakuhin, Ltd., Otsuka Pharmaceutical, AstraZeneca K.K, received manuscript fee from Nippon Rinsho, received research funding from Mitsubishi Tanabe Pharma Corporation, Nippon Boehringer Ingelheim Co., Ltd., IQVIA Services Japan K.K, medinet,inc, Medical Innovation Kyushu, Co., Ltd., Kowa Company, Daiichi Sankyo Company, Johnson & Johnson, NEC Corporation, received scholarship funds from Nippon Boehringer Ingelheim Co., Ltd., St.Mary's Hospital, TEIJIN PHARMA, Daiichi Sankyo Company, Mitsubishi Tanabe Pharma Corporation. Hiroyuki, Sakamaki received research funding from TOWA PHARMACEUTICAL CO., LTD. Shin-ichi Momomura received remuneration for attending meeting from Nippon Boehringer Ingelheim Co., Ltd. Yasushi Sakata received remuneration for attending meeting from Otsuka Pharmaceutical, Daiichi Sankyo Company, Mitsubishi Tanabe Pharma Corporation, Nippon Boehringer Ingelheim Co., Ltd., AstraZeneca K.K, Ono Pharmaceutical, CO., LTD, Novartis Pharma K.K, received research funding from Nippon Boehringer Ingelheim, received scholarship funds from Ono Pharmaceutical, CO., LTD, Otsuka Pharmaceutical, Daiichi Sankyo Company, Mitsubishi Tanabe Pharma Corporation, Nippon Boehringer Ingelheim Co., Ltd. Yutaro Kotobuki and Daisuke Nitta are employees of Nippon Boehringer Ingelheim Co., Ltd., while Stephan Linden is employed by Boehringer Ingelheim International GmbH. Tatsunori Murata is an employee of CRECON Medical Assessment Inc. Tetsuaki Hirase is an employee of Eli Lilly Japan K. K. and has stock from Eli Lilly and Company. Odette Reifsnider, Pal Rakonczai, and Matthew Stargardter are employees of Evidera, a biopharmaceutical research and consulting firm. In these salaried positions, they work with a variety of companies and are explicitly precluded from accepting any payment or honoraria directly from those companies for services rendered. Evidera received payment from Nippon Boehringer Ingelheim Co., Ltd. for collaboration on this project and article., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: The incremental prognostic value of the six-minute walking test over conventional risk factors has not been evaluated in an adequate number of patients with heart failure with preserved ejection fraction (HFpEF). Therefore, we aimed to examine its prognostic significance using data from the FRAGILE-HF study., Methods and Results: A total of 513 older patients who were hospitalized for worsening heart failure were examined. Patients were classified according to the tertiles of six-minute walking distance (6MWD): T1 (<166 m), T2 (166-285 m), and T3 (≥285 m). During the 2-year follow-up period after discharge, 90 all-cause deaths occurred. Kaplan-Meier curves showed that the T1 group had significantly higher event rates than the other groups (log-rank p = 0.007). Cox proportional hazard analysis revealed that the T1 group was independently associated with lower survival, even after adjusting for conventional risk factors (T3: hazard ratio 1.79, 95% confidence interval 1.02-3.14, p = 0.042). The addition of the 6MWD to the conventional prognostic model showed a statistically significant incremental prognostic value (net reclassification improvement 0.27, 95% confidence interval 0.04-0.49; p = 0.019)., Conclusions: The 6MWD is associated with survival in patients with HFpEF and has an incremental prognostic value over conventional well-validated risk factors., Competing Interests: Declaration of Competing Interest Y. M. and T. K. are affiliated with a department sponsored by Philips Respironics, ResMed, Teijin Home Healthcare, and Fukuda Denshi. Y. M. received an honorarium from Otsuka Pharmaceutical Co. and Novartis Japan. N. K. was affiliated with a department endowed by grants from Philips, Asahi KASEI Corporation, Toho Holdings Co., Ltd., and Inter Reha Co., Ltd., received research grants from EchoNous. Inc. and AMI Inc., and received an honorarium from Novartis Japan outside the submitted work. K. K. received funding outside the submitted work from Eiken Chemical Co., Ltd. and SoftBank Cor. Ltd. The other authors have no conflicts of interest to declare. All authors take responsibility for all aspects of the reliability and freedom from bias of the data presented and their discussed interpretation., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background: Telemonitoring the use of CPAP devices and remote feedback on device data effectively optimizes CPAP adherence in patients with OSA., Research Question: Can expanding the scope of telemonitoring and remote feedback to body weight (BW), BP, and physical activity enhance efforts for BW reduction in Patients with OSA receiving CPAP?, Study Design and Methods: Participants were recruited from patients at 16 sleep centers in Japan with OSA and obesity who were receiving CPAP therapy. Obesity was defined as a BMI of ≥ 25 kg/m 2 , based on Japanese obesity guidelines. Implementation of CPAP telemonitoring was enhanced with electronic scales, BP monitors, and pedometers that could transmit data from devices wirelessly. Participants were randomized to the multimodal telemonitoring group or the usual CPAP telemonitoring group and were followed up for 6 months. Attending physicians provided monthly telephone feedback calls to the usual CPAP telemonitoring group on CPAP data obtained remotely. In the multimodal telemonitoring group, physicians additionally encouraged participants to reduce their BW, after sharing the remotely obtained data on BW, BP, and step count. The primary outcome was set as ≥ 3% BW reduction from baseline., Results: One hundred sixty-eight participants (BMI, 31.7 ± 4.9 kg/m 2 ) completed the study, and ≥ 3% BW reduction occurred in 33 of 84 participants (39.3%) and 21 of 84 participants (25.0%) in the multimodal telemonitoring and usual CPAP telemonitoring groups, respectively (P = .047). Whereas no significant differences were found between the two groups in the change in office and home BP, daily step counts during the study period were significantly higher in the multimodal telemonitoring group than in the usual CPAP telemonitoring group (4,767 steps/d [interquartile range (IQR), 2,864-6,617 steps/d] vs 3,592 steps/d [IQR, 2,117-5,383 steps/d]; P = .02) INTERPRETATION: Multimodal telemonitoring may enhance BW reduction efforts in patients with OSA and obesity., Trial Registry: UMIN Clinical Trials Registry; No.: UMIN000033607; URL: www.umin.ac.jp/ctr/index.htm., (Copyright © 2022 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

Background: Statins are generally used for patients with coronary artery disease. However, the impact of statins in patients with vasospastic angina (VSA) is not fully understood., Methods: In a multicenter registry study of the Japanese Coronary Spasm Association (n = 1429), patients with or without statins were compared. The primary endpoint was major adverse cardiac events (MACEs), defined as cardiac death, non-fatal myocardial infarction, unstable angina, heart failure, and appropriate implantable cardioverter defibrillator shock. Propensity score matching and a multivariable Cox proportional hazard model were used to adjust for selection bias in treatment and potential confounding factors., Results: In the whole population, 469 patients received statins, while 960 patients did not receive statins. Patients with statins had a greater prevalence of comorbidities, including hypertension, diabetes, dyslipidemia, and smoking, in comparison to those without statins. The prevalence rates of previous myocardial infarction, significant organic stenosis, and medication use (including calcium channel blockers, angiotensin-converting enzyme inhibitor/angiotensin receptor blockers, and beta blockers) were greater in patients with statins than in those without statins. After propensity matching (n = 211 for both groups), a Kaplan-Meier curve analysis revealed that the incidence of MACE was comparable between patients with and without statins (p = 0.686). MACEs occurred in 6.0% of patients with statins and in 5.9% of those without statins (p = 0.98)., Conclusion: In this multicenter registry study, statin therapy did not reduce clinical events in VSA patients., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Background: The purpose of this study was to clarify the prevalence, association with frailty and exercise capacity, and prognostic implication of sarcopenic obesity in patients with heart failure., Methods: The present study included 779 older adults hospitalized with heart failure (median age: 81 years; 57.4% men). Sarcopenia was diagnosed based on the guidelines by the Asian Working Group for Sarcopenia. Obesity was defined as the percentage of body fat mass (FM) obtained by bioelectrical impedance analysis. The FM cut-off points for obesity were 38% for women and 27% for men. The primary endpoint was 1-year all-cause death. We assessed the associations of sarcopenic obesity occurrence with the short physical performance battery (SPPB) score and 6-minute walk distance (6MWD)., Results: The rates of sarcopenia and obesity were 19.3 and 26.2%, respectively. The patients were classified into the following groups: non-sarcopenia/non-obesity (58.5%), non-sarcopenia/obesity (22.2%), sarcopenia/non-obesity (15.3%), and sarcopenia/obesity (4.0%). The sarcopenia/obesity group had a lower SPPB score and shorter 6MWD, which was independent of age and sex (coefficient, - 0.120; t-value, - 3.74; P < 0.001 and coefficient, - 77.42; t-value, - 3.61; P < 0.001; respectively). Ninety-six patients died during the 1-year follow-up period. In a Cox proportional hazard analysis, sarcopenia and obesity together were an independent prognostic factor even after adjusting for a coexisting prognostic factor (non-sarcopenia/non-obesity vs. sarcopenia/obesity: hazard ratio, 2.48; 95% confidence interval, 1.22-5.04; P = 0.012)., Conclusion: Sarcopenic obesity is a risk factor for all-cause death and low physical function in older adults with heart failure., Trial Registration: University Hospital Information Network (UMIN-CTR: UMIN000023929 )., (© 2022. The Author(s).)

Aims: Although evidence suggests that cognitive decline and physical frailty in elderly patients with heart failure (HF) are associated with prognosis, the impact of concurrent physical frailty and cognitive impairment, that is, cognitive frailty, on prognosis has yet to be fully investigated. The current study sought to investigate the prevalence and prognostic impact of cognitive frailty in elderly patients with HF., Methods and Results: This study is a sub-analysis of FRAGILE-HF, a prospective multicentre observational study involving patients aged ≥65 years hospitalized for HF. The Fried criteria and Mini-Cog were used to diagnose physical frailty and cognitive impairment, respectively. The association between cognitive frailty and the combined endpoint of mortality and HF rehospitalization within 1 year was then evaluated. Among the 1332 patients identified, 1215 who could be assessed using Mini-Cog and the Fried criteria were included in this study. Among those included, 279 patients (23.0%) had cognitive frailty. During the follow-up 1 year after discharge, 398 combined events were observed. Moreover, cognitive frailty was determined to be associated with a higher incidence of combined events (log-rank: P = 0.0146). This association was retained even after adjusting for other prognostic factors (hazard ratio: 1.55, 95% confidence interval: 1.13-2.13). Furthermore, a sensitivity analysis using grip strength, short physical performance battery, and gait speed to determine physical frailty instead of the Fried criteria showed similar results., Conclusions: This cohort study found that 23% of elderly patients with HF had cognitive frailty, which was associated with a 1.55-fold greater risk for combined events within 1 year compared with patients without cognitive frailty., (© 2022 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Heart failure (HF) is a progressive cardiac disorder associated with high mortality and morbidity. Previous studies have shown that sleep apnea (SA) is associated with a poor prognosis in HF patients. When HF coexists with SA, both central and obstructive respiratory events often occur. However, few studies have investigated the association between the frequency of central respiratory events coexisting with obstructive events and clinical outcomes in patients with HF and SA. This was a retrospective observational study. Patients with stable HF, defined as a left ventricular ejection fraction of ≤50%, New York Heart Association class ≥ II, and SA (apnea-hypopnea index of ≥15/h on overnight polysomnography) were enrolled. The primary endpoint was a composite of all-cause death and hospitalization for HF. Overall, 144 patients were enrolled. During a period of 23.4 ± 16 months, 45.8% of patients experienced the outcome. The cumulative event-free survival rates were higher in the central SA-predominant group. Multivariate analyses showed that a greater percentage of central respiratory events was associated with an increased risk of clinical outcomes. In patients with HF and SA, the frequency of central respiratory events was an independent factor for all-cause death and hospitalization for HF.

Aims: A patient's understanding of his or her own comorbidities is part of the recommended patient education for those with heart failure. The accuracy of patients' understanding of their comorbidities and its prognostic impact have not been reported., Methods and Results: Patients hospitalized for heart failure (n = 1234) aged ≥65 years (mean age: 80.1 ± 7.7 years; 531 females) completed a questionnaire regarding their diagnoses of diabetes, malignancy, stroke, hypertension, chronic obstructive pulmonary disease (COPD), and coronary artery disease (CAD). The patients were categorized into three groups based on the number of agreements between self-reported comorbidities and provider-reported comorbidities: low (1-2, n = 19); fair (3-4, n = 376); and high (5-6, n = 839) agreement groups. The primary outcome was a composite of all-cause mortality or heart failure rehospitalization at 1 year. The low agreement group had more comorbidities and a higher prevalence of a history of heart failure. The agreement was good for diabetes (κ = 0.73), moderate for malignancy (κ = 0.56) and stroke (κ = 0.50), and poor-to-fair for hypertension (κ = 0.33), COPD (κ = 0.25), and CAD (κ = 0.30). The fair and low agreement groups had poorer outcomes than the good agreement group [fair agreement group: hazard ratio (HR): 1.25; 95% confidence interval (CI): 1.01-1.56; P = 0.041; low agreement group: HR: 2.74: 95% CI: 1.40-5.35; P = 0.003]., Conclusions: The ability to recognize their own comorbidities among older patients with heart failure was low. Patients with less accurate recognition of their comorbidities may be at higher risk for a composite of all-cause mortality or heart failure rehospitalization., (© 2022 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Background: Obstructive sleep apnea (OSA) is a potential risk factor in cardiovascular diseases, including arrhythmia, coronary artery disease, and heart failure (HF). Continuous positive airway pressure (CPAP) therapy is an effective therapy for OSA and the underlying HF, partly through a 5-9% increase in the left ventricular ejection fraction (LVEF). However, the data on the factors associated with the efficacy of CPAP on LVEF in patients with HF complicated by OSA are scarce. This study aimed to investigate whether LVEF improves in patients with OSA and HF after 1 month of CPAP therapy, and to clarify which factors are associated with the degree of LVEF improvement., Method: This was a prospective, single-arm, open-label study. We enrolled moderate-to-severe patients with OSA and HF who were being followed up at the cardiovascular center of Toranomon Hospital (Tokyo, Japan). The parameters of sleep study and LVEF were assessed at the baseline and after 1 month of CPAP. The multivariate regression analyses, with changes in LVEF as a dependent variable, were performed to determine the factors that were associated with the degree of LVEF improvement., Results: We analyzed 55 consecutive patients with OSA and HF (mean age: 60.7 ± 12.2 years, mean LVEF value: 37.2 ± 9.8%). One month of CPAP treatment decreased the apnea-hypopnea index (AHI) from 45.3 ± 16.1 to 5.4 ± 4.1 per hour, and the LVEF improved from 37.2 ± 9.8 to 43.2 ± 11.7%. The multivariate regression analyses demonstrated that age and body mass index (BMI) were significant determinants of LVEF improvement., Conclusion: The LVEF improved significantly after 1 month of CPAP therapy in Japanese patients with OSA and HF. Multivariate regression analyses indicated that an improvement in LVEF was likely to be observed in young patients with obesity., Competing Interests: RN and TK are affiliated with a department endowed by Philips Respironics, ResMed, and Fukuda Denshi. 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 Naito, Kasai, Dohi, Takaya, Narui and Momomura.)

We aimed to investigate the prevalence and the prognostic impact of malnutrition using the geriatric nutritional risk index (GNRI) in elderly patients with acute myocardial infarction (AMI). We investigated 130 consecutive patients aged ≥ 75 years who were discharged following successful primary coronary intervention between March 2009 and December 2016. The mean age of the patients was 81.5 ± 5.0 years, and 55.4% of them were male. At discharge, the patients' nutritional statuses were evaluated using the GNRI, which were calculated as follows: 14.89 × serum albumin (g/dL) + 41.7 × body mass index/22. The patients were divided into two groups, a low GNRI group (GNRI < 92) with nutrition-related risk and a high GNRI group (GNRI ≥ 92) without nutrition-related risk. The mean GNRI score of all patients was 95.2 ± 11.0, and 46 patients (35.4%) had a low GNRI score. During the mean follow-up of 1030 ± 850 days, the all-cause mortality was significantly higher in the low GNRI group than in the high GNRI group (32.6% vs. 13.1%, p < 0.001), while the event rates of AMI recurrence and hospitalization due to heart failure did not differ significantly between the two groups. Multivariate Cox proportional analysis revealed that low GNRI was a modest but independent predictor of mortality (hazard ratio, 0.94; 95% confidence interval 0.90-0.98; p = 0.01). Among elderly patients with AMI, malnutrition assessed using the GNRI was often encountered and was an independent predictor of long-term mortality., (© 2021. Springer Japan KK, part of Springer Nature.)

Background: No reports explicitly examined the relationship between work defined as a certain type of social participation or role and the protective effect on the prognosis of patients with heart failure (HF) by preventing frailty. Therefore, this study examined whether social participation through work before admission relates to future adverse events in HF patients aged ≥65 years, and whether each frailty domain mediates the association between work and prognosis as a second analysis of a multi-centered prospective study (FRAGILE-HF study)., Methods: We retrospectively reviewed 1,332 older patients with HF whose work status before admission to the hospital were investigated. We assessed the physical, cognitive, and social domains of frailty and performed causal mediation analysis to examine the mediating relationship of each frail domain between work status before admission and 1-year combined events (HF-related readmission and all-cause death)., Results: The subjects' median age was 81 years, and 56.9% (758/1,332) were male. Among the three domains of frailty, work before admission reduced only social frailty after adjusting for confounding factors (odds ratio: 0.505, 95% confidence interval: 0.364-0.701). Patients with work before admission had a significantly better prognosis (hazard ratio: 0.720, 95% confidence interval: 0.523-0.989). Only social frailty partly mediated the relationship between work status and combined events (p <0.05)., Conclusions: Work status before admission is associated with 1-year combined events, in part through social frailty., (Copyright © 2021. Published by Elsevier Ltd.)

Although postural hypotension (PH) is reportedly associated with mortality in the general population, the prognostic value for heart failure is unclear. This was a post-hoc analysis of FRAGILE-HF, a prospective multicenter observational study focusing on frailty in elderly patients with heart failure. Overall, 730 patients aged ≥ 65 years who were hospitalized with heart failure were enrolled. PH was defined by evaluating seated PH, and was defined as a fall of ≥ 20 mmHg in systolic and/or ≥ 10 mmHg in diastolic blood pressure within 3 min after transition from a supine to sitting position. The study endpoints were all-cause death and heart failure readmission at 1 year. Predictive variables for the presence of PH were also evaluated. PH was observed in 160 patients (21.9%). Patients with PH were more likely than those without PH to be male with a New York Heart Association classification of III/IV. Logistic regression analysis showed that male sex, severe heart failure symptoms, and lack of administration of angiotensin-converting enzyme inhibitors were independently associated with PH. PH was not associated with 1-year mortality, but was associated with a lower incidence of readmission after discharge after adjustment for other covariates. In conclusion, PH was associated with reduced risk of heart failure readmission but not with 1-year mortality in older patients with heart failure., (© 2022. The Author(s).)

Aims: A mineralocorticoid receptor antagonist (MRA) is effective in patients with chronic heart failure; however, the effects of the early initiation of an MRA in patients with acute heart failure (AHF) have not been elucidated., Methods and Results: In this multicentre, randomized, double-blind, placebo-controlled, parallel-group study, we focused on the safety and effectiveness of the treatment with eplerenone, a selective MRA in 300 patients with AHF, that is, 149 in the eplerenone group and 151 in the placebo group in 27 Japanese institutions. The key inclusion criteria were (i) patients aged 20 years or older and (ii) those with left ventricular ejection fraction of ≤40%. The primary outcome was a composite of cardiac death or first re-hospitalization due to cardiovascular disease within 6 months. The mean age of the participants was 66.8 years, 27.3% were women, and the median levels of brain natriuretic peptide were 376.0 pg/mL. The incidences of the primary outcome were 19.5% in the eplerenone group and 17.2% in the placebo group [hazard ratio (HR): 1.09, 95% confidence interval (CI): 0.642-1.855]. In prespecified secondary outcomes, HR for the composite endpoint, cardiovascular death, or first re-hospitalization due to heart failure within 6 months was 0.55 (95% CI: 0.213-1.434). The safety profile for eplerenone was as expected., Conclusion: The early initiation of eplerenone in patients with AHF could safely be utilized. The reduction of the incidence of a composite of cardiovascular death or first re-hospitalization for cardiovascular diseases by eplerenone is inconclusive because of inadequate power., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2020. For permissions, please email: journals.permissions@oup.com.)

Background and Aims: Frailty and sarcopenia are common and confer poor prognosis in elderly patients with heart failure; however, gender differences in its prevalence or prognostic impact remain unclear., Methods and Results: We included 1332 patients aged ≥65 years, who were hospitalized for heart failure. Frailty and sarcopenia were defined using the Fried phenotype model and Asian Working Group for Sarcopenia criteria, respectively. Gender differences in frailty and sarcopenia, and interactions between sex and prognostic impact of frailty/sarcopenia on 1-year mortality were evaluated. Overall, 53.9% men and 61.0% women and 23.7% men and 14.0% women had frailty and sarcopenia, respectively. Although sarcopenia was more prevalent in men, no gender differences existed in frailty after adjusting for age. On Kaplan-Meier analysis, frailty and sarcopenia were significantly associated with 1-year mortality in both sexes. On Cox proportional hazard analysis, frailty was associated with 1-year mortality only in men, after adjusting for confounding factors (hazard ratio [HR], 1.94; 95% confidence interval [CI], 1.19-3.16; P = 0.008 for men; HR, 1.63; 95% CI, 0.84-3.13; P = 0.147 for women); sarcopenia was an independent prognostic factor in both sexes (HR, 1.93; 95% CI, 1.13-3.31; P = 0.017 for men; HR, 3.18; 95% CI, 1.59-5.64; P = 0.001 for women). There were no interactions between sex and prognostic impact of frailty/sarcopenia (P = 0.806 for frailty; P = 0.254 for sarcopenia)., Conclusions: Frailty and sarcopenia negatively affect older patients with heart failure from both sexes., Clinical Trials: This study was registered at the University Hospital Information Network (UMIN-CTR, unique identifier: UMIN000023929) before the first patient was enrolled., Competing Interests: Declaration of competing interest Dr. Yuya Matsue and Takatoshi Kasai are affiliated with a department endowed by Philips Respironics, ResMed, Teijin Home Healthcare, and Fukuda Denshi; Dr. Yuya Matsue received an honorarium from Otsuka Pharmaceutical Co and Novartis Japan. Dr Kagiyama reports grants from Philips, Asahi KASEI Corporation, Toho Holdings Co. Ltd, and Inter Reha Co. Ltd, that are not related to the content of this article. Dr. Kamiya has received research funding from Eiken Chemical Co., Ltd. The other authors have nothing to declare., (Copyright © 2021 The Italian Diabetes Society, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition and the Department of Clinical Medicine and Surgery, Federico II University. Published by Elsevier B.V. All rights reserved.)

The prevalence of sleep-disordered breathing (SDB) is reportedly very high. Among SDBs, the incidence of obstructive sleep apnea (OSA) is higher than previously believed, with patients having moderate-to-severe OSA accounting for approximately 20% of adult males and 10% of postmenopausal women not only in Western countries but also in Eastern countries, including Japan. Since 1998, when health insurance coverage became available, the number of patients using continuous positive airway pressure (CPAP) therapy for sleep apnea has increased sharply, with the number of patients about to exceed 500,000 in Japan. Although the "Guidelines for Diagnosis and Treatment of Sleep Apnea Syndrome (SAS) in Adults" was published in 2005, a new guideline was prepared to indicate the standard medical care based on the latest trends, as supervised by and in cooperation with the Japanese Respiratory Society and the "Survey and Research on Refractory Respiratory Diseases and Pulmonary Hypertension" Group, of Ministry of Health, Labor and Welfare and other related academic societies, including the Japanese Society of Sleep Research, in addition to referring to the previous guidelines. Since sleep apnea is an interdisciplinary field covering many areas, this guideline was prepared including 36 clinical questions (CQs). In the English version, therapies and managements for SAS, which were written from CQ16 to 36, were shown. The Japanese version was published in July 2020 and permitted as well as published as one of the Medical Information Network Distribution Service (Minds) clinical practice guidelines in Japan in July 2021., Competing Interests: Conflict of interestYuichi Inoue is receiving daily allowances (lecture fees, etc.) from Alfresa Pharma Corporation, Eisai Corporation, MSD Corporation, Takeda Pharmaceutical Company Limited, along with research expenses from Astellas Pharma Corporation, Eisai Corporation, Takeda Pharmaceutical Company Limited, and Jassen Pharmaceutical K,K. He is also affiliated with the donated courses provided by Astellas Pharma Corporation, Alfresa Pharma Corporation, Eisai Corporation, MSD Corporation, Otsuka Pharmaceutical Co., Ltd., Koike Medical Co., Ltd., Takeda Pharmaceutical Company Limited, and Philips Japan, Ltd. Naohisa Uchimura is receiving daily allowances (lecture fees, etc.) from Eisai Co., Ltd., MSD Co., Ltd., Otsuka Pharmaceutical Co., Ltd., Takeda Pharmaceutical Company Limited, Mitsubishi Electric Co., Ltd., and Meiji Seika Furuma Co., Ltd.; manuscript fees from Eisai Co., Ltd., MSD Co., Ltd. and Otsuka Pharmaceutical Co., Ltd.; and scholarship (incentives) donations from Eisai Co., Ltd., MSD Co., Ltd., Otsuka Pharmaceutical Co., Ltd., and Pfizer Japan Inc. Takatoshi Kasai is receiving research funding from Asahi Kasei Co., Ltd., Sanwa Kagaku Kenkyusho Co., Ltd., Paramount Bed Co., Ltd., and ResMed Co., Ltd., along with scholarship (incentives) donations from Philips Japan Co., Ltd. He is also affiliated with the donated courses provided by Philips Japan, Ltd., Fukuda Denshi Co., Ltd., and ResMed Co., Ltd. Fusae Kawana is an officer of the Japan Sleep Comprehensive Examination Association, and is affiliated with the donated courses provided by Philips Japan, Ltd., Fukuda Denshi Co., Ltd., and ResMed Co., Ltd. Shigeru Sakurai is receiving scholarship (incentives) donations from Philips Japan, Ltd. and Kitara Co., Ltd. Takeshi Tanigawa is receiving research funding from Tokyo Electric Power Company Holdings, Inc. Kazuo Chin is receiving daily allowances (lecture fees, etc.) from Philips Japan, Ltd. and Teijin Home Medical Care, and is affiliated with the donated courses provided by Teijin Pharma Limited, Philips Japan, Ltd., Fukuda Denshi Co., Ltd., and ResMed Co., Ltd. Morio Tonogi is receiving research funding from GC Ortholy Corporation. Takeo Nakayama is receiving daily allowances (lecture fees, etc.) from Nippon Boehringer Ingelheim Co., Ltd., Pfizer Co., Ltd., and Janssen Pharmaceutical K.K., as well as receiving scholarship (incentives) donations from JMDC Co., Ltd. Motoo Yamauchi is receiving research funding from Koike Medical Co., Ltd. Toru Oga is affiliated with the donated courses provided by Teijin Pharma Limited, Philips Japan, Ltd., Fukuda Denshi Co., Ltd., and Fukuda Lifetech Keiji Co., Ltd. Yasuhiro Tomita is affiliated with the donated courses provided by Teijin Pharma Limited, Philips Japan, Ltd., Fukuda Denshi Co., Ltd., and ResMed Co., Ltd. Satoshi Hamada is affiliated with a donated course provided by Teijin Pharma Limited. Kimihiko Murase is affiliated with the donated courses provided by Teijin Pharma Limited, Philips Japan, Ltd., Fukuda Denshi Co., Ltd., Fukuda Lifetech Keiji Co., Ltd., and ResMed Co., Ltd. Makoto Uchiyama is receiving daily allowances (lecture fees, etc.) from Eisai Co., Ltd., MSD Co., Ltd., and Takeda Pharmaceutical Company Limited, along with scholarship (incentives) donations from Eisai Co., Ltd. and Meiji Seika Pharma Co., Ltd. Hiromasa Ogawa is affiliated with a donated course provided by Fukuda Lifetech Co., Ltd. Kazuo Mishima is receiving daily allowances (lecture fees, etc.) from Eisai Co., Ltd., MSD Co., Ltd., and Takeda Pharmaceutical Company Limited; research funds from Taisho Pharmaceutical Co., Ltd. and Nobelpharma Co., Ltd.; and scholarship (incentives) donations from Eisai Co., Ltd. and Takeda Pharmaceutical Company Limited. Tsuneto Akashiba, Motoharu Ohi, Misa Takegami, Ryo Tachikawa, Shintaro Chiba, Satoru Tsuiki, Hiroshi Nakamura, Koji Narii, Asako Yagi, Yoshihiro Yamashiro, Masahiro Yoshida, Hiroyuki Mori, Hiroo Wada, Kazumichi Sato, Seiichi Nakata, and Shinichi Momomura have no COIs to declare., (© The Author(s) 2021.)

Background: Low physical performance may contribute to reduced exercise capacity in older patients with heart failure (HF). We sought to identify the determinants of exercise capacity out of a plethora of background factors, including measures of physical performance., Methods: We performed a post-hoc analysis of a cohort study that included 1205 consecutive older (age ≥ 65 years) hospitalized patients (the median age, 80 years; 57.4% males)., Results: Low physical performance, defined as ≤1.0 m/s for gait speed, ≥12 s for the 5-time chair stand test, or ≤ 9 points for the Short Physical Performance Battery in both sexes, was seen in 83.9% of the cohort. Multivariate regression analysis revealed that each parameter of physical performance (i.e., gait speed, chair stand test, and balance test) was identified as an independent determinant of lower exercise capacity assessed using the 6-min walking distance. In a logistic regression model, low physical performance predicted short (<300 m) 6-min walking distance (adjusted odds ratio 10.28, 95% CI 6.01-17.60, p < 0.001). No interaction was detected between patients with preserved and reduced ejection fraction., Conclusions: Low physical performance was prevalent and independently associated with exercise capacity in older patients with HF, irrespective of preserved or reduced ejection fraction., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Competing Interests: Declaration of Competing Interest JCS/JHFS 2021 Guideline Focused Update on Diagnosis and Treatment of Acute and Chronic Heart Failure (January 1, 2018 to December 31, 2020).

Background: Thin-cap fibroatheroma (TCFA) has been suggested as a precursor lesion of coronary plaque rupture. As elevated plasma matrix metalloproteinase-9 (MMP-9) levels have been documented in patients with acute coronary syndrome (ACS), we sought to determine whether the presence of TCFA is linked to MMP-9 levels in these patients., Methods: We evaluated 51 ACS patients with de novo culprit lesions who were examined via optical coherence tomography and intravascular ultrasound. Blood samples were obtained from the peripheral vein (PV) and the ostium and culprit lesion of the infarct-related coronary artery (CA) in the acute phase of ACS and from the PV in the chronic phase (8 months after ACS)., Results: The plasma MMP-9 level in the acute phase was significantly higher than that in the chronic phase. Plasma MMP-9 levels at the culprit lesion of the infarct-related CA were significantly higher than, but positively correlated with those in the PV (10.9 (5.9-16.1) ng/mL and 8.9 (5.6-13.0) ng/mL, p < 0.0001, respectively; Spearman ρ = 0.84, p < 0.0001). Significantly higher PV plasma MMP-9 levels were observed in patients with TCFA than in patients without TCFA (12.1 (7.0-13.5) and 5.7 (4.0-8.2) ng/ml, p<0.0001, respectively). Further, plasma MMP-9 levels in the PV were positively correlated with the remodeling index (Spearman ρ = 0.29, p = 0.039) and negatively correlated with fibrous cap thickness (Spearman ρ = -0.42, p = 0.0021). Receiver operating characteristic curve analysis showed that the plasma MMP-9 levels in the PV could predict the presence of TCFA at a cut-off value of 9.9 ng/mL., Conclusions: Plasma MMP-9 levels were closely associated with MMP-9 levels in the CA and were further linked with TCFA in patients with ACS., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Since slow flow can be a fatal complication in left main coronary artery (LMCA)-acute coronary syndrome (ACS) patients, it should be important to anticipate and prepare slow flow during primary PCI for LMCA-ACS. We hypothesized that intravascular ultrasound (IVUS) findings would be useful to predict slow flow for LMCA-ACS patients without cardiogenic shock (CS). The purpose of this study was to investigate clinical factors associated with slow flow in LMCA-ACS patients without CS. We included 60 LMCA-ACS patients without CS, and divided into the slow flow group (n = 18) and the non-slow flow group (n = 42). Slow flow was defined as either transient or persistent TIMI flow grade ≤ 2. The prevalence of ST-segment elevation myocardial infarction (STEMI) was significantly higher in the slow flow group (55.6%) than in the non-slow flow group (11.9%) (p = 0.002). In the IVUS analysis, remodeling index was significantly greater in the slow flow group (1.15 ± 0.17) than in the non-slow flow group (0.99 ± 0.11) (p = 0.001). The multivariate logistic regression analyses in the IVUS factors revealed that remodeling index was significantly associated with slow flow (0.1 increase: OR 2.238, 95% CI 1.144-4.379, p = 0.019). In conclusion, remodeling index was significantly associated with slow flow. Our results suggest that the remodeling index determined by IVUS would be useful to find high-risk features of slow flow in LMCA-ACS patients without CS., (© 2020. Japanese Association of Cardiovascular Intervention and Therapeutics.)

Left ventricular remodeling (LVR) after ST-elevation myocardial infarction (STEMI) is generally thought to be an adaptive but compromising phenomenon particularly in patients with diabetes mellitus (DM). However, whether the extent of LVR is associated with poor prognostic outcome with or without DM after STEMI in the modern era of reperfusion therapy has not been elucidated. This was a single-center retrospective observational study. Altogether, 243 patients who were diagnosed as having STEMI between January 2016 and March 2019, and examined with echocardiography at baseline (at the time of index admission) and mid-term (from 6 to 11 months after index admission) follow-up were included and divided into the DM (n = 98) and non-DM groups (n = 145). The primary outcome was major adverse cardiovascular events (MACEs) defined as the composite of all-cause death, heart failure (HF) hospitalization, and non-fatal myocardial infarction. The median follow-up duration was 621 days (interquartile range: 304-963 days). The DM group was significantly increased the rate of MACEs (P = 0.020) and HF hospitalization (P = 0.037) compared with the non-DM group, despite of less LVR. Multivariate Cox regression analyses revealed that the patients with DM after STEMI were significantly associated with MACEs (Hazard ratio [HR] 2.79, 95% confidence interval [CI] 1.20-6.47, P = 0.017) and HF hospitalization (HR 3.62, 95% CI 1.19-11.02, P = 0.023) after controlling known clinical risk factors. LVR were also significantly associated with MACEs (HR 2.44, 95% CI 1.03-5.78, P = 0.044) and HF hospitalization (HR 3.76, 95% CI 1.15-12.32, P = 0.029). The patients with both DM and LVR had worse clinical outcomes including MACEs and HF hospitalization, suggesting that it is particularly critical to minimize LVR after STEMI in patients with DM., (© 2021. The Author(s).)

Aims: Although aging is strongly associated with both heart failure and a decline in gait speed, a definition of slowness incorporating an age-related decline has yet to be developed. We aimed to define an event-driven cut-off for the relative decline in gait speed against age-adjusted reference values derived from the general population and evaluate its prognostic implications., Methods and Results: Standardized gait speed (SGS) was defined as the median gait speed stratified by age, sex, and height in 3777 elderly (age ≥ 65 years) individuals without a history of cardiovascular diseases (Tokyo Metropolitan Institute of Gerontology-Longitudinal Interdisciplinary Study on Aging: general population cohort). The mortality event-driven optimal cut-off of the SGS ratio (actual gait speed divided by the respective SGS) was defined using FRAGILE-HF cohort data and externally validated using Kitasato cohort data, comprising 1301 and 1247 hospitalized elderly patients with heart failure, respectively. Using FRAGILE-HF data, the optimal SGS ratio cut-off was determined as 0.527. In the Kitasato cohort, SGS ratio < 0.527 was associated with a higher 1 year [hazard ratio (HR): 1.70, 95% confidence interval (CI): 1.07-2.72, P = 0.024] and long-term (HR: 1.46, 95% CI: 1.05-2.02, P = 0.024) mortality rate, independent of pre-existing covariates., Conclusions: Gait speed was significantly declined in patients with heart failure, even after taking age and sex-related decline into account. A SGS ratio of 0.527 is a validated cut-off for slowness independently associated with mortality in patients with heart failure age ≥65., (© 2021 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Aims: White blood cell (WBC) count in healthy people is associated with the risk of coronary artery disease (CAD) and mortality. This study aimed to determine whether WBC count predicts heart failure (HF) requiring hospitalization as well as all-cause death, acute myocardial infarction (AMI) and stroke in patients with Type 2 diabetes mellitus and established CAD., Methods: We conducted this retrospective registry study that enrolled consecutive patients with Type 2 diabetes mellitus and CAD based on coronary arteriography records and medical charts at 70 teaching hospitals in Japan from 2005 to 2015. A total of 7608 participants (28.2% women, mean age 68 ± 10 years) were eligible. In the cohort, the median (interquartile range) and mean follow-up durations were 39 (16.5-66.1 months) and 44.3 ± 32.7 months, respectively. The primary outcome was HF requiring hospitalization. The secondary outcomes were AMI, stroke, all-cause death, 3-point major adverse cardiovascular events (MACE) (AMI/stroke/death) and 4-point MACE (AMI/stroke/death/HF requiring hospitalization). Outcomes were reported as cumulative incidences (proportion of patients experiencing an event) and incidence rates (events/100 person-years). The primary and secondary outcomes were assessed using the Kaplan-Meier method and were compared using the log-rank test stratified by the baseline WBC count. The association between the WBC count at baseline and each MACE was assessed using the Cox proportional hazard model and expressed as the hazard ratio (HR) and 95% confidence interval (CI) after adjusting for other well-known risk factors for MACE., Results: During the follow-up, 880 patients were hospitalized owing to HF. The WBC Quartile 4 (≥7700 cells/μL) had significantly lower HF event-free survival rate (log-rank test, P < 0.001). The HRs for HF events requiring hospitalization with each WBC quartile compared with the lowest in the first WBC quartile were 1 for Quartile 1 (WBC < 5300 cells/μL), 1.20 (95% CI, 0.96-1.5; P = 0.1) for Quartile 2 (5300 ≤ WBC < 6400), 1.34 (95% CI, 1.08-1.67; P = 0.009) for Quartile 3 (6400 ≤ WBC < 7700) and 1.62 (95% CI, 1.31-2.00; P < 0.001) for Quartile 4 after adjusting for covariates. Similar findings were observed for the risk of AMI and death; however, no significant difference was found for stroke. WBC Quartile 4 patients had a significantly lower 3- or 4-point MACE-free survival rate (log-rank test, P < 0.0001)., Conclusions: A higher WBC count is a predictor of hospitalization for HF, all-cause death and AMI but not for stroke in patients with concurrent Type 2 diabetes mellitus and established CAD., (© 2021 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Background Frailty is conceptualized as an accumulation of deficits in multiple areas and is strongly associated with the prognosis of heart failure (HF). However, the social domain of frailty is less well investigated. We prospectively evaluated the clinical characteristics and prognostic impact of social frailty (SF) in elderly patients with HF. Methods and Results FRAGILE-HF (prevalence and prognostic value of physical and social frailty in geriatric patients hospitalized for heart failure) is a multicenter, prospective cohort study focusing on patients hospitalized for HF and aged ≥65 years. We defined SF by Makizako's 5 items, which have been validated as associated with future disability. The primary end point was a composite of all-cause death and rehospitalization because of HF. The impact of SF on all-cause mortality alone was also evaluated. Among 1240 enrolled patients, 825 (66.5%) had SF. During the 1-year observation period after discharge, the rates of the combined end point and all-cause mortality were significantly higher in patients with SF than in those without SF (Log-rank test: both P  < 0.05). SF remained as significantly associated with both the combined end point (hazard ratio, 1.30; 95% CI, 1.02-1.66; P  = 0.038) and all-cause mortality (hazard ratio, 1.53; 95% CI, 1.01-2.30; P  = 0.044), even after adjusting for key clinical risk factors. Furthermore, SF showed significant incremental prognostic value over known risk factors for both the combined end point (net-reclassification improvement: 0.189, 95% CI, 0.063-0.316, P  = 0.003) and all-cause mortality (net-reclassification improvement: 0.234, 95% CI, 0.073-0.395, P  = 0.004). Conclusions Among hospitalized geriatric patients with HF, two thirds have SF. Evaluating SF provides additive prognostic information in elderly patients with HF. Registration URL: https://upload.umin.ac.jp/. Unique identifier: UMIN000023929.