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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: Patients with heart failure (HF) often suffer from hepato-renal dysfunction. The associations between hepato-renal function changes and mortality remain unclear. Further, the effect of cardiac rehabilitation (CR) on mortality and motor functions in patients with HF and hepato-renal dysfunction requires investigation., Methods: We reviewed 2522 patients with HF (63.2 % male; median age: 74 years). The association between changes in hepato-renal function assessed by the Model for End-stage Liver Disease eXcluding INR (MELD-XI) score and mortality was examined. The association of CR participation with mortality and physical functions was investigated in patients with HF with decreased, unchanged, and increased MELD-XI scores., Results: During the follow-up period, 519 (20.6 %) patients died. Worsened MELD-XI score was independently associated with all-cause death [adjusted hazard ratio (aHR): 1.099; 95 % confidence interval (CI): 1.061-1.138; p < 0.001]. CR participation was associated with low mortality, even in the increased MELD-XI score group (aHR: 0.498; 95 % CI: 0.333-0.745; p < 0.001). Trajectory of the MELD-XI score was not associated with physical function changes. There were no time by MELD-XI score interaction effects on handgrip strength (p = 0.084), leg strength (p = 0.082), walking speed (p = 0.583), and 6-min walking distance (p = 0.833) in patients participating in outpatient CR., Conclusions: Hepato-renal dysfunction predicts high mortality. CR participation may be helpful for a better prognosis of patients with HF and hepato-renal dysfunction., Competing Interests: Declaration of competing interest The authors have no conflicts of interest directly relevant to the content of this article., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Aims: Atrial fibrillation (AF) frequently coexists with heart failure with preserved ejection fraction (HFpEF), and clinical outcomes of patients with AF vary depending on its subtype. While AF progression characterized by the transition from paroxysmal AF to persistent AF is sometimes observed, the incidence and clinical impact of AF progression in patients with HFpEF remain to be explored., Methods and Results: We enrolled patients with HFpEF and paroxysmal AF from the Chronic Heart Failure Analysis and Registry in the Tohoku District-2 (CHART-2) Study. AF progression was defined as the transition from paroxysmal AF to persistent AF. A total of 718 patients (median age: 72 years, 36% were female) were enrolled. For a median follow-up of 6.0 years (interquartile range: 3.0-10.2 years), AF progression occurred in 105 patients (14.6%), with a cumulative incidence of 16.7% at 10 years. In the multivariable Cox proportional hazards model, previous hospitalization for heart failure [hazard ratio (HR) 1.74, 95% confidence interval (CI) 1.16-2.60; P = 0.007] and left atrial diameter (per 5-mm increase) (HR 1.37, 95% CI 1.20-1.55; P < 0.001) were significantly associated with AF progression. Furthermore, AF progression was significantly linked to worsening heart failure (adjusted HR 1.68, 95% CI 1.18-2.40; P = 0.004). Notably, 27 cases (26%) of worsening heart failure occurred within 1 year following AF progression., Conclusion: In patients with HFpEF, AF progression is significantly associated with adverse outcomes, particularly worsening heart failure. An increased risk is observed in the early phases following progression to persistent AF., Registration: Clinical Trials.gov Identifier: NCT00418041., Competing Interests: Conflict of interest: H.S. has received lecture fees from Bayer Yakuhin (Osaka, Japan) and Daiichi Sankyo (Tokyo, Japan). S.Y. has received lecture fees from Bristol-Meyers (Tokyo, Japan), Bayer Yakuhin (Osaka, Japan) and Daiichi Sankyo (Tokyo, Japan). T.N. has recieved Grants-in-Aid for Scientific Research (22K08092) from the Ministry of Education, Culture, Sports, Science, and Technology of Japan and personal fees from Bayer Yakuhin (Osaka, Japan), Medtronic Japan (Tokyo, Japan), and Biotronik Japan (Tokyo, Japan). The remaining authors have no conflicts of interest to be disclosed., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Background: Diagnosing sarcopenia in heart failure (HF) patients is important, but how to assess skeletal muscle mass in HF patients with fluid retention is controversial. We aimed to examine the association between sarcopenia, defined by different skeletal muscle mass measurements, and clinical outcomes in older HF patients., Methods: We included 546 older HF patients (≥ 65 years) who were assessed for sarcopenia at discharge (median age 77 years, 309 males). Sarcopenia was diagnosed using grip strength, usual gait speed, and skeletal muscle mass according to international criteria. We used mid-upper arm circumference (MUAC), mid-upper arm muscle circumference (MAMC), calf circumference (CC), and skeletal muscle mass index (SMI) assessed by bioelectrical impedance analysis to assess skeletal muscle mass and defined sarcopenia in each of these measurements. Prognostic outcomes were composite events (all-cause death and HF rehospitalization) and cardiovascular disease (CVD) events (CVD death and CVD rehospitalization). Quality of life (QOL) was assessed using the 36-item Short-Form Health Survey physical functioning (SF-36PF) score., Results: The sarcopenia defined by MUAC [hazard ratio (HR): 2.50; 95 % confidence interval (95 % CI): 1.64-3.81; p < 0.001] or MAMC (HR: 1.98; 95 % CI: 1.35-2.92; p = 0.001) were associated with higher composite event rates than the non-sarcopenia. The sarcopenia defined by MUAC (HR: 1.88; 95 % CI: 1.25-2.83; p = 0.002) or MAMC (HR: 1.70; 95 % CI: 1.16-2.49; p = 0.007) were associated with higher CVD event rates than the non-sarcopenia. The sarcopenia defined by CC or SMI were not associated with prognoses. The sarcopenia defined by MUAC, MAMC, or CC were associated with low SF-36PF scores (all p < 0.05)., Conclusions: These results suggest that a diagnosis of sarcopenia based on MUAC or MAMC rather than CC or SMI reflects prognosis and QOL in older HF patients., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Background: Cardiac resynchronization therapy (CRT) is effective for patients with heart failure with QRS duration (QRSd) ≥150 ms. However, its beneficial effect seems to be limited for those with "mid-range" QRSd (120-149 ms). Recent studies have demonstrated that modifying QRSd to left ventricular end-diastolic volume (LVEDV)-modified QRSd-improves the prediction of clinical outcomes of CRT., Objective: The purpose of this study was to investigate the clinical impact of the modified QRSd on the efficacy of CRT in patients with "mid-range" QRSd., Methods: We conducted a retrospective, multicenter, observational study, with heart failure hospitalization (HFH) after CRT as the primary endpoint. Modified QRSd is defined as QRSd divided by LVEDV, determined through the Teichholtz method of echocardiography., Results: Among the 506 consecutive patients considered, 119 (mean age 61 ± 15 years; 80% male, QRSd 135 ± 9 ms) with a "mid-range" QRSd who underwent de novo CRT device implantation were included for analysis. During median follow-up of 878 days [interquartile range 381-1663 days], HFH occurred in 45 patients (37%). Fine-Gray analysis revealed modified QRSd was an independent predictor of HFH (hazard ratio [HR] 0.97; 95% confidence interval [CI] 0.96-0.99; P <.01). Receiver operating characteristic curve analysis revealed a cutoff value of 0.65 ms/mL for the modified QRSd in predicting HFH. Patients above the threshold exhibited a significantly lower incidence of HFH than patients below the threshold (HR 0.46; 95% CI 0.25-0.86; P = .01)., Conclusion: Modified QRSd can effectively predict the efficacy of CRT in patients with a "mid-range" QRSd., Competing Interests: Disclosures The authors have no conflicts to disclose., (Copyright © 2024 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

Aims: Patients with heart failure (HF) frequently experience decreased physical function, including walking speed. Slower walking speed is associated with poorer prognosis. However, most of these reports focused on patients with stable HF, and the relationship between walking speed in acute phase and clinical outcomes is unclear. Therefore, we aimed to investigate the associations between walking speed early after admission and clinical events in patients with acute decompensated HF (ADHF)., Methods and Results: We reviewed consecutive 1391 patients admitted due to ADHF. We measured walking speed the first time to walk on the ward more than 10 m after admission, and the speed within 4 days after admission was included in this study. The primary outcome was combined events (all-cause death and/or re-admission due to HF). The follow-up period was up to 1 year from the discharge. The study population had a median age of 74 years [interquartile range (IQR): 65-80 years], and 35.9% of patients were females. The median walking speed was 0.70 m/s (IQR: 0.54-0.88 m/s). Combined events occurred in 429 (30.8%) patients. Faster walking speed was independently associated with lower rate of combined events (adjusted hazard ratio per 0.1 m/s increasing: 0.951, 95% confidence interval: 0.912-0.992)., Conclusion: Faster walking speed within 4 days after admission was associated with favourable clinical outcomes in patients with ADHF. The results suggest that measuring walking speed in acute phase is useful for earlier risk stratification., Competing Interests: Conflict of interest: None declared in all authors., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Aims: The risk of developing heart failure (HF) after acute coronary syndrome (ACS) remains high. It is unclear whether skeletal muscle strength, in addition to existing risk factors, is a predictor for developing HF after ACS. We aimed to clarify the relationship between quadriceps isometric strength (QIS), a skeletal muscle strength indicator, and the risk of developing HF in patients with ACS., Methods and Results: We included 1053 patients with ACS without a prior HF or complications of HF during hospitalization. The median (interquartile range) age was 67 (57-74) years. The patients were classified into two groups-high and low QIS-using the sex-specific median QIS. The endpoint was HF admissions. During a mean follow-up period of 4.4 ± 3.7 years, 75 (7.1%) HF admissions were observed. After multivariate adjustment, a high QIS was associated with a lower risk of HF [hazard ratio: 0.52, 95% confidence interval (CI): 0.32-0.87]. Hazard ratio (95% CI) per 5% body weight increment increase of QIS for HF incidents was 0.87 (0.80-0.95). Even when competing risks of death were taken into account, the results did not change. The inclusion of QIS was associated with increases in net reclassification improvement (0.26; 95% CI: 0.002-0.52) and an integrated discrimination index (0.01; 95% CI: 0.004-0.02) for HF., Conclusion: The present study showed that a higher level of QIS was strongly associated with a lower risk of developing HF after ACS. These findings suggest that skeletal muscle strength could be one of the factors contributing to the risk of developing HF after ACS., Competing Interests: Conflict of interest: K.K. received funding outside of the submitted work from Eiken Chemical Co. Ltd and SoftBank Corporation. M.Y. has no conflict of interest related to the conduct of this study, but he holds company stock (<5% of the total) and receives a salary as one of the directors of an employer. All other authors have nothing to disclose., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Objectives: Sarcopenia in patients with heart failure (HF) is associated with poor prognosis. Cardiac rehabilitation (CR) decreases the incidence of adverse events in patients with HF. However, the clinical implications of improving sarcopenia status through CR remain unclear. This study investigated the relationship between the changes in sarcopenia status in patients with HF undergoing outpatient CR and the risk of mortality and adverse events., Design: This was a retrospective cohort study of patients hospitalized at the Kitasato University Hospital Cardiovascular Center for the treatment of HF between January 2007 and December 2020., Setting and Participants: Patients with HF whose sarcopenia status was assessed at hospital discharge and following at least 3 months of outpatient CR were included. Based on the sarcopenia status, all patients were divided into 3 groups: patients without sarcopenia at discharge (ie, robust), patients with sarcopenia at discharge but no sarcopenia following CR (ie, improved), and patients with sarcopenia at discharge and following CR (ie, unimproved)., Methods: Cox regression analysis was used to examine the risk of all-cause death associated with the 3 sarcopenia status groups., Results: Of 546 patients with HF (median age: 70 years; male: 63.6%), 377 (69.0%), 54 (9.9%), and 115 (21.1%) were classified as robust, improved, and unimproved, respectively. Multivariate Cox regression analysis showed that the unimproved group had a significantly greater risk of all-cause death when compared to the robust group [hazard ratio (HR) 2.603, 95% CI 1.375-4.930, P = .004], but it did not differ from the improved group (HR 1.403, 95% CI 0.598-3.293, P = .43)., Conclusions and Implications: No improvement in sarcopenia status in patients with HF undergoing outpatient CR was associated with a higher risk of all-cause death. Sarcopenia may be an important target to improve the prognosis of patients with HF., Competing Interests: Disclosure 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., (Copyright © 2023 AMDA – The Society for Post-Acute and Long-Term Care Medicine. Published by Elsevier Inc. All rights reserved.)

Background: Conflicting data are available on whether ventricular arrhythmia (VA) or shock therapy increases mortality. Although cardiac resynchronization therapy (CRT) reduces the risk of VA, little is known about the prognostic value of VA among patients with CRT devices., Objectives: The purpose of this study was to evaluate the implications of VA as a prognostic marker for CRT., Methods: We investigated 330 CRT patients within 1 year after CRT device implantation. The primary endpoint was the composite endpoint of all-cause death or hospitalization for heart failure., Results: Forty-three patients had VA events. These patients had a significantly higher risk of the primary endpoint, even among CRT responders (P = .009). Fast VA compared to slow VA was associated with an increased risk of the primary endpoint (hazard ratio [HR] 2.14; 95% confidence interval [CI] 1.06-4.34; P = .035). Shock therapy was not associated with a primary endpoint (shock therapy vs antitachycardia pacing: HR 1.49; 95% CI 0.73-3.03; P = .269). The patients with VA had a lower prevalence of response to CRT (23 [53%] vs 202 [70%]; P = .031) and longer left ventricular paced conduction time (174 ± 23 ms vs 143 ± 36 ms; P = .003) than the patients without VA., Conclusion: VA occurrence within 1 year was related to paced electrical delay and poor response to CRT. VA could be associated with poor prognosis among CRT patients., Competing Interests: Disclosures Dr Ueda received honoraria from Medtronic Japan Co., Ltd. for providing lectures. Dr Ishibashi received honoraria for teaching lectures from BIOTRONIK Japan and Medtronic Japan Co., Ltd. Dr Noda received honoraria for lectures from Medtronic Japan Co., Ltd. and BIOTRONIK Japan, Inc.; and belongs to a department endowed by BIOTRONIK Japan. Dr Dr Nagase is affiliated with a department endowed by Japan Medtronic Inc. Dr Kusano received honoraria from BIOTRONIK Japan and Medtronic Japan; and research grants from Medtronic Japan. However, none of these disclosures were directly associated with this study. All other authors have no conflicts to disclose., (Copyright © 2023 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

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: Sarcopenia is associated with risks of various adverse outcomes, and the assessment of skeletal muscle mass is necessary for its diagnosis. However, heart failure (HF) is a syndrome characterised by fluid retention, which affects muscle mass measurements. Different measurement methods have been reported to have different prognostic implications. We investigated the association between skeletal muscle mass metrics measured with the use of bioelectrical impedance analysis (BIA) and anthropometric measures and prognosis in patients with HF., Methods: The findings of 869 consecutive patients with HF were reviewed. We investigated the skeletal muscle mass index (SMI) measured with the use of BIA, the mid-upper arm circumference (MUAC), the arm muscle circumference (AMC), and the calf circumference (CC), and the patients were divided into 3 groups according to the sex-specific tertiles of the skeletal muscle mass metrics. The end points were all-cause death and readmission due to HF., Results: The high MUAC and AMC groups showed significantly better prognoses than their respective low groups (combined events: high MUAC group hazard ratio [HR] 0.559, 95% confidence interval [CI] 0.395-0.789 [P < 0.01]; high AMC group HR 0.505, 95% CI 0.359-0.710 [P < 0.01]), although high SMI and high CC were not associated with better prognoses., Conclusions: Among patients with HF, MUAC and AMC are more associated with prognosis than SMI and CC, which are recommended in preexisting sarcopenia guidelines. MUAC and AMC may also be useful measures in sarcopenia assessments., (Copyright © 2023 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.)

Background: High percent ventricular pacing maximizes cardiac resynchronization therapy (CRT) response. An effective CRT algorithm classifies each left ventricular (LV) pace as effective or ineffective on the basis of the detection of QS or QS-r morphology on the electrogram; however, the relationship between percent effective CRT pacing (%e-CRT) and responses is unclear., Objective: We aimed to clarify the association between %e-CRT and clinical outcomes., Methods: Of the 136 consecutive CRT patients, 49 using the adaptive and effective CRT algorithm with percent ventricular pacing > 90% were evaluated. The primary and secondary outcomes were heart failure (HF) hospitalization and prevalence of CRT responders, defined as patients with an improvement in LV ejection fraction of ≥10% or a reduction in LV end-systolic volume of ≥15% after CRT device implantation, respectively., Results: We divided the patients into the effective group (n = 25) and the less effective group (n = 24) by the median value of %e-CRT (97.4% [93.7%-98.3%]). During the median follow-up period of 507 days (interquartile range 335-730 days), the effective group had a significantly lower risk of HF hospitalization than the less effective group as revealed by Kaplan-Meier analysis (log-rank, P = .016). Univariate analysis revealed %e-CRT ≥ 97.4% (hazard ratio 0.12; 95% confidence interval 0.01-0.95; P = .045) as a predictor of HF hospitalization. The effective group had a higher prevalence of CRT responders than the less effective group (23 [92%] vs 9 [38%]; P < .001). Univariate analysis revealed that %e-CRT ≥ 97.4% (odds ratio 19.20; 95% confidence interval 3.63-101.00; P < .001) was a predictor of CRT response., Conclusion: High %e-CRT is associated with high CRT responder prevalence and low HF hospitalization risk., (Copyright © 2023 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

Aims: Sodium-glucose cotransporter 2 inhibitor (SGLT2i) improves clinical outcomes in patients with heart failure (HF), but has limited evidence of SGLT2i use in early-phase acute coronary syndrome (ACS). We determined association of early SGLT2i use compared with either non-SGLT2i or dipeptidyl peptidase 4 inhibitor (DPP4i) use in hospitalized patients with ACS., Methods and Results: This retrospective cohort study that used the Japanese nationwide administrative claims database included patients hospitalized with ACS aged ≥20 years between April 2014 and March 2021. The primary outcome was a composite of all-cause mortality or HF/ACS rehospitalization. Using 1:1 propensity score matching, the association with outcomes of the early SGLT2i use (≤14 days after admission) compared with non-SGLT2i or DPP4i use was determined according to the HF treatment. Among 388 185 patients included 115 612 and 272 573 with and without severe HF, respectively. Compared to non-SGLT2i users, the SGLT2i users had a lower hazard ratio (HR) with the primary outcome [HR: 0.83, 95% confidence interval (CI): 0.76-0.91; P < 0.001] in the severe HF group; however, there was no significant difference in the non-severe HF group (HR: 0.92, 95% CI: 0.82-1.03; P = 0.16). SGLT2i use showed a lower risk of the outcome in patients with severe HF and diabetes compared with DPP4i use (HR: 0.83, 95% CI: 0.69-1.00; P = 0.049)., Conclusion: SGLT2i use in patients with early-phase ACS showed a lower risk of primary outcome in patients with severe HF, but the effect was not apparent in patients without severe HF., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Background: Patients with heart failure (HF) often exhibit signs of liver dysfunction such as high bilirubin concentrations, leading to physical dysfunction and poor prognosis. Nevertheless, the relationship between direct bilirubin (DB), a fractionated form of total bilirubin, and dynapenia remains unclear, as does their effect on prognosis., Objectives: This study investigated the association between DB concentrations and dynapenia in patients with HF., Methods: This retrospective study included patients with HF who underwent assessments for DB concentration, and handgrip and leg strengths to evaluate dynapenia and muscle weakness, respectively. Multiple logistic regression analyses examined the associations of DB with muscle strength and dynapenia. Additionally, we examined the prognostic value of comorbid high DB concentrations (≥0.5 mg/dL) and dynapenia. The endpoint was all-cause mortality., Results: Of 853 inpatients, high DB was identified in 147 and dynapenia in 377 (44.2%). Multiple regression analysis revealed that high DB was independently associated with decreased muscle strength (handgrip strength, P = 0.027; leg strength, P = 0.002). After adjusting for covariates, the high DB group (odds ratio: 1.800, 95% confidence interval [CI]: 1.203-2.695, P = 0.004) had a significantly higher risk of dynapenia than the low DB group. During the follow-up period, 189 patients died (median, 1.77 years; interquartile range, 0.64-3.81 years). The risk of death was significantly higher in the high DB and dynapenia group, even after adjusting for HF severity (hazard ratio: 2.610, 95% CI: 1.680-4.051, P<0.001)., Conclusions: High DB is associated with muscle weakness, and when combined with dynapenia, DB predicts a poorer prognosis in patients with HF., Competing Interests: Declaration of Competing Interest The authors have no conflicts of interest directly relevant to the content of this article. Although Mr. Yamashita has no conflict of interest related to the conduct of this study, he holds company stock (less than 5% of the total) and receives a salary as one of the directors of an employer., (Copyright © 2023 Elsevier Inc. All rights reserved.)

In community-dwelling older people, coronavirus disease 2019 (COVID-19) has been reported to be associated with the development of frailty and depressive symptoms. We aimed to investigate whether the spread of COVID-19 is associated with the development of frailty in patients with heart failure (HF). The presence of the multi-domain of frailty in 257 patients with HF was assessed at hospital discharge. The spread of COVID-19 was significantly associated with the development of social frailty and depressive symptoms. Evaluation of these symptoms during hospitalization would support disease management and understanding of their social and psychological conditions., (© 2022. Springer Japan KK, part of Springer Nature.)

Aims: Reactive atrial-based anti-tachycardia pacing (rATP) in pacemakers (PMs) and cardiac resynchronization therapy defibrillators (CRT-Ds) has been reported to prevent progression of atrial fibrillation, and this reduced progression is expected to decrease the risk of complications such as stroke and heart failure (HF). This study aimed to assess the cost-effectiveness of rATP in PMs and CRT-Ds in the Japanese public health insurance system., Methods and Results: We developed a Markov model comprising five states: bradycardia, post-stroke, mild HF, severe HF, and death. For devices with rATP and control devices without rATP, we compared the incremental cost-effectiveness ratio (ICER) from the payer's perspective. Costs were estimated from healthcare resource utilisation data in a Japanese claims database. We evaluated model uncertainty by analysing two scenarios for each device. The ICER was 763 729 JPY/QALY (5616 EUR/QALY) for PMs and 1,393 280 JPY/QALY (10 245 EUR/QALY) for CRT-Ds. In all scenarios, ICERs were below 5 million JPY/QALY (36 765 EUR/QALY), supporting robustness of the results., Conclusion: According to a willingness to pay threshold of 5 million JPY/QALY, the devices with rATP were cost-effective compared with control devices without rATP, showing that the higher reimbursement price of the functional categories with rATP is justified from a healthcare economic perspective., Competing Interests: Conflict of interest: Y.T., Y.I., and T.M. are employees of Medtronic Japan, and J.-E.M. is an employee of Medtronic Korea. T.U., H.Y., and A.S. are employees of Medilead, which was commissioned by Medtronic Japan. K.K., T.N., and N.U. have received compensation for advisory services for this study from Medtronic Japan and other payments, including honoraria, for lectures which were not directly associated with this study from Medtronic Japan. K.K. has received speaker honoraria from Medtronic Japan, Biotronik Japan and Boston Scientific and research grants from Medtronic Japan and Biotronik Japan. The authors have no other conflicts of interest to disclose., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Background: We aimed to validate a claims-based diagnostic algorithm to identify hospitalized patients with acute major cardiovascular diseases (CVDs) from health insurance claims in Japan., Methods and results: This retrospective multicenter validation study was conducted at 4 institutes, including Japanese Circulation Society-certified and uncertified hospitals in Japan. Data on patients with CVDs in departmental lists or with International Classification of Diseases, 10th Revision (ICD-10) codes for CVDs hospitalized between April 2018 and March 2019 were extracted. We examined the sensitivity and positive predictive value of a diagnostic algorithm using ICD-10 codes, medical examinations, and treatments for acute coronary syndrome (ACS), acute heart failure (HF), and acute aortic disease (AAD). We identified 409 patients with ACS (mean age 70.6 years; 24.7% female), 615 patients with acute HF (mean age 77.3 years; 46.2% female), and 122 patients with AAD (mean age 73.4 years; 36.1% female). The respective sensitivity and positive predictive value for the algorithm were 0.86 (95% confidence interval [CI] 0.82-0.89) and 0.95 (95% CI 0.92-0.97) for ACS; 0.74 (95% CI 0.70-0.77) and 0.79 (95% CI 0.76-0.83) for acute HF; and 0.86 (95% CI 0.79-0.92) and 0.83 (95% CI 0.76-0.89) for AAD., Conclusions: The validity of the diagnostic algorithm for Japanese claims data was acceptable. Our results serve as a foundation for future studies on CVDs using nationwide administrative data.

Background: Complex multi-organ interactions such as coexistence of hepato-renal dysfunction in heart failure (HF) adversely affects patient prognosis. However, the association between liver/kidney dysfunction and frailty and effects of their coexistence on HF prognosis remain unclear., Methods: This retrospective cohort study included 922 patients with HF (median age, 72 years; interquartile range: 62-79 years). All patients underwent hepato-renal function testing using the model for end-stage liver disease, excluding international normalized ratio (MELD-XI) score and frailty score. Frailty was measured using a composite of four markers: handgrip strength, gait speed, serum albumin, and activities of daily living status, combined into a total frailty score (range 0-12). Patients were assigned to a frailty score <5 (without frailty) or ≥5 (frailty) group. The multivariable logistic regression model was used to analyze the association between MELD-XI score and frailty; the prognostic value of high MELD-XI score and frailty coexistence was investigated. The endpoint was all-cause mortality., Results: After adjusting for covariates and dividing by the median MELD-XI score, the high MELD-XI score group [odds ratio: 1.663, 95 % confidence interval (CI): 1.200-2.304, p = 0.002] was significantly associated with frailty, compared with the low MELD-XI score group. One hundred and fifty deaths occurred during follow-up (median, 2.13 years; interquartile range, 0.93-4.09 years). Patients in the high MELD-XI score/frailty group had a significantly higher mortality risk, even after adjusting for HF severity (hazard ratio: 4.326, 95 % CI: 2.527-7.403, p < 0.001)., Conclusions: Hepato-renal dysfunction is associated with frailty in patients with HF, which affects patient prognosis., Brief Summary: This study showed that hepato-renal dysfunction in patients with HF, as assessed by the model for end-stage liver disease excluding international normalized ratio (MELD-XI) score, is associated with frailty, even after adjusting for factors involved in the frailty or severity of HF. Additionally, high MELD-XI score combined with frailty is associated with a poorer prognosis. These results suggest that hepato-renal dysfunction and frailty can be used for risk stratification in patients with HF., Competing Interests: Declaration of competing interest The author(s) declare no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (Copyright © 2022. Published by Elsevier Ltd.)

Background: The prospective observational Nippon Storm Study aggregated clinical data from Japanese patients receiving implantable cardioverter-defibrillator (ICD) therapy. This study investigated the usefulness of prophylactic ICD therapy in patients with non-ischemic heart failure (NIHF) enrolled in the study., Methods and results: We analyzed 540 NIHF patients with systolic dysfunction (left ventricular ejection fraction <50%). Propensity score matching was used to select patient subgroups for comparison; 126 patients were analyzed in each of the primary (PP) and secondary (SP) prophylaxis groups. The incidence of appropriate ICD therapy during follow-up in the PP and SP groups was 21.4% and 31.7%, respectively (P=0.044). The incidence of electrical storm (ES) was higher in SP than PP patients (P=0.024). Cox proportional hazard analysis revealed that increased serum creatinine in SP patients (hazard ratio [HR] 1.18; 95% confidence interval [CI] 1.02-1.33; P=0.013) and anemia in PP patients (HR 0.92; 95% CI 0.86-0.98; P=0.008) increased the likelihood of appropriate ICD therapy, whereas long-lasting atrial fibrillation in PP patients (HR, 0.64 [95% CI, 0.45-0.91], P=0.013) decreased that likelihood., Conclusions: In propensity score-matched Japanese NIHF patients, the incidence of appropriate ICD therapy and ES was significantly higher in SP than PP patients. Impaired renal function in SP patients and anemia in PP patients increased the likelihood of appropriate ICD therapy, whereas long-lasting atrial fibrillation reduced that likelihood in PP patients.

Background: Few studies have comprehensively evaluated the trends and factors associated with CR participation across major cardiovascular diseases in Japan., Methods and results: This study performed a nationwide cross-sectional study using the National Database of Health Insurance Claims and Specific Health Checkups of Japan and the Japanese Registry of All Cardiac and Vascular Diseases and the Diagnosis Procedure Combination database. This study described the nationwide trends and evaluated patient- and hospital-level associated factors of CR participation for patients with acute heart failure (AHF), acute coronary syndrome (ACS), acute aortic dissection (AAD), peripheral artery disease (PAD), and after cardiovascular surgery using mixed-effect logistic regression analysis. Although the annual number of patients who underwent CR has increased during the study period, the total number of patients participating in outpatient CR was lower than that of inpatient CR. The outpatient CR participation rate was lower for patients with AHF (3.5%), AAD (3.2%), and PAD (1.7%), compared with ACS (7.9%) and after surgery (9.4%). Age, sex, body mass index, Barthel index, Charlson comorbidity index, and institutional capacity were identified as significant associated factors of CR participation in inpatient and outpatient settings., Conclusions: Participation in outpatient CR was still low, and higher age, multi-comorbidity, and low institutional capacity contributed to the lower outpatient CR participation rate. Identification of the associated factors may help cardiologists to increase CR participation.

Aims: Although the developmental mechanism of respiratory muscle weakness (RMW) and frailty are partly similar in patients with cardiovascular disease (CVD), their relationship remains unclear. This study aimed to investigate the correlation between RMW and frailty and its impact on clinical outcomes in patients with CVD., Methods and Results: In this retrospective observational study, consecutive 1217 patients who were hospitalized for CVD treatment were enrolled. We assessed frailty status by using the Fried criteria and respiratory muscle strength by measuring the maximal inspiratory pressure (PImax) at hospital discharge, with RMW defined as PImax <70% of the predicted value. The endpoint was a composite of all-cause death and/or readmission for heart failure. We examined the prevalence of RMW and frailty and their correlation. The relationships of RMW with the endpoint for each presence or absence of frailty were also investigated. Respiratory muscle weakness and frailty were observed in 456 (37.5%) and 295 (24.2%) patients, respectively, and 149 (12.2%) patients had both statuses. Frailty was detected as a significant indicator of RMW [odds ratio: 1.84, 95% confidence interval (CI): 1.39-2.44]. Composite events occurred in 282 patients (23.2%). Respiratory muscle weakness was independently associated with an increased incidence of events in patients with both non-frailty [hazard ratio (HR): 1.40, 95% CI: 1.04-1.88] and frailty (HR: 1.68, 95% CI: 1.07-2.63)., Conclusions: This is the first to demonstrate a correlation between RMW and frailty in patients with CVD, with 12.2% of patients showing overlap. RMW was significantly associated with an increased risk of poor outcomes in patients with CVD and frailty., Competing Interests: Conflict of interest: none declared., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2022. For permissions, please email: journals.permissions@oup.com.)

Aims: Real-world evidence about heart failure (HF) medical care for elderly patients is limited. The aim of this study was to clarify the age-dependent associations of HF medications at discharge with clinical outcomes in a super-aged society using a real-world big database., Methods and Results: Patients hospitalized with a first episode of acute HF in 2013-2019 were identified in a nationwide claims database in Japan and were analyzed based on the HF medications at discharge. Hazard ratios (HRs) and 95 % confidence intervals (95 % CIs) for clinical outcomes were calculated after adjustment. Among 325,468 patients from 4351 hospitals, 130,230 (40.0 %) were aged ≥ 85 years. All-cause mortality and HF readmission rate within 1 year were 14 % and 23 %, respectively. β-Blockers and angiotensin-converting-enzyme inhibitors or angiotensin II receptor blockers (ACEI/ARB) uses were associated with lower mortality (HR [95 %CI]: 0.84 [0.83,0.86] and 0.73 [0.71,0.74], respectively) and HF readmission (0.98 [0.97,0.99] and 0.89 [0.88,0.90], respectively). The associations were attenuated as the age increased and, in β-blockers use, the favorable associations with mortality and HF readmission were not observed in patients with ≥ 95 years and ≥ 80 years, respectively. In contrast, mineralocorticoid receptor antagonists (MRA) use was associated only with lower HF readmission (0.83 [0.82,0.84]), which was not attenuated with increased age., Conclusions: The favorable associations of β-blockers and ACEI/ARB uses with mortality and HF readmission were age-dependently attenuated in patients across a broad spectrum of HF in a super-aged society. In contrast, positive impact of MRA use on HF readmission was not attenuated with aging., Competing Interests: Conflict of interest statement The authors have no competing interests to declare., (Copyright © 2022 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Background: There is a lack of recent data reflecting the actual use of sodium-glucose cotransporter-2 (SGLT2) inhibitors for heart failure (HF) and type 2 diabetes (DM) in the superaged society. The present study investigated the association between the use of SGLT2 inhibitors and one-year prognosis in patients hospitalized across a broad spectrum of HF patients with DM in the superaged society using the Nationwide Electric Health Database in Japan., Methods: The patients hospitalized with the first episode of acute HF were identified from the National Database of Health Insurance Claims and Specific Health Checkups of Japan between April 2014 and March 2019. A cohort of 2,277 users of SGLT2 inhibitors and 41,410 users of the active comparator, dipeptidyl peptidase-4 (DPP4) inhibitors were compared. A propensity score-matched cohort study of 2,101 users of each inhibitor was also conducted. A multivariable multilevel mixed-effects survival model was conducted with adjustments, and hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated., Results: Among 300,398 patients discharged with HF in 4,176 hospitals, 216,016 (71.9%) were 75 years or older, and 60,999 (20.3%) took antidiabetic medications. Among them, the patients treated with SGLT2 inhibitors were younger and had a more severe status than those treated with DPP4 inhibitors. Kaplan-Meier analysis showed that patients treated with SGLT2 inhibitors had a lower mortality risk and HF readmission. In propensity-matched cohorts, SGLT2 inhibitor use was associated with a lower risk of mortality and HF readmission than DPP-4 inhibitor use (HR [95% CI]; 0.70 [0.56, 0.89] and 0.52 [0.45, 0.61], respectively). Very elderly (≥ 75 years) patients showed similar results. Favorable effects were also observed across all age groups, including ≥ 75 years, in patients with coronary artery disease or atrial fibrillation and with concomitant β-blocker, diuretics, or insulin., Conclusion: The use of SGLT2 inhibitors at discharge was associated with a lower risk of one-year mortality and HF readmission in patients across a broad spectrum of HF with DM in the superaged society. The findings further support the benefits of using SGLT2 inhibitors in very elderly HF care and complement the current evidence., (© 2022. The Author(s).)

Coronavirus disease 2019 (COVID-19) remains prevalent worldwide since its onset was confirmed in Wuhan, China in 2019. Vaccines against the causative virus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), have shown a preventive effect against the onset and severity of COVID-19, and social and economic activities are gradually recovering. However, the presence of vaccine-resistant variants has been reported, and the development of therapeutic agents for patients with severe COVID-19 and related sequelae remains urgent. Drug repurposing, also called drug repositioning or eco-pharma, is the strategy of using previously approved and safe drugs for a therapeutic indication that is different from their original indication. The risk of severe COVID-19 and mortality increases with advancing age, cardiovascular disease, hypertension, diabetes, and cancer. We have reported three protein-protein interactions that are related to heart failure, and recently identified that one mechanism increases the risk of SARS-CoV-2 infection in mammalian cells. This review outlines the global efforts and outcomes of drug repurposing research for the treatment of severe COVID-19. It also discusses our recent finding of a new protein-protein interaction that is common to COVID-19 aggravation and heart failure., Competing Interests: Declaration of competing interest The authors declare no conflicts of interest., (Copyright © 2022 The Authors. Production and hosting by Elsevier B.V. All rights reserved.)

Background: Past studies have shown the sex-related difference in the efficacy of cardiac resynchronization therapy (CRT). However, the data for cardiac sarcoidosis (CS) are limited., Objective: The purpose of this study was to assess the sex-related prognostic differences in CS patients with CRT., Methods: This multicenter CS survey included 430 patients (295 females) who met the diagnostic criteria for CS. Patients were divided into those treated with primary CRT or upgraded CRT from the pacemaker (CRT group; n = 73) and others (control group; n = 357). Sex differences in the incidence of all-cause death, heart failure (HF) death including heart transplantation, ventricular arrhythmia events (VAEs) (sudden death, appropriate device therapy), cardiac adverse events (CAEs) (HF death, VAEs), changes in serum brain natriuretic peptide (BNP) levels, and left ventricular ejection fraction (LVEF) over the follow-up period were analyzed., Results: During median follow-up of 5.2 years, males, but not females, in the CRT group had significantly worse all-cause mortality than patients in the control group (P <.001). In the CRT group, there was no significant sex-related difference in the incidence of HF death; however, females had significantly better VAE- and CAE-free survival than males (P = .033 and P = .008, respectively). Multivariate analysis of the CRT group showed that female sex (hazard ratio 0.37; 95% confidence interval 0.15-0.89; P = .02 and P = .6) independently predicted freedom from CAEs. During follow-up, BNP levels were significantly improved in all groups. LVEF was maintained in females with CRT., Conclusions: In CS patients with CRT, HF death-free survival was similar between sexes. However, females exhibited better VAE- and CAE-free survival than males., (Copyright © 2022 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

Background: Automated optimization algorithm (AdaptivCRT; Medtronic, Mounds View, MN, USA) allowing automated optimization of cardiac resynchronization therapy (CRT), has been introduced. However, little is known concerning its cost-effectiveness. This study aims to evaluate the potential economic benefits of AdaptivCRT of CRT., Methods: Markov modelling was informed by empirical data sourced from the AdaptivCRT Clinical Trial. Published meta-analyses were used to derive the impact of increasing response to hospitalization and mortality risks. Response was assessed via the clinical composite score., Results: Deterministic results suggested a mean survival of 10.97 years with adaptive algorithms against 10.5 years without (+0.47 in favour of novel algorithms). Heart failure hospitalization costs were modelled to ¥1,382,753 (US $12,686) with novel devices against ¥1,524,747 (US $13,989) with previous technology models. Sensitivity analyses show CRT with Adaptive algorithm was projected to provide cost savings in all scenarios., Conclusions: The use of AdaptivCRT was projected to improve average patient survival and avoid costs in a Japanese healthcare setting., Competing Interests: Declaration of Competing Interest Drs Kusano and Noda received honoraria for lectures by Medtronic Japan Co., Ltd, which are not associated with this study. Drs Lu and Tsintzos: employee and shareholder of Medtronic; Dr Ikuemonisan: employee of Medtronic; Ms Ishiguro and Mr Holbrook: employee and shareholder of Medtronic., (Copyright © 2022. Published by Elsevier Ltd.)

Background: Biomarkers that can predict cardiac resynchronization therapy (CRT) response have not yet been identified. The purpose of this study was to assess whether individual measurements of four brain/B-type natriuretic peptide (BNP) forms, coupled with cyclic guanosine monophosphate (cGMP) might contribute to the prediction of echocardiographic CRT responders., Methods: A BNP precursor (proBNP) and total BNP (= proBNP + mature BNP) were measured with newly developed kits, while an N-terminal fragment of proBNP (NT-proBNP) and cGMP were measured with commercial kits on the day before CRT implantation. Estimated mature BNP (emBNP = total BNP-proBNP), and the ratio of cGMP to each BNP form, as well as the concentrations of three other BNP forms, were prospectively investigated for their capability in predicting a response to CRT. A CRT responder was defined as an improvement in left ventricular ejection fraction >10% and/or a reduction in left ventricular end-systolic volume >15% at 6-month follow-up., Results: Out of 77 patients, 46 (60%) were categorized as CRT responders. Among the measurement parameters, only the highest quartile of the cGMP to emBNP ratio was an independent predictor of CRT responders (odds ratio 4.87, 95% confidence interval 1.25-18.89, p = 0.02). The cGMP to emBNP ratio was associated with the cumulative events of heart failure hospitalization within one year following CRT implantation (log-rank p = 0.029)., Conclusions: The cGMP to emBNP ratio could be utilized as a predictive biomarker of CRT responders. (Clinical Study on Responder Prediction in Cardiac Resynchronization Therapy Using Individual Molecular Measurement of Natriuretic Peptide: UMIN R000038927)., Competing Interests: Declaration of Competing Interest None of the authors have any disclosures regarding this work., (Copyright © 2022. Published by Elsevier Ltd.)

Aims: The number of patients with both chronic obstructive pulmonary disease (COPD) and heart failure (HF) is increasing in Asia, and these conditions often coexist. We previously revealed a tendency of beta-blocker underuse among patients with HF with reduced ejection fraction (HFrEF) and COPD in Asian countries other than Japan. Here, we evaluated the impact of cardio-selective beta-blocker use on the long-term outcomes of patients with HF and COPD., Methods and Results: Among the 5232 patients with HFrEF (left ventricular ejection fraction of <40%) prospectively enrolled from 11 Asian regions in the ASIAN-HF registry, 412 (7.9%) had a history of COPD. We compared the clinical characteristics and long-term outcomes of the patients with HF and COPD according to the use and type of beta-blockers used: cardio-selective beta-blockers (n = 149) vs. non-cardio-selective beta-blockers (n = 124) vs. no beta-blockers (n = 139). The heart rate was higher, and the outcome was poorer in the no beta-blocker group than in the beta-blocker groups. The 2 year all-cause mortality was significantly lower in the non-cardio-selective beta-blocker group than in the no beta-blocker group. Further, the cardiovascular mortality significantly decreased in the non-cardio-selective beta-blocker group before (hazard ratio: 0.36; 95% confidence interval: 0.18-0.73; P = 0.004) and after adjustments (hazard ratio: 0.37; 95% confidence interval: 0.19-0.73; P = 0.005), but not in the cardio-selective beta-blocker group., Conclusions: Beta-blockers reduced the all-cause mortality of patients with HFrEF and COPD after adjusting for age and heart rate, although the possibility of selection bias could not be completely excluded due to multinational prospective registry., (© 2021 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Background: Implantable cardioverter-defibrillator and cardiac resynchronization therapy using a defibrillator (ICD/CRT-D) are established means of reducing mortality due to ventricular arrhythmia. Although atrial fibrillation/flutter (AF) is the most common cardiac arrhythmia in patients with heart disease, the impact of AF on the prognosis of patients with ICD/CRT-D remains controversial., Methods and Results: We analyzed data from the Nippon Storm Study, a prospective observational study of 1570 patients that was conducted at 48 Japanese ICD centers. We allocated 1549 participants to AF and non-AF groups, compared their clinical data at the time of enrollment, and monitored the incidences of mortality, hospitalization, and appropriate and inappropriate ICD/CRT-D therapy during a median 28 months. When the AF (n = 257, 16.6%) and non-AF-(n = 1292, 83.4%) groups were compared, the AF group was older (67.7 vs. 61.4 years; p<0.0001), and had lower left ventricular ejection fraction (38.0 ± 17.0% vs. 43.5 ± 18.9%; p<0.0001). During follow up, mortality was significantly higher in the AF than the non-AF group (p<0.0001). In multivariate analysis, AF was significantly associated with all-cause mortality [p = 0.013; hazard ratio (HR)=1.62]. Inappropriate ICD/CRT-D therapy occurred in 40/257 patients (15.6%) and AF was associated with a higher prevalence of inappropriate ICD/CRT-D therapy (p<0.0001; HR=2.25)., Conclusion: The presence of AF at ICD/CRT-D implantation carries subsequent independent risks of 1.62-fold for death and 2.25-fold for inappropriate therapy., (Copyright © 2021. Published by Elsevier Ltd.)

Extravascular cardiac resynchronization therapy (CRT) defibrillators (CRT-Ds) are ideal for recurrent blood stream infections. Furthermore, CRT is useful for patients intolerant to right ventricular (RV) pacing. The case was a 65-year-old man with a CRT-D who presented with a blood stream infection. Because he was hemodynamically unstable with temporary RV pacing, an epicardial CRT device was re-implanted concomitantly through a surgical procedure. After the operation, a subcutaneous implantable cardioverter defibrillator (S-ICD) was placed. However, not all pacing is eligible for S-ICD screening. Combination therapy with an epicardial CRT device and S-ICD might be an alternate option for cardiac surgery cases.

Left ventricular assist device (LVAD) therapy is increasingly used in patients with end-stage heart failure. However, LVADs are associated with challenges, especially in the presence of a cardiac implantable electronic device. Although a leadless pacemaker (PM), the Micra™ Transcatheter Pacing System, can be used with LVADs, data regarding HeartMate 3™ LVAD are limited. In this report, we present a patient with a HeartMate 3™ LVAD who underwent successful leadless PM implantation after the removal of an infected cardiac resynchronization therapy defibrillator., (© 2021 Wiley Periodicals LLC.)

Although heart failure (HF) and liver dysfunction often coexist because of complex cardiohepatic interactions, the association between liver dysfunction and physical dysfunction, and between coexistence of both and prognosis in HF patients remains unclear. We reviewed 895 patients with HF (mean age, 69.4 ± 14.2 years) who underwent liver function test using model for end-stage liver disease excluding international normalized ratio (MELD-XI) score and physical function test (grip strength, leg strength, gait speed, and 6-min walking distance [6MWD]). In the multiple regression analysis, MELD-XI score was independently associated with lower grip strength, leg strength, gait speed, and 6MWD (all P < 0.001). One hundred thirty deaths occurred over a median follow-up period of 1.67 years (interquartile range: 0.62-3.04). For all-cause mortality, patients with high MELD-XI scores and reduced physical functions were found to have a significantly higher mortality risk even after adjusting for several covariates (grip strength, hazard ratio [HR]: 3.80, P < 0.001; leg strength, HR: 4.65, P < 0.001; gait speed, HR: 2.49, P = 0.001, and 6MWD, HR: 5.48, P < 0.001). Liver dysfunction was correlated with reduced physical function. Moreover, the coexistence of lower physical function and liver dysfunction considerably affected prognosis in patients with HF.

Background: Approximately one-third of patients with advanced heart failure (HF) do not respond to cardiac resynchronization therapy (CRT). We investigated whether the left ventricular (LV) conduction pattern on magnetocardiography (MCG) can predict CRT responders., Methods and results: This retrospective study enrolled 56 patients with advanced HF (mean [±SD] LV ejection fraction [LVEF] 23±8%; QRS duration 145±19 ms) and MCG recorded before CRT. MCG-QRS current arrow maps were classified as multidirectional (MDC; n=28) or unidirectional (UDC; n=28) conduction based on a change of either ≥35° or <35°, respectively, in the direction of the maximal current arrow after the QRS peak. Baseline New York Heart Association functional class and LVEF were comparable between the 2 groups, but QRS duration was longer and the presence of complete left bundle branch block and LV dyssynchrony was higher in the UDC than MDC group. Six months after CRT, 30 patients were defined as responders, with significantly more in the UDC than MDC group (89% vs. 14%, respectively; P<0.001). Over a 5-year follow-up, Kaplan-Meyer analysis showed that adverse cardiac events (death or implantation of an LV assist device) were less frequently observed in the UDC than MDC group (6/28 vs. 15/28, respectively; P=0.027). Multivariate analysis revealed that UDC on MCG was the most significant predictor of CRT response (odds ratio 69.8; 95% confidence interval 13.14-669.32; P<0.001)., Conclusions: Preoperative non-invasive MCG may predict the CRT response and long-term outcome after CRT.

Background: Myocardial scarring is associated with nonresponse to cardiac resynchronization therapy (CRT) and conduction delay. Little is known about the significance and cause of left ventricular (LV) paced conduction disturbance (LPCD)., Objective: The purpose of this study was to investigate the clinical impact of paced interlead electrical delay and the difference in each conduction time from LV pace to right ventricular (RV) sense (LVp-RVs) and from RV pace to LV sense (RVp-LVs) [(LVp-RVs) - (RVp-LVs)], in CRT., Methods: Among 137 patients who underwent CRT implantation, LVp-RVs and RVp-LVs were measured intraoperatively. The relationships between [(LVp-RVs) - (RVp-LVs)] and perfusion defects on myocardial perfusion single photon emission computed tomography (SPECT) imaging or [(LVp-RVs) - (RVp-LVs)] and clinical outcomes were assessed., Results: After CRT implantation, 81 patients (59%) responded to CRT. [(LVp-RVs) - (RVp-LVs)] was significantly longer in nonresponders than in responders (9.7 ± 47.3 ms vs -4.5 ± 33.2 ms; P = .041). Patients with LPCD [(LVp-RVs) > (RVp-LVs)] had higher perfusion defects in the anterolateral region (2.7 ± 2.7 vs 1.1 ± 1.6; P = .0015) on SPECT. Multivariate analysis showed that LPCD was the independent predictor of nonresponse to CRT (odds ratio 0.40; 95% confidence interval [CI] 0.17-0.90; P = .026). During median follow-up of 2.3 years (interquartile range 1.3-5.5), LPCD was the independent predictor of cardiac death and/or heart failure hospitalization in multivariate analysis (hazard ratio 2.04; 95% CI 1.19-3.55; P = .010)., Conclusion: LPCD could predict nonresponse to CRT and poor outcome. Further intervention, such as adjustment of pacing timing or multipoint/site pacing, may be needed in such patients., (Copyright © 2020 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

Background: Cardiac resynchronization therapy (CRT) is less effective in patients with mildly wide QRS or non-left bundle branch block (non-LBBB). A new algorithm of every minute's optimization (adaptive CRT: aCRT algorithm) is effective in patients with CRT devices. This study investigated the clinical effect of the aCRT algorithm, especially in mildly wide QRS (120≤QRS<150 ms) or non-LBBB patients receiving CRT., Methods and results: This study included 104 CRT patients (48 patients using the aCRT algorithm [adaptive group] and 56 patients not using the aCRT algorithm [non-adaptive group]). The primary endpoint was a composite clinical outcome of cardiac death and/or heart failure (HF) hospitalization. During a median follow-up of 700 days (interquartile range 362-1,173 days), aCRT reduced the risk of the clinical outcome, even in patients with mildly wide QRS or non-LBBB (log-rank P=0.0030 and P=0.0077, respectively) by Kaplan-Meier analysis. Use of the aCRT algorithm was an independent predictor of clinical outcomes in the multivariate analysis (hazard ratio (HR) 0.28, 95% confidence interval (CI): 0.096-0.78, P=0.015), the same as in patients with mildly wide QRS (HR 0.12, 95% CI: 0.006-0.69, P=0.015)., Conclusions: The new aCRT algorithm was useful and significantly reduced the risk of the clinical outcome, even in patients with mildly wide QRS.

Background: In cardiac resynchronization therapy (CRT) for patients with congenital heart disease (CHD) and a ventricular morphology other than a systemic left ventricle (LV), we previously proposed pacing sites that are different from those used for a systemic LV. The leads should be placed laterally on opposite sides of both ventricles in patients with short-axis dyssynchrony and a single ventricular physiology with two ventricles, whereas they should be placed at the farthest sites along the longitudinal direction in the right ventricle (RV) in patients with long-axis dyssynchrony of the RV. Moreover, in patients with interventricular dyssynchrony and a biventricular physiology with a systemic RV, they should be placed at sites that both ventricles can contract simultaneously. We retrospectively investigated 27 consecutive procedures in 24 patients with CHD who underwent CRT to evaluate the effectiveness of a new ventricular morphology-based CRT strategy. The responder rate was 63% (17/27). The reasons for a non-response to CRT in 10 cases were as follows: non-optimal lead positions during CRT, 4; no systemic ventricular conduction delay or heart failure symptoms before the CRT, 5; short follow-up periods after the CRT, 2; and an extremely dilated systemic RV, 1. The responder rate became 88% (14/16), after excluding the procedures without a ventricular conduction delay or heart failure symptoms and those with non-optimal lead positions. This new strategy for CRT can provide favorable results for CHD patients with a systemic ventricular conduction delay and heart failure.

Objectives: This study aimed to clarify the clinical impact of transient atrial fibrillation (AF) attacks themselves and the efficacy of cardiac resynchronization therapy (CRT) in patients with intermittent AF., Background: The benefit of CRT in patients with intermittent AF, especially the effect of the AF attacks themselves, remains unclear., Methods: Among our cohort of 269 consecutive CRT patients, we compared the percent of biventricular pacing (BIVP%) and other clinical characteristics between patients with intermittent AF and those with sinus rhythm (SR)., Results: During a median follow-up of 942 days (interquartile range: 379 to 1,464 days) a total of 22 patients, including 59% of CRT responders, developed heart failure (HF) due to a transient AF attack itself, and that accounted for 21% of all HF events. The BIVP% during the AF attacks was significantly lower than that during SR (p < 0.05). When compared to the SR groups, patients with intermittent AF had a significantly higher risk of developing HF or death (hazard ratio: 2.2; 95% confidence interval: 1.3 to 3.8). However, the patients who received a BIVP% of ≥90% during AF attacks were comparable to those with SR (hazard ratio: 1.2; 95% confidence interval: 0.4 to 3.0)., Conclusions: A substantial number of patients developed HF due to transient AF attacks themselves even in the CRT responders, and the reason was mainly due to the loss of the BIVP%., (Copyright © 2018 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Left ventricular (LV) properties in hypertension (HTN) could be deteriorated by pressure overload, especially in endocardium, resulting in hypertensive heart failure (HHF). We sought to noninvasively examine LV systolic and diastolic functions at three myocardial layers in HTN and elucidate features of HHF by speckle-tracking echocardiography (STE) with high volume rates. We examined normotensive controls (n = 54), HTN patients without LV hypertrophy (LVH) (n = 50), and HTN patients with LVH (n = 40) and HHF patients (n = 45). The HHF group was divided into two subgroups based on their LVEF (20 heart failure with preserved ejection fraction: HFpEF and 25 heart failure with reduced ejection fraction: HFrEF). LV layer systolic function was assessed by strain rate during systole. Pulmonary capillary wedge pressure (PCWP) was estimated (ePCWP) using kinetics-tracking index (KT index) that we previously reported. HTN patients with LVH had a significant deterioration of systolic and diastolic properties compared with normotensive controls in the absence of a significant reduction in LVEF. Patients with HHF had further deterioration of systolic and diastolic properties compared with HTN patients with LVH. LV strain at entire myocardium and ePCWP in HFrEF was deteriorated compared with those in HFpEF. Deterioration of LV layer SR was more typical during systole, isovolumic relaxation, and early diastole compared with control. LV dilation was independently associated with LVEF (r = -0.48, p < 0.001) and ePCWP (r = 0.47, p < 0.001), and LVH (LV mass index) was independently associated with E/e' (r = 0.37, p = 0.025), LVEF (r = -0.44, p < 0.001), and ePCWP (r = 0.67, p < 0.001). LV layer analysis by STE could detect subtle impairments in systolic function before the deterioration of LVEF in patients with HTN. The ePCWP that was estimated using KT index was the independent factor associated with HHF. The ePCWP may be useful to noninvasively detect the early stage of HHF.

We describe the case of a 37-year-old woman who presented with complete right bundle branch block and right axis deviation. She was admitted to our hospital due to severe heart failure and was dependent on inotropic agents. Cardiac resynchronization therapy was initiated but did not improve her condition. After the optimization of the pacing timing, we performed earlier right ventricular pacing, which led to an improvement of her heart failure. Earlier right ventricular pacing should be considered in patients with complete right bundle branch block and right axis deviation when cardiac resynchronization therapy is not effective.

Background: We previously demonstrated that heart failure (HF) was one of the major causes of death in arrhythmogenic right ventricular cardiomyopathy (ARVC). The purpose of this study was to elucidate the clinical impact and risk factors of HF in patients with ARVC., Methods and Results: We evaluated cardiac adverse outcomes including HF in 113 consecutive patients with ARVC (85 men, mean age: 44±15years). During a median follow-up of 10.0years (interquartile range: 5.2 to 15.7years), 29 patients (26%) were hospitalized for progressive HF. The patients with one or more episodes of HF hospitalization had about a 10-fold increased incidence of cardiac death (14/29 [48%] vs. 4/84 [4.7%], p<0.0001). Left ventricular ejection fraction (LVEF) and right ventricular ejection fraction (RVEF) were significantly lower in the patients with HF hospitalization compared to the patients without HF hospitalization (LVEF, 45±15 vs. 54±13%, p=0.001; RVEF, 26±10 vs. 33±11%, p=0.003, respectively). Regarding the ECG findings, the prevalence of first-degree atrioventricular block (AVB, PR interval >200ms) and epsilon waves were significantly higher in patients with HF hospitalization than those without HF hospitalization (first-degree AVB, 14/29 [48%] vs. 11/84 [13%], p<0.0001; epsilon waves, 10/29 [34%] vs. 12/84 [14%], p=0.02). In multivariate analysis, first-degree AVB at baseline was the strongest independent risk factor for HF hospitalization in patients with ARVC (hazard ratio 4.24, 95% confidence interval 1.79-10.47, p=0.0011)., Conclusion: HF hospitalization has a significant relation with malignant clinical course in ARVC patients. First-degree AVB was an independent determinant for increased risk of HF hospitalization., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Activation of β-catenin-dependent canonical Wnt signaling in endothelial cells plays a key role in angiogenesis during development and ischemic diseases, however, other roles of Wnt/β-catenin signaling in endothelial cells remain poorly understood. Here, we report that sustained activation of β-catenin signaling in endothelial cells causes cardiac dysfunction through suppressing neuregulin-ErbB pathway in the heart. Conditional gain-of-function mutation of β-catenin, which activates Wnt/β-catenin signaling in Bmx-positive arterial endothelial cells (Bmx/CA mice) led to progressive cardiac dysfunction and 100% mortality at 40 weeks after tamoxifen treatment. Electron microscopic analysis revealed dilatation of T-tubules and degeneration of mitochondria in cardiomyocytes of Bmx/CA mice, which are similar to the changes observed in mice with decreased neuregulin-ErbB signaling. Endothelial expression of Nrg1 and cardiac ErbB signaling were suppressed in Bmx/CA mice. The cardiac dysfunction of Bmx/CA mice was ameliorated by administration of recombinant neuregulin protein. These results collectively suggest that sustained activation of Wnt/β-catenin signaling in endothelial cells might be a cause of heart failure through suppressing neuregulin-ErbB signaling, and that the Wnt/β-catenin/NRG axis in cardiac endothelial cells might become a therapeutic target for heart failure.

Objective: Upgrading to biventricular (BiV) pacing benefits heart failure patients with right ventricular (RV) apical pacing. However, the impact of switching from RV apical pacing to BiV pacing on the left ventricular (LV) function accompanied by changes in the QRS duration remains unknown. We aimed to investigate the effects of BiV pacing in heart failure patients under RV apical pacing., Methods: In 37 patients with heart failure (LV ejection fraction: 22±9%), the maximum rate of LV pressure rise (LV dP/dtmax) and time constant of LV relaxation (tau) were determined in order to assess LV contractility and diastolic relaxation, respectively, under RV apical pacing and BiV pacing. Switching from RV pacing to BiV pacing, the QRS duration was shortened from 209±42 to 162±28 ms (p<0.001) and the LV dP/dtmax values were increased in all patients (+18.4±11.3%, p<0.001), whereas the LV tau values varied (-1.5±13.0%, p=0.723). Shortening of the QRS duration correlated with the increase in LV dP/dtmax (r=-0.689, p<0.001); however, it was not closely associated with the changes in LV tau., Conclusion: Switching from RV apical pacing to BiV pacing improves the LV contractile function in proportion to the degree of QRS shortening. BiV pacing is recommended in patients with systolic heart failure and a prolonged RV-paced QRS duration.

Background: Little is known about predictors of response to cardiac resynchronization therapy (CRT) in patients with intraventricular conduction delay (IVCD). The purpose of this study was to investigate the benefits of CRT and significant variables on surface electrocardiogram (ECG) to predict response to CRT in those patients., Methods and Results: Among the cohort of 152 CRT patients, 40 patients with IVCD were evaluated. Sixteen patients (40%) were responders. At baseline, responders had a wider QRS duration (158±18 vs. 144±18ms, P=0.02) and a higher frequency of left axis deviation (LADEV; 75% vs. 29%, P=0.004) compared with non-responders. After CRT, greater shortening of QRS duration (ΔQRS; 26±24 vs. 7±24ms, P=0.02), axis shift from LADEV to right axis deviation (RADEV; 69% vs. 13%, P<0.001), and both rightward forces in lead I and anterior forces in V1 (56% vs. 13%, P=0.003) were found more frequently in responders. Multivariable logistic regression analysis showed that LADEV at baseline, or ΔQRS and axis shift from LADEV to RADEV after CRT were independent predictors of response to CRT., Conclusions: Patients with IVCD may not respond to CRT, but LADEV at baseline and reversal of ventricular activation after CRT on surface ECG could be important to predict response to CRT.

This case report describes abrupt heart rate fallings below the lower pacing rate limit in a patient with cardiac resynchronization therapy (CRT). Interrogated information including stored episodes or data regarding the lead did not show any device problems and only simultaneous intracardiac electrogram revealed the cause, T-wave oversensing during biventricular pacing. At this moment, CRT has become an established modality for patients with severe heart failure. However, bradycardia below the lower rate limit during biventricular pacing due to T-wave oversensing would exacerbate heart failure in patients with CRT. We should notice this latent risk and correct the malfunction immediately., (©2010, The Authors. Journal compilation ©2010 Wiley Periodicals, Inc.)

Various clinical data demonstrate that cardiac resynchronization therapy (CRT) provides a favorable structural as well as electrical remodeling. The CArdiac Resynchronization-Heart Failure study, which tested the pure effect of CRT (using CRT devices without the capability of defibrillation) clearly showed a significant reduction in the total mortality by partly preventing sudden cardiac death. The antiarrhythmic effects of CRT are explained, at least in part, by ionic and genetic modulation of ventricular myocytes. It has been revealed in animal experiments to mimic disorganized ventricular contraction that CRT reverses down-regulation of certain K(+) channels and abnormal Ca(2+) homeostasis in the failing heart. However, CRT can be proarrhythmic in some particular cases especially in the early phase of this therapy. According to our study, proarrhythmic effects after CRT can be observed in approximately 10% of patients. The relatively high incidence of the proarrhythmic effects of CRT may promote a trend toward selecting CRT-D rather than CRT-P., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Objectives: This study sought to examine plasma levels of soluble Fas/APO-1 receptor (sFas), an inhibitor of apoptosis, and soluble Fas ligand (sFas-L), an inducer of apoptosis, and their relation to each other and to other clinical variables, such as New York Heart Association functional class, tumor necrosis factor (TNF) and interleukin-6 (IL-6) in congestive heart failure (CHF)., Background: It has been recently reported that apoptotic cell death occurs in myocytes of dogs with CHF. Hypoxia is frequently seen in advanced CHF and can stimulate Fas/APO-1 receptors (Fas) to induce apoptosis in cultured myocytes. Fas and Fas ligand (Fas-L) are cell-surface proteins and representative apoptosis-signaling molecules. Fas on the cell membrane induces apoptosis when it binds Fas-L or sFas-L. However, plasma sFas, a molecule lacking the transmembrane domain of Fas, blocks apoptosis by inhibiting binding between Fas and Fas-L or sFas-L on the cell membrane. At present, it is unknown whether plasma sFas-L and plasma sFas increase in the presence of cardiac disease., Methods: The study included 70 patients (mean [+/-SEM] age 65 +/- 2 years, range 21 to 93) with chronic CHF (coronary artery disease in 28, dilated cardiomyopathy in 27, valvular heart disease in 15) and 62 age- and gender-matched normal control subjects. Plasma levels of sFas, sFas-L, TNF-alpha and IL-6 were measured by enzyme-linked immunosorbent assays using monoclonal anti-human antibodies., Results: There was no significant difference in sFas-L levels between normal subjects and patients in functional classes I to IV; however, sFas increased with severity of functional classification, independent of the underlying disease. sFas levels were significantly higher even in patients in functional class II than in normal subjects and those in functional class I, and were highest in patients in functional class IV (normal subjects; 2.2 +/- 0.1 ng/ml; functional class I: 2.2 +/- 0.2 ng/ml; functional class II: 3.1 +/- 0.2 ng/ml; functional class III: 3.9 +/- 0.3 ng/ml; functional class IV: 5.1 +/- 0.6 ng/ml). Plasma sFas levels were significantly higher in patients with elevated pulmonary artery wedge pressure and a decresed cardiac index than in those with values in the normal range. In patients in functional class IV, there was no significant difference in plasma sFas levels between the survivors and non-survivors during 6-month follow-up. However, plasma levels of sFas tended to decrease in nine patients with clinical improvement (baseline sFas: 5.2 +/- 0.8 ng/ml; 6-month sFas: 4.3 +/- 0.5 ng/ml, p = 0.07) but were similar in patients with no change in functional class. TNF-alpha and IL-6 were increased significantly only in patients in functional class IV, as previously reported, but were not related to sFas., Conclusions: We found elevated levels of plasma sFas and no increase in plasma sFas-L in human CHF. The increase in sFas may play an important role in the pathophysiologic mechanisms of CHF.

The exercise response of left ventricular (LV) filling dynamics may be altered by congestive heart failure (CHF). Accordingly, we studied 18 conscious dogs, instrumented to measure micromanometer LV and left atrial (LA) pressures and determine LV volume from three dimensions. CHF was produced by 4-5 weeks of right ventricular rapid pacing. Before CHF, exercise (5.5-8.5 mph for 8-15 minutes) increased the maximum rate of LV filling (dV/dtmax) (197 +/- 37 versus 297 +/- 56 ml/sec [mean +/- SD], p < 0.05) in response to an increase in the maximum early diastolic LA to LV pressure gradient (5.8 +/- 2.0 versus 9.8 +/- 1.9 mm Hg, p < 0.05) produced by a fall in minimum LV pressure (1.0 +/- 2.9 versus -3.9 +/- 3.1 mm Hg, p < 0.01), whereas mean LA pressure was unchanged (6.4 +/- 3.1 versus 6.4 +/- 4.2 mm Hg, p = NS). The time constant of LV relaxation was shortened (28.1 +/- 3.2 versus 21.0 +/- 4.2 msec, p < 0.05). After CHF, dV/dtmax (141 +/- 51 versus 200 +/- 59 ml/sec, p < 0.05) and the maximum LA to LV pressure gradient (6.0 +/- 1.1 versus 11.1 +/- 2.7 mm Hg, p < 0.05) continued to increase with exercise (3-5.0 mph for 4-8 minutes). However, the time constant of LV relaxation was prolonged (35.6 +/- 4.8 versus 38.9 +/- 5.5 msec, p < 0.05), and minimum LV pressure (15.1 +/- 5.6 versus 17.6 +/- 5.9 mm Hg, p < 0.05) and mean LA pressure increased (22.6 +/- 7.2 versus 29.1 +/- 7.3 mm Hg, p < 0.05). These altered effects of exercise on LV diastolic filling dynamics persisted when heart rate and wall stress during exercise before and after CHF were matched by varying the level of exercise. We conclude that, during normal exercise, mitral valve flow is augmented by a fall of early diastolic LV pressure without a rise in LA pressure. After CHF, early diastolic LV pressure does not fall but increases during exercise. Thus, the increase in the early diastolic LA to LV pressure gradient and the rate of mitral valve flow results from an increase in LA pressure during exercise after CHF. This study suggests that the failure of the enhancement of LV relaxation and an increase in early diastolic LV pressure with exercise after CHF may contribute to exercise intolerance in CHF.