The drug-specific properties of hypoxia-inducible factor-prolyl hydroxylase inhibitors in mice reveal a significant contribution of the kidney compared to the liver to erythropoietin induction.

AIMS: Kidney disease often leads to anemia due to a defect in the renal production of the erythroid growth factor erythropoietin (EPO), which is produced under the positive regulation of hypoxia-inducible transcription factors (HIFs). Chemical compounds that inhibit HIF-prolyl hydroxylases (HIF-PHs), which suppress HIFs, have been developed to reactivate renal EPO production in renal anemia patients. Currently, multiple HIF-PH inhibitors, in addition to conventional recombinant EPO reagents, are used for renal anemia treatment. This study aimed to elucidate the therapeutic mechanisms and drug-specific properties of HIF-PH inhibitors. METHODS AND KEY FINDINGS: Gene expression analyses and mass spectrometry revealed that HIF-PH inhibitors (daprodustat, enarodustat, molidustat, and vadadustat) alter Epo gene expression levels in the kidney and liver in a drug-specific manner, with different pharmacokinetics in the plasma and urine after oral administration to mice. The drug specificity revealed the dominant contribution of EPO induction in the kidneys rather than in the liver to plasma EPO levels after HIF-PH inhibitor administration. We also found that several HIF-PH inhibitors directly induce duodenal gene expression related to iron intake, while these drugs indirectly suppress hepatic hepcidin expression to mobilize stored iron for hemoglobin synthesis through induction of the EPO-erythroferrone axis. SIGNIFICANCE: Renal EPO induction is the major target of HIF-PH inhibitors for their therapeutic effects on erythropoiesis. Additionally, the drug-specific properties of HIF-PH inhibitors in EPO induction and iron metabolism have been shown in mice, providing useful information for selecting the proper HIF-PH inhibitor for each renal anemia patient.

CORRIGENDUM: Preprocedural Controlling Nutritional Status Score as a Predictor of Mortality in Patients Undergoing Transcatheter Mitral Valve Repair　- A Single Center Experience in Japan.

[This corrects the article DOI: 10.1253/circrep.CR-23-0055.].

Impact of the MitraClip G4 System on Routine Practice and Outcomes in Patients With Secondary Mitral Regurgitation.

BACKGROUND: The MitraClip G4 system is a new iteration of the transcatheter edge-to-edge repair system. We assessed the impact of the G4 system on routine practice and outcomes in secondary mitral regurgitation (2°MR).Methods and Results: Consecutive patients with 2°MR treated with either the MitraClip G2 (n=89) or G4 (n=63) system between 2018 and 2021 were included. Baseline characteristics, procedures, and outcomes were compared. Inverse probability of treatment weighting and Cox regression were used to adjust for baseline differences. Baseline characteristics were similar, except for a lower surgical risk in the G4 group (Society of Thoracic Surgeons Predicted Risk of Mortality ≥8: 38.1% vs. 56.2%; P=0.03). In the G4 group, more patients had short (≤2 mm) coaptation length (83.7% vs. 54.0%; P<0.001) and fewer clips were used (17.5% vs. 36.0%; P=0.02). Acceptable MR reduction was observed in nearly all patients, with no difference between the G4 and G2 groups (100% vs. 97.8%, respectively; P=0.51). The G4 group had fewer patients with high transmitral gradients (>5mmHg; 3.3% vs. 13.6%; P=0.03). At 1 year, there was no significant difference between groups in the composite endpoint (death or heart failure rehospitalization) after baseline adjustment (10.5% vs. 20.2%; hazard ratio 0.39; 95% confidence interval 0.11-1.32; P=0.13). CONCLUSIONS: The G4 system achieved comparable device outcomes to the early-generation G2, despite treating more challenging 2°MR with fewer clips.

Preprocedural Controlling Nutritional Status Score as a Predictor of Mortality in Patients Undergoing Transcatheter Mitral Valve Repair　- A Single Center Experience in Japan.

Background: A high score for controlling nutritional status (CONUT) due to poor nutritional status has been associated with adverse outcomes in patients with chronic heart failure. However, because little is known about the effect of CONUT score on mortality rates after transcatheter mitral valve repair, we evaluated nutrition screening tools for prognosis prediction in patients undergoing transcatheter mitral valve repair using the MitraClipTM system. Methods and Results: We retrospectively analyzed 148 patients with severe mitral regurgitation (MR) who underwent MitraClipTM implantation between April 2018 and April 2021. The preprocedural CONUT scores were assessed at the time of hospitalization, the primary outcome was all-cause death, and the analysis was of the mortality and incidence rates of cardiac events 1 year post-operation. Functional MR was of ischemic origin in the majority of patients (69.6%), with a mean left ventricular ejection fraction of 48.9±15.8%. Kaplan-Meier curves indicated that all-cause death was significantly worse in the high-CONUT score group than in the low-CONUT score group. Cox hazard analysis showed a significant association between all-cause death and CONUT score, as well as MitraScore. Conclusions: Preprocedural CONUT score, as well as MitraScore, in patients undergoing transcatheter edge-to-edge mitral valve repair may predict an increased risk of all-cause death. This knowledge should allow the heart team to accurately assess the clinical implications and prognostic benefits of the procedure in individual patients.

Characteristics and Treatment Strategies for Basicervical and Transcervical Shear Fractures of the Femoral Neck.

This study aimed to define basicervical and transcervical shear fractures using area classification and to determine the optimal osteosynthesis implants for them. The clinical outcomes of 1042 proximal femur fractures were investigated. A model of the proximal femur of a healthy adult was created from computed tomography images, and basicervical and transcervical shear fractures were established in the model. Osteosynthesis models were created using a short femoral nail with a single lag screw or two lag screws and a long femoral nail with a single lag screw or two lag screws. The minimum principal strains of the fracture surfaces were compared when the maximum loads during walking were applied to these models using finite element analysis software. Basicervical fractures accounted for 0.96% of all proximal femur fractures, 67% of which were treated with osteosynthesis; the failure rate was 0%. Transcervical shear fractures accounted for 9.6% of all proximal femur fractures, 24% of which were treated with osteosynthesis; the failure rate was 13%. Finite element analysis showed that transcervical shear fracture has high instability. To perform osteosynthesis, multiple screw insertions into the femoral head and careful postoperative management are required; joint replacement should be considered to achieve early mobility.

Nrf2 alleviates spaceflight-induced immunosuppression and thrombotic microangiopathy in mice.

Spaceflight-related stresses impact health via various body systems, including the haematopoietic and immune systems, with effects ranging from moderate alterations of homoeostasis to serious illness. Oxidative stress appears to be involved in these changes, and the transcription factor Nrf2, which regulates expression of a set of cytoprotective and antioxidative stress response genes, has been implicated in the response to spaceflight-induced stresses. Here, we show through analyses of mice from the MHU-3 project, in which Nrf2-knockout mice travelled in space for 31 days, that mice lacking Nrf2 suffer more seriously from spaceflight-induced immunosuppression than wild-type mice. We discovered that a one-month spaceflight-triggered the expression of tissue inflammatory marker genes in wild-type mice, an effect that was even more pronounced in the absence of Nrf2. Concomitant with induction of inflammatory conditions, the consumption of coagulation-fibrinolytic factors and platelets was elevated by spaceflight and further accelerated by Nrf2 deficiency. These results highlight that Nrf2 mitigates spaceflight-induced inflammation, subsequent immunosuppression, and thrombotic microangiopathy. These observations reveal a new strategy to relieve health problems encountered during spaceflight.

Drugs activating hypoxia-inducible factors correct erythropoiesis and hepcidin levels via renal EPO induction in mice.

The erythroid growth factor erythropoietin (EPO) is mainly produced by the kidneys in adult mammals and induces expansion of erythroid cells and iron use for hemoglobin synthesis. The liver also produces EPO at a lower level than the kidneys. Renal and hepatic EPO production is fundamentally regulated by hypoxia-inducible transcription factors (HIFs) in a hypoxia/anemia-inducible manner. Recently, small compounds that activate HIFs and EPO production in the kidneys by inhibiting HIF-prolyl hydroxylases (HIF-PHIs) have been launched to treat EPO-deficiency anemia in patients with kidney disease. However, the roles of the liver in the HIF-PHI-mediated induction of erythropoiesis and iron mobilization remain controversial. Here, to elucidate the liver contributions to the therapeutic effects of HIF-PHIs, genetically modified mouse lines lacking renal EPO-production ability were analyzed. In the mutant mice, HIF-PHI administration marginally increased plasma EPO concentrations and peripheral erythrocytes by inducing hepatic EPO production. The effects of HIF-PHIs on the mobilization of stored iron and on the suppression of hepatic hepcidin, an inhibitory molecule for iron release from iron-storage cells, were not observed in the mutant mice. These findings demonstrate that adequate induction of EPO mainly in the kidney is essential for achieving the full therapeutic effects of HIF-PHIs, which include hepcidin suppression. The data also show that HIF-PHIs directly induce the expression of duodenal genes related to dietary iron intake. Furthermore, hepatic EPO induction is considered to partially contribute to the erythropoietic effects of HIF-PHIs but to be insufficient to compensate for the abundant EPO induction by the kidneys.

Efficacy and Safety of Home-Based Cardiac Telemonitoring Rehabilitation in Patients After Transcatheter Aortic Valve Implantation: Single-Center Usability and Feasibility Study.

BACKGROUND: No consensus exists on the efficacy of home-based cardiac rehabilitation (CR) in patients who have undergone transcatheter aortic valve implantation (TAVI). Additionally, there are no reports on home-based cardiac telemonitoring rehabilitation (HBTR) in patients after TAVI. OBJECTIVE: We aimed to investigate the efficacy of HBTR in patients who have undergone TAVI. METHODS: This single-center preliminary study introduced HBTR to patients after TAVI, and the efficacy outcomes of the rehabilitation method were compared to that of a historical control cohort. The historical control cohort (control group) consisted of 6 consecutive patients who underwent ordinary outpatient CR after TAVI from February 2016 to March 2020. Patients who participated in the HBTR program were only recruited after the TAVI procedure and before discharge between April 2021 and May 2022. In the first 2 weeks after TAVI, patients underwent outpatient CR and were trained using telemonitoring rehabilitation systems. Thereafter, patients underwent HBTR twice a week for 12 weeks. The control group performed standard outpatient CR at least once a week for 12 to 16 weeks. Efficacy was assessed using peak oxygen uptake (VO2) prior to and after CR. RESULTS: Eleven patients were included in the HBTR group. All patients underwent 24 HBTR sessions during the 12-week training period, and no adverse events were observed. The control group participants performed 19 (SD 7) sessions during the training period, and no adverse events were observed. Participants in the HBTR and control groups had a mean age of 80.4 (SD 6.0) years and 79.0 (SD 3.9) years, respectively. In the HBTR group, preintervention and postintervention peak VO2 values were 12.0 (SD 1.7) mL/min/kg and 14.3 (SD 2.7) mL/min/kg (P=.03), respectively. The peak VO2 changes in the HBTR and control groups were 2.4 (SD 1.4) mL/min/kg and 1.3 (SD 5.0) mL/min/kg (P=.64), respectively. CONCLUSIONS: Home-based CR using a telemonitoring system is a safe outpatient rehabilitation method. Its efficacy is not inferior to that of standard CR in patients who have undergone TAVI. TRIAL REGISTRATION: Japan Registry of Clinical Trials jRCTs032200122; https://jrct.niph.go.jp/latest-detail/jRCTs032200122.

Hospital-acquired disability in older heart failure patients decreases independence and increases difficulties in activities of daily living.

AIMS: The aim of this study was to clarify whether worsening of independence in activities of daily living (ADL) and also difficulties in ADL are triggered by hospitalization in older patients with heart failure (HF) and whether difficulties in ADL can predict readmission for HF regardless of independence in ADL in these patients. METHODS AND RESULTS: We enrolled 241 HF patients in the present multi-institutional, prospective, observational study. The patients were divided according to age into the non-older patient group (<75 years, n = 137) and the older patient group (≥75 years, n = 104). The Katz index and the Performance Measure for Activities of Daily Living-8 (PMADL-8) were used to evaluate independence and difficulties in ADL, respectively. The endpoint of this study was rehospitalization for HF. Independence as indicated by the Katz index at discharge was significantly lower than that before admission only in the older patient group, and the value of the PMADL-8 at discharge was significantly higher than that before admission (P < 0.001). In all patients, after adjusting for the Katz index and other variables, PMADL-8 score was a significant predictor of rehospitalization for HF (hazard ratio 1.50; 95% confidence interval 1.07-2.13; P = 0.021). CONCLUSIONS: Worsening of both independence and difficulties in ADL was triggered by hospitalization in older HF patients, and difficulties in ADL were relevant factors for risk of rehospitalization regardless of independence in ADL. These findings indicate the importance of preventing not only decreased independence but also increased difficulties in ADL during and after hospitalization.

Nutritional management of heart failure.

Nutrition in the cardiovascular field to date has focused on improving lifestyle-related diseases such as hypertension and diabetes from the viewpoint of secondary prevention. For these conditions, "nutrition for weight loss" is recommended, and nutritional guidance that restricts calories is provided. On the other hand, in symptomatic Stage C and D heart failure, it is known that underweight patients who manifest poor nutrition, sarcopenia, and cardiac cachexia have a poor prognosis. This is referred to as the "Obesity paradox". In order to "avoid weight loss" in patients with heart failure, a paradigm shift to nutritional management to prevent weight loss is needed. Rather than prescribing uniform recommendation for salt reduction of 6 g/day or less, awareness of the behavior change stage model is attracting attention. In this setting, the value of salt restriction will need to be determined to determine the priority level of intervention for undernutrition versus the need to prevent congestive signs and symptoms. In the Intensive Care Unit (ICU)/Cardiac Care Unit (CCU) for acute heart failure, nutritional intervention should be considered within 48 h of admission. Key points are selection of access route, timing of intervention, and monitoring of side effects. In nutritional management at home and in end-of-life care, food is a reflection of an individual's values, as well as a source of joy and encouragement. The importance of digestive tract should also be recognized in heart failure from oral flail to intestinal edema, constipation, and the intestinal bacteria called the heart-gut axis. Finally, we would like to propose a new term "heart nutrition" for nutritional management in patients with heart failure in this review. Compared to the evidence for exercise therapy in heart failure, studies assessing nutritional management remain scarce and there is a need for research in this area in the future.

Noteworthy sequelae after COVID-19 pneumonia in a patient with heart failure due to cardiomyopathy.

Coronavirus disease 2019 (COVID-19) is endemic worldwide. Cardiovascular disease, particularly myocarditis, is one of the most common comorbidities in patients with COVID-19. However, heart failure due to COVID-19-triggered cardiomyopathy is not well understood. Additionally, "pseudo" heart failure symptoms have been reported in patients with a compensated condition, in which the heart works well enough that symptoms are unnoticeable or very easy to manage. Here, we report a case of heart failure due to cardiomyopathy in a patient with COVID-19 and postural orthostatic tachycardia syndrome after heart failure treatment. Learning objective: Postural orthostatic tachycardia syndrome (POTS) symptoms after coronavirus disease 2019 may be mistaken for heart failure symptoms; thus, it is essential to suspect POTS when symptoms such as shortness of breath and palpitations are noted upon standing, along with the relevant physical findings.

Occurrence and clinical outcome of lateral wall fractures in proximal femoral fractures whose fracture line runs from femoral basal neck to subtrochanteric area.

Treatment methods for proximal femoral fractures, when the fractures run from the femoral basal neck to the subtrochanteric area, have not yet been fully reported. Thus, we aimed to clarify osteosynthesis methods based on the fracture frequency and clinical results. We classified the proximal femoral fractures using the Area classification method based on the location (area) of the fracture line. The proximal femur has 4 areas with 3 boundaries; the center of the femoral neck, the boundary between femoral neck and trochanter, and the plane connecting the lower ends of the greater trochanter and the lesser trochanter. Fractures occurring only in Area-1 (proximal from the center of the femoral neck) were classified as Type 1; those in both Areas 1 and 2 (base of the femoral neck) were classified as Type 1-2. Therefore, fractures running from femoral basal neck to the subtrochanteric area were classified as Type 2-3-4. We targeted 60 Type 2-3-4 cases (average age 81 years, 10 men, 50 women) out of 1042 proximal femoral fracture cases who visited 8 hospitals in 2 years. We investigated the presence or absence of lateral trochanteric wall fractures, the selection of internal fixator, and the proportion of poor results. The lateral trochanteric wall fracture was observed in 48% of subjects. Long nails were selected to treat 46% cases, and nails with 2 or 3 proximal lag screws were used in 58% cases. Long nails and those with 2 or 3 lag screws were also used in 59% and 69% of lateral trochanteric wall fractures. Poor results such as cutout or excessive telescoping of lag screw occurred in 11.7% of cases and 17.2% of lateral trochanteric wall fractures. Even in cases where long nails and multiple lag screws were used for femoral trochanteric fractures whose fracture line ran from the femoral basal neck to subtrochanteric area were used, the failure rate was high in the presence of a lateral wall fracture. Therefore, it is necessary to consider careful post-operative treatment for proximal femoral fractures with lateral wall fracture, whose fracture line runs from femoral basal neck to subtrochanteric area.

Improving lipophilicity of 5-(1-acetyl-5-phenylpyrazolidin-3-ylidene)-1,3-dimethylbarbituric acid increases its efficacy to activate hypoxia-inducible factors.

Hypoxia-inducible factor (HIF) activators aid the treatment of renal anemia and ischemia. Recently, PyrzA (5-(1-acetyl-5-phenylpyrazolidin-3-ylidene)-1,3-dimethylbarbituric acid), a HIF activator by PHD inhibition without a 2-oxoglutarate moiety was reported. However, PyrzA has low lipophilicity, and it was necessary to improve its solubility by synthesizing derivatives. In this study, we synthesized and evaluated a higher lipophilic derivative of PyrzA and found that it exhibited higher HIF activity and stabilizing ability at low concentrations compared to Roxadustat, a commercially available HIF activator.

Comparing the Effects of Canagliflozin vs. Glimepiride by Body Mass Index in Patients with Type 2 Diabetes and Chronic Heart Failure: A Subanalysis of the CANDLE Trial.

Background: We present results of a 24-week comparative study of the effects of the sodium−glucose cotransporter 2 (SGLT2) inhibitor canagliflozin vs. the sulfonylurea glimepiride, by baseline body mass index (BMI), in patients with type 2 diabetes and chronic heart failure. Methods: We conducted a post hoc analysis of the CANDLE trial. This subanalysis evaluated NT-proBNP, BMI, and other laboratory parameters, according to the subgroups stratified by BMI ≥ 25 kg/m2 vs. BMI < 25 kg/m2. Results: A group ratio of proportional changes in the geometric means of NT-proBNP was 0.99 (p = 0.940) for the subgroup with BMI ≥ 25 kg/m2 and 0.85 (p = 0.075) for the subgroup with BMI < 25 kg/m2, respectively. When baseline BMI was modeled as a continuous variable, results for patients with BMI < 30 kg/m2 showed a slightly smaller increase in NT-proBNP in the canagliflozin group vs. the glimepiride group (p = 0.295); that difference was not seen among patients with BMI ≥30 kg/m2 (p = 0.948). Irrespective of obesity, the canagliflozin group was associated with significant reduction in BMI compared to the glimepiride group. Conclusion: There was no significant difference in the effects of canagliflozin, relative to glimepiride, on NT-proBNP concentrations irrespective of baseline obesity. UMIN clinical trial registration number: UMIN000017669.

Diagnostic reasoning in rehabilitation nutrition: Position paper by the Japanese Association of Rehabilitation Nutrition (secondary publication).

Diagnostic reasoning is the thought process used to arrive at a diagnosis based on symptoms, examination findings, and laboratory values. Diagnosis is categorized as nonanalytic reasoning (intuition) and analytic reasoning (analysis). Rehabilitation nutrition involves the diagnosis of nutritional disorders, sarcopenia, and excess or deficient nutrient intake. There is usually only one correct answer for the presence or absence of these. On the other hand, there may be no single correct answer for the causes of anorexia, weight loss, or sarcopenia, and analytical reasoning is required. In this case, diagnostic reasoning involves hypotheses. Simply using nutritional supplements without performing diagnostic reasoning about these causes is like prescribing antipyretic analgesics to a patient with a headache without diagnosing the cause of the headache. To maximize function and quality of life in rehabilitation nutrition, it is necessary to suspect the common causes of anorexia, weight loss, and sarcopenia in all cases.

Correction to "Prolyl Hydroxylase Domain Protein Inhibitor Not Harboring a 2-Oxoglutarate Scaffold Protects against Hypoxic Stress".

[This corrects the article DOI: 10.1021/acsptsci.2c00002.].

Prolyl Hydroxylase Domain Protein Inhibitor Not Harboring a 2-Oxoglutarate Scaffold Protects against Hypoxic Stress.

Hypoxia-inducible factor-α (HIF-α) activation has shown promising results in the treatment of ischemia, such as stroke, myocardial infarction, and chronic kidney disease. A number of HIF-α activators have been developed to improve the symptoms of these diseases. Many feature 2-oxoglutarate (2-OG) scaffolds that interact with the active centers of prolyl hydroxylase domain-containing proteins (PHDs), displacing the coenzyme 2-OG. This stabilizes HIF-α. Therefore, the specificity of the 2-OG analogs is not high. Here, we identified 5-(1-acetyl-5-phenylpyrazolidin-3-ylidene)-1,3-dimethylbarbituric acid (PyrzA) among over 10 000 compounds as a novel HIF activator that does not contain a 2-OG scaffold. In cultured cells, PyrzA enhanced HIF-α stability and upregulated the expression of HIF target genes. Interestingly, PyrzA decreased HIF-1α prolyl hydroxylation, suggesting that PyrzA may activate HIF to prevent the degradation of HIF-α. These results indicate that PyrzA stabilizes HIF via a novel mechanism and could be a potential HIF activator candidate.

Esterification promotes the intracellular accumulation of roxadustat, an activator of hypoxia-inducible factors, to extend its effective duration.

Kidney injury often causes anemia due to a lack of production of the erythroid growth factor erythropoietin (EPO) in the kidneys. Roxadustat is one of the first oral medicines inducing EPO production in patients with renal anemia by activating hypoxia-inducible factors (HIFs), which are activators of EPO gene expression. In this study, to develop prodrugs of roxadustat with improved permeability through cell membrane, we investigated the effects of 8 types of esterification on the pharmacokinetics and bioactivity of roxadustat using Hep3B hepatoma cells that HIF-dependently produce EPO. Mass spectrometry of cells incubated with the esterified roxadustat derivatives revealed that the designed compounds were deesterified after being taken up by cells and showed low cytotoxicity compared to the original compound. Esterification prolonged the effective duration of roxadustat with respect to EPO gene induction and HIF activation in cells transiently exposed to the compounds. In the kidneys and livers of mice, both of which are unique sites of EPO production, a majority of the methyl-esterified roxadustat was deesterified within 6 h after drug administration. The deesterified roxadustat derivative was continuously detectable in plasma and urine for at least 48 h after administration, while the administered compound became undetectable 24 h after administration. Additionally, we confirmed that methyl-esterified roxadustat activated erythropoiesis in mice by inducing Epo mRNA expression exclusively in renal interstitial cells, which have intrinsic EPO-producing potential. These data suggest that esterification could lead to the development of roxadustat prodrugs with improvements in cell membrane permeability, effective duration and cytotoxicity.

D-dimer levels in patients with nonvalvular atrial fibrillation and acute heart failure treated with edoxaban.

BACKGROUND: D-dimer levels can predict ischemic stroke in patients with acute heart failure (AHF). However, the effects of direct oral anticoagulants on D-dimer levels have not been investigated during admission for AHF in patients with atrial fibrillation (AF). This study examined D-dimer levels immediately after admission and following edoxaban initiation as a sub-analysis of a multi-center study that investigated the pharmacokinetics and pharmacodynamics of edoxaban in patients with nonvalvular AF (NVAF) and AHF. METHODS: Hospitalized patients with NVAF and AHF received edoxaban according to the label. The primary measure was the change in D-dimer levels on 7 consecutive days after admission for AHF. We also investigated differences according to prior edoxaban use (de novo at the time of admission or continuation). RESULTS: In 10/13 (76.9%) de novo patients, D-dimer levels exceeded the reference value (1.0 µg/mL) at admission (mean, 2.12 µg/mL) and subsequently decreased in 9 patients (at final blood sampling: mean, 1.12 µg/mL); 1 patient did not fall below the reference value due to stasis dermatitis. In the continuation group, most patients had D-dimer levels below the reference value from Day 1 (mean, 0.93 µg/mL), and levels remained stable or decreased (at final blood sampling: mean, 0.49 µg/mL). No events of stroke were observed. CONCLUSIONS: D-dimer levels may be elevated in patients with NVAF and AHF, particularly in those without prior anticoagulant treatment. Edoxaban may be effective for lowering and keeping D-dimer levels, a biomarker for predicting ischemic stroke, below the reference value in patients with NVAF and AHF.

Relevant factors of leg strength at hospital discharge in patients hospitalized due to acute decompensated heart failure: multi-institutional prospective observational study.

BACKGROUND: Lower leg strength at hospital discharge is strongly associated with poor prognosis in older patients with acute decompensated heart failure (ADHF). Improving leg strength is important in acute-phase cardiac rehabilitation (CR). AIMS: This study aimed to clarify whether a change in leg strength occurs during hospitalization of older ADHF patients receiving CR and whether it affects leg strength at discharge. METHODS AND RESULTS: We enrolled 247 ADHF patients who underwent CR during hospitalization. They were divided into the non-older patient group (<75 years; n = 142) and older patient group (≥75 years; n = 105). Quadriceps isometric strength (QIS), body mass-corrected QIS (%BM QIS), and change in QIS during hospitalization (QIS ratio) were evaluated in all patients. Physical function in the stable phase was measured by the Performance Measure for Activities of Daily Living-8 (PMADL-8). The QIS value increased during hospitalization in the non-older patient group (30.0 ± 11.1 vs. 31.6 ± 10.9 kgf, P < 0.001) but did not increase in the older patient group (19.1 ± 6.3 vs. 19.5 ± 6.1 kgf, P = 0.275). Multiple regression analysis revealed that PMADL-8 significantly predicted %BM QIS at discharge in the non-older patient group (ß = -0.254, P = 0.004), whereas in the older patient group, QIS ratio and PMADL-8 significantly predicted %BM QIS at discharge (ß = 0.264, P = 0.008 for QIS ratio and ß = -0.307, P = 0.003 for PMADL-8). CONCLUSIONS: Leg strength was not improved in older ADHF patients during hospitalization even if they received CR, and this affected leg strength at discharge, suggesting that careful skeletal muscle intervention should be provided during hospitalization, and patients need to continue exercise after discharge.