Myonectin protects against skeletal muscle dysfunction in male mice through activation of AMPK/PGC1α pathway.

To maintain and restore skeletal muscle mass and function is essential for healthy aging. We have found that myonectin acts as a cardioprotective myokine. Here, we investigate the effect of myonectin on skeletal muscle atrophy in various male mouse models of muscle dysfunction. Disruption of myonectin exacerbates skeletal muscle atrophy in age-associated, sciatic denervation-induced or dexamethasone (DEX)-induced muscle atrophy models. Myonectin deficiency also contributes to exacerbated mitochondrial dysfunction and reduces expression of mitochondrial biogenesis-associated genes including PGC1α in denervated muscle. Myonectin supplementation attenuates denervation-induced muscle atrophy via activation of AMPK. Myonectin also reverses DEX-induced atrophy of cultured myotubes through the AMPK/PGC1α signaling. Furthermore, myonectin treatment suppresses muscle atrophy in senescence-accelerated mouse prone (SAMP) 8 mouse model of accelerated aging or mdx mouse model of Duchenne muscular dystrophy. These data indicate that myonectin can ameliorate skeletal muscle dysfunction through AMPK/PGC1α-dependent mechanisms, suggesting that myonectin could represent a therapeutic target of muscle atrophy.

Adipolin protects against renal injury via PPARα-dependent reduction of inflammasome activation.

Although chronic kidney disease (CKD) is a major health problem worldwide, its underlining mechanism is incompletely understood. We previously identified adipolin as an adipokine which provides benefits for cardiometabolic diseases. Here, we investigated the role of adipolin in the development of CKD. Adipolin-deficiency exacerbated urinary albumin excretion, tubulointerstitial fibrosis and oxidative stress of remnant kidneys in mice after subtotal nephrectomy through inflammasome activation. Adipolin positively regulated the production of ketone body, ß-hydroxybutyrate (BHB) and expression of a catalytic enzyme producing BHB, HMGCS2 in the remnant kidney. Treatment of proximal tubular cells with adipolin attenuated inflammasome activation through the PPARα/HMGCS2-dependent pathway. Furthermore, systemic administration of adipolin to wild-type mice with subtotal nephrectomy ameliorated renal injury, and these protective effects of adipolin were diminished in PPARα-deficient mice. Thus, adipolin protects against renal injury by reducing renal inflammasome activation through its ability to induce HMGCS2-dependent ketone body production via PPARα activation.

Prognostic efficacy of a post-discharge visiting program for patients with heart failure.

We aimed to investigate the impact of post-discharge scheduled hospital visits on readmission due to heart failure (HF). In this retrospective study, a total of 245 patients (N = 101 in the scheduled hospital visit group, N = 144 in the non-scheduled hospital visit group) who were alive with free from readmission due to HF for 90 days after discharge were enrolled. The patients had been hospitalized with acute decompensated HF between August 2018 and July 2019. Scheduled hospital visits were recommended 90 days after the patients had been discharged. After checking their self-care adherence, nurse-led self-care maintenance and monitoring were provided. To determine the effectiveness of the scheduled hospital visits, we conducted landmark analyses divided into two periods: Scheduled visits within 180 days, and after 180 days. The readmission rate due to HF within 180 days was lower in the scheduled visit group. In the landmark analysis, the 1-year incidence rate of readmission was significantly lower in patients with a scheduled hospital visit than in those without, in the period within 180 days (2.0% vs 9.0%, P = 0.029) but not after 180 days. After adjusting for age and estimated glomerular filtration rate as confounders, scheduled hospital visits tended to reduce readmission due to HF (P = 0.060); however, readmission was significantly reduced in the period within 180 days (P = 0.007). In conclusion, scheduled hospital visits at 90 days after discharge may be beneficial in delaying readmission due to HF by reducing risk of readmission during the early post-visit period.

Factor Xa inhibitor, edoxaban ameliorates renal injury after subtotal nephrectomy by reducing epithelial-mesenchymal transition and inflammatory response.

Chronic kidney disease (CKD) is an increasing and life-threatening disease worldwide. Recent evidence indicates that blood coagulation factors promote renal dysfunction in CKD patients. Activated factor X (FXa) inhibitors are safe and first-line drugs for the prevention of thrombosis in patients with atrial fibrillation. Here, we investigated the therapeutic effects of edoxaban on CKD using the mouse 5/6 nephrectomy model. Eight-week-old wild-type mice were subjected to 5/6 nephrectomy surgery and randomly assigned to two groups, edoxaban or vehicle admixture diet. Edoxaban treatment led to reduction of urinary albumin excretion and plasma UN levels compared with vehicle group, which was accompanied with reduced glomerular cross-sectional area and cell number. Edoxaban treatment also attenuated fibrinogen positive area in the remnant kidneys after subtotal nephrectomy. Moreover, edoxaban treatment resulted in attenuated tubulointerstitial fibrosis after 5/6 nephrectomy, which was accompanied by reduced expression levels of epithelial-mesenchymal transition (EMT) markers, inflammatory mediators, and oxidative stress markers in the remnant kidneys. Treatment of cultured proximal tubular cells, HK-2 cells, with FXa protein led to increased expression levels of EMT markers, inflammatory mediators, and oxidative stress markers, which were abolished by pretreatment with edoxaban. Treatment of HK-2 cells with edoxaban attenuated FXa-stimulated phosphorylation levels of extracellular signal-regulated kinase (ERK) and NF-κB. Our findings indicate that edoxaban can improve renal injury after subtotal nephrectomy by reducing EMT and inflammatory response, suggesting that FXa inhibition could be a novel therapeutic target for CKD patients with atrial fibrillation.

＜Editors' Choice＞ Prognostic utility of multipoint nutritional screening for hospitalized patients with acute decompensated heart failure.

This study aimed to evaluate the impact of serial changes in nutritional status on 1-year events including all-cause mortality or rehospitalization owing to heart failure (HF) among hospitalized patients with acute decompensated HF (ADHF). The study subjects comprised 253 hospitalized patients with ADHF. The controlling nutritional status (CONUT) score was assessed both at hospital admission and discharge. The subjects were divided into three groups according to nutritional status using CONUT score: normal (0 and 1), mild risk (2-4), and moderate to severe risk defined as malnutrition (5-12). We observed nutritional status was improved or not. The incidence of malnutrition was 30.4% at hospital admission and 23.7% at discharge, respectively. Malnutrition was independently associated with 1-year events among hospitalized patients with ADHF. Presence or absence of improvement in nutritional status was significantly associated with 1-year events (P < 0.05), that was independent of percentage change in plasma volume in multivariate Cox regression analyses. We determined a reference model, including gender and estimated glomerular filtration rate, using multivariate logistic regression analysis (P < 0.05). Adding the absence of improvement in nutritional status during hospitalization to the reference model significantly improved both NRI and IDI (0.563, P < 0.001 and 0.039, P = 0.001). Furthermore, malnutrition at hospital discharge significantly improved NRI (0.256, P = 0.036) In conclusion, serial changes in the nutritional status evaluated on the basis of multiple measurements may provide more useful information to predict 1-year events than single measurement at hospital admission or discharge in hospitalized patients with ADHF.

Efficacy of Rapid Decongestion Strategy in Patients Hospitalized for Acute Heart Failure.

BACKGROUND: Clinical congestion is the most dominant feature in patients with acute decompensated heart failure (HF). However, uncertainty exists due to the permutations and combinations of congestion status and decongestion strategies. This study investigated the effect of congestion status and its improvement on 1-year mortality.Methods and Results:In all, 453 consecutive patients hospitalized for acute decompensated HF between July 2015 and March 2017 were prospectively included in the study. Congestion was evaluated using the congestion score. The 1-year mortality rate was 22.7%. The mean (±SD) congestion scores at admission, on Day 3, and at discharge were 10.7±3.9, 3.4±3.5, and 0.3±0.8, respectively. The improvement rate in congestion scores during the first 3 days was 78%; 46.6% of patients had residual congestion. The Day 3 congestion score and the improvement rate during the first 3 days were related to 1-year all-cause mortality and cardiovascular mortality. Combined predictive values were examined by calculating multivariable-adjusted hazard ratios for associations of residual congestion and improvement rate during the first 3 days, and prognostic variables identified by the Cox regression model. Residual congestion and lesser improvement (<64%) were associated with higher relative risk of 1-year all-cause mortality and cardiovascular mortality than residual congestion and higher improvement (≥64%) or resolved congestion. CONCLUSIONS: Rapid decongestion could be a prerequisite regardless of residual congestion in hospitalized acute decompensated HF patients.

Prognostic Importance of Multiple Nutrition Screening Indexes for 1-Year Mortality in Hospitalized Acute Decompensated Heart Failure Patients.

Background: The purpose of the study was to evaluate the impact of nutritional status on 1-year mortality in hospitalized patients with acute decompensated heart failure (ADHF). Methods and Results: We enrolled 457 hospitalized ADHF patients. Previously established objective nutritional indexes (controlling nutritional status [CONUT], prognostic nutritional index [PNI], geriatric nutritional risk index [GNRI], and subjective global assessment [SGA]) were evaluated at hospital admission. Malnutrition was defined as CONUT score ≥5, PNI score <38, GNRI score <92, and SGA scores B and C. The frequencies of malnutrition based on CONUT, PNI, GNRI, and SGA were 31.5%, 21.4%, 44.9%, and 27.8%, respectively. All indexes were related to the occurrence of 1-year mortality on univariate Cox regression analysis (P<0.05). We constructed a reference model using age, body mass index, systolic blood pressure, sodium concentration, and renal function on multivariable Cox regression analysis. Adding SGA to the reference model significantly improved both net reclassification improvement (NRI) and integrated discrimination improvement (0.344, P=0.002; 0.012, P=0.049; respectively). Other indexes (CONUT, PNI, and GNRI scores) significantly improved NRI (0.254, P=0.019; 0.273, P=0.013; 0.306, P=0.006; respectively). Conclusions: Nutritional screening assessed at hospital admission was appropriate for the prediction of 1-year mortality in hospitalized patients with ADHF.

Hemorrhagic Pericardial Cyst Complicated with Constrictive Pericarditis.

Pericardial cysts are rare abnormalities and are usually asymptomatic. Although several case reports on their diagnosis and treatment have been published, those on hemorrhagic pericardial cysts remain limited. We herein report the case of a 70-year-old man with a hemorrhagic pericardial cyst complicated with constrictive pericarditis 2 years after the initial diagnosis.

Comparison of two dosing methods for immediate administration of tolvaptan in acute decompensated heart failure.

BACKGROUND: The clinical dosing method for tolvaptan in patients with acute heart failure (HF) is still unclear. We aimed to compare the differences in clinical effect between two dosing regimens: once-daily 7.5mg and twice-daily 3.75mg. METHODS: In this randomized trial, tolvaptan was administered within 12h from hospital admission. The primary outcome was the serial change in congestion scores measured every day from enrollment until dosing day 7. Outcomes including safety parameters were also evaluated. RESULTS: The subjects were assigned to either the once-daily 7.5mg dosing regimen (N=15) or the twice-daily 3.75mg dosing regimen (N=16). The time-course changes in body weight, serum sodium and creatinine levels, systolic blood pressure, daily urine output, and congestion scores were similar between the two groups. In the twice-daily 3.75mg dosing group, the serum sodium levels on days 3 and 4 were significantly (p<0.05) increased compared with those on day 1. The congestion scores significantly (p<0.05) decreased from day 2 to day 7 in both groups compared with those on day 1. However, the difference in the serial change in the congestion scores did not reach statistical significance. CONCLUSIONS: Our present results suggest that the early administration of tolvaptan within 12h after hospital admission significantly improved congestion from the first day after administration by either dosing regimen, i.e. once-daily 7.5mg or twice-daily 3.75mg in patients with acute HF.