Effects of Exercise Training on Mitochondrial Fatty Acid ß-Oxidation in the Kidneys of Dahl Salt-Sensitive Rats.

Exercise training (Ex) has anti-hypertensive and renal protective effects. In this study, we investigate the effects of Ex on mitochondrial fatty acid metabolism in the kidneys of Dahl salt-sensitive (Dahl-S) rats fed a high-salt (HS) diet. Eight-week-old, male Dahl-S rats were divided into three groups: (1) normal-salt diet, sedentary (NS-Sed), (2) HS diet, sedentary (HS-Sed), and (3) HS-Ex. The NS and HS groups were fed a diet containing 0.6% and 8% NaCl, respectively. The HS-Ex group performed treadmill running for 8 weeks (5 days/week; 60 min/day at 16-20 m/min, 0% gradient). Renal function and the expression of enzymes and regulators of ß-oxidation and electron transport chain (ETC) complexes were assessed. HS increased systolic blood pressure and proteinuria, and Ex ameliorated these defects. HS also reduced creatinine clearance, and Ex ameliorated it. HS reduced the renal expression of enzymes of ß-oxidation (carnitine palmitoyltransferase type I (CPTI) and acyl-CoA dehydrogenases (CADs)) and the related transcription factors peroxisome proliferator-activated receptor α (PPARα) and PPARγ-coactivator-1α (PGC-1α), and Ex restored this. HS also reduced the renal expression of enzymes in ETC complexes, and Ex restored this expression. Ex ameliorates HS-induced renal damage by upregulating enzymes involved in fatty acid ß-oxidation and ETC complexes via increases in PPAR-α and PGC-1α expressions in the kidneys of Dahl-S rats. These results suggest that Ex may have beneficial effects on HS-induced mitochondrial dysfunction in the kidney.

Associations of body mass index and hospital-acquired disability with post-discharge mortality in older patients with acute heart failure.

OBJECTIVES: To investigate the effect of hospital-acquired disability (HAD) on all-cause mortality after discharge according to the body mass index (BMI) in older patients with acute decompensated heart failure. METHODS: We included 408 patients aged ≥ 65 years who were hospitalized for acute decompensated heart failure and had undergone an acute phase of cardiac rehabilitation at the Sakakibara Heart Institute between April 2013 and September 2015 (median age: 82 years, interquartile range (IQR): 76-86; 52% male). Patients were divided into three groups based on BMI at hospital admission: underweight (< 18.5 kg/m2), normal weight (18.5 to 25 kg/m2), and overweight (≥ 25 kg/m2). HAD was defined as a decrease of at least five points at discharge compared to before hospitalization according to the Barthel Index. RESULTS: The median follow-up period was 475 (IQR: 292-730) days, and all-cause mortality during the follow-up period was 84 deaths (21%). According to multivariate Cox regression analysis, being underweight (HR: 1.941, 95% CI: 1.134-3.321,P = 0.016) or overweight (HR: 0.371, 95% CI: 0.171-0.803,P = 0.012), with normal BMI as the reference, and HAD (HR: 1.857, 95% CI: 1.062-3.250,P = 0.030) were independently associated with all-cause mortality. Patients with HAD exhibited a significantly lower cumulative survival rate in the underweight group (P = 0.001) and tended to have a lower cumulative survival rate in the normal weight group (P = 0.072). HAD was not significantly associated with cumulative survival in the overweight group (P = 0.392). CONCLUSIONS: BMI and HAD independently predicted all-cause mortality after discharge in older patients with acute decompensated heart failure. Furthermore, HAD was significantly associated with higher all-cause mortality after discharge, especially in the underweight group.

Effects of Exercise Training on the Renin-Angiotensin System in the Kidneys of Dahl Salt-Sensitive Rats.

PURPOSE: Exercise training (Ex) has antihypertensive and renal protective effects; however, the precise mechanisms remain unclear. The renal renin-angiotensin system (RAS) plays a vital role in renal function and pathology. Therefore, we investigated the effects of Ex on the renal RAS components in Dahl salt-sensitive (Dahl-S) rats. METHODS: Male Dahl-S rats were divided into four groups: normal salt diet + sedentary, normal salt diet + Ex, high-salt diet (HS, 8% NaCl) + sedentary, and HS + Ex. Treadmill running was performed for 8 wk in the Ex groups. RESULTS: Ex attenuated the HS-induced renal dysfunction and glomerular injury without causing blood pressure alterations. HS increased urinary excretion of both total and intact angiotensinogen. Ex decreased the HS-induced increased urinary excretion of total angiotensinogen. However, it did not change the HS-induced urinary excretion of intact angiotensinogen, indicating reduced intact angiotensinogen cleaving. Ex restored the HS-induced increased angiotensinogen and angiotensin II type 1 receptor expressions in the outer medulla and the HS-induced increased angiotensin-converting enzyme expression in the cortex. Ex restored the HS-induced decreased renin expression in the cortex and outer medulla, and the HS-induced decreased angiotensin-converting enzyme 2, angiotensin II type 2 receptor, and Mas receptor expressions in the outer medulla. CONCLUSIONS: Ex attenuates HS-induced renal dysfunction, glomerular injury, and renal RAS dysregulation in Dahl-S rats.

Febuxostat ameliorates high salt intake-induced hypertension and renal damage in Dahl salt-sensitive rats.

OBJECTIVE: Several clinical studies have reported that xanthine oxidoreductase inhibitors have antihypertensive and renal protective effects but their mechanisms have not been fully determined. This study aims to clarify these mechanisms by examining the effects of febuxostat, which is a novel selective xanthine oxidoreductase inhibitor, in Dahl salt-sensitive rats. METHODS: Eight-week-old male Dahl salt-sensitive rats were fed a normal salt (0.6% NaCl) or high salt (8% NaCl) diet for 8 weeks. A portion of the rats that were fed high salt diet were treated with febuxostat (3 mg/kg per day) simultaneously. Additionally, acute effects of febuxostat (3 mg/kg per day) were examined after high salt diet feeding for 4 or 8 weeks. RESULTS: Treatment with febuxostat for 8 weeks attenuated high salt diet-induced hypertension, renal dysfunction, glomerular injury, and renal interstitial fibrosis. Febuxostat treatment reduced urinary excretion of H2O2 and malondialdehyde and renal thiobarbituric acid reactive substances content. High salt diet increased xanthine oxidoreductase activity and expression in the proximal tubules and medullary interstitium. Febuxostat completely inhibited xanthine oxidoreductase activity and attenuated the high salt diet-increased xanthine oxidoreductase expression. Febuxostat transiently increased urine volume and Na+ excretion without change in blood pressure or urinary creatinine excretion after high salt diet feeding for 4 or 8 weeks. CONCLUSION: Febuxostat ameliorates high salt diet-induced hypertension and renal damage with a reduction of renal oxidative stress in Dahl salt-sensitive rats. The antihypertensive effect of febuxostat may be mediated in part by diuretic and natriuretic action.

Protocol for a multicentre, prospective observational cohort study in Japan: association among hospital-acquired disability, regular exercise and long-term care dependency in older patients after cardiac surgery.

INTRODUCTION: Cardiac surgery for older patients, postoperative functional decline and the need for long-term care have received increasing attention as essential outcomes in recent years. Therefore, prevention of functional decline and long-term care dependency after cardiac surgery are important; however, our current understanding of postoperative functional trajectory and effects of postoperative regular exercise on long-term functional decline and long-term care dependency is limited. Therefore, we will conduct a multicentre, prospective cohort study to (1) examine the effect of hospital-acquired disability on long-term functional decline and long-term care dependency and (2) investigate the favourable effect of postoperative regular exercise on long-term functional decline and long-term care dependency in older patients after cardiac surgery. METHODS AND ANALYSIS: We designed a prospective, multicentre cohort study to enrol older patients aged≥65 years undergoing elective coronary artery bypass graft or valve surgery. We will conduct medical record reviews to collect data on patient demographics, comorbidities, operative details, progression of in-hospital postoperative cardiac rehabilitation and functional trajectory from a few days before cardiac surgery to the day before hospital discharge. They will be followed up for 2 years to obtain information on their health status including functional status, regular exercise and clinical events by mail. Primary endpoints of this study are long-term functional decline and long-term care dependency after cardiac surgery. Secondary endpoints are readmission due to cardiac events or all-cause mortality. ETHICS AND DISSEMINATION: The study protocol was approved by the Ethics Committee of the Department of Physical Therapy, Faculty of Health Science, Juntendo University, and of each collaborating hospital. We obtained written informed consent from all study participants after the description of the study procedures. Publication of the study results is anticipated in 2025.

The Relationship between Sarcopenia and Respiratory Muscle Weakness in Community-Dwelling Older Adults.

An association between respiratory muscle weakness and sarcopenia may provide a clue to the mechanism of sarcopenia development. We aimed to clarify this relationship among community-dwelling older adults. In total, 117 community-dwelling older adults were assessed and classified into 4 groups: robust, respiratory muscle weakness, sarcopenia, and respiratory sarcopenia. The respiratory sarcopenia group (12%) had a significantly higher percentage of males and had lower BMI, skeletal muscle index, skeletal muscle mass, phase angle, and oral function than the robust group (32.5%). All physical functions were significantly lower. The respiratory muscle weakness group (54.7%) had a significantly lower BMI and slower walking speed, compared with the robust group. The sarcopenia group (0.8%) was excluded from the analysis. The percent maximum inspiratory pressure was significantly lower in both the respiratory muscle weakness and respiratory sarcopenia groups, compared with the robust group. Almost all participants with sarcopenia showed respiratory muscle weakness. In addition, approximately 50% had respiratory muscle weakness, even in the absence of systemic sarcopenia, suggesting that respiratory muscle weakness may be the precursor of sarcopenia. The values indicating physical function and skeletal muscle mass in the respiratory muscle weakness group were between those in the robust and the respiratory sarcopenia groups.

Psoas Muscle Volume and Attenuation are Better Predictors than Muscle Area for Hospital Readmission in Older Patients after Transcatheter Aortic Valve Implantation.

OBJECTIVE: This study aimed to determine whether the psoas muscle volume (PMV) and its muscle attenuation (MA) are associated with hospital readmission after transcatheter aortic valve implantation (TAVI). METHOD: We included 113 older patients with aortic stenosis who underwent TAVI at Sakakibara Heart Institute (mean age 85 ± 5 years, 69% women). We measured PMV and psoas muscle area (PMA) as well as total muscle area (TMA) at the third lumbar vertebra using preoperative computed tomography (CT) images. The crude values of the PMV, PMA, and TMA were normalized by dividing by height squared. RESULTS: The median follow-up period was 724 days (interquartile range: 528-730 days), and there were 25 all-cause readmissions during the follow-up period (22% of all patients). In the multivariate Cox regression analysis adjusted for age, sex, and EuroSCORE II, the PMV and its MA and crude PMA were significantly associated with all-cause readmission [HR: 0.957 (0.930-0.985), p = 0.003, HR: 0.927 (0.862-0.997), p = 0.040], whereas the PMA and TMA and each MA were not (all p > 0.05). The groups with low PMV and MA had significantly higher incidences of all-cause readmission than that with high PMV and MA (log-rank test: p = 0.011). CONCLUSION: PMV and its MA measured from preoperative CT images were independent predictors of all-cause readmission in TAVI patients.

Hospitalization-Associated Disability After Cardiac Surgery in Elderly Patients　- Exploring the Risk Factors Using Machine Learning Algorithms.

Background: Hospitalization-associated disability (HAD) is associated with prolonged functional decline and increased mortality after discharge. Therefore, we examined the incidence and risk factors associated with HAD in elderly patients undergoing cardiac surgery in Japan. Methods and Results: We retrospectively examined 2,262 elderly patients who underwent elective cardiac surgery at Sakakibara Heart Institute. HAD was defined as a functional decline between time of admission and discharge measured by the Barthel Index. We analyzed clinical characteristics using machine learning algorithms to identify the risk factors associated with HAD. After excluding 203 patients, 2,059 patients remained, of whom 108 (5.2%) developed HAD after cardiac surgery. The risk factors identified were age, serum albumin concentration, estimated glomerular filtration rate, Revised Hasegawa's Dementia Scale, N-terminal pro B-type natriuretic peptide, vital capacity, preoperative Short Physical Performance Battery (SPPB) score, operation times, cardiopulmonary bypass times, ventilator times, length of postoperative intensive care unit stay, and postoperative ambulation start day. The highest incidence of HAD was found in patients with an SPPB score ≤9 and in those who started ambulation >6 days after surgery (76.9%). Conclusions: Several risk factors for HAD are components of frailty, suggesting that preoperative rehabilitation to reduce the risk of HAD is feasible. Furthermore, the association between HAD and a delayed start of ambulation reaffirms the importance of early mobilization and rehabilitation.

Hospital-Acquired Functional Decline and Clinical Outcomes in Older Patients Undergoing Transcatheter Aortic Valve Implantation.

BACKGROUND: This study aimed to assess the relationship between hospital-acquired functional decline and the risk of mid-term all-cause death in older patients undergoing transcatheter aortic valve implantation (TAVI).Methods and Results:In total, 463 patients (mean age 85 years, interquartile range [IQR]: 82, 88) undergoing elective TAVI at Sakakibara Heart Institute between 2010 and 2018, who were followed up for 3 years, were enrolled in the study. Hospital-acquired functional decline after TAVI, which was defined by at least a 1-point decrease on the Short Physical Performance Battery before discharge compared to the preoperative score, was assessed. A total of 113 patients (24.4%) showed hospital-acquired functional decline after TAVI, and 50 (11.3%) patients died over a mean follow-up period of 1.9±0.8 years. Kaplan-Meier survival curves indicated that hospital-acquired functional decline was significantly associated with all-cause mortality (log-rank test, P=0.001). On multivariate Cox regression analysis, hospital-acquired functional decline was associated with a higher risk of all-cause mortality (OR 2.108, 95% CI 1.119-3.968, P=0.021) independent of sex, body mass index, advanced chronic kidney disease, and preoperative frailty, as assessed by the modified essential frail toolkit. CONCLUSIONS: Hospital-acquired functional decline is associated with mid-term all-cause mortality in older patients following TAVI. Trajectory of functional status is a vital sign, and it is useful for risk stratification in older patients following TAVI.

Exercise training delays renal disorders with decreasing oxidative stress and increasing production of 20-hydroxyeicosatetraenoic acid in Dahl salt-sensitive rats.

OBJECTIVE: Exercise training has antihypertensive and renoprotective effects in humans and rats. However, the effects of exercise training on renal disorders that occur with salt-sensitive hypertension remains unclear. The study aim was to investigate the effects and mechanisms of exercise training on renal function in a rat model of salt-sensitive hypertension. METHODS: Six-week-old male Dahl salt-sensitive rats were divided into normal-salt (0.6% NaCl) diet, high-salt (8% NaCl) diet, and high-salt diet with exercise training groups. The high-salt diet with exercise training group underwent daily treadmill running for 8 weeks. RESULTS: The high-salt diet induced severe hypertension and renal dysfunction. Exercise training significantly improved high-salt diet-induced urinary protein, albumin, and L-type fatty acid-binding protein excretion, and glomerulosclerosis but not renal interstitial fibrosis without changing blood pressure. Exercise training significantly attenuated high-salt diet-induced oxidative stress in the kidneys and decreased high-salt diet-stimulated xanthine oxidoreductase activity but not nicotinamide adenine dinucleotide phosphate oxidase activity. The high-salt diet did not change urinary excretion of 20-hydroxyeicosatetraenoic acid and decreased cytochrome P450 4A protein expression in the kidneys. Exercise training increased urinary 20-hydoroxyeicosatetraenoic acid excretion and renal cytochrome P450 4A protein expression. CONCLUSION: Exercise training improved renal disorders without lowering blood pressure in Dahl salt-sensitive rats. Exercise training also decreased oxidative stress and increased 20-hydroxyeicosatetraenoic acid production in the kidneys. These results suggest that improvements in oxidative stress and 20-hydroxyeicosatetraenoic acid production may be potential mechanisms by which exercise training improved renal disorders in Dahl salt-sensitive rats.

Xanthine Oxidase Inhibitor, Febuxostat Ameliorates the High Salt Intake-Induced Cardiac Hypertrophy and Fibrosis in Dahl Salt-Sensitive Rats.

BACKGROUND: Xanthine oxidase (XO) is a source of reactive oxygen species production in the heart. However, pathophysiological role of XO has not been clarified in hypertensive heart disease. Thus, the present study examined the impacts of high salt (HS) intake and febuxostat (Fx), a XO inhibitor in Dahl salt-sensitive (Dahl-S) rats. METHODS: Eight-week old, male Dahl-S rats were fed a normal salt diet (0.6% NaCl) or a HS diet (8% NaCl) for 8 weeks. A part of the rats fed the HS diet were simultaneously treated with Fx (3 mg/kg/day). RESULTS: HS intake increased blood pressure and heart weight with cardiomyocyte hypertrophy and interstitial fibrosis in the left ventricle (LV), and Fx diminished them. HS increased the XO activity 4.7-fold and nicotinamide-adenine dinucleotide phosphate (NADPH) oxidase activity 1.5-fold, and Fx not only blocked the XO activity but also inhibited the HS-increased NADPH oxidase activity. HS increased the expression of XO, collagen, transforming growth factor-ß1 (TGF-ß1), angiotensin-converting enzyme, and angiotensin II type 1 receptor and the phosphorylation of extracellular signal-regulated kinase (ERK) in the LV, and Fx reduced the expression and phosphorylation of these proteins except XO. CONCLUSIONS: Fx ameliorates the HS intake-induced hypertension, LV hypertrophy, and fibrosis with decreasing the TGF-ß1 expression and ERK phosphorylation in Dahl-S rats. Fx also down-regulates cardiac NADPH oxidase and renin-angiotensin system. The XO inhibition may be an effective therapy for hypertensive heart disease.

Pitavastatin Upregulates Nitric Oxide Synthases in the Kidney of Spontaneously Hypertensive Rats and Wistar-Kyoto Rats.

BACKGROUND: Clinical trials show potent renoprotective effects of pitavastatin (PTV), although the precise mechanism for these renoprotective effects is not fully clarified. The aim of this study was to examine the antihypertensive and renoprotective effects of PTV, focusing on the nitric oxide (NO) system. METHODS: Male, 6-week-old, spontaneously hypertensive rats (SHR) and Wistar-Kyoto rats (WKY) were randomized to receive vehicle or PTV (2 mg/kg bodyweight) for 8 weeks. Blood pressure and urinary albumin excretion were measured every 2 weeks. After 8 weeks, plasma biochemical parameters and renal histology were examined. NO synthase isoform (neuronal, nNOS; inducible, iNOS; and endothelial, eNOS) expression and eNOS phosphorylation were examined by western blotting. RESULTS: PTV attenuated hypertension and albuminuria development in SHR. PTV decreased glomerular desmin expression and medullary interstitial fibrosis in SHR. PTV tended to increase plasma NO in both strains but significantly increased urinary NO excretion only in WKY. PTV significantly increased nNOS and eNOS expression, enhanced eNOS phosphorylation at serine1177, and inhibited eNOS phosphorylation at threonine495 in the kidney of both strains. CONCLUSIONS: PTV treatment led to increased renal NOS expression and upregulated eNOS activity in both SHR and WKY. The antihypertensive and renoprotective effects of PTV may be related to upregulation of the NO system.