Effect of change in hepato-renal function and cardiac rehabilitation on mortality in patients with heart failure.

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.

Transcapillary PO2 Gradients in Contracting Muscles of Type I Diabetic Rats.

OBJECTIVE: This study aimed to clarify the effect of Type I diabetes (DIA) on transcapillary PO2 gradients, which are oxygen-driving factors between the blood and the interstitium, in the contracting muscle of rats. METHODS: Wistar male rats were divided into the diabetic (streptozocin i.p.) and sham groups. Microvascular and interstitial PO2 were measured in the extensor digitorum longus muscle during electrical stimulation-induced muscle contraction, using the phosphorescence quenching method. Transcapillary PO2 gradient, ΔPO2, was calculated as microvascular minus interstitial PO2. RESULTS: Resting microvascular PO2 was higher in the diabetic group than in the sham group (6.3 ± 1.7 vs. 4.7 ± 0.9 mmHg, p < 0.05) and remained for 180 s. Interstitial PO2 from rest to muscle contraction did not differ between the groups. The ΔPO2 was higher in the diabetic group than in the sham group at rest and during muscle contraction (4.03 ± 1.42 vs. 2.46 ± 0.90 mmHg at rest; 3.67 ± 1.51 vs. 2.22 ± 0.65 mmHg during muscle contraction, p < 0.05). Marked muscle atrophy was observed in the diabetic group. CONCLUSION: DIA increased microvascular and transcapillary PO2 gradients in the skeletal muscle. The enhanced PO2 gradients were maintained from rest to muscle contraction in diabetic muscle.

Adaptations of bone and bone vasculature to muscular stretch training.

The magnitude of bone formation and remodeling is linked to both the magnitude of strain placed on the bone and the perfusion of bone. It was previously reported that an increase in bone perfusion and bone density occurs in the femur of old rats with moderate aerobic exercise training. This study determined the acute and chronic effects of static muscle stretching on bone blood flow and remodeling. Old male Fischer 344 rats were randomized to either a naive or stretch-trained group. Static stretching of ankle flexor muscles was achieved by placement of a dorsiflexion splint on the left ankle for 30 min/d, 5d/wk for 4wk. The opposite hindlimb served as a contralateral control (nonstretched) limb. Bone blood flow was assessed during and after acute stretching in naive rats, and at rest and during exercise in stretch-trained rats. Vascular reactivity of the nutrient artery of the proximal tibia was also assessed in stretch-trained rats. MicroCT analysis was used to assess bone volume and micro-architecture of the trabecular bone of both tibias near that growth plate. In naive rats, static stretching increased blood flow to the proximal tibial metaphasis. Blood flow to the proximal tibial metaphysis during treadmill exercise was higher in the stretched limb after 4 wk of daily stretching. Daily stretching also increased tibial bone weight and increased total volume in both the proximal and distal tibial metaphyses. In the trabecular bone immediately below the proximal tibial growth plate, total volume and bone volume increased, but bone volume/total volume was unchanged and trabecular connectivity decreased. In contrast, intravascular volume increased in this region of the bone. These data suggest that blood flow to the tibia increases during bouts of static stretching of the hindlimb muscles, and that 4 wk of daily muscle stretching leads to bone remodeling and an increase in intravascular volume of the tibial bone.

Cancer history and physical function in patients with cardiovascular disease.

Both cancer and cardiovascular disease (CVD) cause skeletal muscle mass loss, thereby increasing the likelihood of a poor prognosis. We investigated the association between cancer history and physical function and their combined association with prognosis in patients with CVD. We retrospectively reviewed 3,796 patients with CVD (median age: 70 years; interquartile range [IQR]: 61-77 years) who had undergone physical function tests (gait speed and 6-minute walk distance [6MWD]) at discharge. We performed multiple linear regression analyses to assess potential associations between cancer history and physical function. Moreover, Kaplan-Meier curves and Cox regression analyses were used to evaluate prognostic associations in four groups of patients categorized by the absence or presence of cancer history and of high or low physical function. Multiple regression analyses showed that cancer history was significantly and independently associated with a lower gait speed and 6MWD performance. A total of 610 deaths occurred during the follow-up period (median: 3.1 years; IQR: 1.4-5.4 years). The coexistence of low physical function and cancer history in patients with CVD was associated with a significantly higher mortality risk, even after adjusting for covariates (cancer history/low gait speed, hazard ratio [HR]: 1.93, P < 0.001; and cancer history/low 6MWD, HR: 1.61, P = 0.002). Cancer history is associated with low physical function in patients with CVD, and the combination of both factors is associated with a poor prognosis.

Drug-drug conjugates of MEK and Akt inhibitors for RAS-mutant cancers.

Controlling RAS mutant cancer progression remains a significant challenge in developing anticancer drugs. Whereas Ras G12C-covalent binders have received clinical approval, the emergence of further mutations, along with the activation of Ras-related proteins and signals, has led to resistance to Ras binders. To discover novel compounds to overcome this bottleneck, we focused on the concurrent and sustained blocking of two major signaling pathways downstream of Ras. To this end, we synthesized 25 drug-drug conjugates (DDCs) by combining the MEK inhibitor trametinib with Akt inhibitors using seven types of linkers with structural diversity. The DDCs were evaluated for their cell permeability/accumulation and ability to inhibit proliferation in RAS-mutant cell lines. A representative DDC was further evaluated for its effects on signaling proteins, induction of apoptosis-related proteins, and the stability of hepatic metabolic enzymes. These in vitro studies identified a series of DDCs, especially those containing a furan-based linker, with promising properties as agents for treating RAS-mutant cancers. Additionally, in vivo experiments in mice using the two selected DDCs revealed prolonged half-lives and anticancer efficacies comparable to those of trametinib. The PK profiles of trametinib and the Akt inhibitor were unified through the DDC formation. The DDCs developed in this study have potential as drug candidates for the broad inhibition of RAS-mutant cancers.

Trajectory of Abdominal Skeletal Muscle Changes During Cardiac Rehabilitation in Patients With Aortic Disease.

OBJECTIVE: This study focused on routine computed tomography imaging for aortic disease management and evaluated the trajectory of skeletal muscle changes through inpatient and outpatient cardiac rehabilitation. DESIGN: Prospective observational study included patients who underwent abdominal computed tomography three times (baseline, postacute care, and follow-up). The area and density of the all-abdominal and erector spine muscles and intramuscular adipose tissue were measured. A generalized linear model with patients as random effects was used to investigate skeletal muscle changes. RESULTS: Thirty-nine patients completed outpatient cardiac rehabilitation, and 60 were incomplete. Skeletal muscle area significantly decreased from baseline to the follow-up period only in the incomplete rehabilitation group. Skeletal muscle density significantly decreased from baseline to postacute care and increased at the follow-up period, but only patients who completed rehabilitation showed recovery up to baseline at the follow-up period. These trajectories were more pronounced in the erector spine muscle. Intramuscular adipose tissue showed a trend of gradual increase, but only the incomplete rehabilitation group showed a significant difference from baseline to the follow-up period. CONCLUSIONS: The density of skeletal muscle may reflect the most common clinical course; skeletal muscle area and intramuscular adipose tissue are unlikely to improve positively, and their maintenance seemed optimal.

The Association between the Level of Ankle-Brachial Index and the Risk of Poor Physical Function in Patients with Cardiovascular Disease.

AIMS: The progression of atherosclerosis and decline in physical function are poor prognostic factors in patients with cardiovascular disease (CVD). The ankle-brachial index (ABI) is a widely used indicator of the degree of progression of atherosclerosis, which may be used to identify patients with CVD who are at risk of poor physical function. This study examined the association between ABI and poor physical function in patients with CVD. METHODS: We reviewed the data of patients with CVD who completed the ABI assessment and physical function tests (6-min walking distance, gait speed, quadriceps isometric strength, and short physical performance battery). Patients were divided into five categories according to the level of ABI, and the association between ABI and poor physical function was examined using multiple logistic regression analysis. Additionally, restricted cubic splines were used to examine the nonlinear association between ABI and physical function. RESULTS: A total of 2982 patients (median [interquartile range] age: 71[62-78] years, 65.8% males) were included in this study. Using an ABI range of 1.11-1.20 as a reference, logistic regression analysis showed that ABI ≤ 1.10 was associated with poor physical function. The restricted cubic spline analysis showed that all physical functions increased with an increase in ABI level. The increase in physical function plateaued at an ABI level of approximately 1.1. CONCLUSIONS: ABI may be used to identify patients with poor physical function. ABI levels below 1.1 are potentially associated with poor physical function in patients with CVD.

The effect of sepsis and reactive oxygen species on skeletal muscle interstitial oxygen pressure during contractions.

OBJECTIVE: This study aims to examine the effect of sepsis on the dynamics of skeletal muscle partial oxygen pressure during muscle contractions as well as the effect of reactive oxygen species (ROS) scavenger (ascorbic acid, Asc). METHODS: Twenty-seven male Sprague-Dawley rats (2-3 months old) were randomly assigned to three groups; sham, cecal ligation and puncture (CLP), or CLP plus ascorbic acid treatment group (CLP + Asc). Electrical stimuli-induced muscle contractions and partial oxygen pressure measurements were performed at 3 h after CLP. The interstitial oxygen pressure (PO2 is) in the spinotrapezius muscle was measured by the phosphorescence quenching method. RESULTS: The PO2 is at rest was not different between the three groups. The PO2 is decreased from rest to contraction in all groups. Compared to the sham, the time to decrease PO2 is was significantly faster in CLP but not in CLP + Asc (p < .05). Compared to the sham, the PO2 is during muscle contractions was significantly lower in both CLP and CLP + Asc (p < .05, respectively). CONCLUSIONS: Our results suggest that CLP-induced sepsis accelerated the decay of PO2 is at the onset of muscle contractions and maintained a low level of PO2 is during muscle contractions.

Association of sarcopenia defined by different skeletal muscle mass measurements with prognosis and quality of life in older patients with heart failure.

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.

Leg strength and incidence of heart failure in patients with acute coronary syndrome.

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.

The risk of developing heart failure (HF) after acute coronary syndrome (ACS) remains high. Basic attributes, coronary risk factors, and cardiac and renal function have been reported as risk factors for developing HF after ACS. However, the association between skeletal muscle strength and the development of HF after ACS is unclear. We included 1053 patients with ACS without a prior HF or complications of HF during hospitalization and used quadriceps isometric strength (QIS) as a measure of skeletal muscle strength. We found that higher QIS was associated with a lower risk of developing HF after ACS. The results of our study suggest the benefit of assessing skeletal muscle strength in addition to basic attributes, coronary risk factors, and cardiac and renal function to assess the risk of developing HF after ACS.

Association between walking speed early after admission and all-cause death and/or readmission in patients with acute decompensated heart failure.

AIM: 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 four days after admission was included in this study. The primary outcome was combined events (all-cause death and/or readmission due to HF). The follow-up period was up to one 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 four 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.

Prognostic Utility of Skeletal Muscle Mass Metrics in Patients With Heart Failure.

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.

Perceived Exertion Correlates with Multiple Physiological Parameters During Cardiopulmonary Exercise Testing.

The purpose of this study was to investigate the relationship of the Borg scale score with leg-muscle oxygenated haemoglobin (O2Hb) and deoxygenated haemoglobin (HHb) levels on near infrared spectroscopy (NIRS) and the work rate, heart rate (HR), oxygen uptake (VO2) and minute ventilation (VE) during supine cardiopulmonary exercise testing (CPET) in healthy adult men. We also investigated the relationships between the leg-muscle O2Hb and HHb levels and the work rate during supine CPET. Fifteen healthy male volunteers (mean age, 20.7 ± 0.6 years; mean height, 172.1 ± 5.7 cm; mean body weight, 61.7 ± 6.6 kg) participated in this study. The cardiopulmonary and NIRS parameters were assessed during each minute of supine CPET and at the end of the test. The Borg scale score significantly correlated with the work rate, HR, VO2, and VE during supine CPET (Rs = 0.86-0.94, p < 0.05). Furthermore, the Borg scale score significantly correlated with the leg-muscle O2Hb and HHb levels during supine CPET (Rs = -0.6, and 0.8, respectively; p < 0.05). The leg-muscle O2Hb and HHb levels had significant correlations with the work rate (R = -0.62 and 0.8, respectively; p < 0.05). The Borg scale score may be used to determine the rating of perceived exertion, whole-body fatigue and local-muscle fatigue during supine exercise. Moreover, leg-muscle oxygenation is associated with the work rate in supine exercise, similar to that observed in upright exercise.

Overlapping states of AWGS muscle dysfunction and inverse feasibility of ADL recovery by rehabilitation in older inpatients.

Rehabilitation based on guided walking is effective to recover activity of daily living (ADL) in frail older adults, even octogenarians. However, muscle dysfunction obviously reflects disability, and few studies have focused on ADL recovery by rehabilitation. We employed the state of muscle dysfunctions proposed by the Asian Working Group for Sarcopenia (AWGS) in 2019 and attempted to clarify the relation between the overlapping dysfunctions and the feasibility of ADL recovery after rehabilitation. In total, 297 frail older patients (the mean age: 82.8 years, 46.1% of patients were male) participated in a walking-guided rehabilitation program to achieve the goal of ambulatory discharge. Muscle dysfunction was categorized by four standardized methods at the start of rehabilitation (grip strength, gait speed, time of five sit-to-stand, and short physical performance battery: SPPB), according to the AWGS proposal. ADLs were monitored by Barthel index before admission, at the start of rehabilitation, and at discharge. At least one dysfunction was present in 95.3% of patients. If a single patient had three or more muscle dysfunction, the ADLs recovery was significantly limited (interaction: p < 0.05). The overlapped counts of AWGS muscle dysfunction helps to predict inverse feasibility of ADL recovery in frail older patients through rehabilitation.

The impacts of preoperative frailty on readmission after cardiac implantable electrical device implantation.

Cardiac implantable electrical devices (CIED) such as pacemakers, implantable cardioverter defibrillators, and cardiac resynchronization therapies are generally recommended for older patients and those with severe heart failure (HF). However, there is currently a lack of evidence on the relationship between frailty and readmission rates among patients with CIED. This study investigated whether preoperative frailty influenced readmission rates among patients with CIED over a one-year period following implantation. The study retrospectively analyzed 101 patients who underwent CIED implantations. To compare frailty-based differences in their characteristics and readmission rates, these participants were categorized into frailty and non-frailty groups via the modified frailty index (mFI). The frailty group had a significantly higher readmission rate than the non-frailty group (non-frailty group vs. frailty group = 1 vs. 8 patients: P < 0.05). Further, a multivariate analysis showed that frailty was a significant readmission factor. Based on individual analyses with/without histories of HF, the readmission rate also tended to be higher among individuals considered frail via the mFI (readmission rate in HF patients: non-frailty group vs. frailty group = 1 vs. 5 patients: P = 0.65; non-HF patients: non-frailty group vs. frailty group = 0 vs. 3 patients: P = 0.01). Participants with preoperative frailty showed higher readmission rates within a one-year period following implantation compared to those without preoperative frailty. This tendency was consistent regardless of HF history. The mFI may thus help predict readmission among patients with CIED.

Association between SGLT2 Inhibitors and Cardiac Rehabilitation Outcomes in Patients with Cardiovascular Disease and Type 2 Diabetes Mellitus.

The use of sodium-glucose cotransporter 2 (SGLT2) inhibitors in patients with type 2 diabetes mellitus (T2DM) has been associated with decreased skeletal muscle mass but remains unclear in patients with cardiovascular disease (CVD) undergoing comprehensive outpatient cardiac rehabilitation (CR). Therefore, this study investigates the effect of SGLT2 inhibitors on the outcomes of patients with CVD and T2DM undergoing comprehensive outpatient CR. The study included 402 patients with CVD and T2DM who participated in comprehensive outpatient CR. Physical functions (grip strength, maximal quadriceps isometric strength, usual gait speed, and 6-minute walking distance) were measured at discharge as baseline and 5 months thereafter, and the association between physical functions and SGLT2 inhibitor use was reviewed. Physical functions improved regardless of SGLT2 inhibitor use. Multiple regression analysis showed that SGLT2 inhibitor use was not associated with improvement or decline in physical functions (p ≥ 0.05). The use of SGLT2 inhibitors in patients with CVD and T2DM undergoing outpatient CR did not impair improvement in physical functions.

Temporal changes in cortical oxygenation in the motor-related areas and bilateral prefrontal cortex based on exercise intensity and respiratory metabolism during incremental exercise in male subjects: A near-Infrared spectroscopy study.

A recent study has reported that prefrontal cortex (PFC) activity during incremental exercise may be related to exercise termination on exhaustion. However, few studies have focused on motor-related areas during incremental exercise. This study investigated changes in the oxygenation of the PFC and motor-related areas using near-infrared spectroscopy during incremental exercise. Moreover, we analyzed the effect of exercise termination on changes in cortical oxygenation based on exercise intensity and respiratory metabolism. Sixteen healthy young male patients participated in this study. After a 4-min rest and 4-min warm-up period, incremental exercise was started at an incremental load corresponding to 20 W/min. Oxyhemoglobin (O2Hb), deoxyhemoglobin (HHb), and total hemoglobin (THb) in the bilateral PFC, supplementary motor area, and primary motor cortex were measured. We evaluated changes in oxygenation in each cortex before and after the anaerobic threshold (AT) and respiratory compensation point to identify changes due to respiratory metabolism. O2Hb and THb increased from moderate intensity or after AT to maximal exercise, and HHb increased slowly compared to O2Hb and THb; these changes in hemoglobin levels were consistent in all cortical areas we measured. However, the increase in each hemoglobin level in the bilateral PFC during incremental exercise was faster than that in motor-related areas. Moreover, changes in cortical oxygenation in the right PFC were faster than those in the left PFC. These results suggest changes based on differences in neural activity due to the cortical area.

Microvascular Adaptations to Muscle Stretch: Findings From Animals and the Elderly.

Microcirculation in skeletal muscle is disturbed with advancing aging, causing limited capillary blood flow and exercise incapacity. Muscle stretch has been widely performed in physical therapy, sports medicine, and health promotion. However, the effect of stretch on microvascular reactivity and muscle blood flow remains unknown. This review focuses on stretch-induced microvascular adaptations based on evidence from cultured cells, small animals, and human studies. Vascular endothelium senses and responds to mechanical stimuli including stretch. This endothelial mechanotransduction potentially plays a vital role in the stretch-induced microvascular adaptation alongside hypoxia. Aging impairs microvascular endothelial function, but muscle stretch has the potential to restore it. Muscle stretch may be an alternative to improve vascular function and enhance exercising blood flow, especially for those who have difficulties in participating in exercise due to medical, functional, or psychological reasons.

The safety of exercise for older patients with severe aortic stenosis undergoing conservative management: A narrative review.

The incidence of aortic stenosis (AS) increases with age and is a serious problem in an aging society. In recent years, transcatheter aortic valve implantation (TAVI) has been performed widely; however, older patients may be ineligible for TAVI or surgical treatment because of medical ineligibility. Symptom-based rehabilitation is required for these patients to maintain and improve their physical function and ability to perform activities of daily living. No studies have examined exercise safety for older patients with severe AS who are ineligible for TAVI or surgery. We summarized the safety of exercise for older patients with severe AS, collecting 7 studies on maximal exercise stress tests and 16 studies on preoperative physical examinations. From this review, it may be unlikely that exercise under appropriate management can cause hemodynamic changes, leading to death. However, there were no studies on exercise intervention for older patients with AS who are chosen for conservative management. The optimal exercise intensity for symptomatic older patients with AS undergoing conservative management and the effects of continuous exercise intervention require future study.

Characterization of Aripiprazole Uptake Transporter in the Blood-Brain Barrier Model hCMEC/D3 Cells by Targeted siRNA Screening.

AIM: Identification of blood-brain barrier (BBB) uptake transporters is a major challenge in the research and development of central nervous system (CNS) drugs. However, conventional methods that consider known drug uptake characteristics have failed at identifying the responsible transporter molecule. The present study aimed at identifying aripiprazole uptake transporters in BBB model hCMEC/D3 cells using a knockdown screening study targeting various transporters, including uncharacterized ones. METHODS: We evaluated the effect of 214 types of siRNA targeting transporters on the uptake of aripiprazole, an atypical antipsychotic drug, in hCMEC/D3 cells. Aripiprazole uptake was determined using Xenopus oocytes expressing the candidate genes extracted from the siRNA screening assay. RESULTS: The estimated unbound brain to plasma concentration ratio (Kp,uu,brain) of aripiprazole was estimated as 0.67 in wild-type mice and 1.94 in abcb1a/1b/abcg2 knockout mice, suggesting the involvement of both uptake and efflux transporters in BBB permeation. According to siRNA knockdown screening studies, organic cation/carnitine transporter 2 (OCTN2) and long-chain fatty acid transporter 1 (FATP1) were identified as candidate genes. The uptake of aripiprazole by hCMEC/D3 cells was decreased by OCTN2 inhibitors, but not by FATP1 inhibitors. A partially increased uptake of aripiprazole was observed in OCTN2-expressing Xenopus oocytes. Finally, to evaluate transporter-mediated BBB permeation of drugs, the reported and estimated Kp,uu,brain values were summarized. CONCLUSIONS: A knockdown screening study in combination with Kp,uu,brain values showed that aripiprazole was a potential substrate of OCTN2. The technique described in this study can be applied to identifying novel BBB transporters for CNS drugs.