Lymphatic Capillarization in Different Fiber Types of Rat Skeletal Muscles With Growth and Age.

OBJECTIVE: To clarify the effect of growth and advancing age on lymphatic capillarization in rat skeletal muscles, we examined the histological and biochemical changes of lymphatic capillaries in different fiber types of skeletal muscles across juvenile, young, and middle-aged generations. METHODS: We collected the tibialis anterior (TA), extensor digitorum longus (EDL), and soleus (SOL) muscles. Immunohistochemical staining using LYVE-1 and CD31 markers was used for lymphatic and blood capillaries, respectively. Real-time PCR was used to analyze mRNA expression of lymphangiogenic factors. RESULTS: The density of LYVE-1-positive lymphatic capillaries in the muscles peaked during the juvenile period and subsequently decreased with increasing age. In contrast to blood capillaries, fast-twitch dominant muscles (i.e., TA and EDL) exhibited an age-related decrease in lymphatic capillaries. Similar to blood capillaries, lymphatic capillaries were abundant in SOL, a slow-twitch dominant muscle, which showed less susceptibility to age-related lymphatic decline. The mRNA expression of lymphangiogenic factors was significantly upregulated in SOL and decreased in all muscles of middle-aged rats. CONCLUSIONS: The age-related decrease of lymphatic capillaries in fast-twitch muscles might be associated with age-related muscle atrophy.

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.

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.

Association Between Changes in Skeletal Muscle Quality and Prognosis in Postoperative Patients with Early Gastric Cancer.

BACKGROUND: Identifying accurate prognostic factors is crucial for postoperative management of early gastric cancer (EGC) patients. Skeletal muscle quality (SMQ), defined by muscle density on computed tomography (CT) images, has been proposed as a novel prognostic factor. This study compared the prognostic significance of SMQ changes with the well-established factor of body weight (BW) loss in the postoperative EGC setting. METHODS: This single-center retrospective study included 297 postoperative EGC patients (median age 69 years, 68.4% male) who had preoperative and 1-year-postoperative gastrectomy CT images. SMQ was defined as the modified intramuscular adipose tissue content (mIMAC = skeletal muscle density-subcutaneous fat density on CT images) and the change as ΔmIMAC. Log-rank test, Kaplan-Meier survival, and Cox proportional hazards regression analyses were used to assess the associations between prognosis and either ΔmIMAC or BW change (ΔBW). Prognosis prediction by ΔmIMAC and ΔBW was compared by using the area under the curve (AUC) of the receiver operating characteristic curve. RESULTS: ΔmIMAC was significantly associated with prognosis (log-rank test; P = 0.037), but ΔBW was not (P = 0.243). Prognosis was significantly poorer in the severely decreased mIMAC group than in the preserved group (multivariate Cox proportional hazards regression analysis; P = 0.030) but was unaffected by BW changes (P = 0.697). The AUC indicated a higher prognostic value for ΔmIMAC than ΔBW (ΔmIMAC: AUC = 0.697, ΔBW: AUC = 0.542). CONCLUSIONS: One-year post-gastrectomy SMQ changes may be better prognostic EGC predictors than BW changes.

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.

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.

Leg fidgeting alleviates reduced oxygen extraction in the gastrocnemius muscle caused by prolonged sitting: a randomized crossover trial.

PURPOSE: Oxygen extraction in skeletal muscle is an important determinant of exercise tolerance. Prolonged sitting decreases oxygen extraction in the gastrocnemius muscle. However, the underlying mechanism remains unknown, and preventive measures are yet to be established. Therefore, we aimed to elucidate the mechanism by which prolonged sitting decreased muscle oxygen extraction and investigate preventive measures. METHODS: Ten healthy young males (age 21.2 ± 0.4 years; body mass index, 20.5 ± 1.3 kg/m2) were randomly assigned to each of the following conditions: 3-h supine (CON), 3-h sitting (SIT), and 3-h fidgeting of one lower leg during sitting (FID). Oxygen extraction from the gastrocnemius muscle was measured using near-infrared spectroscopy and the vascular occlusion test under each condition. The rate of change in total Hb + Mb (THb) was measured as an indicator of venous stasis and interstitial fluid accumulation in the lower leg. RESULTS: Muscle oxygen extraction was significantly lower at 180 min for SIT and FID than for CON (4384.2 ± 1426.8; 5281.5 ± 1823.7; 6517.4 ± 1390.8 a.u., respectively) and significantly higher for FID than for SIT (5281.5 ± 1823.7 vs. 4384.2 ± 1426.8 a.u., respectively). The rate of THb change was significantly higher at 180 min for SIT than for CON and FID (12.9 ± 15.1; -2.3 ± 5.7; 2.2 ± 11.6%, respectively). However, no significant difference was observed between CON and FID. CONCLUSION: We found that 3-h prolonged sitting reduced oxygen extraction in the gastrocnemius muscles due to reduced oxygen supply to capillaries and increased distance between capillaries and myocytes. However, leg fidgeting alleviated this effect in healthy young males. TRIAL REGISTRATION NUMBER: UMIN000050531 (March 8, 2023).

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.

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.

Relationship Between the Borg Scale Rating of Perceived Exertion and Leg-Muscle Deoxygenation During Incremental Exercise in Healthy Adults.

INTRODUCTION: The Borg scale rating of perceived exertion is a reliable indicator and widely used to monitor and guide exercise intensity. We aimed to evaluate the relationships between the Borg scale score and oxygenated hemoglobin (O2Hb) and deoxygenated hemoglobin (HHb) concentrations in the leg muscle as measured by near-infrared spectroscopy (NIRS) during cardiopulmonary exercise testing (CPET) in healthy adult men. We also investigated the relationships between the Borg scale score and the work rate (WR), heart rate (HR), oxygen uptake (VO2), and minute ventilation (VE). METHODS: Participants comprised 12 healthy men. Cardiopulmonary and NIRS parameters were assessed during each minute of CPET and at the end of the test. RESULTS: The Borg scale score was significantly correlated with cardiopulmonary parameters including WR, HR, VO2, and VE during CPET (Rs = 0.87-0.95; p < 0.05). Furthermore, the Borg scale score was significantly correlated with NIRS parameters including O2Hb and HHb levels during CPET (Rs = -0.48 and 0.45, respectively; p < 0.05). DISCUSSION: The Borg scale score is significantly correlated with cardiopulmonary parameters (WR, HR, VO2, and VE), as well as with leg-muscle oxygenation parameters as assessed by NIRS, during CPET in healthy adults. The correlation coefficients obtained from NIRS parameters were lower than those of cardiopulmonary parameters. CONCLUSIONS: The Borg scale score might better reflect cardiopulmonary responses than muscle deoxygenation during exercise. These results can aid in the planning of rehabilitation programs for healthy adults.

Changes in the Laterality of Oxygenation in the Prefrontal Cortex and Premotor Area During a 20-Min Moderate-Intensity Cycling Exercise.

A recent study based on near-infrared spectrometry (NIRS) showed that a single session of moderate-intensity exercise increases the cortical oxyhemoglobin (O2Hb) level. However, changes in the laterality of O2Hb throughout such exercises remain unknown. In the present study, we evaluated changes in the laterality of O2Hb in the prefrontal cortex (PFC) and premotor area (PMA) during moderate-intensity cycling for 20 min. Twelve healthy volunteers performed the exercise at 50% of the maximal oxygen consumption after a 3-min rest period. O2Hb levels in the right (R-) and left (L-) PFC and PMA were measured using multichannel NIRS and averaged every 5 min during the exercise period, and the laterality index (LI) for each 5-min period was calculated. LI for PFC showed significant changes in each period (first, second, third, and fourth periods: -0.40 ± 0.21, -0.03 ± 0.12, 0.14 ± 0.15, and 0.16 ± 0.10, respectively; p < 0.05), whereas that for PMA showed no significant changes (-0.07 ± 0.09, 0.23 ± 0.08, 0.17 ± 0.12, and 0.19 ± 0.09, respectively; p = 0.12). These findings suggest that the laterality of cortical oxygenation in PFC of healthy, young individuals changes during moderate-intensity exercise for 20 min, thus providing an insight into the mechanisms underlying exercise-induced improvements in brain function.

Relationship Between Decrease of Oxygenation During Incremental Exercise and Partial Pressure End-Tidal Carbon Dioxide: Near-Infrared Spectroscopy Vector Analysis.

A previous study considered that a decrease in cerebral oxyhemoglobin (O2Hb) immediately before maximal exercise during incremental exercise is related to cerebral blood flow (CBF) and partial pressure end-tidal carbon dioxide (PETCO2). This study aimed to investigate the relationship between O2Hb, PETCO2, and the estimated value of cerebral blood volume (CBV) with cerebral oxygen exchange (COE) by using vector analysis. Twenty-four healthy young men participated in this study. They performed the incremental exercise (20 W/min) after a 4-min rest and warm-up. The O2Hb and deoxyhemoglobin (HHb) in the prefrontal cortex (PFC) were measured using near-infrared spectroscopy (NIRS). The PETCO2 was measured using a gas analyzer. The O2Hb, HHb, and PETCO2 were calculated as the amount of change (ΔO2Hb, ΔHHb, and ΔPETCO2) from an average 4-min rest. Changes in the CBV (ΔCBV) and COE (ΔCOE) were estimated using NIRS vector analysis. Moreover, the respiratory compensation point (RCP), which relates to the O2Hb decline, was detected. The Pearson correlation coefficient was used to establish the relationships among ΔO2Hb, ΔPETCO2, ΔCBV, and ΔCOE from the RCP to maximal exercise. The ΔPETCO2 did not significantly correlate with the ΔO2Hb (r = 0.03, p = 0.88), ΔCOE (r = -0.19, p = 0.36), and ΔCBV (r = -0.21, p = 0.31). These results showed that changes in the ΔPETCO2 from the RCP to maximal exercise were not related to changes in the ΔO2Hb, ΔCOE, and ΔCBV. Therefore, we suggested that the decrease of O2Hb immediately before maximal exercise during incremental exercise may be related to cerebral oxygen metabolism by neural activity increase, not decrease of CBF by the PETCO2.

HLA-A26 is a risk factor for Behçet's disease ocular lesions.

BACKGROUND: How HLA-A26 modulates Behçet's disease (BD) ocular lesions such as iridocyclitis and retinochorioiditis has not been scrutinized. METHODS: Ministry of Health, Labour and Welfare of Japan provided us a database of BD patients who were registered from 2003 to 2014. We selected patients who satisfied International Criteria for BD and whose data for HLA-A26 was available. RESULTS: Eligible 557 patients consisting of 238 men (42.7%) and 319 women (57.3%), whose median age was 38 years old (interquartile range 29-47) were analyzed. Prevalence of general ocular lesions, iridocyclitis, retinochorioiditis, and chronic lesions were 43.1%, 30.7%, 34.1%, and 17.4%, respectively. The prevalence of ocular lesions was higher among HLA-A26 carriers compared to that among HLA-A26 non-carriers with odds ratio (OR) of 2.5 (95% confidence interval (95% CI) 1.8-3.5, p < .001) for general ocular lesions, OR of 2.5 (95% CI 1.7-3.6, p < .001) for iridocyclitis, OR of 2.8 (95% CI 1.9-4.0, p < .001) for retinochorioiditis, and OR of 2.7 (95% CI 1.7-4.3, p < .001) for 'chronic ocular lesion following iridocyclitis or retinochorioiditis'. The HLA-A26 had a similar impact on ocular lesions between HLA-B51 positive and negative cases (Breslow-Day test, p > .05). However, the HLA-A26 had a larger impact on iridocyclitis for men compared to women (Breslow-Day test, p = .040). The male HLA-A26 carriers had higher risk of iridocyclitis with OR of 3.4 (95% CI 2.0-5.9, p < .001), while the OR for women was 1.5 (95% CI 0.9-2.6, p = .146). CONCLUSION: HLA-A26 carriers had higher risk for iridocyclitis and retinochorioiditis. However, the impact was more prominent for men.

Vogt-Koyanagi-Harada disease-like uveitis following nivolumab administration treated with steroid pulse therapy: a case report.

BACKGROUND: Immune checkpoint inhibitors can cause various adverse effects. Recently it has been shown that Vogt-Koyanagi-Harada (VKH) disease-like uveitis can occur in patients treated with nivolumab. CASE PRESENTATION: A 69-year-old man developed bilateral panuveitis after nivolumab treatment for recurrent hypopharyngeal cancer. Slit lamp examination revealed bilateral granulomatous keratic precipitates, anterior chamber cells and partial synechiae. Fundus examination revealed bilateral optic disc edema and diffuse serous retinal detachment. His human leukocyte antigen (HLA) typing showed HLA-DRB1*04:05 allele. A lumbar puncture did not demonstrate pleocytosis. Bilateral sub-tenon injections of triamcinolone acetonide were initiated. As his panuveitis did not regress completely, steroid pulse therapy was administered. That therapy led to the resolution of his serous retinal detachment and to rapid improvement in his vision. Following this, we treated him with 50 mg/day of prednisolone for 1 week and then reduced it by 5 mg every week. No bilateral uveitis relapse had occurred by his 3-month follow-up; however, he subsequently died because of his cancer. CONCLUSION: To our knowledge, this is the first report of a patient with NVKH who underwent a lumbar puncture. Unlike VKH, our case did not show meningismus or pleocytosis. NVKH may, therefore, have a different etiology from VKH. In cases of NVKH with posterior uveitis, steroid pulse therapy may be considered as a treatment option, as it is in VKH.

Skeletal muscle interstitial O2 pressures: bridging the gap between the capillary and myocyte.

The oxygen transport pathway from air to mitochondria involves a series of transfer steps within closely integrated systems (pulmonary, cardiovascular, and tissue metabolic). Small and finite O2 stores in most mammalian species require exquisitely controlled changes in O2 flux rates to support elevated ATP turnover. This is especially true for the contracting skeletal muscle where O2 requirements may increase two orders of magnitude above rest. This brief review focuses on the mechanistic bases for increased microvascular blood-myocyte O2 flux (V̇O2 ) from rest to contractions. Fick's law dictates that V̇O2 elevations driven by muscle contractions are produced by commensurate changes in driving force (ie, O2 pressure gradients; ΔPO2 ) and/or effective diffusing capacity (DO2 ). While previous evidence indicates that increased DO2 helps modulate contracting muscle O2 flux, up until recently the role of the dynamic ΔPO2 across the capillary wall was unknown. Recent phosphorescence quenching investigations of both microvascular and novel interstitial PO2 kinetics in health have resolved an important step in the O2 cascade between the capillary and myocyte. Specifically, the significant transmural ΔPO2 at rest was sustained (but not increased) during submaximal contractions. This supports the contention that the blood-myocyte interface provides a substantial effective resistance to O2 diffusion and underscores that modulations in erythrocyte hemodynamics and distribution (DO2 ) are crucial to preserve the driving force for O2 flux across the capillary wall (ΔPO2 ) during contractions. Investigation of the O2 transport pathway close to muscle mitochondria is key to identifying disease mechanisms and develop therapeutic approaches to ameliorate dysfunction and exercise intolerance.

Daily muscle stretching enhances blood flow, endothelial function, capillarity, vascular volume and connectivity in aged skeletal muscle.

KEY POINTS: In aged rats, daily muscle stretching increases blood flow to skeletal muscle during exercise. Daily muscle stretching enhanced endothelium-dependent vasodilatation of skeletal muscle resistance arterioles of aged rats. Angiogenic markers and capillarity increased in response to daily stretching in muscles of aged rats. Muscle stretching performed with a splint could provide a feasible means of improving muscle blood flow and function in elderly patients who cannot perform regular aerobic exercise. ABSTRACT: Mechanical stretch stimuli alter the morphology and function of cultured endothelial cells; however, little is known about the effects of daily muscle stretching on adaptations of endothelial function and muscle blood flow. The present study aimed to determine the effects of daily muscle stretching on endothelium-dependent vasodilatation and muscle blood flow in aged rats. The lower hindlimb muscles of aged Fischer rats were passively stretched by placing an ankle dorsiflexion splint for 30 min day-1 , 5 days week-1 , for 4 weeks. Blood flow to the stretched limb and the non-stretched contralateral limb was determined at rest and during treadmill exercise. Endothelium-dependent/independent vasodilatation was evaluated in soleus muscle arterioles. Levels of hypoxia-induced factor-1α, vascular endothelial growth factor A and neuronal nitric oxide synthase were determined in soleus muscle fibres. Levels of endothelial nitric oxide synthase and superoxide dismutase were determined in soleus muscle arterioles, and microvascular volume and capillarity were evaluated by microcomputed tomography and lectin staining, respectively. During exercise, blood flow to plantar flexor muscles was significantly higher in the stretched limb. Endothelium-dependent vasodilatation was enhanced in arterioles from the soleus muscle from the stretched limb. Microvascular volume, number of capillaries per muscle fibre, and levels of hypoxia-induced factor-1α, vascular endothelial growth factor and endothelial nitric oxide synthase were significantly higher in the stretched limb. These results indicate that daily passive stretching of muscle enhances endothelium-dependent vasodilatation and induces angiogenesis. These microvascular adaptations may contribute to increased muscle blood flow during exercise in muscles that have undergone daily passive stretch.

Exercise-based cardiac rehabilitation for people with implantable ventricular assist devices.

BACKGROUND: Heart failure is the end stage of heart disease, and the prevalence and incidence of the condition is rapidly increasing. Although heart transplantation is one type of surgical treatment for people with end-stage heart failure, donor availability is limited. Implantable ventricular assist devices (VADs) therefore offer an alternative treatment to heart transplantation. Although two studies reported the beneficial effects of exercise-based cardiac rehabilitation (CR) on functional capacity and quality of life (QOL) by performing systematic reviews and meta-analyses, both systematic reviews included studies with limited design (e.g. non-randomised, retrospective studies) or participants with implantable or extracorporeal VADs. OBJECTIVES: To determine the benefits and harms of exercise-based CR for people with implantable VADs. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) in the Cochrane Library, MEDLINE, Embase, PsycINFO, Conference Proceedings Citation Index-Science (CPCI-S) on Web of Science, CINAHL, and LILACS on 3 October 2017 with no limitations on date, language, or publication status. We also searched two clinical trials registers on 10 August 2017 and checked the reference lists of primary studies and review articles. SELECTION CRITERIA: Randomised controlled trials (RCTs) regardless of cluster or individual randomisation, and full-text studies, those published as abstract only, and unpublished data were eligible. However, only individually RCTs and full-text publications were included. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted outcome data from the included studies. We double-checked that data were entered correctly by comparing the data presented in the systematic review with the study reports. We had no dichotomous data to analyse and used mean difference or standardised mean difference with 95% confidence intervals (CIs) for continuous data. Furthermore, we assessed the quality of evidence as it relates to those studies that contribute data to the meta-analyses for the prespecified outcomes, using GRADEpro software. MAIN RESULTS: We included two studies with a total of 40 participants in the review. Exercise-based CR consisted of aerobic or resistance training or both three times per week for six to eight weeks. Exercise intensity was 50% of oxygen consumption (VO2) reserve, or ranged from 60% to 80% of heart rate reserve. Two serious adverse events were observed in one trial, in which participants did not complete the study due to infections. Furthermore, a total of four participants in each group required visits to the emergency department, although these participants did complete the study. Summary scores from the 36-item Short Form Health Survey (SF-36) and the Kansas City Cardiomyopathy Questionnaire (KCCQ) were measured as quality of life. One trial reported that the KCCQ summary score improved by 14.4 points in the exercise group compared with 0.5 points in the usual care group. The other trial reported that the SF-36 total score improved by 29.2 points in the exercise group compared with 16.3 points in the usual care group. A large difference in quality of life was observed between groups at the end of follow-up (standardised mean difference 0.88, 95% CI -0.12 to 1.88; 37 participants; 2 studies; very low-quality of evidence). However, there was no evidence for the effectiveness of exercise-based CR due to the young age of the participants, high risk of performance bias, very small sample size, and wide confidence intervals, which resulted in very low-quality evidence. Furthermore, we were not able to determine the effect of exercise-based CR on mortality, rehospitalisation, heart transplantation, and cost, as these outcomes were not reported. AUTHORS' CONCLUSIONS: The evidence is currently inadequate to assess the safety and efficacy of exercise-based CR for people with implantable VADs compared with usual care. The amount of RCT evidence was very limited and of very low quality. In addition, the training duration was very short term, that is from six to eight weeks. Further high-quality and well-reported RCTs of exercise-based CR for people with implantable VADs are needed. Such trials need to collect data on events (mortality and rehospitalisation), patient-related outcomes (including quality of life), and cost-effectiveness.

Exercise training reverses age-induced diastolic dysfunction and restores coronary microvascular function.

KEY POINTS: In a rat model of ageing that is free of atherosclerosis or hypertension, E/A, a diagnostic measure of diastolic filling, decreases, and isovolumic relaxation time increases, indicating that both active and passive ventricular relaxation are impaired with advancing age. Resting coronary blood flow and coronary functional hyperaemia are reduced with age, and endothelium-dependent vasodilatation declines with age in coronary resistance arterioles. Exercise training reverses age-induced declines in diastolic and coronary microvascular function. Thus, microvascular dysfunction and inadequate coronary perfusion are likely mechanisms of diastolic dysfunction in aged rats. Exercise training, initiated at an advanced age, reverses age-related diastolic and microvascular dysfunction; these data suggest that late-life exercise training can be implemented to improve coronary perfusion and diastolic function in the elderly. ABSTRACT: The risk for diastolic dysfunction increases with advancing age. Regular exercise training ameliorates age-related diastolic dysfunction; however, the underlying mechanisms have not been identified. We investigated whether (1) microvascular dysfunction contributes to the development of age-related diastolic dysfunction, and (2) initiation of late-life exercise training reverses age-related diastolic and microvascular dysfunction. Young and old rats underwent 10 weeks of exercise training or remained as sedentary, cage-controls. Isovolumic relaxation time (IVRT), early diastolic filling (E/A), myocardial performance index (MPI) and aortic stiffness (pulse wave velocity; PWV) were evaluated before and after exercise training or cage confinement. Coronary blood flow and vasodilatory responses of coronary arterioles were evaluated in all groups at the end of training. In aged sedentary rats, compared to young sedentary rats, a 42% increase in IVRT, a 64% decrease in E/A, and increased aortic stiffness (PWV: 6.36 ± 0.47 vs.4.89 ± 0.41, OSED vs. YSED, P < 0.05) was accompanied by impaired coronary blood flow at rest and during exercise. Endothelium-dependent vasodilatation was impaired in coronary arterioles from aged rats (maximal relaxation to bradykinin: 56.4 ± 5.1% vs. 75.3 ± 5.2%, OSED vs. YSED, P < 0.05). After exercise training, IVRT, a measure of active ventricular relaxation, did not differ between old and young rats. In old rats, exercise training reversed the reduction in E/A, reduced aortic stiffness, and eliminated impairment of coronary blood flow responses and endothelium-dependent vasodilatation. Thus, age-related diastolic and microvascular dysfunction are reversed by late-life exercise training. The restorative effect of exercise training on coronary microvascular function may result from improved endothelial function.

Low-intensity resistance training with blood flow restriction improves vascular endothelial function and peripheral blood circulation in healthy elderly people.

PURPOSE: The present study aimed to investigate the effects of low-intensity resistance training with blood flow restriction (BFR resistance training) on vascular endothelial function and peripheral blood circulation. METHODS: Forty healthy elderly volunteers aged 71 ± 4 years were divided into two training groups. Twenty subjects performed BFR resistance training (BFR group), and the remaining 20 performed ordinary resistance training without BFR. Resistance training was performed at 20 % of each estimated one-repetition maximum for 4 weeks. We measured lactate (Lac), norepinephrine (NE), vascular endothelial growth factor (VEGF) and growth hormone (GH) before and after the initial resistance training. The reactive hyperemia index (RHI), von Willebrand factor (vWF) and transcutaneous oxygen pressure in the foot (Foot-tcPO2) were assessed before and after the 4-week resistance training period. RESULTS: Lac, NE, VEGF and GH increased significantly from 8.2 ± 3.6 mg/dL, 619.5 ± 243.7 pg/mL, 43.3 ± 15.9 pg/mL and 0.9 ± 0.7 ng/mL to 49.2 ± 16.1 mg/dL, 960.2 ± 373.7 pg/mL, 61.6 ± 19.5 pg/mL and 3.1 ± 1.3 ng/mL, respectively, in the BFR group (each P < 0.01). RHI and Foot-tcPO2 increased significantly from 1.8 ± 0.2 and 62.4 ± 5.3 mmHg to 2.1 ± 0.3 and 68.9 ± 5.8 mmHg, respectively, in the BFR group (each P < 0.01). VWF decreased significantly from 175.7 ± 20.3 to 156.3 ± 38.1 % in the BFR group (P < 0.05). CONCLUSIONS: BFR resistance training improved vascular endothelial function and peripheral blood circulation in healthy elderly people.

Effect of diabetes on microvascular morphology and permeability of rat skeletal muscle: in vivo imaging using two-photon laser scanning microscopy.

This investigation evaluated the microvascular permeability and ultrastructure of skeletal muscle capillaries in the skeletal muscle of diabetic (DIA) rats using two-photon laser scanning microscopy (TPLSM) and transmission electron microscopy (TEM). Microvascular permeability was assessed in the tibialis anterior muscle of control (CON) and DIA (streptozocin) male Wistar rats (n = 20, 10-14 wk) by in vivo imaging using TPLSM after fluorescent dye intravenous infusion. Fluorescent dye leakage was quantified to determine microvascular permeability. The ultrastructure was imaged by TEM ex vivo to calculate the size and number of intercellular clefts between capillary endothelial cells and also intracellular vesicles. Compared with control, the volumetrically determined interstitial fluorescent dye leakage, the endothelial cell thickness, and the number of intercellular clefts per capillary perimeter were significantly higher, and the cleft width was significantly narrower in tibialis anterior (TA) of DIA (interstitial fluorescent dye leakage, 2.88 ± 1.40 vs. 10.95 ± 1.41 µm3 × min × 106; endothelial thickness, 0.28 ± 0.02 vs. 0.45 ± 0.03 µm; number of intercellular clefts per capillary perimeter, 6.3 ± 0.80 vs. 13.6 ± 1.7/100 µm; cleft width, 11.92 ± 0.95 vs. 8.40 ± 1.03 nm, CON vs. DIA, respectively, all P < 0.05). The size of intracellular vesicles in the vascular endothelium showed an increased proportion of large vesicles in the DIA group compared with the CON group (P < 0.05). Diabetes mellitus enhances the microvascular permeability of skeletal muscle microvessels due, in part, to a higher density and narrowing of the endothelial intercellular clefts, and larger intracellular vesicles.NEW & NOTEWORTHY Microvascular permeability in diabetic muscle was investigated using our original two-photon scanning laser microscopy method. Compared with controls, the leakage volume was increased in diabetic muscle, which was atrophic with smaller capillary diameter, endothelial cell thickening, and the appearance of more endothelial intercellular gaps or clefts, and large vesicles. Hyperpermeability was closely related to ultrafine structural changes of the capillary endothelial cell junctions.