Moderate-intensity aerobic exercise training improves CD8+ tumor-infiltrating lymphocytes effector function by reducing mitochondrial loss.

Aerobic exercise training (AET) has emerged as a strategy to reduce cancer mortality, however, the mechanisms explaining AET on tumor development remain unclear. Tumors escape immune detection by generating immunosuppressive microenvironments and impaired T cell function, which is associated with T cell mitochondrial loss. AET improves mitochondrial content and function, thus we tested whether AET would modulate mitochondrial metabolism in tumor-infiltrating lymphocytes (TIL). Balb/c mice were subjected to a treadmill AET protocol prior to CT26 colon carcinoma cells injection and until tumor harvest. Tissue hypoxia, TIL infiltration and effector function, and mitochondrial content, morphology and function were evaluated. AET reduced tumor growth, improved survival, and decreased tumor hypoxia. An increased CD8+ TIL infiltration, IFN-γ and ATP production promoted by AET was correlated with reduced mitochondrial loss in these cells. Collectively, AET decreases tumor growth partially by increasing CD8+ TIL effector function through an improvement in their mitochondrial content and function.

Coronary Inflammation by Computed Tomography Pericoronary Fat Attenuation and Increased Cytokines in Young Male Anabolic Androgenic Steroid Users. / Inflamação Coronária Avaliada pela Atenuação de Gordura Pericoronária na Tomografia Computadorizada e Elevação de Citocinas em Usuários Jovens de Esteroides Anabólicos Androgênicos.

BACKGROUND: Anabolic androgenic steroid (AAS) abuse has been associated with coronary artery disease (CAD). Pericoronary fat attenuation (pFA) is a marker of coronary inflammation, which is key in the atherosclerotic process. OBJECTIVE: To evaluate pFA and inflammatory profile in AAS users. METHODS: Twenty strength-trained AAS users (AASU), 20 AAS nonusers (AASNU), and 10 sedentary controls (SC) were evaluated. Coronary inflammation was evaluated by mean pericoronary fat attenuation (mPFA) in the right coronary artery (RCA), left anterior descending coronary artery (LAD), and left circumflex (LCx). Interleukin (IL)-1 (IL-1), IL-6, IL-10, and TNF-alpha were evaluated by optical density (OD) in a spectrophotometer with a 450 nm filter. P<0.05 indicated statistical significance. RESULTS: AASU had higher mPFA in the RCA (-65.87 [70.51-60.70] vs. -78.07 [83.66-72.87] vs.-78.46 [85.41-71.99] Hounsfield Units (HU), respectively, p<0.001) and mPFA in the LAD (-71.47 [76.40-66.61] vs. -79.32 [84.37-74.59] vs. -82.52 [88.44-75.81] HU, respectively, p=0.006) compared with AASNU and SC. mPFA in the LCx was not different between AASU, AASNU, and SC (-72.41 [77.17-70.37] vs. -80.13 [86.22-72.23] vs. -78.29 [80.63-72.29] HU, respectively, p=0.163). AASU compared with AASNU and SC, had higher IL-1, (0.975 [0.847-1.250] vs. 0.437 [0.311-0.565] vs. 0.530 [0.402-0.780] OD, respectively, p=0.002), IL-6 (1.195 [0.947-1.405] vs. 0.427 [0.377-0.577] vs. 0.605 [0.332-0.950] OD, p=0.005) and IL-10 (1.145 [0.920-1.292] vs. 0.477 [0.382-0.591] vs. 0.340 [0.316-0.560] OD, p<0.001). TNF-α was not different between the AASU, AASNU, and SC groups (0.520 [0.250-0.610] vs. 0.377 [0.261-0.548] vs. 0.350 [0.182-430]), respectively. CONCLUSION: Compared with ASSNU and controls, AASU have higher mPFA and higher systemic inflammatory cytokines profile suggesting that AAS may induce coronary atherosclerosis through coronary and systemic inflammation.

FUNDAMENTO: O uso abusivo de esteroides anabólicos androgênicos (EAA) tem sido associado à doença arterial coronariana (DAC). A atenuação de gordura pericoronária (AGp) é um marcador de inflamação coronária, a qual exerce um papel chave no processo aterosclerótico. OBJETIVO: Avaliar AGp e perfil inflamatório em usuários de EAA. MÉTODO: Vinte indivíduos que realizavam treinamento de força, usuários de EAA (UEAA), 20 não usuários de EAA (NUEAA), e 10 indivíduos sedentários controle (SC) foram avaliados. Inflamação coronária foi avaliada por atenuação de gordura pericoronária média (AGPm) artéria coronária direita (ACD), artéria descendente anterior esquerda (ADA) e artéria circunflexa (ACX). Interleucina (IL)-1 (IL-1), IL-6, IL-10, e TNF-alfa foram avaliados por densidade ótica (DO) em um espectrofotômetro com um filtro de 450 nm. Um p<0,05 indicou significância estatística. RESULTADOS: Os UEAA apresentaram maior AGPm na ACD [-65,87 (70,51-60,70) vs. -78,07 (83,66-72,87) vs.-78,46 (85,41-71,99] unidades Hounsfield (HU), respectivamente, p<0,001) e AGPm na ADA [-71,47 (76,40-66,610 vs. -79,32 (84,37-74,59) vs. -82,52 (88,44-75,81) HU, respectivamente, p=0,006) em comparação aos NUEAA e CS. A AGPm na ACX não foi diferente entre os grupos UEAA, NUEAA e CS [-72,41 (77,17-70,37) vs. -80,13 (86,22-72,23) vs. -78,29 (80,63-72,29) HU, respectivamente, p=0,163). Em comparação aos NUEAA e aos CS, o grupo UEAA apresentaram maiores níveis de IL-1 [0,975 (0,847-1,250) vs. 0,437 (0,311-0,565) vs. 0,530 (0,402-0,780) DO, respectivamente, p=0,002), IL-6 [1,195 (0,947-1,405) vs. 0,427 (0,377-0,577) vs. 0,605 (0,332-0,950) DO, p=0,005) e IL-10 [1,145 (0,920-1,292) vs. 0,477 (0,382-0,591) vs. 0,340 (0,316-0,560) DO, p<0,001]. TNF-α não foi diferente entre os grupos UEAA, NUEAA e CS [0,520 (0,250-0,610) vs. 0,377 (0.261-0,548) vs. 0,350 (0,182-430)]. CONCLUSÃO: Em comparação aos NUEAA e controles, os UEAA apresentam maior AGPm e maior perfil de citocinas inflamatórias sistêmicas, sugerindo que os EAA podem induzir aterosclerose por inflamação coronária e sistêmica.

Effects of exercise on platelet reactivity after myocardial infarction: a randomized clinical trial.

Exercise training (ET) can lower platelet reactivity in patients with cardiovascular risk factors. However, the effects of ET on platelet reactivity in higher-risk patients is unknown. The aim of this study was to evaluate the effects of ET on platelet reactivity in patients with recent myocardial infarction (MI). Ninety patients were randomly assigned 1 month post-MI to the intervention (patients submitted to a supervised ET program) or control group. All patients were on dual antiplatelet therapy (DAPT). Platelet reactivity by VerifyNow-P2Y12 (measured by P2Y12 reaction units - PRUs) test was determined at baseline and at the end of 14 ± 2 weeks of follow-up at rest (primary endpoint), and multiplate electrode aggregometry (MEA) adenosine diphosphate (ADP) and aspirin (ASPI) tests were performed immediately before and after the maximal cardiopulmonary exercise test (CPET) at the same time points (secondary endpoints). Sixty-five patients (mean age 58.9 ± 10 years; 73.8% men; 60% ST elevation MI) completed follow-up (control group, n = 31; intervention group, n = 34). At the end of the follow-up, the mean platelet reactivity was 172.8 ± 68.9 PRUs and 166.9 ± 65.1 PRUs for the control and intervention groups, respectively (p = .72). Platelet reactivity was significantly increased after the CPET compared to rest at the beginning and at the end of the 14-week follow-up (among the intervention groups) by the MEA-ADP and MEA-ASPI tests (p < .01 for all analyses). In post-MI patients on DAPT, 14 weeks of supervised ET did not reduce platelet reactivity. Moreover, platelet reactivity was increased after high-intensity exercise (ClinicalTrials.gov: NCT02958657; https://clinicaltrials.gov/ct2/show/NCT02958657).

What is the context? Platelet reactivity is reduced after exercise training in healthy individuals and patients with cardiovascular risk factors, but the effect in higher-risk patients is unknown.High-intensity exercise in untrained individuals increases platelet reactivity. The effect of dual antiplatelet therapy in inhibiting exercise-induced hyperreactivity is poorly understood.What's new?Exercise training did not reduce platelet reactivity in post-myocardial infarction patients.High-intensity exercise increased platelet reactivity in post-myocardial infarction patients on dual antiplatelet therapy.Exercise training did not attenuate the exercise-induced increase in platelet reactivity.What's the impact?The study suggests that strenuous exercise, if indicated, should be applied carefully to patients with high risk of recurrent ischemic events, even if on optimal medical therapy and after being trained.

Inflamação Coronária Avaliada pela Atenuação de Gordura Pericoronária na Tomografia Computadorizada e Elevação de Citocinas em Usuários Jovens de Esteroides Anabólicos Androgênicos / Coronary Inflammation by Computed Tomography Pericoronary Fat Attenuation and Increased Cytokines in Young Male Anabolic Androgenic Steroid Users

Resumo Fundamento O uso abusivo de esteroides anabólicos androgênicos (EAA) tem sido associado à doença arterial coronariana (DAC). A atenuação de gordura pericoronária (AGp) é um marcador de inflamação coronária, a qual exerce um papel chave no processo aterosclerótico. Objetivo Avaliar AGp e perfil inflamatório em usuários de EAA. Método Vinte indivíduos que realizavam treinamento de força, usuários de EAA (UEAA), 20 não usuários de EAA (NUEAA), e 10 indivíduos sedentários controle (SC) foram avaliados. Inflamação coronária foi avaliada por atenuação de gordura pericoronária média (AGPm) artéria coronária direita (ACD), artéria descendente anterior esquerda (ADA) e artéria circunflexa (ACX). Interleucina (IL)-1 (IL-1), IL-6, IL-10, e TNF-alfa foram avaliados por densidade ótica (DO) em um espectrofotômetro com um filtro de 450 nm. Um p<0,05 indicou significância estatística. Resultados Os UEAA apresentaram maior AGPm na ACD [-65,87 (70,51-60,70) vs. -78,07 (83,66-72,87) vs.-78,46 (85,41-71,99] unidades Hounsfield (HU), respectivamente, p<0,001) e AGPm na ADA [-71,47 (76,40-66,610 vs. -79,32 (84,37-74,59) vs. -82,52 (88,44-75,81) HU, respectivamente, p=0,006) em comparação aos NUEAA e CS. A AGPm na ACX não foi diferente entre os grupos UEAA, NUEAA e CS [-72,41 (77,17-70,37) vs. -80,13 (86,22-72,23) vs. -78,29 (80,63-72,29) HU, respectivamente, p=0,163). Em comparação aos NUEAA e aos CS, o grupo UEAA apresentaram maiores níveis de IL-1 [0,975 (0,847-1,250) vs. 0,437 (0,311-0,565) vs. 0,530 (0,402-0,780) DO, respectivamente, p=0,002), IL-6 [1,195 (0,947-1,405) vs. 0,427 (0,377-0,577) vs. 0,605 (0,332-0,950) DO, p=0,005) e IL-10 [1,145 (0,920-1,292) vs. 0,477 (0,382-0,591) vs. 0,340 (0,316-0,560) DO, p<0,001]. TNF-α não foi diferente entre os grupos UEAA, NUEAA e CS [0,520 (0,250-0,610) vs. 0,377 (0.261-0,548) vs. 0,350 (0,182-430)]. Conclusão Em comparação aos NUEAA e controles, os UEAA apresentam maior AGPm e maior perfil de citocinas inflamatórias sistêmicas, sugerindo que os EAA podem induzir aterosclerose por inflamação coronária e sistêmica.

Abstract Background Anabolic androgenic steroid (AAS) abuse has been associated with coronary artery disease (CAD). Pericoronary fat attenuation (pFA) is a marker of coronary inflammation, which is key in the atherosclerotic process. Objective To evaluate pFA and inflammatory profile in AAS users. Methods Twenty strength-trained AAS users (AASU), 20 AAS nonusers (AASNU), and 10 sedentary controls (SC) were evaluated. Coronary inflammation was evaluated by mean pericoronary fat attenuation (mPFA) in the right coronary artery (RCA), left anterior descending coronary artery (LAD), and left circumflex (LCx). Interleukin (IL)-1 (IL-1), IL-6, IL-10, and TNF-alpha were evaluated by optical density (OD) in a spectrophotometer with a 450 nm filter. P<0.05 indicated statistical significance. Results AASU had higher mPFA in the RCA (-65.87 [70.51-60.70] vs. -78.07 [83.66-72.87] vs.-78.46 [85.41-71.99] Hounsfield Units (HU), respectively, p<0.001) and mPFA in the LAD (-71.47 [76.40-66.61] vs. -79.32 [84.37-74.59] vs. -82.52 [88.44-75.81] HU, respectively, p=0.006) compared with AASNU and SC. mPFA in the LCx was not different between AASU, AASNU, and SC (-72.41 [77.17-70.37] vs. -80.13 [86.22-72.23] vs. -78.29 [80.63-72.29] HU, respectively, p=0.163). AASU compared with AASNU and SC, had higher IL-1, (0.975 [0.847-1.250] vs. 0.437 [0.311-0.565] vs. 0.530 [0.402-0.780] OD, respectively, p=0.002), IL-6 (1.195 [0.947-1.405] vs. 0.427 [0.377-0.577] vs. 0.605 [0.332-0.950] OD, p=0.005) and IL-10 (1.145 [0.920-1.292] vs. 0.477 [0.382-0.591] vs. 0.340 [0.316-0.560] OD, p<0.001). TNF-α was not different between the AASU, AASNU, and SC groups (0.520 [0.250-0.610] vs. 0.377 [0.261-0.548] vs. 0.350 [0.182-430]), respectively. Conclusion Compared with ASSNU and controls, AASU have higher mPFA and higher systemic inflammatory cytokines profile suggesting that AAS may induce coronary atherosclerosis through coronary and systemic inflammation.

Ocorre Lesão Miocárdica após uma Sessão de Exercício Aeróbico Agudo em Pacientes com Angina Refratária? / Does Myocardial Injury Occur After an Acute Aerobic Exercise Session in Patients with Refractory Angina?

Resumo Fundamento Não está claro se o exercício é seguro em pacientes com formas mais avançadas de doença arterial coronariana, como aqueles com angina refratária (AR). Objetivo Visamos determinar o efeito de uma sessão de exercício aeróbico agudo (SEAA) nos níveis de troponina T cardíaca de alta sensibilidade (TnT-as) em pacientes com AR. Métodos Trata-se de um estudo clínico longitudinal, não randomizado e não controlado. Os participantes foram recrutados de abril de 2015 a janeiro de 2019. Em uma escala visual de dor de 0 a 10, a dor classificada até 3 foi considerada como o nível máximo permitido para continuar o exercício. Avaliamos TnT-as na linha de base e 3 horas após a SEAA. O protocolo consistiu em 5 minutos de aquecimento, 30 minutos de exercício aeróbico contínuo na frequência cardíaca correspondente ao limiar anaeróbio ou limiar de angina obtido no teste de esforço cardiopulmonar e 5 minutos de resfriamento. Foram considerados estatisticamente significativos valores de p menores que 0,05. Resultados Foram incluídos 32 pacientes com AR (61 ± 9 anos, 59,4% do sexo masculino). A concentração basal de TnT-as foi de 10,9 ng/L (intervalo de confiança de 95%: 9,1 a 13,0 ng/L). A TnT-as coletada 3 horas após a SEAA foi de 11,1 ng/L (intervalo de confiança de 95%: 9,1 a 13,5 ng/L). Nenhuma diferença ocorreu na TnT-as antes e após a SEAA (p = 0,657). Conclusões Uma única SEAA realizada no limiar de angina com correspondente escala visual de dor não alterou a TnT-as em pacientes com AR, sugerindo que nenhuma lesão miocárdica significativa foi provocada pelo exercício e que este protocolo de exercício pode ser considerado seguro.

Abstract Background It is unclear whether exercise is safe in patients with more advanced forms of coronary artery disease, such as those with refractory angina (RA). Objective We aimed to determine the effect of an acute aerobic exercise session (AAES) on high-sensitivity cardiac troponin T (hs-cTnT) levels in patients with RA. Methods This was a longitudinal, non-randomized, and non-controlled clinical study. Participants were recruited from April 2015 to January 2019. On a visual pain scale from 0 to 10, pain rated up to 3 was considered as the top level allowed to continue exercising. We assessed hs-cTnT at baseline and 3 hours after the AAES. The protocol consisted of 5 minutes of warm-up, 30 minutes of continuous aerobic exercise at heart rate corresponding to the anaerobic threshold or angina threshold obtained in the cardiopulmonary exercise testing, and 5 minutes of cooling down. P values less than 0.05 were considered statistically significant. Results Thirty-two patients with RA were included (61 ± 9 years, 59.4% male). The baseline hs-cTnT concentration was 10.9 ng/L (95% confidence interval: 9.1 to 13.0 ng/L). The hs-cTnT collected 3 hours after the AAES was 11.1 ng/L (95% confidence interval: 9.1 to 13.5 ng/L). No difference occurred in hs-cTnT before and after AAES (p = 0.657). Conclusions A single AAES performed at the angina threshold with corresponding visual pain scale did not alter hs-cTnT in patients with RA, suggesting that no significant myocardial injury was elicited by exercising and that this exercise protocol can be considered safe.

Effects of Aerobic Exercise Training on MyomiRs Expression in Cachectic and Non-Cachectic Cancer Mice.

We investigated the effects of AET on myomiRs expression in the skeletal muscle and serum of colon cachectic (CT26) and breast non-cachectic (MMTV-PyMT) cancer mice models. Colon cancer decreased microRNA-486 expression, increasing PTEN in tibialis anterior muscle (TA), decreasing the PI3K/mTOR protein pathway, body and muscle wasting, fibers' cross-sectional area and muscle dysfunction, that were not preserved by AET. In contrast, breast cancer decreased those muscle functions, but were preserved by AET. In circulation, the downregulation of microRNA-486 and -206 in colon cancer, and the downregulation of microRNA-486 and upregulation of microRNA-206 expression in breast cancer might be good cancer serum biomarkers. Since the microRNA-206 is skeletal muscle specific, their expression was increased in the TA, serum and tumor in MMTV, suggesting a communication among these three compartments. The AET prevents these effects on microRNA-206, but not on microRNA-486 in MMTV. In conclusion, cancer induced a downregulation of microRNA-486 expression in TA and serum of CT26 and MMTV mice and these effects were not prevented by AET; however, to MMTV, the trained muscle function was preserved, probably sustained by the downregulation of microRNA-206 expression. Serum microRNA-206 is a potential biomarker for colon (decreased) and breast (increased) cancer to monitor the disease evolution and the effects promoted by the AET.

Effects of inspiratory muscle training combined with aerobic exercise training on neurovascular control in chronic heart failure patients.

AIMS: We tested the hypothesis that the effects of combined inspiratory muscle training and aerobic exercise training (IMT + AET) on muscle sympathetic nerve activity (MSNA) and forearm blood flow in patients with heart failure with reduced ejection fraction are more pronounced than the effects of AET alone. METHODS AND RESULTS: Patients aged 30-70 years, New York Heart Association Functional Class II-III, and left ventricular ejection fraction ≤40% were randomly assigned to four groups: IMT (n = 11), AET (n = 12), IMT + AET (n = 9), and non-training (NT; n = 10). MSNA was recorded using microneurography. Forearm blood flow was measured by venous occlusion plethysmography and inspiratory muscle strength by maximal inspiratory pressure. IMT consisted of 30 min sessions, five times a week, for 4 months. Moderate AET consisted of 60 min sessions, three times a week for 4 months. AET (-10 ± 2 bursts/min, P = 0.03) and IMT + AET (-13 ± 4 bursts/min, P = 0.007) reduced MSNA. These responses in MSNA were not different between AET and IMT + AET groups. IMT (0.22 ± 0.08 mL/min/100 mL, P = 0.03), AET (0.27 ± 0.09 mL/min/100 mL, P = 0.01), and IMT + AET (0.35 ± 0.12 mL/min/100 mL, P = 0.008) increased forearm blood flow. No differences were found between groups. AET (3 ± 1 mL/kg/min, P = 0.006) and IMT + AET (4 ± 1 mL/kg/min, P = 0.001) increased peak oxygen consumption. These responses were similar between these groups. IMT (20 ± 3 cmH2 O, P = 0.005) and IMT + AET (18 ± 3 cmH2 O, P = 0.01) increased maximal inspiratory pressure. No significant changes were observed in the NT group. CONCLUSIONS: IMT + AET causes no additive effects on neurovascular control in patients with heart failure with reduced ejection fraction compared with AET alone. These findings may be, in part, because few patients had inspiratory muscle weakness.

Exercise training reduces sympathetic nerve activity and improves executive performance in individuals with obstructive sleep apnea

OBJECTIVE: To investigate the effects of exercise training (ET) on muscle sympathetic nerve activity (MSNA) and executive performance during Stroop Color Word Test (SCWT) also referred to as mental stress test. METHODS: Forty-four individuals with obstructive sleep apnea (OSA) and no significant co-morbidities were randomized into 2 groups; 15 individuals completed the control period, and 18 individuals completed the ET. Mini-mental state of examination and intelligence quotient were also assessed. MSNA assessed by microneurography, heart rate by electrocardiography, blood pressure (automated oscillometric device) were measured at baseline and during 3 min of the SCWT. Peak oxygen uptake (VO2 peak) was evaluated using cardiopulmonary exercise testing. Executive performance was assessed by the total correct responses during 3 min of the SCWT. ET consisted of 3 weekly sessions of aerobic exercise, resistance exercises, and flexibility (72 sessions, achieved in 40±3.9 weeks). RESULTS: Baseline parameters were similar between groups. Heart rate, blood pressure, and MSNA responses during SCWT were similar between groups (p>0.05). The comparisons between groups showed that the changes in VO2 (4.7±0.8 vs -1.2±0.4) and apnea-hypopnea index (-7.4±3.1 vs 5.5±3.3) in the exercise-trained group were significantly greater than those observed in the control group respectively (p<0.05) after intervention. ET reduced MSNA responses (p<0.05) and significantly increased the number of correct answers (12.4%) during SCWT. The number of correct answers was unchanged in the control group (p>0.05). CONCLUSIONS: ET improves sympathetic response and executive performance during SCWT, suggesting a prominent positive impact of ET on prefrontal functioning in individuals with OSA. ClinicalTrials.gov: NCT002289625.

Effects of aerobic and inspiratory training on skeletal muscle microRNA-1 and downstream-associated pathways in patients with heart failure.

BACKGROUND: The exercise intolerance in chronic heart failure with reduced ejection fraction (HFrEF) is mostly attributed to alterations in skeletal muscle. However, the mechanisms underlying the skeletal myopathy in patients with HFrEF are not completely understood. We hypothesized that (i) aerobic exercise training (AET) and inspiratory muscle training (IMT) would change skeletal muscle microRNA-1 expression and downstream-associated pathways in patients with HFrEF and (ii) AET and IMT would increase leg blood flow (LBF), functional capacity, and quality of life in these patients. METHODS: Patients age 35 to 70 years, left ventricular ejection fraction (LVEF) ≤40%, New York Heart Association functional classes II-III, were randomized into control, IMT, and AET groups. Skeletal muscle changes were examined by vastus lateralis biopsy. LBF was measured by venous occlusion plethysmography, functional capacity by cardiopulmonary exercise test, and quality of life by Minnesota Living with Heart Failure Questionnaire. All patients were evaluated at baseline and after 4 months. RESULTS: Thirty-three patients finished the study protocol: control (n = 10; LVEF = 25 ± 1%; six males), IMT (n = 11; LVEF = 31 ± 2%; three males), and AET (n = 12; LVEF = 26 ± 2%; seven males). AET, but not IMT, increased the expression of microRNA-1 (P = 0.02; percent changes = 53 ± 17%), decreased the expression of PTEN (P = 0.003; percent changes = -15 ± 0.03%), and tended to increase the p-AKTser473 /AKT ratio (P = 0.06). In addition, AET decreased HDAC4 expression (P = 0.03; percent changes = -40 ± 19%) and upregulated follistatin (P = 0.01; percent changes = 174 ± 58%), MEF2C (P = 0.05; percent changes = 34 ± 15%), and MyoD expression (P = 0.05; percent changes = 47 ± 18%). AET also increased muscle cross-sectional area (P = 0.01). AET and IMT increased LBF, functional capacity, and quality of life. Further analyses showed a significant correlation between percent changes in microRNA-1 and percent changes in follistatin mRNA (P = 0.001, rho = 0.58) and between percent changes in follistatin mRNA and percent changes in peak VO2 (P = 0.004, rho = 0.51). CONCLUSIONS: AET upregulates microRNA-1 levels and decreases the protein expression of PTEN, which reduces the inhibitory action on the PI3K-AKT pathway that regulates the skeletal muscle tropism. The increased levels of microRNA-1 also decreased HDAC4 and increased MEF2c, MyoD, and follistatin expression, improving skeletal muscle regeneration. These changes associated with the increase in muscle cross-sectional area and LBF contribute to the attenuation in skeletal myopathy, and the improvement in functional capacity and quality of life in patients with HFrEF. IMT caused no changes in microRNA-1 and in the downstream-associated pathway. The increased functional capacity provoked by IMT seems to be associated with amelioration in the respiratory function instead of changes in skeletal muscle. ClinicalTrials.gov (Identifier: NCT01747395).

Testosterona e doença cardiovascular: do tratamento ao uso abusivo / Testosterone and cardiovascular disease: from treatment to abuse

A testosterona, hormônio masculino com efeitos androgênicos e anabólicos, também exerce efeito sobre o leito vascular. Este hormônio promove vasodilatação através da liberação de óxido nítrico e modulação dos canais de cálcio que impacta a função endotelial. Em pacientes com doença arterial coronariana (DAC) e insuficiência cardíaca (IC), reduções nas concentrações de testosterona total (<300 ng/dL) estão relacionadas com maior mortalidade e severidade dessas doenças. Em pacientes com DAC, a reposição de testosterona (RT) tem relação com melhora do tônus vascular coronário e melhora do limiar de isquemia. Em pacientes com IC, os efeitos parecem estar mais relacionados à melhora da capacidade funcional, aumento na distância percorrida em testes funcionais, maior VO2máx, menor razão VE/VCO2, e melhora adicional da sensibilidade barorreflexa. No entanto, embora os efeitos da testosterona sobre o aumento de massa muscular e força muscular estejam bem estabelecidos na literatura, os efeitos dessa substância no sistema cardiovascular precisam ser elucidados. O aumento das concentrações de antígeno prostático específico da próstata tem sido constantemente discutido quando a RT é proposta no tratamento de pacientes com doenças cardiovasculares. Por se tratar de um hormônio com grande potencial anabólico, os efeitos do uso de quantidades suprafisiológicas de testosterona e seus análogos sobre as alterações cardiovasculares em jovens atletas têm sido estudados. Portanto, o objetivo dessa revisão é abordar os efeitos benéficos da RT em homens com hipogonadismo com DAC e IC, e mostrar os riscos relacionados com a prática indiscriminada do uso de anabolizantes em jovens sem deficiência de testosterona

Testosterone, the male hormone with androgenic and anabolic effects, also has an effect on the vascular bed. This hormone promotes vasodilation by releasing nitric oxide and calcium channel modulation that impacts endothelial function. In patients with coronary artery disease (CAD) and heart failure (HF), reductions in total testosterone concentrations (<300 ng/dL) are related to higher mortality and severity of these diseases. In patients with CAD, testosterone replacement (TR) is related to improved coronary vascular tone and improved ischemia threshold. In HF patients, the effects seem be more related to improved functional capacity, increased distance covered in functional tests, higher VO2max, lower LV/VCO2 ratio, and further improvement of baroreflex sensitivity. However, although the effects of testosterone on muscle mass gain and muscle strength are well established in the literature, the effects of testosterone on the cardiovascular system need to be elucidated. Increased prostate-specific prostate antigen concentrations have been constantly discussed when TR is proposed in the treatment of patients with cardiovascular disease. Because it is a hormone with great anabolic potential, the effects of supraphysiological amounts of testosterone and its analogues on cardiovascular disorders in young athletes have been studied. Therefore, the objective of this review is to address the beneficial effects of TR in men with hypogonadism with CAD and HF, and to show the risks related to anabolic steroids abuse in young people without testosterone deficiency

Sympatho-Vagal Imbalance is Associated with Sarcopenia in Male Patients with Heart Failure / Desequilíbrio Simpático-Vagal está Associado com Sarcopenia em Pacientes do Sexo Masculino com Insuficiência Cardíaca

Abstract Background: Resting sympathetic hyperactivity and impaired parasympathetic reactivation after exercise have been described in patients with heart failure (HF). However, the association of these autonomic changes in patients with HF and sarcopenia is unknown. Objective: The aim of this study was to evaluate the impact of autonomic modulation on sarcopenia in male patients with HF. Methods: We enrolled 116 male patients with HF and left ventricular ejection fraction < 40%. All patients underwent a maximal cardiopulmonary exercise testing. Maximal heart rate was recorded and delta heart rate recovery (∆HRR) was assessed at 1st and 2nd minutes after exercise. Muscle sympathetic nerve activity (MSNA) was recorded by microneurography. Dual-energy X-ray absorptiometry was used to measure body composition and sarcopenia was defined by the sum of appendicular lean muscle mass (ALM) divided by height in meters squared and handgrip strength. Results: Sarcopenia was identified in 33 patients (28%). Patients with sarcopenia had higher MSNA than those without (47 [41-52] vs. 40 [34-48] bursts/min, p = 0.028). Sarcopenic patients showed lower ∆HRR at 1st (15 [10-21] vs. 22 [16-30] beats/min, p < 0.001) and 2nd min (25 [19-39] vs. 35 [24-48] beats/min, p = 0.017) than non-sarcopenic. There was a positive correlation between ALM and ∆HRR at 1st (r = 0.26, p = 0.008) and 2nd min (r = 0.25, p = 0.012). We observed a negative correlation between ALM and MSNA (r = -0.29, p = 0.003). Conclusion: Sympatho-vagal imbalance seems to be associated with sarcopenia in male patients with HF. These results highlight the importance of a therapeutic approach in patients with muscle wasting and increased peripheral sympathetic outflow.

Resumo Fundamento: Hiperatividade simpática de repouso e uma reativação parassimpática diminuída pós-exercício têm sido descritas em pacientes com insuficiência cardíaca (IC). No entanto, a associação dessas alterações autonômicas em pacientes com IC sarcopênicos ainda não são conhecidas. Objetivo: O objetivo deste estudo foi avaliar o impacto da modulação autonômica sobre sarcopenia em pacientes com IC do sexo masculino. Métodos: Foram estudados 116 pacientes com IC e fração de ejeção ventricular esquerda inferior a 40%. Todos os pacientes foram submetidos ao teste de exercício cardiopulmonar máximo. A frequência cardíaca máxima foi registrada, e o delta de recuperação da frequência cardíaca (∆RFC) foi avaliado no primeiro e no segundo minuto após o exercício. A atividade nervosa simpática muscular (ANSM) foi registrada por microneurografia. A Absorciometria Radiológica de Dupla Energia foi usada para medir composição cpororal, e a sarcopenia definida como a soma da massa muscular apendicular (MMA) dividida pela altura em metros ao quadrado e força da mão. Resultados: A sarcopenia foi identificada em 33 pacientes (28%). Os pacientes com sarcopenia apresentaram maior ANSM que aqueles sem sarcopenia - 47 (41-52) vs. 40 (34-48) impulsos (bursts)/min, p = 0,028). Pacientes sarcopênicos apresentaram ∆RFC mais baixo no primeiro [15 (10-21) vs. 22 (16-30) batimentos/min, p < 0,001) e no segundo [25 (19-39) vs. 35 (24-48) batimentos/min, p = 0,017) minuto que pacientes não sarcopênicos. Observou-se uma correlação positiva entre a MMA e a ANSM (r = -0,29; p = 0,003). Conclusão: Um desequilíbrio simpático-vagal parece estar associado com sarcopenia em pacientes com IC do sexo masculino. Esses resultados destacam a importância de uma abordagem terapêutica em pacientes com perda muscular e fluxo simpático periférico aumentado.

Chemotherapy acutely impairs neurovascular and hemodynamic responses in women with breast cancer.

The purpose of the present study was to test the hypothesis that doxorubicin (DX) and cyclophosphamide (CY) adjuvant chemotherapy (CHT) acutely impairs neurovascular and hemodynamic responses in women with breast cancer. Sixteen women (age: 47.0 ± 2.0 yr; body mass index: 24.2 ± 1.5 kg/m) with stage II-III breast cancer and indication for adjuvant CHT underwent two experimental sessions, saline (SL) and CHT. In the CHT session, DX (60 mg/m2) and CY (600 mg/m2) were administered over 45 min. In the SL session, a matching SL volume was infused in 45 min. Muscle sympathetic nerve activity (MSNA) from peroneal nerve (microneurography), calf blood flow (CBF; plethysmography) and calf vascular conductance (CVC), heart rate (HR; electrocardiography), and beat-to-beat blood pressure (BP; finger plethysmography) were measured at rest before, during, and after each session. Venous blood samples (5 ml) were collected before and after both sessions for assessment of circulating endothelial microparticles (EMPs; flow cytometry), a surrogate marker for endothelial damage. MSNA and BP responses were increased (P < 0.001), whereas CBF and CVC responses were decreased (P < 0.001), during and after CHT session when compared with SL session. Interestingly, the vascular alterations were also observed at the molecular level through an increased EMP response to CHT (P = 0.03, CHT vs. SL session). No difference in HR response was observed (P > 0.05). Adjuvant CHT with DX and CY in patients treated for breast cancer increases sympathetic nerve activity and circulating EMP levels and, in addition, reduces muscle vascular conductance and elevates systemic BP. These responses may be early signs of CHT-induced cardiovascular alterations and may represent potential targets for preventive interventions. NEW & NOTEWORTHY It is known that chemotherapy regimens increase the risk of cardiovascular events in patients treated for cancer. Here, we identified that a single cycle of adjuvant chemotherapy with doxorubicin and cyclophosphamide in women treated for breast cancer dramatically increases sympathetic nerve activity and circulating endothelial microparticle levels, reduces the muscle vascular conductance, and elevates systemic blood pressure.

Blunted peripheral blood supply and underdeveloped skeletal muscle in Fontan patients: The impact on functional capacity.

BACKGROUND: Changes in circulatory physiology are common in Fontan patients due to suboptimal cardiac output, which may reduce the peripheral blood flow and impair the skeletal muscle. The objective of this study was to investigate the forearm blood flow (FBF), cross-sectional area (CSA) of the thigh and functional capacity in asymptomatic clinically stable patients undergoing Fontan surgery. METHODS: Thirty Fontan patients and 27 healthy subjects underwent venous occlusion plethysmography, magnetic resonance imaging of the thigh musculature and maximal cardiopulmonary exercise testing. Muscle sympathetic nerve activity (MSNA), norepinephrine measures, cardiovascular magnetic resonance, handgrip strength and 6-minute walk test were also performed. RESULTS: Fontan patients have blunted FBF (1.59 ±â€¯0.33 vs 2.17 ±â€¯0.52 mL/min/100 mL p < 0.001) and forearm vascular conductance (FVC) (1.69 ±â€¯0.04 vs 2.34 ±â€¯0.62 units p < 0.001), reduced CSA of the thigh (81.2 ±â€¯18.6 vs 116.3 ±â€¯26.4 cm2p < 0.001), lower peak VO2 (29.3 ±â€¯6 vs 41.5 ±â€¯9 mL/kg/min p < 0.001), walked distance (607 ±â€¯60 vs 701 ±â€¯58 m p < 0.001) and handgrip strength (21 ±â€¯9 vs 30 ±â€¯8 kgf p < 0.001). The MSNA (30 ±â€¯4 vs 22 ±â€¯3 bursts/min p < 0.001) and norepinephrine concentration [265 (236-344) vs 222 (147-262) pg/mL p = 0.006] were also higher in Fontan patients. Multivariate linear regression showed FVC (ß = 0.653; CI = 0.102-1.205; p = 0.022) and stroke volume (ß = 0.018; CI = 0.007-0.029; p = 0.002) to be independently associated with reduced CSA of the thigh adjusted for body mass index. The CSA of the thigh adjusted for body mass index (ß = 5.283; CI = 2.254-8.312; p = 0.001) was independently associated with reduced peak VO2. CONCLUSION: Patients with Fontan operation have underdeveloped skeletal muscle with reduced strength that is associated with suboptimal peripheral blood supply and diminished exercise capacity.

Exercise training induces eNOS coupling and restores relaxation in coronary arteries of heart failure rats.

Exercise training (ET) has emerged as a nonpharmacological therapy for cardiovascular diseases because of its helpful milieu for improving vascular function. The aim of the present study was to assess whether ET reverses the alterations in vascular reactivity observed in heart failure (HF)-related coronary arteries and to elucidate the molecular mechanisms involved in these adjustments. Male Wistar rats were subjected to either coronary artery ligation or sham operation. Four weeks after the surgery, rats were divided into two groups: untrained HF (UHF) and exercise-trained HF (THF). ET was conducted on a treadmill for 8 wk. An untrained SO group was included in the study as a normal control. ET restored the impaired acetylcholine (ACh)- and sodium nitroprusside-induced relaxation in coronary arteries to levels of the control. Oxidative stress and reduced nitric oxide (NO) production were observed in UHF, whereas ET restored both parameters to the levels of the control. Expression levels of endothelial NO synthase (eNOS) and soluble guanylyl cyclase subunits were increased in coronary arteries of UHF rats but reduced in THF rats. Tetrahydrobiopterin restored ACh-induced NO production in the UHF group, indicating that eNOS was uncoupled. ET increased the eNOS dimer-to-monomer ratio and expression of GTP cyclohydrolase 1, thus increasing NO bioavailability. Taken together, these findings demonstrate that ET reverses the dysfunction of the NO/soluble guanylyl cyclase pathway present in coronary arteries of HF rats. These effects of ET are associated with increased GTP cyclohydrolase 1 expression, restoration of NO bioavailability, and reduced oxidative stress through eNOS coupling. NEW & NOTEWORTHY The present study provides a molecular basis for the exercise-induced improvement in coronary arteries function in heart failure. Increasing the expression of GTP cyclohydrolase 1, the rate-limiting enzyme in the de novo biosynthesis of tetrahydrobiopterin, exercise training couples endothelial nitric oxide synthase, reduces oxidative stress, and increases nitric oxide bioavailability and sensitivity in coronary arteries of heart failure rats.