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.

Decreased Native T1 Values and Impaired Myocardial Contractility in Anabolic Steroid Users.

Anabolic androgenic steroid (AAS) abuse leads to myocardial toxicity. Human studies are conflicting about the myocardial fibrosis in AAS users. We evaluated cardiac tissue characterization, left ventricle (LV) function, and cardiac structure by cardiovascular magnetic resonance (CMR). Twenty strength-trained AAS users (AASU) aged 29±5 yr, 20 strength-trained AAS nonusers (AASNU), and 7 sedentary controls (SC) were enrolled. Native T1 mapping, late-gadolinium enhancement (LGE), extracellular volume (ECV), and myocardial strain were evaluated. AASU showed lower Native T1 values than AASNU (888±162 vs. 1020±179 ms p=0.047). Focal myocardial fibrosis was found in 2 AASU. AASU showed lower LV radial strain (30±8 vs. 38±6%, p<0.01), LV circumferential strain (-17±3 vs. -20±2%, p<0.01), and LV global longitudinal strain (-17±3 vs. -20±3%, p<0.01) than AASNU by CMR. By echocardiography, AASU demonstrated lower 4-chamber longitudinal strain than AASNU (-15±g3 vs. -18±2%, p=0.03). ECV was similar among AASU, AASNU, and SC (28±10 vs. 28±7 vs. 30±7%, p=0.93). AASU had higher LV mass index than AASNU and SC (85±14 vs. 64±8 vs. 58±5 g/m2, respectively, p<0.01). AAS abuse may be linked to decreased myocardial native T1 values, impaired myocardial contractility, and focal fibrosis. These alterations may be associated with maladaptive cardiac hypertrophy in young AAS users.

Sacubitril/valsartan versus enalapril on exercise capacity in patients with heart failure with reduced ejection fraction: A randomized, double-blind, active-controlled study.

Sacubitril/valsartan reduces mortality in patients with heart failure with reduced ejection fraction (HFrEF) when compared with enalapril. However, it is unknown the effect of both treatments on exercise capacity. We compared sacubitril/valsartan versus enalapril in patients with HFrEF based on peak oxygen consumption (VO2) and 6-minute walk test (6-MWT). METHODS: We included 52 participants with HFrEF with a left ventricular ejection fraction <40% to receive either sacubitril/valsartan (target dose of 400 mg daily) or enalapril (target dose of 40 mg daily). Peak VO2 was measured by using cardiopulmonary exercise testing. Six-minute walk test was also performed. RESULTS: At 12 weeks, the sacubitril/valsartan (mean dose 382.6 ± 57.6 mg daily) group had increased peak VO2 of 13.1% (19.35 ± 0.99 to 21.89 ± 1.04 mL/kg/min) and enalapril (mean dose 34.4 ± 9.2 mg daily) 5.6% (18.58 ± 1.19 to 19.62 ± 1.25 mL/kg/min). However, no difference was found between groups (P = .332 interaction). At 24 weeks, peak VO2 increased 13.5% (19.35 ± 0.99 to 21.96 ± 0.98 mL/kg/min) and 12.0% (18.58 ± 1.19 to 20.82 ± 1.18 mL/kg/min) in sacubitril/valsartan (mean dose 400 ± 0 mg daily) and enalapril (mean dose 32.7 ± 11.0 mg daily), respectively. However, no differences were found between groups (P= .332 interaction). At 12 weeks, 6-MWT increased in both groups (sacubitril/valsartan: 459 ± 18 to 488 ± 17 meters [6.3%] and enalapril: 443 ± 22 to 477 ± 21 meters [7.7%]). At 24 weeks, sacubitril/valsartan increased 18.3% from baseline (543 ± 26 meters) and enalapril decreased slightly to 6.8% (473 ± 31 meters), but no differences existed between groups (P= .257 interaction). CONCLUSIONS: Compared to enalapril, sacubitril/valsartan did not substantially improve peak VO2 or 6-MWT after 12 or 24 weeks in participants with HFrEF. (NEPRIExTol-HF Trial, ClinicalTrials.gov number, NCT03190304).

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.

Retrograde and oscillatory shear rate in young anabolic androgenic steroid users.

Disturbed shear rate (SR), characterized by increased retrograde and oscillatory SR in the brachial artery, is associated with inflammation, atherosclerosis, endothelial dysfunction, and sympathetic hyperactivity. Young subjects do not have disturbed SR; however, elderly subjects do, which seems to be associated with sympathetic hyperactivity. Anabolic androgenic steroids (AAS) abuse in young is associated with increased muscle sympathetic nerve activity (MSNA). We hypothesized that AAS users might have disturbed SR. We tested the association between retrograde and oscillatory SR with MSNA. In addition, we measured the high-sensitivity C-reactive protein (hs-CRP). We evaluated 10 male AAS users, age 27 ± 4 years, and 10 age-matched AAS nonusers, age 29 ± 5 years. At rest, retrograde and oscillatory SR were evaluated by Doppler ultrasound, MSNA was measured with microneurography, and hs-CRP was measured in blood sample. Flow-mediated dilation (FMD) was also assessed. AAS users had higher retrograde SR (24.42 ± 17.25 vs 9.15 ± 6.62 s- 1 , P = 0.01), oscillatory SR (0.22 ± 0.13 vs 0.09 ± 0.07 au P = 0.01), and MSNA (42 ± 9 vs 32 ± 4 bursts/100 heart beats, P = 0.018) than nonusers. MSNA (bursts/100 heart beats) was correlated with retrograde SR (r = 0.50, P = 0.050) and oscillatory SR (r = 0.51, P = 0.042). AAS users had higher hs-CRP [1.17 (0.44-3.63) vs 0.29 (0.17-0.70) mg/L, P = 0.015] and decreased FMD (6.42 ± 2.07 vs 8.28% ± 1.53%, P = 0.035) than nonusers. In conclusion, AAS abuse is associated with retrograde and oscillatory SR which were associated with augmented sympathetic outflow. In addition, AAS seems to lead to inflammation characterized by increased hs-CRP. These alterations may have the potential of increasing the early risk of atherosclerotic disease in young AAS users.

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.

PBMCs express a transcriptome signature predictor of oxygen uptake responsiveness to endurance exercise training in men.

Peripheral blood cells are an accessible environment in which to visualize exercise-induced alterations in global gene expression patterns. We aimed to identify a peripheral blood mononuclear cell (PBMC) signature represented by alterations in gene expression, in response to a standardized endurance exercise training protocol. In addition, we searched for molecular classifiers of the variability in oxygen uptake (V̇o2). Healthy untrained policemen recruits (n = 13, 25 ± 3 yr) were selected. Peak V̇o2 (measured by cardiopulmonary exercise testing) and total RNA from PBMCs were obtained before and after 18 wk of running endurance training (3 times/wk, 60 min). Total RNA was used for whole genome expression analysis using Affymetrix GeneChip Human Gene 1.0 ST. Data were normalized by the robust multiarray average algorithm. Principal component analysis was used to perform correlations between baseline gene expression and V̇o2peak. A set of 211 transcripts was differentially expressed (ANOVA, P < 0.05 and fold change > 1.3). Functional enrichment analysis revealed that transcripts were mainly related to immune function, cell cycle processes, development, and growth. Baseline expression of 98 and 53 transcripts was associated with the absolute and relative V̇o2peak response, respectively, with a strong correlation (r > 0.75, P < 0.01), and this panel was able to classify the 13 individuals according to their potential to improve oxygen uptake. A subset of 10 transcripts represented these signatures to a similar extent. PBMCs reveal a transcriptional signature responsive to endurance training. Additionally, a baseline transcriptional signature was associated with changes in V̇o2peak. Results might illustrate the possibility of obtaining molecular classifiers of endurance capacity changes through a minimally invasive blood sampling procedure.

Exercise-induced muscle vasodilatation and treadmill exercise test responses in individuals without overt heart disease.

BACKGROUND: The beneficial effects of exercise on cardiovascular health may be related to the improvement in several physiologic pathways, including peripheral vascular function. The aim of this study was to evaluate the relationship between cardiovascular responses during the treadmill exercise test and exercise-induced muscle vasodilatation in individuals without overt heart disease. METHODS: The study included 796 asymptomatic subjects (431 females and 365 males) without overt heart disease. We evaluated the heart rate (chronotropic reserve and heart rate recovery), blood pressure (maximum systolic and diastolic blood pressure as well as systolic blood pressure recovery) and exercise capacity during symptom-limited treadmill exercise testing. Exercise-induced muscle vasodilatation was studied with venous occlusion plethysmography and estimated by forearm blood flow and vascular conductance responses during a 3-min handgrip maneuver. RESULTS: Forearm blood flow increase during the handgrip exercise was positively associated with heart rate recovery during treadmill exercise testing (p < 0.001). Forearm vascular conductance increase during the handgrip exercise was inversely associated with exercise diastolic blood pressure during exercise treadmill testing (p = 0.038). No significant association was found between exercise capacity and exercise-induced muscle vasodilation. CONCLUSION: In a sample of individuals without overt heart disease, exercise-induced muscle vasodilatation was associated with heart rate and blood pressure responses during treadmill exercise testing, but was not associated with exercise capacity. These findings suggest that favorable hemodynamic and chronotropic responses are associated with better vasodilator capacity, but exercise capacity does not predict muscle vasodilatation.

Acute physical exercise is safe in patients with primary antiphospholipid syndrome with exclusive venous thrombosis and under oral anticoagulation with warfarin.

The purpose of present study was to evaluate the effects of maximal acute physical exercise on prothrombin time/international normalized ratio (PT/INR) in patients with primary antiphospholipid syndrome (PAPS) under oral anticoagulation with warfarin and the safety of acute exercise in regard to thrombosis and bleeding risk. Eighteen physically inactive women with PAPS (Sydney criteria) with exclusive venous events and without thrombocytopenia were included. All patients were under stable warfarin therapy (PT/INR target: 2.0-3.0). Eighteen age-matched healthy sedentary women without thrombosis/bleeding disorders were selected as controls. All subjects performed a maximal exercise test, and capillary blood samples were obtained pre-, post- and at 1-h post-exercise (recovery time) for PT/INR analysis using a portable CoaguCheck. PAPS patients and controls had similar mean age (31.50 ± 8.06 vs. 29.61 ± 7.05 years, p = 0.46) and body mass index (24.16 ± 3.67 vs. 24.66 ± 2.71 kg/m(2), p = 0.65). PAPS had a mild but significant increase in PT/INR value at 1-h post-exercise (recovery) compared with pre- (2.33 ± 0.34 vs. 2.26 ± 0.29, p = 0.001) and post-exercise (2.33 ± 0.34 vs. 2.26 ± 0.32, p = 0.001) that was observed in 61.11 % of these patients. None of the subjects had thrombotic or bleeding complications related to the acute exercise. Acute exercise in patients with PAPS with exclusive venous thrombosis was safe with a minor increase in PT/INR. This is an important step to introduce regular exercise training as a therapeutic tool in the management of these patients.

Association of Sarcopenia and Oxygen Uptake Efficiency Slope in Male Patients With Heart Failure.

PURPOSE: Sarcopenia, the loss of muscle mass and function, is a common comorbidity in patients with heart failure (HF). The skeletal muscle modulates the respiratory response during exercise. However, whether ventilatory behavior is affected by sarcopenia is still unknown. METHODS: We enrolled 169 male patients with HF. Muscle strength was measured by a handgrip dynamometer. Body composition was measured with dual-energy X-ray absorptiometry. Sarcopenia was defined by handgrip strength <27 kg and appendicular lean mass divided by height squared (ALM/height 2 ) <7.0 kg/m 2 . Oxygen uptake efficiency slope (OUES), ventilation (VE), oxygen uptake (VO 2 ), and carbon dioxide output (VCO 2 ) were measured by a cardiopulmonary exercise test. RESULTS: Sarcopenia was identified in 29 patients (17%). At the first ventilatory threshold, VE/VO 2 (36.9 ± 5.9 vs 32.7 ± 6.5; P = .003) and VE/VCO 2 (39.8 ± 7.2 vs 35.3 ± 6.9; P = .004) were higher in patients with sarcopenia compared to those without sarcopenia. At the exercise peak, compared to patients without sarcopenia, patients with sarcopenia had lower OUES (1186 ± 295 vs 1634 ± 564; P < .001), relative VO 2 (16.2 ± 5.0 vs 19.5 ± 6.5 mL/kg/min; P = .01), and VE (47.3 ± 10.1 vs 63.0 ± 18.2 L/min; P < .0001), while VE/VCO 2 (42.9 ± 8.9 vs 38.7 ± 8.4; P = .025) was increased. OUES was positively correlated with ALM/height 2 ( r = 0.36; P < .0001) and handgrip strength ( r = 0.31; P < .001). Hemoglobin (OR = 1.149; 95% CI, 0.842-1.570; P = .038), ALM/height 2 (OR = 2.166; 95% CI, 1.338-3.504; P = .002), and VO 2peak (OR = 1.377; 95% CI, 1.218-1.557; P < .001) were independently associated with OUES adjusted by cofounders. CONCLUSIONS: Our results suggest that sarcopenia is related to impaired ventilatory response during exercise in patients with HF.

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.

Vascular reactivity and ACE activity response to exercise training are modulated by the +9/-9 bradykinin B2 receptor gene functional polymorphism.

The bradykinin receptor B2 (BDKRB2) gene +9/-9 polymorphism has been associated with higher gene transcriptional activity, and characteristics of cardiovascular phenotypes and physical performance. We hypothesized that vasodilation and ACE activity response to exercise training is modulated by BDKRB2 gene. We genotyped 71 healthy volunteers were genotyped for the BDKRB2 gene polymorphism. Heart rate (HR), mean blood pressure (MBP), and forearm blood flow (FBF) were evaluated. Angiotensin-I converting enzyme (ACE) activity was measured by fluorescence. Aerobic training was performed for 16 wk. All variables were reassessed after completion of the training period. In pretraining period, HR, MBP, FBF, and forearm vascular conductance (FVC) were similar among all genotypes. After physical training, the FBF and the FVC response during handgrip exercise such as area under the curve were higher in -9/-9 carriers than the other two groups. However, there were no changes in HR and MBP for all three groups. In addition, in posttraining period the decrease in ACE activity was higher in the -9/-9 group than the other two groups. These results suggest that reflex muscle vasodilation and ACE activity in response to exercise training are modulated by BDKRB2 gene +9/-9 polymorphism in healthy individuals.

Symptoms of anxiety and mood disturbance alter cardiac and peripheral autonomic control in patients with metabolic syndrome.

Previous investigations show that metabolic syndrome (MetSyn) causes sympathetic hyperactivation. Symptoms of anxiety and mood disturbance (AMd) provoke sympatho-vagal imbalance. We hypothesized that AMd would alter even further the autonomic function in patients with MetSyn. Twenty-six never-treated patients with MetSyn (ATP-III) were allocated to two groups, according to the levels of anxiety and mood disturbance: (1) with AMd (MetSyn + AMd, n = 15), and (2) without AMd (MetSyn, n = 11). Ten healthy control subjects were also studied (C, n = 10). AMd was determined using quantitative questionnaires. Muscle sympathetic nerve activity (MSNA, microneurography), blood pressure (oscillometric beat-to-beat basis), and heart rate (ECG) were measured during a baseline 10-min period. Spectral analysis of RR interval and systolic arterial pressure were analyzed, and the power of low (LF) and high (HF) frequency bands were determined. Sympatho-vagal balance was obtained by LF/HF ratio. Spontaneous baroreflex sensitivity (BRS) was evaluated by calculation of α-index. MSNA was greater in patients with MetSyn + AMd compared with MetSyn and C. Patients with MetSyn + AMd showed higher LF and lower HF power compared with MetSyn and C. In addition, LF/HF balance was higher in MetSyn + AMd than in MetSyn and C groups. BRS was decreased in MetSyn + AMd compared with MetSyn and C groups. Anxiety and mood disturbance alter autonomic function in patients with MetSyn. This autonomic dysfunction may contribute to the increased cardiovascular risk observed in patients with mood alterations.

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.

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

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.

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.

Mutations in the human phospholamban gene in patients with heart failure.

BACKGROUND: Phospholamban (PLN) is a crucial Ca(2+) cycling protein and a primary mediator of the ß-adrenergic effects resulting in enhanced cardiac output. Mutations in the gene encoding PLN have been associated with idiopathic dilated cardiomyopathy; however, no systematic search for PLN mutations in heart failure has been conducted. METHODS: We screened a cohort of 1,014 Brazilian patients with heart failure for mutations in the PLN gene. Molecular modeling studies of the mutations found were developed. Different disease etiologies were present in our sample: idiopathic, ischemic, Chagas, valvular, hypertensive, and others. RESULTS: We identified 4 unrelated patients with PLN mutations (prevalence of 0.4%), 3 of them in the same amino acid residue (R9). Two patients presented a G-T missense mutation at the G26 nucleotide, which encodes an Arg-Leu substitution at codon 9 (R9L). One patient presented a G-A missense mutation at the same nucleotide, which encodes an Arg-His substitution at codon 9 (R9H). The fourth affected patient presented a T-G nonsense mutation at the nucleotide 116, substituting a termination codon for Leu-39 (L39stop). Molecular modeling studies suggested that R9L and R9H mutations might affect the region involved in protein kinase A docking and probably affect the mechanism modulating the release of phosphorylated PLN from the substrate binding site of protein kinase A. CONCLUSIONS: Mutations in the PLN gene are a rare cause of heart failure, present almost exclusively in patients with dilated cardiomyopathy etiology. The Arg9 and Leu39 residues are the leading location of mutations described at this locus to date. Despite the few mutated residues described to date, the clinical spectrum of presentation appears to vary considerably.

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.

Association of physical activity levels and the prevalence of COVID-19-associated hospitalization.

OBJECTIVES: We compared physical activity levels before the outbreak and quarantine measures with COVID-19-associated hospitalization prevalence in surviving patients infected with SARS-CoV-2. Additionally, we investigated the association of physical activity levels with symptoms of the disease, length of hospital stay, and mechanical ventilation. DESIGN: Observational, cross-sectional. METHODS: Between June 2020 and August 2020, we invited Brazilian survivors and fully recovered patients infected with SARS-CoV-2 to respond to an online questionnaire. We shared the electronic link to the questionnaire on the internet. We collected data about clinical outcomes (symptoms, medications, hospitalization, and length of hospital stay) and cofactors, such as age, sex, ethnicity, preexisting diseases, socioeconomic and educational, and physical activity levels using the International Physical Activity Questionnaire (IPAQ short version). RESULTS: Out of 938 patients, 91 (9.7%) were hospitalized due to COVID-19. In a univariate analysis, sex, age, and BMI were all associated with hospitalizations due to COVID-19. Men had a higher prevalence of hospitalization (66.6%, p = 0.013). Patients older than 65 years, obese, and with preexisting disease had a higher prevalence of COVID-19-related hospitalizations. In a multivariate regression model, performance of at least 150 min/wk (moderate) and/or 75 min/wk (vigorous) physical activity was associated with a lower prevalence of hospitalizations after adjustment for age, sex, BMI, and preexisting diseases (PR = 0.657; p = 0.046). CONCLUSIONS: Sufficient physical activity levels were associated with a lower prevalence of COVID-19-related hospitalizations. Performing at least 150 min a week of moderate-intensity, or 75 min a week of vigorous-intensity physical activity was associated with 34.3% reduction in prevalence.

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.

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.