RESUMEN
BACKGROUND: COVID-19 has become a dramatic health problem during this century. In addition to high mortality rate, COVID-19 survivors are at increased risk for cardiovascular diseases 1-year after infection. Explanations for these manifestations are still unclear but can involve a constellation of biological alterations. We hypothesized that COVID-19 survivors compared with controls exhibit sympathetic overdrive, vascular dysfunction, cardiac morpho-functional changes, impaired exercise capacity, and increased oxidative stress. METHODS: Nineteen severe COVID-19 survivors and 19 well-matched controls completed the study. Muscle sympathetic nerve activity (microneurography), brachial artery flow-mediated dilation and blood flow (Doppler-Ultrasound), carotid-femoral pulse wave velocity (Complior), cardiac morpho-functional parameters (echocardiography), peak oxygen uptake (cardiopulmonary exercise testing), and oxidative stress were measured ~3 months after hospital discharge. Complementary experiments were conducted on human umbilical vein endothelial cells cultured with plasma samples from subjects. RESULTS: Muscle sympathetic nerve activity and carotid-femoral pulse wave velocity were greater and brachial artery flow-mediated dilation, brachial artery blood flow, E/e' ratio, and peak oxygen uptake were lower in COVID-19 survivors than in controls. COVID-19 survivors had lower circulating antioxidant markers compared with controls, but there were no differences in plasma-treated human umbilical vein endothelial cells nitric oxide production and reactive oxygen species bioactivity. Diminished peak oxygen uptake was associated with sympathetic overdrive, vascular dysfunction, and reduced diastolic function in COVID-19 survivors. CONCLUSIONS: Our study revealed that COVID-19 survivors have sympathetic overactivation, vascular dysfunction, cardiac morpho-functional changes, and reduced exercise capacity. These findings indicate the need for further investigation to determine whether these manifestations are persistent longer-term and their impact on the cardiovascular health of COVID-19 survivors.
Asunto(s)
COVID-19 , Enfermedades Vasculares , Rigidez Vascular , Humanos , Endotelio Vascular , Análisis de la Onda del Pulso , Tolerancia al Ejercicio , Células Endoteliales , Arteria Braquial , Oxígeno , Rigidez Vascular/fisiologíaRESUMEN
PURPOSE: Patients with chronic chagasic cardiomyopathy with preserved ventricular function present with autonomic imbalance. This study evaluated the effects of exercise training (ET) in restoring peripheral and cardiac autonomic control and skeletal muscle phenotype in patients with subclinical chronic chagasic cardiomyopathy. METHODS: This controlled trial (NCT02295215) included 24 chronic chagasic cardiomyopathy patients who were randomized www.random.org/lists/ into two groups: those who underwent exercise training (n = 12) and those who continued their usual activities (n = 12). Eight patients completed the exercise training protocol, and 10 patients were clinically followed up for 4 months. Muscular sympathetic nerve activity was measured by microneurography and muscle blood flow (MBF) using venous occlusion plethysmography. The low-frequency component of heart rate variability in normalized units (LFnuHR) reflects sympathetic activity in the heart, and the low-frequency component of systolic blood pressure variability in normalized units reflects sympathetic activity in the vessels. The infusion of vasoactive drugs (phenylephrine and sodium nitroprusside) was used to evaluate cardiac baroreflex sensitivity, and a vastus lateralis muscle biopsy was performed to evaluate atrogin-1 and MuRF-1 gene expression. RESULTS: The baroreflex sensitivity for increases (p = 0.002) and decreases (p = 0.02) in systolic blood pressure increased in the ET group. Muscle blood flow also increased only in the ET group (p = 0.004). Only the ET group had reduced resting muscular sympathetic nerve activity levels (p = 0.008) and sympathetic activity in the heart (LFnu; p = 0.004) and vessels (p = 0.04) after 4 months. Regarding skeletal muscle, after 4 months, participants in the exercise training group presented with lower atrogin-1 gene expression than participants who continued their activities as usual (p = 0.001). The reduction in muscular sympathetic nerve activity was positively associated with reduced atrogin-1 (r = 0.86; p = 0.02) and MuRF-1 gene expression (r = 0.64; p = 0.06); it was negatively associated with improved baroreflex sensitivity both for increases (r = -0.72; p = 0.020) and decreases (r = -0.82; p = 0.001) in blood pressure. CONCLUSIONS: ET improved cardiac and peripheral autonomic function in patients with subclinical chagasic cardiomyopathy. ET reduced MSNA and sympathetic activity in the heart and vessels and increased cardiac parasympathetic tone and baroreflex sensitivity. Regarding peripheral muscle, after 4 months, patients who underwent exercise training had an increased cross-sectional area of type I fibers and oxidative metabolism of muscle fibers, and decreased atrogin-1 gene expression, compared to participants who continued their activities as usual. In addition, the reduction in MSNA was associated with improved cardiac baroreflex sensitivity, reduced sympathetic cardiovascular tone, and reduced atrogin-1 and MuRF-1 gene expression. TRIAL REGISTRATION: ID: NCT02295215. Registered in June 2013.
Asunto(s)
Cardiomiopatía Chagásica , Sistema Nervioso Autónomo , Barorreflejo , Presión Sanguínea , Cardiomiopatía Chagásica/terapia , Ejercicio Físico , Frecuencia Cardíaca , Humanos , Músculo Esquelético , Sistema Nervioso SimpáticoRESUMEN
BACKGROUND: Adjuvant chemotherapy with 5-fluorouracil (5-FU) and oxaliplatin increases recurrence-free and overall survival in patients with colon adenocarcinoma. It is known that these drugs have been associated with cardio- and neurotoxicity. We investigated the effects of 5-FU ± oxaliplatin on cardiac function, vascular responses, neurovascular control, and physical capacity in patients with colon cancer. METHODS: Twenty-nine patients with prior colectomy for stage II-III adenocarcinoma and clinical indication for adjuvant chemotherapy were allocated to receive 5-FU (n = 12) or 5-FU + oxaliplatin (n = 17), according to the oncologist's decision. All the analyses were performed just before and after the end of chemotherapy. Cardiac function was assessed by echocardiography and speckle tracking, and cardiac autonomic control was assessed by heart rate variability (HRV). Vascular endothelial function was assessed by flow-mediated dilation (FMD). Muscle sympathetic nerve activity (MSNA) was directly recorded by microneurography technique, and muscle blood flow by venous occlusion plethysmography. Physical capacity was evaluated by cardiopulmonary exercise test. RESULTS: Chemotherapy (pooled data) did not significantly change left ventricular ejection fraction (58 ± 1 vs. 55 ± 2%, p = .14), longitudinal strain (-18 ± 1 vs. -18 ± 1%, p = .66), and HRV. Likewise, chemotherapy did not significantly change FMD, muscle blood flow, and MSNA (33 ± 2 vs. 32 ± 1 bursts/min, p = .31). Physical capacity was not significantly changed in both groups. Similar findings were observed when the patients were subdivided in 5-FU and 5-FU + oxaliplatin treatment groups. 5-FU and 5-FU + oxaliplatin did not significantly change cardiac function, HRV, vascular responses, MSNA, and physical capacity. CONCLUSION: This study provides evidence that adjuvant treatment with 5-FU ± oxaliplatin is well tolerated and does not promote changes compatible with long-term cardiotoxicity. IMPLICATIONS FOR PRACTICE: Adjuvant chemotherapy with 5-fluorouracil (5-FU) and oxaliplatin increases recurrence-free and overall survival in patients with colon adenocarcinoma; however, these drugs have been associated with cardio- and neurotoxicity. This study investigated the effects of these drugs on cardiac function, vascular responses, neurovascular control, and physical capacity in patients with colon cancer. It was found that 5-FU and oxaliplatin did not significantly change cardiac function, cardiac autonomic control, vascular endothelial function, muscle sympathetic nerve activity, and physical capacity. This study provides evidence that adjuvant treatment with 5-FU ± oxaliplatin is well tolerated and does not promote changes compatible with long-term cardiotoxicity.
Asunto(s)
Neoplasias del Colon , Fluorouracilo , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Quimioterapia Adyuvante , Neoplasias del Colon/tratamiento farmacológico , Neoplasias del Colon/patología , Fluorouracilo/uso terapéutico , Humanos , Leucovorina/uso terapéutico , Recurrencia Local de Neoplasia/patología , Estadificación de Neoplasias , Compuestos Organoplatinos/uso terapéutico , Oxaliplatino/uso terapéutico , Volumen Sistólico , Función Ventricular IzquierdaRESUMEN
OBJECTIVE: We tested the hypothesis that exercise training would attenuate metabolic impairment in a model of severe cancer cachexia. METHODS: We used multiple in vivo and in vitro methods to explore the mechanisms underlying the beneficial effects induced by exercise training in tumor-bearing rats. RESULTS: Exercise training improved running capacity, prolonged lifespan, reduced oxidative stress, and normalized muscle mass and contractile function in tumor-bearing rats. An unbiased proteomic screening revealed COP9 signalosome complex subunit 2 (COPS2) as one of the most downregulated proteins in skeletal muscle at the early stage of cancer cachexia. Exercise training normalized muscle COPS2 protein expression in tumor-bearing rats and mice. Lung cancer patients with low endurance capacity had low muscle COPS2 protein expression as compared to age-matched control subjects. To test whether decrease in COPS2 protein levels could aggravate or be an intrinsic compensatory mechanism to protect myotubes from cancer effects, we performed experiments in vitro using primary myotubes. COPS2 knockdown in human myotubes affected multiple cellular pathways, including regulation of actin cytoskeleton. Incubation of cancer-conditioned media in mouse myotubes decreased F-actin expression, which was partially restored by COPS2 knockdown. Direct repeat 4 (DR4) response elements have been shown to positively regulate gene expression. COPS2 overexpression decreased the DR4 activity in mouse myoblasts, and COPS2 knockdown inhibited the effects of cancer-conditioned media on DR4 activity. CONCLUSIONS: These studies demonstrated that exercise training may be an important adjuvant therapy to counteract cancer cachexia and uncovered novel mechanisms involving COPS2 to regulate myotube homeostasis in cancer cachexia.
Asunto(s)
Complejo del Señalosoma COP9/metabolismo , Músculo Esquelético/metabolismo , Neoplasias/metabolismo , Estrés Oxidativo , Condicionamiento Físico Animal , Proteínas Represoras/metabolismo , Animales , Biomarcadores , Complejo del Señalosoma COP9/genética , Caquexia/etiología , Caquexia/metabolismo , Línea Celular Tumoral , Citocinas/metabolismo , Modelos Animales de Enfermedad , Metabolismo Energético , Técnicas de Silenciamiento del Gen , Humanos , Masculino , Ratones , Fibras Musculares Esqueléticas/metabolismo , Atrofia Muscular/etiología , Atrofia Muscular/metabolismo , Mioblastos/metabolismo , Neoplasias/complicaciones , Oxidación-Reducción , Proteómica/métodos , Ratas , Receptores del Ligando Inductor de Apoptosis Relacionado con TNF/genética , Receptores del Ligando Inductor de Apoptosis Relacionado con TNF/metabolismo , Proteínas Represoras/genética , Transducción de SeñalRESUMEN
PURPOSE: Previous studies report abnormal muscle metaboreflex control of muscle sympathetic nerve activity (MSNA) in obesity, hypertension, and heart failure. We hypothesized that obstructive sleep apnea (OSA) is associated with augmented metaboreflex control of MSNA. METHODS: Thirty-one sedentary individuals with no comorbidities (age = 52 ± 1 yr, body mass index = 28 ± 1 kg·m) without (control, n = 14) and with OSA (n = 17) defined by polysomnography, underwent echocardiography. HR, blood pressure (BP), MSNA (microneurography), and forearm blood flow measured by venous occlusion plethysmography were continuously measured 4 min at baseline, during 3 min of 30% handgrip static exercise, and during 2 min of post-handgrip muscle ischemia (PHMI). RESULTS: Control and OSA groups were similar in age, body mass index, and ejection fraction. Baseline HR, BP, and forearm blood flow increased similarly during handgrip exercise. Blood pressure remained significantly elevated in relation to baseline during PHMI, but HR and forearm blood flow returned toward baseline during PHMI in both groups. Baseline MSNA was significantly higher in the OSA group than in controls (P < 0.05). During peak 30% static handgrip exercise, MSNA increased significantly in both control and OSA groups, but MSNA responses were higher in patients with OSA. During PHMI, MSNA in control subjects remained significantly elevated compared with that at baseline. In contrast, in patients with OSA, MSNA decreased to baseline values. A significant correlation was found between changes in MSNA due to PHMI and apnea-hypopnea index (r = -0.61, P < 0.001), and with minimum O2 saturation (r = 0.70, P < 0.001). CONCLUSIONS: These findings suggest an association between OSA and decreased metaboreflex control of MSNA. Muscle vasodilation during handgrip static exercise is preserved in patients with OSA.
Asunto(s)
Músculo Esquelético/inervación , Músculo Esquelético/fisiopatología , Apnea Obstructiva del Sueño/fisiopatología , Sistema Nervioso Simpático/fisiopatología , Adulto , Anciano , Barorreflejo/fisiología , Presión Sanguínea/fisiología , Ejercicio Físico/fisiología , Femenino , Antebrazo/irrigación sanguínea , Frecuencia Cardíaca/fisiología , Humanos , Masculino , Persona de Mediana Edad , Músculo Esquelético/irrigación sanguínea , Flujo Sanguíneo Regional , Vasodilatación/fisiologíaRESUMEN
Arterial baroreflex control of muscle sympathetic nerve activity (ABRMSNA) is impaired in chronic systolic heart failure (CHF). The purpose of the study was to test the hypothesis that exercise training would improve the gain and reduce the time delay of ABRMSNA in CHF patients. Twenty-six CHF patients, New York Heart Association Functional Class II-III, EF ≤ 40%, peak VÌo2 ≤ 20 ml·kg(-1)·min(-1) were divided into two groups: untrained (UT, n = 13, 57 ± 3 years) and exercise trained (ET, n = 13, 49 ± 3 years). Muscle sympathetic nerve activity (MSNA) was directly recorded by microneurography technique. Arterial pressure was measured on a beat-to-beat basis. Time series of MSNA and systolic arterial pressure were analyzed by autoregressive spectral analysis. The gain and time delay of ABRMSNA was obtained by bivariate autoregressive analysis. Exercise training was performed on a cycle ergometer at moderate intensity, three 60-min sessions per week for 16 wk. Baseline MSNA, gain and time delay of ABRMSNA, and low frequency of MSNA (LFMSNA) to high-frequency ratio (HFMSNA) (LFMSNA/HFMSNA) were similar between groups. ET significantly decreased MSNA. MSNA was unchanged in the UT patients. The gain and time delay of ABRMSNA were unchanged in the ET patients. In contrast, the gain of ABRMSNA was significantly reduced [3.5 ± 0.7 vs. 1.8 ± 0.2, arbitrary units (au)/mmHg, P = 0.04] and the time delay of ABRMSNA was significantly increased (4.6 ± 0.8 vs. 7.9 ± 1.0 s, P = 0.05) in the UT patients. LFMSNA-to-HFMSNA ratio tended to be lower in the ET patients (P < 0.08). Exercise training prevents the deterioration of ABRMSNA in CHF patients.
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Presión Arterial , Barorreflejo , Sistema Cardiovascular/inervación , Terapia por Ejercicio , Insuficiencia Cardíaca/terapia , Músculo Esquelético/inervación , Sistema Nervioso Simpático/fisiopatología , Adulto , Anciano , Ciclismo , Brasil , Enfermedad Crónica , Terapia por Ejercicio/métodos , Femenino , Insuficiencia Cardíaca/diagnóstico , Insuficiencia Cardíaca/fisiopatología , Humanos , Masculino , Persona de Mediana Edad , Factores de Tiempo , Resultado del TratamientoRESUMEN
The objective of this study was to evaluate the effects of exercise training on plasma removal of a cholesterol-rich nanoemulsion (LDE) that mimics low-density lipoprotein (LDL) lipid structure and binds to LDL receptors. LDE-derived cholesteryl ester plasma kinetics was studied in 24 exercise-trained and 20 sedentary male subjects. LDE labeled with [(14)C]cholesteryl ester was injected intravenously, and plasma samples were collected over a 24-h period to determine radioisotope decay curves. LDL cholesterol concentration was similar in both groups. Fractional clearance rate (FCR) of the nanoemulsion label was greater in the exercise-trained group compared with the sedentary group (0.138 +/- 0.152 and 0.0261 +/- 0.023 h(-1), respectively). A positive correlation was found (r = 0.60, P < 0.01) between FCR and peak O(2) consumption in trained subjects. Circulating oxidized LDL levels were lower in trained subjects compared with the sedentary group (9.0 +/- 2.0 and 16.0 +/- 3.0 mU/l). LDE was also injected into control and LDL receptor gene knockout mice submitted and not submitted to training. Muscle LDE uptake percentage was increased in the trained mice compared with the untrained mice (1.1 +/- 0.8 and 0.2 +/- 0.1, respectively, P < 0.0001) in the control group but not in the knockout animals, indicating that the LDL receptor is involved in the increased uptake elicited by exercise. These results show that exercise training increases LDE plasma removal, which in turn suggests that it also increases LDL receptors or LDL receptor activity.
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LDL-Colesterol/sangre , Ejercicio Físico/fisiología , Emulsiones Grasas Intravenosas/farmacocinética , Aptitud Física/fisiología , Descanso/fisiología , Adolescente , Adulto , Animales , Silenciador del Gen , Humanos , Estilo de Vida , Hígado/metabolismo , Masculino , Tasa de Depuración Metabólica/fisiología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Persona de Mediana Edad , Músculo Esquelético/metabolismo , Nanotecnología , Tamaño de la Partícula , Condicionamiento Físico Animal/fisiologíaRESUMEN
The effects of exercise training on baroreflex control of sympathetic nerve activity in human hypertension are unknown. We hypothesized that exercise training would improve baroreflex control of muscle sympathetic nerve activity (MSNA) and heart rate (HR) in patients with hypertension and that exercise training would reduce MSNA and blood pressure (BP) in hypertensive patients. Twenty never-treated hypertensive patients were randomly divided into 2 groups: exercise-trained (n=11; age: 46+/-2 years) and untrained (n=9; age: 42+/-2 years) patients. An age-matched normotensive exercise-trained group (n=12; age: 42+/-2 years) was also studied. Baroreflex control of MSNA (microneurography) and HR (ECG) was assessed by stepwise intravenous infusions of phenylephrine and sodium nitroprusside and analyzed by linear regression. BP was monitored on a beat-to-beat basis. Exercise training consisted of three 60-minute exercise sessions per week for 4 months. Under baseline conditions (before training), BP and MSNA were similar between hypertensive groups but significantly increased when compared with the normotensive group. Baroreflex control of MSNA and HR was similar between hypertensive groups but significantly decreased when compared with the normotensive group. In hypertensive patients, exercise training significantly reduced BP (P<0.01) and MSNA (P<0.01) levels and significantly increased baroreflex control of MSNA and HR during increases (P<0.01 and P<0.03, respectively) and decreases (P<0.01 and P<0.03, respectively) in BP. The baseline (preintervention) difference in baroreflex sensitivity between hypertensive patients and normotensive individuals was no longer observed after exercise training. No significant changes were found in untrained hypertensive patients. In conclusion, exercise training restores the baroreflex control of MSNA and HR in hypertensive patients. In addition, exercise training normalizes MSNA and decreases BP levels in these patients.
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Barorreflejo/fisiología , Presión Sanguínea/fisiología , Terapia por Ejercicio , Hipertensión/terapia , Adulto , Femenino , Frecuencia Cardíaca/fisiología , Humanos , Hipertensión/fisiopatología , Modelos Lineales , Masculino , Persona de Mediana Edad , Músculo Esquelético/inervación , Sistema Nervioso Simpático/fisiologíaRESUMEN
Although the vasodilatory response during mental stress is blunted in heart failure (HF), the mechanisms underlying this phenomenon are not fully understood. We tested the hypothesis that sympathetic activity limits the endothelium-dependent vasodilatation during mental stress in chronic HF patients. Twenty-one HF patients (age 45 +/- 2 yr, functional classes III and IV, New York Heart Association) and 22 age-matched normal controls (NC; age 42 +/- 2 yr, P = 0.13) were studied at rest and during 4 min of Stroop color-word test with brachial intra-arterial saline, acetylcholine (endothelium dependent), phentolamine (alpha-blocker), and phentolamine plus acetylcholine infusion. Forearm blood flow was measured by venous occlusion plethysmography. Baseline forearm vascular conductance (FVC) was significantly lower in HF patients (2.18 +/- 0.12 vs. 3.66 +/- 0.22 units, P = 0.001). During mental stress with saline, the changes in FVC were significantly blunted in HF patients compared with NC (0.92 +/- 0.20 vs. 2.13 +/- 0.39 units, P = 0.001). In HF, the vasodilatation with acetylcholine was similar to saline control and significantly lower than in NC. In HF patients, phentolamine significantly increased FVC responses (1.16 +/- 0.20 vs. 2.09 +/- 0.29 units, P = 0.001), and the difference between HF patients and NC tended to decrease (2.09 +/- 0.29 vs. 3.61 +/- 0.74 units, P = 0.052). The vasodilatation with phentolamine plus acetylcholine was similar between HF and NC (4.23 +/- 0.73 vs. 4.76 +/- 1.03 units, P = 0.84). In conclusion, sympathetic activation mediates the blunted muscle endothelium-mediated vasodilatation during mental stress in HF patients.
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Gasto Cardíaco Bajo/fisiopatología , Endotelio Vascular/fisiopatología , Músculo Esquelético/irrigación sanguínea , Sistema Nervioso Simpático/fisiopatología , Vasodilatación , Acetilcolina/farmacología , Antagonistas Adrenérgicos alfa/farmacología , Adulto , Gasto Cardíaco Bajo/complicaciones , Estudios de Casos y Controles , Enfermedad Crónica , Hemodinámica/efectos de los fármacos , Humanos , Persona de Mediana Edad , Fentolamina/farmacología , Flujo Sanguíneo Regional/efectos de los fármacos , Descanso , Estrés Psicológico/complicaciones , Estrés Psicológico/fisiopatología , Vasodilatadores/farmacologíaRESUMEN
We hypothesized that the muscle vasodilatation during mental stress and exercise would vary among humans who are polymorphic at alleles 16 and 27 of the beta(2)-adrenoceptors. From 216 preselected volunteers, we studied 64 healthy, middle-aged normotensive women selected to represent three genotypes: homozygous for the alleles Arg(16) and Gln(27) (Arg(16)/Gln(27), n = 34), Gly(16) and Gln(27) (Gly(16)/Gln(27), n = 20), and Gly(16) and Glu(27) (Gly(16)/Glu(27), n = 10). Forearm blood flow (plethysmography) and muscle sympathetic nerve activity (microneurography) were recorded during 3-min Stroop color-word test and 3-min handgrip isometric exercise (30% maximal voluntary contraction). Baseline muscle sympathetic nerve activity, forearm vascular conductance, mean blood pressure, and heart rate were not different among groups. During mental stress, the peak forearm vascular conductance responses were greater in Gly(16)/Glu(27) group than in Gly(16)/Gln(27) and Arg(16)/Gln(27) groups (1.79 +/- 0.66 vs. 0.70 +/- 0.11 and 0.58 +/- 0.12 units, P = 0.03). Similar results were found during exercise (0.80 +/- 0.25 vs. 0.28 +/- 0.08 and 0.31 +/- 0.08 units, P = 0.02). Further analysis in a subset of subjects showed that brachial intra-arterial propranolol infusion abolished the difference in vasodilatory response between Gly(16)/Glu(27) (n = 6) and Arg(16)/Gln(27) (n = 7) groups during mental stress (0.33 +/- 0.20 vs. 0.46 +/- 0.21 units, P = 0.50) and exercise (0.08 +/- 0.06 vs. 0.03 +/- 0.03 units, P = 0.21). Plasma epinephrine concentration in Arg(16)/Gln(27) and Gly(16)/Glu(27) groups was similar. In conclusion, women who are homozygous for Gly(16)/Glu(27) of the beta(2)-adrenoceptors have augmented muscle vasodilatory responsiveness to mental stress and exercise.