RESUMO
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.
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Antineoplásicos/efeitos adversos , Neoplasias da Mama/tratamento farmacológico , Ciclofosfamida/efeitos adversos , Doxorrubicina/efeitos adversos , Endotélio Vascular/efeitos dos fármacos , Frequência Cardíaca/efeitos dos fármacos , Sistema Nervoso Simpático/efeitos dos fármacos , Adulto , Antineoplásicos/administração & dosagem , Antineoplásicos/uso terapêutico , Micropartículas Derivadas de Células/efeitos dos fármacos , Quimioterapia Adjuvante , Ciclofosfamida/administração & dosagem , Ciclofosfamida/uso terapêutico , Doxorrubicina/administração & dosagem , Doxorrubicina/uso terapêutico , Feminino , Humanos , Pessoa de Meia-Idade , Músculo Esquelético/irrigação sanguínea , Músculo Esquelético/inervação , Nervo Fibular/fisiologiaRESUMO
PURPOSE: We tested the hypothesis that (i) diet associated with exercise would improve arterial baroreflex (ABR) control in metabolic syndrome (MetS) patients with and without obstructive sleep apnea (OSA) and (ii) the effects of this intervention would be more pronounced in patients with OSA. METHODS: Forty-six MetS patients without (noOSA) and with OSA (apnea-hypopnea index, AHI > 15 events/h) were allocated to no treatment (control, C) or hypocaloric diet (- 500 kcal/day) associated with exercise (40 min, bicycle exercise, 3 times/week) for 4 months (treatment, T), resulting in four groups: noOSA-C (n = 10), OSA-C (n = 12), noOSA-T (n = 13), and OSA-T (n = 11). Muscle sympathetic nerve activity (MSNA), beat-to-beat BP, and spontaneous arterial baroreflex function of MSNA (ABRMSNA, gain and time delay) were assessed at study entry and end. RESULTS: No significant changes occurred in C groups. In contrast, treatment in both patients with and without OSA led to a significant decrease in weight (P < 0.05) and the number of MetS factors (P = 0.03). AHI declined only in the OSA-T group (31 ± 5 to 17 ± 4 events/h, P < 0.05). Systolic BP decreased in both treatment groups, and diastolic BP decreased significantly only in the noOSA-T group. Treatment decreased MSNA in both groups. Compared with baseline, ABRMSNA gain increased in both OSA-T (13 ± 1 vs. 24 ± 2 a.u./mmHg, P = 0.01) and noOSA-T (27 ± 3 vs. 37 ± 3 a.u./mmHg, P = 0.03) groups. The time delay of ABRMSNA was reduced only in the OSA-T group (4.1 ± 0.2 s vs. 2.8 ± 0.3 s, P = 0.04). CONCLUSIONS: Diet associated with exercise improves baroreflex control of sympathetic nerve activity and MetS components in patients with MetS regardless of OSA.
Assuntos
Barorreflexo/fisiologia , Exercício Físico/fisiologia , Síndrome Metabólica/terapia , Apneia Obstrutiva do Sono/terapia , Sistema Nervoso Simpático/fisiopatologia , Adulto , Estudos de Casos e Controles , Dieta Redutora/métodos , Terapia por Exercício/métodos , Feminino , Frequência Cardíaca/fisiologia , Humanos , Masculino , Síndrome Metabólica/complicações , Síndrome Metabólica/dietoterapia , Pessoa de Meia-Idade , Apneia Obstrutiva do Sono/complicações , Apneia Obstrutiva do Sono/dietoterapia , Sistema Nervoso Simpático/metabolismo , Resultado do TratamentoRESUMO
Heart failure (HF) is characterized by decreased exercise capacity, attributable to neurocirculatory and skeletal muscle factors. Cardiac resynchronization therapy (CRT) and exercise training have each been shown to decrease muscle sympathetic nerve activity (MSNA) and increase exercise capacity in patients with HF. We hypothesized that exercise training in the setting of CRT would further reduce MSNA and vasoconstriction and would increase Ca2+-handling gene expression in skeletal muscle in patients with chronic systolic HF. Thirty patients with HF, ejection fraction <35% and CRT for 1 mo, were randomized into two groups: exercise-trained (ET, n = 14) and untrained (NoET, n = 16) groups. The following parameters were compared at baseline and after 4 mo in each group: VÌo2 peak, MSNA (microneurography), forearm blood flow, and Ca2+-handling gene expression in vastus lateralis muscle. After 4 mo, exercise duration and VÌo2 peak were significantly increased in the ET group (P = 0.04 and P = 0.01, respectively), but not in the NoET group. MSNA was significantly reduced in the ET (P = 0.001), but not in NoET, group. Similarly, forearm vascular conductance significantly increased in the ET (P = 0.0004), but not in the NoET, group. The expression of the Na+/Ca2+ exchanger (P = 0.01) was increased, and ryanodine receptor expression was preserved in ET compared with NoET. In conclusion, the exercise training in the setting of CRT improves exercise tolerance and neurovascular control and alters Ca2+-handling gene expression in the skeletal muscle of patients with systolic HF. These findings highlight the importance of including exercise training in the treatment of patients with HF even following CRT.
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Cálcio/metabolismo , Terapia de Ressincronização Cardíaca , Terapia por Exercício , Exercício Físico , Insuficiência Cardíaca/terapia , Acoplamento Neurovascular , Músculo Quadríceps/metabolismo , Sistema Nervoso Simpático/metabolismo , Ecocardiografia , Teste de Esforço , Tolerância ao Exercício , Feminino , Antebraço/irrigação sanguínea , Expressão Gênica , Insuficiência Cardíaca/genética , Humanos , Masculino , Pessoa de Meia-Idade , Músculo Esquelético/inervação , Músculo Esquelético/metabolismo , Consumo de Oxigênio , Músculo Quadríceps/inervação , RNA Mensageiro/metabolismo , Fluxo Sanguíneo Regional , Canal de Liberação de Cálcio do Receptor de Rianodina/genética , Trocador de Sódio e Cálcio/genéticaRESUMO
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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Pressão Arterial , Barorreflexo , Sistema Cardiovascular/inervação , Terapia por Exercício , Insuficiência Cardíaca/terapia , Músculo Esquelético/inervação , Sistema Nervoso Simpático/fisiopatologia , Adulto , Idoso , Ciclismo , Brasil , Doença Crônica , Terapia por Exercício/métodos , Feminino , Insuficiência Cardíaca/diagnóstico , Insuficiência Cardíaca/fisiopatologia , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de Tempo , Resultado do TratamentoRESUMO
Previous studies have demonstrated that muscle mechanoreflex and metaboreflex controls are altered in heart failure (HF), which seems to be due to changes in cyclooxygenase (COX) pathway and changes in receptors on afferent neurons, including transient receptor potential vanilloid type-1 (TRPV1) and cannabinoid receptor type-1 (CB1). The purpose of the present study was to test the hypotheses: 1) exercise training (ET) alters the muscle metaboreflex and mechanoreflex control of muscle sympathetic nerve activity (MSNA) in HF patients. 2) The alteration in metaboreflex control is accompanied by increased expression of TRPV1 and CB1 receptors in skeletal muscle. 3) The alteration in mechanoreflex control is accompanied by COX-2 pathway in skeletal muscle. Thirty-four consecutive HF patients with ejection fractions <40% were randomized to untrained (n = 17; 54 ± 2 yr) or exercise-trained (n = 17; 56 ± 2 yr) groups. MSNA was recorded by microneurography. Mechanoreceptors were activated by passive exercise and metaboreceptors by postexercise circulatory arrest (PECA). COX-2 pathway, TRPV1, and CB1 receptors were measured in muscle biopsies. Following ET, resting MSNA was decreased compared with untrained group. During PECA (metaboreflex), MSNA responses were increased, which was accompanied by the expression of TRPV1 and CB1 receptors. During passive exercise (mechanoreflex), MSNA responses were decreased, which was accompanied by decreased expression of COX-2, prostaglandin-E2 receptor-4, and thromboxane-A2 receptor and by decreased in muscle inflammation, as indicated by increased miRNA-146 levels and the stable NF-κB/IκB-α ratio. In conclusion, ET alters muscle metaboreflex and mechanoreflex control of MSNA in HF patients. This alteration with ET is accompanied by alteration in TRPV1 and CB1 expression and COX-2 pathway and inflammation in skeletal muscle.
Assuntos
Terapia por Exercício , Insuficiência Cardíaca/metabolismo , Insuficiência Cardíaca/terapia , Músculo Esquelético/metabolismo , Músculo Esquelético/fisiopatologia , Reflexo/fisiologia , Adulto , Idoso , Doença Crônica , Ciclo-Oxigenase 2/fisiologia , Teste de Esforço , Feminino , Insuficiência Cardíaca/fisiopatologia , Humanos , Masculino , Pessoa de Meia-Idade , Receptor CB1 de Canabinoide/biossíntese , Transdução de Sinais/fisiologia , Volume Sistólico/fisiologia , Sistema Nervoso Simpático/fisiopatologia , Canais de Cátion TRPV/biossínteseRESUMO
The incidence and strength of muscle sympathetic nerve activity (MSNA) depend on the magnitude (gain) and latency (time delay) of the arterial baroreflex control (ABR). However, the impact of metabolic syndrome (MetS) and obstructive sleep apnea (OSA) on oscillatory pattern of MSNA and time delay of the ABR of sympathetic activity is unknown. We tested the hypothesis that MetS and OSA would impair the oscillatory pattern of MSNA and the time delay of the ABR of sympathetic activity. Forty-three patients with MetS were allocated into two groups according to the presence of OSA (MetS + OSA, n = 21; and MetS - OSA, n = 22). Twelve aged-paired healthy controls (C) were also studied. OSA (apnea-hypopnea index > 15 events/h) was diagnosed by polysomnography. We recorded MSNA (microneurography), blood pressure (beat-to-beat basis), and heart rate (EKG). Oscillatory pattern of MSNA was evaluated by autoregressive spectral analysis and the ABR of MSNA (ABRMSNA, sensitivity and time delay) by bivariate autoregressive analysis. Patients with MetS + OSA had decreased oscillatory pattern of MSNA compared with MetS - OSA (P < 0.01) and C (P < 0.001). The sensitivity of the ABRMSNA was lower and the time delay was greater in MetS + OSA compared with MetS - OSA (P < 0.001 and P < 0.01, respectively) and C (P < 0.001 and P < 0.001, respectively). Patients with MetS - OSA showed decreased oscillatory pattern of MSNA compared with C (P < 0.01). The sensitivity of the ABRMSNA was lower in MetS - OSA than in C group (P < 0.001). In conclusion, MetS decreases the oscillatory pattern of MSNA and the magnitude of the ABRMSNA. OSA exacerbates these autonomic dysfunctions and further increases the time delay of the baroreflex response of MSNA.
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Barorreflexo/fisiologia , Síndrome Metabólica/fisiopatologia , Tempo de Reação , Apneia Obstrutiva do Sono/fisiopatologia , Sistema Nervoso Simpático/fisiopatologia , Adulto , Pressão Sanguínea , Estudos de Casos e Controles , Feminino , Frequência Cardíaca , Humanos , Masculino , Pessoa de Meia-Idade , Polissonografia , Apneia Obstrutiva do Sono/diagnósticoRESUMO
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.
Assuntos
Ansiedade/complicações , Sistema Nervoso Autônomo/fisiopatologia , Sistema Cardiovascular/fisiopatologia , Síndrome Metabólica/complicações , Síndrome Metabólica/fisiopatologia , Transtornos do Humor/complicações , Adulto , Ansiedade/epidemiologia , Ansiedade/fisiopatologia , Doenças do Sistema Nervoso Autônomo/epidemiologia , Doenças do Sistema Nervoso Autônomo/etiologia , Doenças do Sistema Nervoso Autônomo/fisiopatologia , Barorreflexo/fisiologia , Pressão Sanguínea/fisiologia , Doenças Cardiovasculares/epidemiologia , Doenças Cardiovasculares/etiologia , Doenças Cardiovasculares/fisiopatologia , Sistema Cardiovascular/inervação , Estudos de Casos e Controles , Feminino , Frequência Cardíaca/fisiologia , Humanos , Masculino , Pessoa de Meia-Idade , Transtornos do Humor/epidemiologia , Transtornos do Humor/fisiopatologia , Fatores de Risco , Sistema Nervoso Simpático/fisiopatologiaRESUMO
BACKGROUND: Exercise training improves physical capacity in patients with heart failure with reduced ejection fraction (HFrEF), but the mechanisms involved in this response is not fully understood. The aim of this study was to determine if physical capacity increase in patients HFrEF is associated with muscle sympathetic nerve activity (MSNA) reduction and muscle blood flow (MBF) increase. METHODS: The study included 124 patients from a 17-year database, divided according to exercise training status: 1) exercise-trained (ET, n = 83) and 2) untrained (UNT, n = 41). MSNA and MBF were obtained using microneurography and venous occlusion plethysmography, respectively. Physical capacity was evaluated by cardiopulmonary exercise test. Moderate aerobic exercise was performed 3 times/wk. for 4 months. RESULTS: Exercise training increased peak oxygen consumption (VÌO2, 16.1 ± 0.4 vs 18.9 ± 0.5 mL·kg-1·min-1, P < 0.001), LVEF (28 ± 1 vs 30 ± 1%, P = 0.027), MBF (1.57 ± 0.06 vs 2.05 ± 0.09 mL.min-1.100 ml-1, P < 0.001) and muscle vascular conductance (MVC, 1.82 ± 0.07 vs 2.45 ± 0.11 units, P < 0.001). Exercise training significantly decreased MSNA (45 ± 1 vs 32 ± 1 bursts/min, P < 0.001). The logistic regression analyses showed that MSNA [(OR) 0.921, 95% CI 0.883-0.962, P < 0.001] was independently associated with peak VÌO2. CONCLUSIONS: The increase in physical capacity provoked by aerobic exercise in patients with HFrEF is associated with the improvement in MSNA.
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Insuficiência Cardíaca , Humanos , Insuficiência Cardíaca/diagnóstico , Insuficiência Cardíaca/terapia , Músculo Esquelético , Volume Sistólico , Exercício Físico , Terapia por Exercício , Sistema Nervoso Simpático , Pressão SanguíneaRESUMO
INTRODUCTION: Exaggerated blood pressure response to exercise (EEBP = SBP ≥ 190 mmHg for women and ≥210 mmHg for men) during cardiopulmonary exercise test (CPET) is a predictor of cardiovascular risk. Sympathetic hyperactivation and decreased baroreflex sensitivity (BRS) seem to be involved in the progression of metabolic syndrome (MetS) to cardiovascular disease. OBJECTIVE: To test the hypotheses: (1) MetS patients within normal clinical blood pressure (BP) may present EEBP response to maximal exercise and (2) increased muscle sympathetic nerve activity (MSNA) and reduced BRS are associated with this impairment. METHODS: We selected MetS (ATP III) patients with normal BP (MetS_NT, n = 27, 59.3% males, 46.1 ± 7.2 years) and a control group without MetS (C, n = 19, 48.4 ± 7.4 years). We evaluated BRS for increases (BRS+) and decreases (BRS-) in spontaneous BP and HR fluctuations, MSNA (microneurography), BP from ambulatory blood pressure monitoring (ABPM), and auscultatory BP during CPET. RESULTS: Normotensive MetS (MetS_NT) had higher body mass index and impairment in all MetS risk factors when compared to the C group. MetS_NT had higher peak systolic BP (SBP) (195 ± 17 vs. 177 ± 24 mmHg, P = 0.007) and diastolic BP (91 ± 11 vs. 79 ± 10 mmHg, P = 0.001) during CPET than C. Additionally, we found that MetS patients with normal BP had lower spontaneous BRS- (9.6 ± 3.3 vs. 12.2 ± 4.9 ms/mmHg, P = 0.044) and higher levels of MSNA (29 ± 6 vs. 18 ± 4 bursts/min, P < 0.001) compared to C. Interestingly, 10 out of 27 MetS_NT (37%) showed EEBP (MetS_NT+), whereas 2 out of 19 C (10.5%) presented (P = 0.044). The subgroup of MetS_NT with EEBP (MetS_NT+, n = 10) had similar MSNA (P = 0.437), but lower BRS+ (P = 0.039) and BRS- (P = 0.039) compared with the subgroup without EEBP (MetS_NT-, n = 17). Either office BP or BP from ABPM was similar between subgroups MetS_NT+ and MetS_NT-, regardless of EEBP response. In the MetS_NT+ subgroup, there was an association of peak SBP with BRS- (R = -0.70; P = 0.02), triglycerides with peak SBP during CPET (R = 0.66; P = 0.039), and of triglycerides with BRS- (R = 0.71; P = 0.022). CONCLUSION: Normotensive MetS patients already presented higher peak systolic and diastolic BP during maximal exercise, in addition to sympathetic hyperactivation and decreased baroreflex sensitivity. The EEBP in MetS_NT with apparent well-controlled BP may indicate a potential depressed neural baroreflex function, predisposing these patients to increased cardiovascular risk.
RESUMO
Sympathetic hyperactivation and baroreflex dysfunction are hallmarks of heart failure with reduced ejection fraction (HFrEF). However, it is unknown whether the progressive loss of phasic activity of sympathetic nerve bursts is associated with baroreflex dysfunction in HFrEF patients. Therefore, we investigated the association between the oscillatory pattern of muscle sympathetic nerve activity (LFMSNA/HFMSNA) and the gain and coupling of the sympathetic baroreflex function in HFrEF patients. In a sample of 139 HFrEF patients, two groups were selected according to the level of LFMSNA/HFMSNA index: (1) Lower LFMSNA/HFMSNA (lower terciles, n = 46, aged 53 ± 1 y) and (2) Higher LFMSNA/HFMSNA (upper terciles, n = 47, aged 52 ± 2 y). Heart rate (ECG), arterial pressure (oscillometric method), and muscle sympathetic nerve activity (microneurography) were recorded for 10 min in patients while resting. Spectral analysis of muscle sympathetic nerve activity was conducted to assess the LFMSNA/HFMSNA, and cross-spectral analysis between diastolic arterial pressure, and muscle sympathetic nerve activity was conducted to assess the sympathetic baroreflex function. HFrEF patients with lower LFMSNA/HFMSNA had reduced left ventricular ejection fraction (26 ± 1 vs. 29 ± 1%, P = 0.03), gain (0.15 ± 0.03 vs. 0.30 ± 0.04 a.u./mmHg, P < 0.001) and coupling of sympathetic baroreflex function (0.26 ± 0.03 vs. 0.56 ± 0.04%, P < 0.001) and increased muscle sympathetic nerve activity (48 ± 2 vs. 41 ± 2 bursts/min, P < 0.01) and heart rate (71 ± 2 vs. 61 ± 2 bpm, P < 0.001) compared with HFrEF patients with higher LFMSNA/HFMSNA. Further analysis showed an association between the LFMSNA/HFMSNA with coupling of sympathetic baroreflex function (R = 0.56, P < 0.001) and left ventricular ejection fraction (R = 0.23, P = 0.02). In conclusion, there is a direct association between LFMSNA/HFMSNA and sympathetic baroreflex function and muscle sympathetic nerve activity in HFrEF patients. This finding has clinical implications, because left ventricular ejection fraction is less in the HFrEF patients with lower LFMSNA/HFMSNA.
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Allele T at promoter region of the eNOS gene has been associated with an increase in coronary disease mortality, suggesting that this allele increases susceptibility for endothelial dysfunction. In contrast, exercise training improves endothelial function. Thus, we hypothesized that: 1) Muscle vasodilatation during exercise is attenuated in individuals homozygous for allele T, and 2) Exercise training improves muscle vasodilatation in response to exercise for TT genotype individuals. From 133 preselected healthy individuals genotyped for the T786C polymorphism, 72 participated in the study: TT (n = 37; age 27 ± 1 yr) and CT+CC (n = 35; age 26 ± 1 yr). Forearm blood flow (venous occlusion plethysmography) and blood pressure (oscillometric automatic cuff) were evaluated at rest and during 30% handgrip exercise. Exercise training consisted of three sessions per week for 18 wk, with intensity between anaerobic threshold and respiratory compensation point. Resting forearm vascular conductance (FVC, P = 0.17) and mean blood pressure (P = 0.70) were similar between groups. However, FVC responses during handgrip exercise were significantly lower in TT individuals compared with CT+CC individuals (0.39 ± 0.12 vs. 1.08 ± 0.27 units, P = 0.01). Exercise training significantly increased peak VO(2) in both groups, but resting FVC remained unchanged. This intervention significantly increased FVC response to handgrip exercise in TT individuals (P = 0.03), but not in CT+CC individuals (P = 0.49), leading to an equivalent FVC response between TT and CT+CC individuals (1.05 ± 0.18 vs. 1.59 ± 0.27 units, P = 0.27). In conclusion, exercise training improves muscle vasodilatation in response to exercise in TT genotype individuals, demonstrating that genetic variants influence the effects of interventions such as exercise training.
Assuntos
Exercício Físico/fisiologia , Músculo Esquelético/irrigação sanguínea , Óxido Nítrico Sintase Tipo III/genética , Vasodilatação/fisiologia , Adolescente , Adulto , Feminino , Genótipo , Frequência Cardíaca/genética , Frequência Cardíaca/fisiologia , Humanos , Masculino , Vasodilatação/genética , Adulto JovemRESUMO
STUDY OBJECTIVES: Metabolic syndrome (MetSyn) increases overall cardiovascular risk. MetSyn is also strongly associated with obstructive sleep apnea (OSA), and these 2 conditions share similar comorbidities. Whether OSA increases cardiovascular risk in patients with the MetSyn has not been investigated. We examined how the presence of OSA in patients with MetSyn affected hemodynamic and autonomic variables associated with poor cardiovascular outcome. DESIGN: Prospective clinical study. PARTICIPANTS: We studied 36 patients with MetSyn (ATP-III) divided into 2 groups matched for age and sex: (1) MetSyn+OSA (n = 18) and (2) MetSyn-OSA (n = 18). MEASUREMENTS: OSA was defined by an apnea-hypopnea index (AHI) > 15 events/hour by polysomnography. We recorded muscle sympathetic nerve activity (MSNA - microneurography), heart rate (HR), and blood pressure (BP - Finapres). Baroreflex sensitivity (BRS) was analyzed by spontaneous BP and HR fluctuations. RESULTS: MSNA (34 +/- 2 vs 28 +/- 1 bursts/min, P = 0.02) and mean BP (111 +/- 3 vs. 99 +/- 2 mm Hg, P = 0.003) were higher in patients with MetSyn+OSA versus patients with MetSyn-OSA. Patients with MetSyn+OSA had lower spontaneous BRS for increases (7.6 +/- 0.6 vs 12.2 +/- 1.2 msec/mm Hg, P = 0.003) and decreases (7.2 +/- 0.6 vs 11.9 +/- 1.6 msec/mm Hg, P = 0.01) in BP. MSNAwas correlated with AHI (r = 0.48; P = 0.009) and minimum nocturnal oxygen saturation (r = -0.38, P = 0.04). CONCLUSION: Patients with MetSyn and comorbid OSA have higher BP, higher sympathetic drive, and diminished BRS, compared with patients with MetSyn without OSA. These adverse cardiovascular and autonomic consequences of OSA may be associated with poorer outcomes in these patients. Moreover, increased BP and sympathetic drive in patients with MetSyn+OSA may be linked, in part, to impairment of baroreflex gain.
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Doenças Cardiovasculares/etiologia , Síndrome Metabólica/complicações , Síndrome Metabólica/fisiopatologia , Apneia Obstrutiva do Sono/complicações , Apneia Obstrutiva do Sono/fisiopatologia , Adulto , Barorreflexo , Pressão Sanguínea , Estudos de Casos e Controles , Estudos de Coortes , Feminino , Frequência Cardíaca , Humanos , Masculino , Síndrome Metabólica/metabolismo , Pessoa de Meia-Idade , Consumo de Oxigênio , Fatores de Risco , Apneia Obstrutiva do Sono/metabolismo , VasodilataçãoRESUMO
BACKGROUND: Forearm blood flow responses during mental stress are greater in individuals homozygous for the Glu27 allele. A high-fat meal is associated with impaired endothelium-dependent dilatation. We investigated the impact of high-fat ingestion on the muscle vasodilatory responses during mental stress in individuals with the Glu27 allele and those with the Gln27 allele of the beta2-adrenoceptor gene. METHODS: A total of 162 preselected individuals were genotyped for the Glu27Gln beta2-adrenoceptor polymorphism. Twenty-four individuals participated in the study. Fourteen were homozygous for the Gln27 allele (Gln27Gln, 40 +/- 2 years; 64 +/- 2 kg), and 10 were homozygous for the Glu27 allele (Glu27Glu, 40 +/- 3 years; 65 +/- 3 kg). Forearm blood flow was evaluated by venous occlusion plethysmography before and after ingestion of 62 g of fat. RESULTS: The high-fat meal caused no changes in baseline forearm vascular conductance (FVC, 2.2 +/- 0.1 vs. 2.4 +/- 0.2; P = 0.27, respectively), but reduced FVC responses to mental stress (1.5 +/- 0.2 vs. 0.8 +/- 0.2 units; P = 0.04). When volunteers were divided according to their genotypes, baseline FVC was not different between groups (Glu27Glu = 2.4 +/- 0.1 vs. Gln27Gln = 2.1 +/- 0.1 units; P = 0.08), but it was significantly greater in Glu27Glu individuals during mental stress (1.9 +/- 0.4 vs. 1.0 +/- 0.3 units; P = 0.04). High-fat intake eliminated the difference in FVC responses between Glu27Glu and Gln27Gln individuals (FVC, 1.3 +/- 0.4 vs. 1.2 +/- 0.4; P = 0.66, respectively). CONCLUSION: These findings demonstrate that a high-fat meal impairs muscle vasodilatation responses to mental stress in humans. However, this reduction can be attributed to the presence of the homozygous Glu27 allele of the beta2-adrenoceptor gene.
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Gorduras na Dieta/farmacologia , Músculo Esquelético/irrigação sanguínea , Polimorfismo Genético , Receptores Adrenérgicos beta 2/genética , Estresse Psicológico/fisiopatologia , Vasodilatação/fisiologia , Adulto , Gorduras na Dieta/administração & dosagem , Genótipo , Humanos , Fluxo Sanguíneo Regional , Vasodilatação/efeitos dos fármacosRESUMO
The influence of Glu298Asp endothelial nitric oxide synthase (eNOS) polymorphism in exercise-induced reflex muscle vasodilatation is unknown. We hypothesized that nonexercising forearm blood flow (FBF) responses during handgrip isometric exercise would be attenuated in individuals carrying the Asp298 allele. In addition, these responses would be mediated by reduced eNOS function and NO-mediated vasodilatation or sympathetic vasoconstriction. From 287 volunteers previously genotyped, we selected 33 healthy individuals to represent three genotypes: Glu/Glu [n = 15, age 43 +/- 3 yr, body mass index (BMI) 22.9 +/- 0.3 kg/m(2)], Glu/Asp (n = 9, age 41 +/- 3 yr, BMI 23.7 +/- 1.0 kg/m(2)), and Asp/Asp (n = 9, age 40 +/- 4 yr, BMI 23.5 +/- 0.9 kg/m(2)). Heart rate (HR), mean blood pressure (MBP), and FBF (plethysmography) were recorded for 3 min at baseline and 3 min during isometric handgrip exercise. Baseline HR, MBP, FBF, and forearm vascular conductance (FVC) were similar among genotypes. FVC responses to exercise were significantly lower in Asp/Asp when compared with Glu/Asp and Glu/Glu (Delta = 0.07 +/- 0.14 vs. 0.64 +/- 0.20 and 0.57 +/- 0.09 units, respectively; P = 0.002). Further studies showed that intra-arterial infusion of NG-monomethyl-L-arginine (L-NMMA) did not change FVC responses to exercise in Asp/Asp, but significantly reduced FVC in Glu/Glu (Delta = 0.79 +/- 0.14 vs. 0.14 +/- 0.09 units). Thus the differences between Glu/Glu and Asp/Asp were no longer observed (P = 0.62). l-NMMA + phentolamine increased similarly FVC responses to exercise in Glu/Glu and Asp/Asp (P = 0.43). MBP and muscle sympathetic nerve activity increased significant and similarly throughout experimental protocols in Glu/Glu and Asp/Asp. Individuals who are homozygous for the Asp298 allele of the eNOS enzyme have attenuated nonexercising muscle vasodilatation in response to exercise. This genotype difference is due to reduced eNOS function and NO-mediated vasodilatation, but not sympathetic vasoconstriction.
Assuntos
Exercício Físico/fisiologia , Contração Isométrica/fisiologia , Óxido Nítrico Sintase Tipo III/genética , Polimorfismo Genético , Adulto , Substituição de Aminoácidos , Análise de Variância , Pressão Sanguínea , Índice de Massa Corporal , Inibidores Enzimáticos/administração & dosagem , Inibidores Enzimáticos/farmacologia , Feminino , Antebraço/irrigação sanguínea , Frequência do Gene , Genótipo , Força da Mão/fisiologia , Frequência Cardíaca , Humanos , Infusões Intra-Arteriais , Contração Isométrica/efeitos dos fármacos , Masculino , Pessoa de Meia-Idade , Óxido Nítrico Sintase Tipo III/antagonistas & inibidores , Vasodilatação/efeitos dos fármacos , ômega-N-Metilarginina/administração & dosagem , ômega-N-Metilarginina/farmacologiaRESUMO
Heart failure (HF) is a complex syndrome representing the clinical endpoint of many cardiovascular diseases of different etiology. Given its prevalence, incidence and social impact, a better understanding of HF pathophysiology is paramount to implement more effective anti-HF therapies. Based on left ventricle (LV) performance, HF is currently classified as follows: (1) with reduced ejection fraction (HFrEF); (2) with mid-range EF (HFmrEF); and (3) with preserved EF (HFpEF). A central tenet of HFrEF pathophysiology is adrenergic hyperactivity, featuring increased sympathetic nerve discharge and a progressive loss of rhythmical sympathetic oscillations. The role of reflex mechanisms in sustaining adrenergic abnormalities during HFrEF is increasingly well appreciated and delineated. However, the same cannot be said for patients affected by HFpEF or HFmrEF, whom also present with autonomic dysfunction. Neural mechanisms of cardiovascular regulation act as "controller units," detecting and adjusting for changes in arterial blood pressure, blood volume, and arterial concentrations of oxygen, carbon dioxide and pH, as well as for humoral factors eventually released after myocardial (or other tissue) ischemia. They do so on a beat-to-beat basis. The central dynamic integration of all these afferent signals ensures homeostasis, at rest and during states of physiological or pathophysiological stress. Thus, the net result of information gathered by each controller unit is transmitted by the autonomic branch using two different codes: intensity and rhythm of sympathetic discharges. The main scope of the present article is to (i) review the key neural mechanisms involved in cardiovascular regulation; (ii) discuss how their dysfunction accounts for the hyperadrenergic state present in certain forms of HF; and (iii) summarize how sympathetic efferent traffic reveal central integration among autonomic mechanisms under physiological and pathological conditions, with a special emphasis on pathophysiological characteristics of HF.
RESUMO
BACKGROUND: Gln27Glu (rs1042714) polymorphism of the ß2-adrenergic receptor (ADRB2) has been association with cardiovascular functionality in healthy subjects. However, it is unknown whether the presence of the ADRB2 Gln27Glu polymorphism influences neurovascular responses during exercise in patients with acute coronary syndromes (ACS). We tested the hypothesis that patients with ACS homozygous for the Gln allele would have increased muscle sympathetic nerve activity (MSNA) responses and decreased forearm vascular conductance (FVC) responses during exercise compared with patients carrying the Glu allele (Gln27Glu and Glu27Glu). In addition, exercise training would restore these responses in Gln27Gln patients. METHODS AND RESULTS: Thirty-days after an ischemic event, 61 patients with ACS without ventricular dysfunction were divided into 2 groups: (1) Gln27Gln (n = 35, 53±1years) and (2) Gln27Glu+Glu27Glu (n = 26, 52±2years). MSNA was directly measured using the microneurography technique, blood pressure (BP) was measured with an automatic oscillometric device, and blood flow was measured using venous occlusion plethysmography. MSNA, mean BP, and FVC were evaluated at rest and during a 3-min handgrip exercise. The MSNA (P = 0.02) and mean BP (P = 0.04) responses during exercise were higher in the Gln27Gln patients compared with that in the Gln27Glu+Glu27Glu patients. No differences were found in FVC. Two months of exercise training significantly decreased the MSNA levels at baseline (P = 0.001) and in their response during exercise (P = 0.02) in Gln27Gln patients, but caused no changes in Gln27Glu+Glu27Glu patients. Exercise training increased FVC responses in Gln27Glu+Glu27Glu patients (P = 0.03), but not in Gln27Gln patients. CONCLUSION: The exaggerated MSNA and mean BP responses during exercise suggest an increased cardiovascular risk in patients with ACS and Gln27Gln polymorphism. Exercise training emerges as an important strategy for restoring this reflex control. Gln27Glu polymorphism of ADRB2 influences exercise-induced vascular adaptation in patients with ACS.
Assuntos
Síndrome Coronariana Aguda/genética , Antebraço/irrigação sanguínea , Receptores Adrenérgicos beta 2/genética , Sistema Vasomotor , Síndrome Coronariana Aguda/fisiopatologia , Síndrome Coronariana Aguda/terapia , Terapia por Exercício , Feminino , Frequência do Gene , Estudos de Associação Genética , Força da Mão , Humanos , Masculino , Pessoa de Meia-Idade , Contração Muscular , Polimorfismo de Nucleotídeo Único , Fatores de RiscoRESUMO
Metabolic syndrome (MetS) causes autonomic alteration and vascular dysfunction. The authors investigated whether impaired fasting glucose (IFG) is the main cause of vascular dysfunction via elevated sympathetic tone in nondiabetic patients with MetS. Pulse wave velocity, muscle sympathetic nerve activity (MSNA), and forearm vascular resistance was measured in patients with MetS divided according to fasting glucose levels: (1) MetS+IFG (blood glucose ≥100 mg/dL) and (2) MetS-IFG (<100 mg/dL) compared with healthy controls. Patients with MetS+IFG had higher pulse wave velocity than patients with MetS-IFG and controls (median 8.0 [interquartile range, 7.2-8.6], 7.3 [interquartile range, 6.9-7.9], and 6.9 [interquartile range, 6.6-7.2] m/s, P=.001). Patients with MetS+IFG had higher MSNA than patients with MetS-IFG and controls, and patients with MetS-IFG had higher MSNA than controls (31±1, 26±1, and 19±1 bursts per minute; P<.001). Patients with MetS+IFG were similar to patients with MetS-IFG but had higher forearm vascular resistance than controls (P=.008). IFG was the only predictor variable of MSNA. MSNA was associated with pulse wave velocity (R=.39, P=.002) and forearm vascular resistance (R=.30, P=.034). In patients with MetS, increased plasma glucose levels leads to an adrenergic burden that can explain vascular dysfunction.
Assuntos
Glicemia/análise , Intolerância à Glucose/complicações , Síndrome Metabólica/fisiopatologia , Sistema Nervoso Simpático/fisiopatologia , Glicemia/metabolismo , Feminino , Intolerância à Glucose/epidemiologia , Intolerância à Glucose/fisiopatologia , Humanos , Resistência à Insulina , Masculino , Síndrome Metabólica/complicações , Síndrome Metabólica/epidemiologia , Pessoa de Meia-Idade , Estado Pré-Diabético/complicações , Estudos Prospectivos , Análise de Onda de Pulso/métodos , Fatores de Risco , Resistência Vascular/fisiologia , Rigidez Vascular/fisiologia , Circunferência da CinturaRESUMO
BACKGROUND: Muscle metaboreflex control in hypertensive subjects has not been described yet. We investigated the integrity of muscle metaboreflex control of muscle sympathetic nerve activity (MSNA) and blood pressure (BP) in never-treated hypertensive subjects. METHODS: Eighteen hypertensive (42+/-1 years) and 22 normotensive subjects (38+/-1 years) were studied. The MSNA was measured by microneurography and forearm blood flow (FBF) by venous occlusion plethysmography. The BP was noninvasively monitored. RESULTS: Baseline MSNA was significantly increased in hypertensive subjects when compared with normal subjects (34+/-2 v 22+/-2 bursts/min, P<.001). Baseline FBF was significantly decreased in hypertensive subjects (2.66+/-0.2 v 2.05+/-0.1 mL/min/100 mL, P=.04). During moderate handgrip exercise (30% maximal voluntary contraction), MSNA levels were significantly higher in hypertensive subjects. However, MSNA responses were significantly lower in hypertensive subjects (1+/-3 v 10+/-2 bursts/100 heart beats, P = .001). Similarly, FBF responses were significantly lower in hypertensive subjects when compared with normotensive subjects (0.70+/-0.19 v 1.60+/-0.36 mL/min/100 mL, P=.04). During the postexercise circulatory arrest, when the metaboreflex control is isolated, MSNA levels returned toward baseline in hypertensive subjects (58+/-4 v 55+/-3 bursts/100 heart beats, P=.98). In contrast, in normotensive subjects, MSNA levels remained significantly elevated when compared with baseline (48+/-3 v 35+/-1 bursts/100 heart beats, P<.001). CONCLUSIONS: These findings suggest an association between hypertension and decreased muscle metaboreflex control of MSNA.
Assuntos
Barorreflexo , Hipertensão/fisiopatologia , Músculo Esquelético/fisiopatologia , Sistema Nervoso Simpático/fisiopatologia , Adulto , Análise de Variância , Pressão Sanguínea , Estudos de Casos e Controles , Fatores de Confusão Epidemiológicos , Exercício Físico , Feminino , Antebraço/irrigação sanguínea , Força da Mão , Frequência Cardíaca , Humanos , Hipertensão/epidemiologia , Masculino , Contração Muscular , Pletismografia , Fluxo Sanguíneo Regional , VasodilataçãoRESUMO
OBJECTIVE: To analyze the predictive value of respiratory, metabolic, and hemodynamic variables obtained during the cardiopulmonary stress test for the risk of death in patients with heart failure. METHODS: Eighty-seven NYHA Functional Class II and III patients were analyzed, ages 51 +/- 0.5 years, 26 of them with Chagas' disease, 30 with coronary ischemia, and 31 with idiopathic etiology. The cardiopulmonary stress test consisted of a ramp-protocol with 5 to 15 W/min workload increments performed on a bicycle-ergonometer until exhaustion. RESULTS: In this study, the multiple Cox regression analysis of age, height, weight, body surface, and gender showed that these parameters were not statistically significant control factors. Oxygen uptake, ventilatory equivalent of oxygen, ventilatory equivalent of carbon dioxide production, oxygen pulse, and end-tidal partial pressure of carbon dioxide at the anaerobic threshold, respiratory compensation point, and peak exercise proved to be important death predictors in heart failure patients. The relationship between the increase in carbon dioxide output as a function of the increase in minute ventilation, and the association between the oxygen uptake increase and the elevation of the workload from the beginning of exercise to the anaerobic threshold were statistically significant predictors of death in heart failure patients (p<0.05). CONCLUSION: The cardiopulmonary stress test makes it possible to evaluate ventilatory, metabolic, and hemodynamic variables that may be utilized as important markers of life prognosis in these patients.
Assuntos
Dióxido de Carbono/fisiologia , Baixo Débito Cardíaco/mortalidade , Teste de Esforço , Consumo de Oxigênio/fisiologia , Troca Gasosa Pulmonar/fisiologia , Baixo Débito Cardíaco/fisiopatologia , Ecocardiografia Doppler , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Prognóstico , Medição de Risco , Índice de Gravidade de DoençaRESUMO
OBJECTIVES: The goal of this study was to test the hypothesis that exercise training reduces resting sympathetic neural activation in patients with chronic advanced heart failure. BACKGROUND: Exercise training in heart failure has been shown to be beneficial, but its mechanisms of benefit remain unknown. METHODS: Sixteen New York Heart Association class II to III heart failure patients, age 35 to 60 years, ejection fraction < or =40% were divided into two groups: 1) exercise-trained (n = 7), and 2) sedentary control (n = 9). A normal control exercise-trained group was also studied (n = 8). The four-month supervised exercise training program consisted of three 60 min exercise sessions per week, at heart rate levels that corresponded up to 10% below the respiratory compensation point. Muscle sympathetic nerve activity (MSNA) was recorded directly from peroneal nerve using the technique of microneurography. Forearm blood flow was measured by venous plethysmography. RESULTS: Baseline MSNA was greater in heart failure patients compared with normal controls; MSNA was uniformly decreased after exercise training in heart failure patients (60 +/- 3 vs. 38 +/- 3 bursts/100 heart beats), and the mean difference in the change was significantly (p < 0.05) greater than the mean difference in the change in sedentary heart failure or trained normal controls. In fact, resting MSNA in trained heart failure patients was no longer significantly greater than in trained normal controls. In heart failure patients, peak VO(2) and forearm blood flow, but not left ventricular ejection fraction, increased after training. CONCLUSIONS: These findings demonstrate that exercise training in heart failure patients results in dramatic reductions in directly recorded resting sympathetic nerve activity. In fact, MSNA was no longer greater than in trained, healthy controls.