Exaggerated Exercise Blood Pressure as a Marker of Baroreflex Dysfunction in Normotensive Metabolic Syndrome Patients.

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.

Effect of exercise training on cardiovascular autonomic and muscular function in subclinical Chagas cardiomyopathy: a randomized controlled trial.

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.

Identifying the risk of obstructive sleep apnea in metabolic syndrome patients: Diagnostic accuracy of the Berlin Questionnaire.

BACKGROUND: Obstructive sleep apnea (OSA) is a risk factor frequently present in patients with metabolic syndrome (MetS). Additionally, moderate and severe OSA are highly prevalent in patients with cardiac disease, as they increase the riskfor cardiovascular events by 80%. The gold standard diagnostic method for OSA is overnight polysomnography (PSG), which remains unaffordable for the overall population. The aim of the present study was to evaluate whether the Berlin Questionnaire (BQ) is anuseful tool for assessing the risk of OSA in patients with MetS. METHODS: 97 patients, previously untreated and recently diagnosed with MetS (National Cholesterol Education Program, Adult Treatment Panel III, ATP-III) underwent a PSG. OSA was characterized by the apnea-hypopnea index (AHI). BQ was administered before PSG and we evaluated sensitivity, specificity, positive and negative predictive values, and accuracy. RESULTS: Of the 97 patients with MetS, 81 patients had OSA, with 47 (48.5%) presenting moderate and severe OSA. For all MetS with OSA (AHI≥5 events/hour), the BQ showed good sensitivity (0.65, 95% CI 0.54 to 0.76) and fair specificity (0.38, 95% CI 0.15-0.65) with a positive predictive value of 0.84, a negative predictive value of 0.18 and an 84% accuracy. Similarly, for moderate-to-severe OSA (AHI≥15 events/hour) we found good sensitivity (0.73, 95% CI 0.58-0.85) and fair specificity (0.40, 95% CI 0.27-0.55). Interestingly, for severe OSA (AHI≥30 events/hour), there was a very good sensitivity (0.91, 95% CI 0.72-0.99) and moderate specificity (0.42, 95% CI 0.31-0.54). CONCLUSION: The BQ is a valid tool for screening the risk of OSA in MetS patients in general, and it is particularly useful in predicting severe OSA.

Diet associated with exercise improves baroreflex control of sympathetic nerve activity in metabolic syndrome and sleep apnea patients.

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.

Exercise Training Improves Heart Rate Recovery after Exercise in Hypertension

Abstract Aim: This study tested the hypothesis that: 1- the exercise training would improve the heart rate recovery (HRR) decline after maximal exercise test in hypertensive patients and; 2- the exercise training would normalize HRR decline when compared to normotensive individuals. Methods: Sixteen hypertensive patients were consecutively allocated into two groups: Exercise-trained (n = 9, 47±2 years) and untrained (n = 7, 42±3 years). An exercise-trained normotensive group (n = 11, 41±2 years) was also studied. Heart rate was evaluated by electrocardiogram. The autonomic function was evaluated based on heart rate changes on the first and the second min of recovery after the maximal exercise test. Exercise training consisted of three 60-minute exercise sessions/week for 4 months. Results: In hypertensive patients, exercise training significantly increased the HRR decline in the first (-19±2 vs. -34±3 bpm, P = 0.001) and second (-33±3 vs. -49±2 bpm, P = 0.006) minutes after the maximal exercise test. In addition, after exercise training, the initial differences in the HRR decline after exercise between hypertensive patients and normotensive individuals were no longer observed (first minute: -34±3 vs. -29±3 bpm, P = 0.52, and second minute: -49±2 vs. -47±4 bpm, P = 0.99). Conclusion: Hypertension causes a delay in HRR after the maximal exercise test yet the exercise training normalizes HRR during the post-exercise period in hypertensive patients.

Predictors of Obstructive Sleep Apnea in Consecutive Patients with Metabolic Syndrome.

BACKGROUND: Recent evidence suggests that obstructive sleep apnea (OSA) is common in patients with metabolic syndrome (MetS) and may contribute to metabolic deregulation, inflammation, and atherosclerosis in these patients. In clinical practice, however, OSA is frequently underdiagnosed. We sought to investigate the clinical predictors of OSA in patients with MetS. METHODS: We studied consecutive patients newly diagnosed with MetS (Adult Treatment Panel-III). All participants underwent clinical evaluation, standard polysomnography, and laboratory measurements. We performed a logistic regression model, including the following variables: gender, age >50 years, neck and waist circumferences, hypertension, diabetes, body mass index (BMI) >30 kg/m2, high risk for OSA by Berlin questionnaire, presence of excessive daytime somnolence (Epworth Sleepiness Scale), abnormal serum glucose, triglycerides, high-density lipoprotein cholesterol, and low-density lipoprotein cholesterol. RESULTS: We studied 197 patients (60% men; age: 49 ± 10 years; BMI: 32.9 ± 5.1 kg/m2). OSA (defined by an apnea-hypopnea index ≥15 events per hour) was diagnosed in 117 patients [59%; 95% confidence interval (CI): 52-66]. In multivariate analysis, male gender [odds ratio (OR): 3.28; 95% CI: 1.68-6.41; P < 0.01], abnormal glucose levels (OR: 3.01; 95% CI: 1.50-6.03; P < 0.01), excessive daytime sleepiness (OR: 2.38; 95% CI: 1.13-5.04; P = 0.02), and high risk for OSA by Berlin questionnaire (OR: 4.33; 95% CI: 2.06-9.11; P < 0.001) were independently associated with OSA. CONCLUSIONS: Simple clinical and metabolic characteristics may help to improve the underdiagnosis of OSA in patients with MetS.

Arterial stiffness and its association with clustering of metabolic syndrome risk factors.

BACKGROUND: Metabolic syndrome (MetS) is associated with structural and functional vascular abnormalities, which may lead to increased arterial stiffness, more frequent cardiovascular events and higher mortality. However, the role played by clustering of risk factors and the combining pattern of MetS risk factors and their association with the arterial stiffness have yet to be fully understood. Age, hypertension and diabetes mellitus seem to be strongly associated with increased pulse wave velocity (PWV). This study aimed at determining the clustering and combining pattern of MetS risk factors and their association with the arterial stiffness in non-diabetic and non-hypertensive patients. METHODS: Recently diagnosed and untreated patients with MetS (n = 64, 49 ± 8 year, 32 ± 4 kg/m2) were selected, according to ATP III criteria and compared to a control group (Control, n = 17, 49 ± 6 year, 27 ± 2 kg/m2). Arterial stiffness was evaluated by PWV in the carotid-femoral segment. Patients were categorized and analyzed according MetS risk factors clustering (3, 4 and 5 factors) and its combinations. RESULTS: Patients with MetS had increased PWV when compared to Control (7.8 ± 1.1 vs. 7.0 ± 0.5 m/s, p < 0.001). In multivariate analysis, the variables that remained as predictors of PWV were age (ß = 0.450, p < 0.001), systolic blood pressure (ß = 0.211, p = 0.023) and triglycerides (ß = 0.212, p = 0.037). The increased number of risk factors reflected in a progressive increase in PWV. When adjusted to systolic blood pressure, PWV was greater in the group with 5 risk factors when compared to the group with 3 risk factors and Control (8.5 ± 0.4 vs. 7.5 ± 0.2, p = 0.011 and 7.2 ± 0.3 m/s, p = 0.012). Similarly, the 4 risk factors group had higher PWV than the Control (7.9 ± 0.2 vs. 7.2 ± 0.3, p = 0.047). CONCLUSIONS: The number of risk factors seems to increase arterial stiffness. Notably, besides age and increased systolic blood pressure, alterations in the triglycerides worsened the stiffness of large vessels, emphasizing the importance in addressing this risk factor in MetS patients.

Prevalence and severity of syndrome Z in women with metabolic syndrome on waiting list for bariatric surgery: a cross-sectional study.

BACKGROUND: In recent years, obesity has become one of the most important public health problems in the world, with a growing prevalence in both developed and developing countries. Recent studies show that sleep disturbances, especially obstructive sleep apnoea (OSA) may be a manifestation of metabolic syndrome (MetS). Although the association of OSA with the MetS is largely attributed to obesity, the exact pathophysiological mechanisms and their individual characteristics still need to be identified. This study investigated the prevalence and severity of syndrome Z in obese women with MetS on waiting list for bariatric surgery. METHODS: In this double-center cross-sectional study, female patients aged ≥18 years, stage III severe obesity with MetS, on waiting list for bariatric surgery were recruited. The diagnosis for MetS was made according to the criteria of the national cholesterol education program, adult treatment panel III. Clinical, anthropometric, demographic, biochemistry, and sleep measurements were collected. Correlations between continuous variables with sleep parameters were performed using the Pearson correlation test or Spearman correlation test. RESULTS: The mean age of 83 patients was 44.8 ± 11.2 years and mean BMI was 42.6 ± 8.1 kg/m2. There was a significant correlation between OSA and metabolic score (r = 0.336; P = 0.002), neck circumference (r = 0.218; P = 0.048), basal systolic blood pressure (r = 0.280; P = 0.01), total cholesterol (r = 0.277; P = 0.011) and abdomen circumference (r = 0.284; P = 0.009). The mean values of excessive daytime sleepiness were 10.5 ± 7 demonstrating a value considered normal for its presence. However, a high risk for OSA was observed in practically the entire population. It was observed that the prevalence of Syndrome Z (75.9%) increased significantly according to apnoea hypopnoea index (AHI) (P for trend <0.0000). A prevalence of 27.71% for mild OSA, 20.48% for moderate OSA, and 27.71% for severe OSA was observed. An association of AHI severity with all components of MetS was also observed. CONCLUSIONS: We can conclude that syndrome Z presents a high prevalence in a female population with MetS and a considerable severity according to the presence of OSA. Therefore, patients with MetS should be investigated for the presence of sleep disorders. Trial registration The study has been registered on ClinicalTrials.gov NCT02409160 and followed the standards of The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) Statement: guidelines for reporting observational studies.

The role of increased glucose on neurovascular dysfunction in patients with the metabolic syndrome.

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.

Cardiac and peripheral autonomic control in restrictive cardiomyopathy.

AIMS: Autonomic dysfunction determines the advance of dilated cardiomyopathy (DCM) and is related to poor outcomes. However, this autonomic imbalance is unknown in patients with restrictive cardiomyopathy (RCM) even though they have similar symptoms and poor quality of life as DCM patients have. The aim of this study was to evaluate if autonomic and neurovascular controls were altered in RCM patients. METHODS AND RESULTS: Fifteen RCM patients, 10 DCM patients, and 10 healthy subjects were evaluated. Heart rate and blood pressure (BP) were recorded. Peripheral sympathetic activity [muscle sympathetic nerve activity (MSNA)] by microneurography and cardiac sympathetic activity by power spectrum analysis of heart rate variability. Spontaneous baroreflex sensitivity (BRS) was evaluated by the sequence method and forearm blood flow by venous occlusion plethysmography. Both cardiomyopathy groups had higher MSNA frequency (P < 0.001) and MSNA incidence (P < 0.001), higher cardiac sympathovagal balance (P < 0.02), reduced BRS for increase (P = 0.002) and for decrease in BP (P = 0.002), and lower forearm blood flow (P < 0.001) compared with healthy subjects. We found an inverse correlation between BRS for increase and decrease in BP and peripheral sympathetic activity (r = -0.609, P = 0.001 and r = -0.648, P < 0.001, respectively) and between BRS for increase and decrease in BP and cardiac sympathetic activity (r = -0.503, P = 0.03 and r = -0.487, P = 0.04, respectively). CONCLUSIONS: The RCM patients had cardiac and peripheral autonomic dysfunctions associated with peripheral vasoconstriction. Nonetheless, the presence of normal ejection fraction underestimates the evolution of the disease and makes clinical treatment difficult. These alterations could lead to a similar cardiovascular risk as that observed in DCM patients.

Muscle Metaboreflex Control of Sympathetic Activity in Obstructive Sleep Apnea.

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.

Neurovascular control during exercise in acute coronary syndrome patients with Gln27Glu polymorphism of ß2-adrenergic receptor.

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.

The Role of Acute Intermittent Hypoxia in Neutrophil-Generated Superoxide, Sympathovagal Balance, and Vascular Function in Healthy Subjects.

Introduction: Recurrent hypoxia (HPX), a hallmark of the obstructive sleep apnea (OSA), impairs autonomic balance, and increases arterial blood pressure (BP). Oxidative stress is one of the mechanisms involved in these alterations. The cumulative effect of acute intermittent HPX and the chronicity may determine whether the response crosses the threshold from having protective value to pathology. However, the impact of acute intermittent HPX-reoxygenation on markers of oxidative stress in healthy individuals remains to be fully understood. Objective: To analyze the effects of the acute intermittent HPX on the generation of neutrophil-derived superoxide, sympathovagal balance, and vascular function in healthy subjects. Methods: We applied six cycles of intermittent HPX (10% O2 and 90% N2) for 5 min followed by 2 min of room-air in 15 healthy volunteers (34 ± 2 years; 22.3 ± 0.46 kg/m2), without OSA (polysomnography), during wakefulness. During the experimental protocol, we recorded O2 saturation, end-tidal CO2, heart rate (HR), systolic, and diastolic BP, cardiac output (CO) and peripheral resistance (PR). Cardiac sympathovagal balance was determined by HR variability analysis (low frequency and high frequency bands, LF/HF). Superoxide generation in polymorphonuclear neutrophil cells were established using relative luminescence units (PMNs RLU) at baseline (pre-HPX) and immediately after hypoxia induction (post-HPX6). Results: The studied subjects had normal levels of BP, plasma glucose, lipid profile, and inflammatory marker (C-reactive protein). Acute intermittent HPX increased HR, systolic BP, CO, and decreased PR. Additionally, acute intermittent HPX increased PMNs RLU, measured post-HPX6 (470 ± 50 vs. 741 ± 135, P < 0.05). We found a similar increase in LF/HF post-HPX6 (0.91 ± 0.11 vs. 2.85 ± 0.40, P < 0.05). PR was diminished from pre-HPX to post-HPX6 (1.0 ± 0.03 vs. 0.85 ± 0.06, P < 0.05). Further analysis showed significant association between O2 saturation and PMNs RLU (R = -0.62, P = 0.02), and with LF/HF (R = -0.79, P = 0.02) post-HPX6. In addition, an association was found between PMNs RLU and PR post-HPX6 (R = 0.58, P = 0.04). Conclusion: Acute exposure to intermittent HPX not only increased superoxide generation in neutrophils, but also impaired cardiac sympathovagal balance in healthy subjects. These data reinforce the role of intermittent HPX in superoxide generation on neutrophils, which may lead to an impairment in peripheral vascular resistance.

Peripheral vascular reactivity and serum BDNF responses to aerobic training are impaired by the BDNF Val66Met polymorphism.

Besides neuronal plasticity, the neurotrophin brain-derived neurotrophic factor (BDNF) is also important in vascular function. The BDNF has been associated with angiogenesis through its specific receptor tropomyosin-related kinase B (TrkB). Additionally, Val66Met polymorphism decreases activity-induced BDNF. Since BDNF and TrkB are expressed in vascular endothelial cells and aerobic exercise training can increase serum BDNF, this study aimed to test the hypotheses: 1) Serum BDNF levels modulate peripheral blood flow; 2) The Val66Met BDNF polymorphism impairs exercise training-induced vasodilation. We genotyped 304 healthy male volunteers (Val66Val, n = 221; Val66Met, n = 83) who underwent intense aerobic exercise training on a running track three times/wk for 4 mo. We evaluated pre- and post-exercise training serum BDNF and proBDNF concentration, heart rate (HR), mean blood pressure (MBP), forearm blood flow (FBF), and forearm vascular resistance (FVR). In the pre-exercise training, BDNF, proBDNF, BDNF/proBDNF ratio, FBF, and FVR were similar between genotypes. After exercise training, functional capacity (V̇o2 peak) increased and HR decreased similarly in both groups. Val66Val, but not Val66Met, increased BDNF (interaction, P = 0.04) and BDNF/proBDNF ratio (interaction, P < 0.001). Interestingly, FBF (interaction, P = 0.04) and the FVR (interaction, P = 0.01) responses during handgrip exercise (HG) improved in Val66Val compared with Val66Met, even with similar responses of HR and MBP. There were association between BDNF/proBDNF ratio and FBF (r = 0.64, P < 0.001) and FVR (r = -0.58, P < 0.001) during HG exercise. These results show that peripheral vascular reactivity and serum BDNF responses to exercise training are impaired by the BDNF Val66Met polymorphism and such responsiveness is associated with serum BDNF concentrations in healthy subjects.

Diet and exercise improve chemoreflex sensitivity in patients with metabolic syndrome and obstructive sleep apnea.

OBJECTIVE: Chemoreflex hypersensitity was caused by obstructive sleep apnea (OSA) in patients with metabolic syndrome (MetS). This study tested the hypothesis that hypocaloric diet and exercise training (D+ET) would improve peripheral and central chemoreflex sensitivity in patients with MetS and OSA. METHODS: Patients were assigned to: (1) D+ET (n = 16) and (2) no intervention control (C, n = 8). Minute ventilation (VE, pre-calibrated pneumotachograph) and muscle sympathetic nerve activity (MSNA, microneurography) were evaluated during peripheral chemoreflex sensitivity by inhalation of 10% O2 and 90% N2 with CO2 titrated and central chemoreflex by 7% CO2 and 93% O2 for 3 min at study entry and after 4 months. RESULTS: Peak VO2 was increased by D+ET; body weight, waist circumference, glucose levels, systolic/diastolic blood pressure, and apnea-hypopnea index (AHI) (34 ± 5.1 vs. 18 ± 3.2 events/h, P = 0.04) were reduced by D+ET. MSNA was reduced by D+ET at rest and in response to hypoxia (8.6 ± 1.2 vs. 5.4 ± 0.6 bursts/min, P = 0.02), and VE in response to hypercapnia (14.8 ± 3.9 vs. 9.1 ± 1.2 l/min, P = 0.02). No changes were found in the C group. A positive correlation was found between AHI and MSNA absolute changes (R = 0.51, P = 0.01) and body weight and AHI absolute changes (R = 0.69, P < 0.001). CONCLUSIONS: Sympathetic peripheral and ventilatory central chemoreflex sensitivity was improved by D+ET in MetS+OSA patients, which may be associated with improvement in sleep pattern.

Obstructive Sleep Apnea Impairs Postexercise Sympathovagal Balance in Patients with Metabolic Syndrome.

STUDY OBJECTIVES: The attenuation of heart rate recovery after maximal exercise (ΔHRR) is independently impaired by obstructive sleep apnea (OSA) and metabolic syndrome (MetS). Therefore, we tested the hypotheses: (1) MetS + OSA restrains ΔHRR; and (2) Sympathetic hyperactivation is involved in this impairment. DESIGN: Cross-sectional study. PARTICIPANTS: We studied 60 outpatients in whom MetS had been newly diagnosed (ATP III), divided according to apnea-hypopnea index (AHI) ≥ 15 events/h in MetS + OSA (n = 30, 49 ± 1.7 y) and AHI < 15 events/h in MetS - OSA (n = 30, 46 ± 1.4 y). Normal age-matched healthy control subjects (C) without MetS and OSA were also enrolled (n = 16, 46 ± 1.7 y). INTERVENTIONS: Polysomnography, microneurography, cardiopulmonary exercise test. MEASUREMENTS AND RESULTS: We evaluated OSA (AHI - polysomnography), muscle sympathetic nerve activity (MSNA - microneurography) and cardiac autonomic activity (LF = low frequency, HF = high frequency, LF/HF = sympathovagal balance) based on spectral analysis of heart rate (HR) variability. ΔHRR was calculated (peak HR minus HR at first, second, and fourth minute of recovery) after cardiopulmonary exercise test. MetS + OSA had higher MSNA and LF, and lower HF than MetS - OSA and C. Similar impairment occurred in MetS - OSA versus C (interaction, P < 0.01). MetS + OSA had attenuated ΔHRR at first, second, and at fourth minute than did C, and attenuated ΔHRR at fourth minute than did MetS - OSA (interaction, P < 0.001). Compared with C, MetS - OSA had attenuated ΔHRR at second and fourth min (interaction, P < 0.001). Further analysis showed association of the ΔHRR (first, second, and fourth minute) and AHI, MSNA, LF and HF components (P < 0.05 for all associations). CONCLUSIONS: The attenuation of heart rate recovery after maximal exercise is impaired to a greater degree where metabolic syndrome (MetS) is associated with moderate to severe obstructive sleep apnea (OSA) than by MetS with no or mild or no OSA. This is at least partly explained by sympathetic hyperactivity.

Effects of cardiac resynchronization therapy on muscle sympathetic nerve activity.

INTRODUCTION: Muscle sympathetic nerve activity (MSNA) is an independent prognostic marker in patients with heart failure (HF). Therefore, its relevance to the treatment of HF patients is unquestionable. OBJECTIVES: In this study, we investigated the effects of cardiac resynchronization therapy (CRT) on MSNA response at rest and during exercise in patients with advanced HF. METHODS: We assessed 11 HF patients (51 ± 3.4 years; New York Heart Association class III-IV; left ventricular ejection fraction 27.8 ± 2.2%; optimal medical therapy) submitted to CRT. Evaluations were made prior to and 3 months after CRT. MSNA was performed at rest and during moderate static exercise (handgrip). Peak oxygen consumption (VO2 ) was evaluated by means of cardiopulmonary exercise test. HF patients with advanced NYHA class without CRT and healthy individuals were also studied. RESULTS: CRT reduced MSNA at rest (48.9 ± 11.1 bursts/min vs 33.7 ± 15.3 bursts/min, P < 0.05) and during handgrip exercise (MSNA 62.3 ± 13.1 bursts/min vs 46.9 ± 14.3 bursts/min, P < 0.05). Among HF patients submitted to CRT, the peak VO2 increased (12.9 ± 2.8 mL/kg/min vs 16.5 ± 3.9 mL/kg/min, P < 0.05) and an inverse correlation between peak VO2 and resting MSNA (r = -0.74, P = 0.01) was observed. CONCLUSIONS: In patients with advanced HF and severe systolic dysfunction: (1) a significant reduction of MSNA (at rest and during handgrip) occurred after CRT, and this behavior was significantly superior to HF patients receiving only medical therapy; (2) MSNA reduction after CRT had an inverse correlation with O2 consumption outcomes.

Time delay of baroreflex control and oscillatory pattern of sympathetic activity in patients with metabolic syndrome and obstructive sleep apnea.

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.