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.

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.

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.

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.

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.

Obstructive sleep apnea is associated with increased chemoreflex sensitivity in patients with metabolic syndrome.

STUDY OBJECTIVES: Obstructive sleep apnea (OSA) is often observed in patients with metabolic syndrome (MetS). In addition, the association of MetS and OSA substantially increases sympathetic nerve activity. However, the mechanisms involved in sympathetic hyperactivation in patients with MetS + OSA remain to be clarified. We tested the hypothesis that chemoreflex sensitivity is heightened in patients with MetS and OSA. DESIGN: Prospective clinical study. PARTICIPANTS: Forty-six patients in whom MetS was newly diagnosed (ATP-III) were allocated into: (1) MetS + OSA (n = 24, 48 ± 1.8 yr); and (2) MetS - OSA (n = 22, 44 ± 1.7 yr). Eleven normal control subjects were also studied (C, 47 ± 2.3 yr). MEASUREMENTS: OSA was defined as an apnea-hypopnea index ≥ 15 events/hr (polysomnography). Muscle sympathetic nerve activity (MSNA) was measured by microneurography technique. Peripheral chemoreflex sensitivity was assessed by inhalation of 10% oxygen and 90% nitrogen (carbon dioxide titrated), and central chemoreflex sensitivity by 7% carbon dioxide and 93% oxygen. RESULTS: Physical characteristics and MetS measures were similar between MetS + OSA and MetS - OSA. MSNA was higher in MetS + OSA patients compared with MetS - OSA and C (33 ± 1.3 versus 28 ± 1.2 and 18 ± 2.2 bursts/min, P < 0.05). Isocapnic hypoxia caused a greater increase in MSNA in MetS + OSA than MetS - OSA and C (P = 0.03). MSNA in response to hyperoxic hypercapnia was greater in MetS + OSA compared with C (P = 0.005). Further analysis showed a significant association between baseline MSNA and peripheral (P < 0.01) and central (P < 0.01) chemoreflex sensitivity. Min ventilation in response to hyperoxic hypercapnia was greater in MetS + OSA compared with C (P = 0.001). CONCLUSION: OSA increases sympathetic peripheral and central chemoreflex response in patients with MetS, which seems to explain, at least in part, the increase in sympathetic nerve activity in these patients. In addition, OSA increases ventilatory central chemoreflex response in patients with MetS.

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.

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

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