Physical capacity increase in patients with heart failure is associated with improvement in muscle sympathetic nerve activity.

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 (V̇O2, 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 V̇O2. CONCLUSIONS: The increase in physical capacity provoked by aerobic exercise in patients with HFrEF is associated with the improvement in MSNA.

Effects of Exercise Training on Left Ventricular Diastolic Function Markers in Patients with Obstructive Sleep Apnea: A Randomized Study

Abstract Background Exercise training (ET) is an adjunctive treatment for obstructive sleep apnea (OSA) and its consequences. However, the effects of exercise on heart remodeling are unknown in the population with OSA. Objective We investigated the effect of ET on markers of diastolic function, sleep parameters, and functional capacity in patients with OSA. Methods Sedentary patients with OSA (apnea-hypopnea index, AHI ≥15 events/hr) were randomly assigned to untrained (n=18) and trained (n=20) strategies. Polysomnography, cardiopulmonary exercise test, and echocardiography were evaluated at the beginning and end of the study. ET consisted of 3 weekly sessions of aerobic exercise, resistance exercises, and flexibility training (72 sessions, completed in 11.65±0.86 months). A two-way analysis of variance (ANOVA) was used, followed by Tukey's post-hoc test. The level of statistical significance was set at p<0.05 for all analyses. Result Thirty-eight patients were included (AHI:45±29 events/hr, age:52±7 y, body mass index: 30±4 kg/m2). They had similar baseline parameters. ET caused a significant change in OSA severity (AHI:4.5±18 versus -5.7±13 events/hr; arousal index:1.5±8 versus -6.1±13 events/hr, in untrained and trained groups respectively, p<0.05). The trained patients had an increase in functional capacity after intervention. ET improved isovolumetric relaxation time (IVRT, untrained=6.5±17.3 versus trained=-5.1±17.1 msec, p<0.05). There was a significant correlation between changes in IVRT and arousal index in the trained group (r =-0.54, p<0.05). No difference occurred in the other diastolic function parameters evaluated. Conclusion ET promotes modest but significant improvement in AHI, functional capacity, and cardiac IVRT, a validated parameter of diastolic function.

Effects of exercise training on brain metabolism and cognitive functioning in sleep apnea.

Impaired glucose metabolism reflects neuronal/synaptic dysfunction and cognitive function decline in patients with obstructive sleep apnea (OSA). The study investigated the extent to which exercise training (ET) improves cerebral metabolic glucose rate (CMRgl) and cognitive function in patients with OSA. Patients with moderate to severe OSA were randomly assigned to ET (3 times/week, n = 23) or no intervention (control, n = 24). Echocardiography and apolipoprotein ε4 (APOEε4) genotyping were obtained at baseline. Both groups underwent cardiopulmonary exercise testing, polysomnography, cognitive tests, brain magnetic resonance imaging, and 18F-fluoro-2-deoxy-D-Glucose positron emission tomography (18FDG-PET) at baseline and study end. Compared with control, exercise-trained group had improved exercise capacity, decreased apnea-hypopnea index (AHI), oxygen desaturation and arousal index; increased attention/executive functioning, increased CMRgl in the right frontal lobe (P < 0.05). After ET an inverse relationships occurred between CMRgl and obstructive AHI (r = - 0.43, P < 0.05) and apnea arousal index (r = - 0.53, P < 0.05), and between the changes in CMRgl and changes in mean O2 saturation during sleep and non-rapid eye movement sleep (r = - 0.43, P < 0.05), desaturation during arousal (r = - 0.44, P < 0.05), and time to attention function testing (r = - 0.46, P < 0.05). ET improves OSA severity and CMRg in the frontal lobe, which helps explain the improvement in attention/executive functioning. Our study provides promising data that reinforce the growing idea that ET may be a valuable tool to prevent hypoxia associated with decreased brain metabolism and cognitive functioning in patients with moderate to severe OSA.Trial registration: NCT02289625 (13/11/2014).

Oscillatory Pattern of Sympathetic Nerve Bursts Is Associated With Baroreflex Function in Heart Failure Patients With Reduced Ejection Fraction.

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.

Exercise Training Increases Metaboreflex Control in Patients with Obstructive Sleep Apnea.

INTRODUCTION/PURPOSE: We demonstrated that patients with obstructive sleep apnea (OSA) have reduced muscle metaboreflex control of muscle sympathetic nerve activity (MSNA). In addition, exercise training increased muscle metaboreflex control in heart failure patients. OBJECTIVE: We tested the hypothesis that exercise training would increase muscle metaboreflex control of MSNA in patients with OSA. METHODS: Forty-one patients with OSA were randomized into the following two groups: 1) nontrained (OSANT, n = 21) and 2) trained (OSAT, n = 20). Muscle sympathetic nerve activity was assessed by microneurography technique, muscle blood flow (FBF) by venous occlusion plethysmography, heart rate by electrocardiography, and blood pressure with an automated oscillometric device. All physiological variables were simultaneously assessed at rest, during isometric handgrip exercise at 30% of the maximal voluntary contraction, and during posthandgrip muscle ischemia (PHMI). Muscle metaboreflex sensitivity was calculated as the difference in MSNA between PHMI and the rest period. Patients in the OSAT group underwent 72 sessions of moderate exercise training, whereas patients in the OSANT group were clinical follow-up for 6 months. RESULTS: The OSANT and OSAT groups were similar in anthropometric, neurovascular, hemodynamic and sleep parameters. Exercise training reduced the baseline MSNA (34 ± 2 bursts per minute vs 25 ± 2 bursts per minute; P < 0.05) and increased the baseline FBF (2.1 ± 0.2 mL·min per 100 g vs 2.4 ± 0.2 mL·min per 100 g; P < 0.05). Exercise training significantly reduced MSNA levels and increased FBF responses during isometric exercise. Exercise training significantly increased MSNA responses during PHMI (Δ6.5 ± 1 vs -1.7 ± 1 bursts per minute, P < 0.01). No significant changes in FBF or hemodynamic parameters in OSANT patients were found. CONCLUSIONS: Exercise training increases muscle metaboreflex sensitivity in patients with OSA. This autonomic change associated with increased muscle blood flow may contribute to the increase in exercise performance in this set of patients.

Vascular Response During Mental Stress in Sedentary and Physically Active Patients With Obstructive Sleep Apnea.

STUDY OBJECTIVES: To compare vascular function of sedentary (SED) versus physically active (ACTIVE) patients with obstructive sleep apnea (OSA) during rest and mental stress. METHODS: Patients with untreated OSA without other comorbidities were classified into SED and ACTIVE groups according to the International Physical Activity Questionnaire. Blood pressure (BP), heart rate (HR), forearm blood flow (FBF) (plethysmography), and forearm vascular conductance (FVC = FBF / mean BP × 100) were continuously measured at rest (4 minutes) followed by 3 minutes of mental stress (Stroop Color Word Test). RESULTS: We studied 40 patients with OSA (men = 24, age = 50 ± 1 years, body mass index = 29.3 ± 0.5 kg/m2, apnea-hypopnea index = 39.3 ± 4 events/h). Leisure time physical activity domain in SED (n = 19) and ACTIVE (n = 21) was 20 ± 8 and 239 ± 32 min/wk, (P < .05). Baseline profile and perception of stress were similar in both groups. Baseline FBF (3.5 ± 0.2 mL/min/100 mL versus 2.4 ± 0.14 mL/min/100 mL) and FVC (3.5 ± 0.2 U versus 2.3 ± 0.1 U) were significantly lower in the SED group than in the ACTIVE group, respectively (P < .05). HR and BP increased similarly during mental stress test in both groups. Changes during mental stress in FBF (0.65 ± 0.12 versus 1.04 ± 0.12) and FVC (0.58 ± 0.11 versus 0.99 ± 0.11) were significantly lower in the SED group than in the ACTIVE group, respectively (P < .05). There was a significant correlation between leisure time physical activity and FBF (r = .57, P < .05) and FVC (r = .48, P < .05) during mental stress. CONCLUSIONS: The vascular response among patients with OSA is influenced by the level of physical activity. A high level of physical activity may partially protect against the cardiovascular dysfunction associated with OSA.

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.

The influence of aetiology on the benefits of exercise training in patients with heart failure.

Background Exercise training improves neurovascular control and functional capacity in heart failure (HF) patients. However, the influence of the aetiology on these benefits is unknown. We compared the effects of exercise training on neurovascular control and functional capacity in idiopathic, ischaemic and hypertensive HF patients. Design Subjects consisted of 45 exercise-trained HF patients from our database (2000-2015), aged 40-70 years old, functional class II/III and ejection fraction ≤40%, and they were divided into three groups: idiopathic ( n = 11), ischaemic ( n = 18) and hypertensive ( n = 16). Methods Functional capacity was determined by cardiopulmonary exercise testing. Muscle sympathetic nerve activity (MSNA) was recorded by microneurography. Forearm blood flow (FBF) was measured by venous occlusion plethysmography. Results Four months of exercise training significantly reduced MSNA and significantly increased FBF in all groups. However, the relative reduction in MSNA was greater in hypertensive patients compared with that in idiopathic patients (frequency: -34% vs . -15%, p = 0.01; incidence: -31% vs . -12%, p = 0.02). No differences were found between hypertensive patients and ischaemic patients. The relative increase in FBF was greater in hypertensive patients than in ischaemic and idiopathic patients (42% vs. 15% and 17%, respectively, p = 0.02). The relative increase in forearm vascular conductance was greater in hypertensive patients compared with those in ischaemic and idiopathic patients (57% vs . 13% and 26%, respectively, p = 0.001). Exercise training significantly and similarly increased peak oxygen consumption in all groups. Conclusion The exercise-induced improvement in neurovascular control is more pronounced in hypertensive HF patients than in idiopathic and ischaemic HF patients. The increase in functional capacity is independent of aetiology.

Increased Muscle Sympathetic Nerve Activity and Impaired Executive Performance Capacity in Obstructive Sleep Apnea.

STUDY OBJECTIVES: To investigate muscle sympathetic nerve activity (MSNA) response and executive performance during mental stress in obstructive sleep apnea (OSA). METHODS: Individuals with no other comorbidities (age = 52 ± 1 y, body mass index = 29 ± 0.4, kg/m2) were divided into two groups: (1) control (n = 15) and (2) untreated OSA (n = 20) defined by polysomnography. Mini-Mental State of Examination (MMSE) and Inteligence quocient (IQ) were assessed. Heart rate (HR), blood pressure (BP), and MSNA (microneurography) were measured at baseline and during 3 min of the Stroop Color Word Test (SCWT). Sustained attention and inhibitory control were assessed by the number of correct answers and errors during SCWT. RESULTS: Control and OSA groups (apnea-hypopnea index, AHI = 8 ± 1 and 47 ± 1 events/h, respectively) were similar in age, MMSE, and IQ. Baseline HR and BP were similar and increased similarly during SCWT in control and OSA groups. In contrast, baseline MSNA was higher in OSA compared to controls. Moreover, MSNA significantly increased in the third minute of SCWT in OSA, but remained unchanged in controls (P < 0.05). The number of correct answers was lower and the number of errors was significantly higher during the second and third minutes of SCWT in the OSA group (P < 0.05). There was a significant correlation (P < 0.01) between the number of errors in the third minute of SCWT with AHI (r = 0.59), arousal index (r = 0.55), and minimum O2 saturation (r = -0.57). CONCLUSIONS: As compared to controls, MSNA is increased in patients with OSA at rest, and further significant MSNA increments and worse executive performance are seen during mental stress. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov, registration number: NCT002289625.