Muscle sympathetic nerve activity and ventilation during exercise in subjects with and without chronic heart failure

BACKGROUND:

Changes within skeletal muscle, including augmentation of its capacity to elicit reflex increases in both efferent muscle sympathetic nerve activity (MSNA) and ventilation during work, contribute significantly to exercise intolerance in heart failure (HF). Previously, we demonstrated that peak oxygen uptake (pVO₂) in HF relates inversely to MSNA at rest and during exercise.

OBJECTIVE:

To test the hypothesis that there is an independent positive relationship between resting MSNA and the ratio of ventilation to carbon dioxide output during exercise (VE/VCO₂) that is augmented in HF.

METHODS:

MSNA at rest and VE/VCO₂ during stationary cycling were measured in 30 patients (27 men) with HF (mean ± SD ejection fraction 20±6%) and in 31 age-matched controls (29 men).

RESULTS:

MSNA was higher in HF patients than in controls (51.5±14.3 bursts/min versus 33.0±11.1 bursts/min; P<0.0001). The VE/VCO₂ slope was also higher in HF patients than in controls (33.7±5.7 versus 26.0±3.5; P<0.0001), whereas pVO₂ was lower in HF patients than in controls (18.6±6.6 versus 31.4±8.4 mL/kg/min; P<0.0001). There were significant relationships between MSNA and VE/VCO₂ in both HF (r=0.50; P=0.005) and control subjects (r=0.36; P=0.046). The slope of this regression equation was steeper in HF (0.20 versus 0.11 × MSNA; P=0.001). An analysis of covariance for main effects, including age and pVO₂, identified a significant independent relationship between MSNA burst frequency and VE/VCO₂ (P=0.013) that differed between HF and controls (P<0.01).

CONCLUSIONS:

The magnitude of resting sympathetic activity correlates positively with the VE/VCO₂ slope. Augmentation of this relationship in HF patients is consistent with the concept that enhanced mechanoreceptor reflex activity exaggerates their ventilatory response to exercise.     

Inhibition of awake sympathetic nerve activity of heart failure patients with obstructive sleep apnea by nocturnal continuous positive airway pressure

OBJECTIVES: This study was designed to determine whether reductions in morning systolic blood pressure (BP) elicited by treatment of moderate to severe obstructive sleep apnea (OSA) in heart failure (HF) patients are associated with a reduction in sympathetic vasoconstrictor tone. BACKGROUND: Daytime muscle sympathetic nerve activity (MSNA) is elevated in HF patients with coexisting OSA. In our recent randomized trial in HF, abolition of OSA by continuous positive airway pressure (CPAP) increased left ventricular ejection fraction (LVEF) and lowered morning systolic BP. METHODS: Muscle sympathetic nerve activity, BP, and heart rate (HR) of medically treated HF patients (EF <45%) and OSA (apnea-hypopnea index > or =20/h of sleep) were recorded on the morning after overnight polysomnography, and again one month after patients were randomly allocated nocturnal CPAP treatment or no CPAP (control). RESULTS: In nine control patients, there were no significant changes in the severity of OSA, MSNA, systolic BP, or HR. In contrast, in the 8 CPAP-treated patients, OSA was attenuated, and there were significant reductions in daytime MSNA (from 58 +/- 4 bursts/min to 48 +/- 5 bursts/min; 84 +/- 4 bursts/100 heart beats to 72 +/- 5 bursts/100 heart beats; p < 0.001 and p = 0.003, respectively), systolic BP (from 135 +/- 5 mm Hg to 120 +/- 6 mm Hg, p = 0.03), and HR (from 69 +/- 2 min(-1) to 66 +/- 2 min(-1); p = 0.013). CONCLUSIONS: Treatment of coexisting OSA by CPAP in HF patients lowers daytime MSNA, systolic BP, and HR. Inhibition of increased central sympathetic vasoconstrictor outflow is one mechanism by which nocturnal CPAP reduces awake BP in HF patients with moderate to severe OSA.     

Periodicity of obstructive sleep apnea in patients with and without heart failure

STUDY OBJECTIVE: To determine whether the duration of the apnea-hyperpnea cycle is longer in patients with congestive heart failure (CHF) and obstructive sleep apnea (OSA) than in patients with OSA alone, and whether this is related to prolonged circulation time. DESIGN: Retrospective study. SETTING: Sleep laboratory of a university teaching hospital.Patients and intervention: Male patients with OSA and CHF (n = 22) or without CHF (n = 18) underwent overnight polysomnography. MEASUREMENTS AND RESULTS: Hyperpnea duration, time to peak tidal volume (Vt), and lung-to-ear circulation time (LECT) were measured in all patients. Compared to the non-CHF patients, those with CHF had significantly longer hyperpneas (25.7 +/- 7.8 s vs 17.6 +/- 5.6 s, p < 0.001) and LECT (14.9 +/- 3.4 s vs 9.0 +/- 1.8 s, p < 0.001) [mean +/- SD]. There was also a significant relationship between LECT and hyperpnea duration (r = 0.67, p < 0.001). CONCLUSION: In patients with CHF, prolonged lung-to-chemoreceptor circulation time influences the cycling characteristics of OSA such that it prolongs hyperpnea and sculpts a pattern resembling Cheyne-Stokes respiration. These findings further suggest that the increased tendency to periodic breathing in CHF may predispose to, or alter the physiologic manifestations of OSA.     

Genioglossus activity in children with obstructive sleep apnea during wakefulness and sleep onset

A prominent role for upper airway neuromuscular control mechanisms in the pathophysiology of pediatric obstructive sleep apnea syndrome (OSAS) is suggested by the observation that obstruction does not occur during wakefulness and is infrequently seen during non-REM sleep. Using a custom intraoral surface electrode to record genioglossal activity (genioglossal electromyography [EMGgg]), normalized with a maximal maneuver, we studied 10 children with OSAS and 6 normal control subjects to determine EMGgg activity during (1) wakefulness, (2) the sleep onset period, and (3) stable non-REM sleep. We observed that the EMGgg activity in patients with OSAS compared with control subjects was significantly greater during wakefulness (3.6 +/- 1.8 vs. 1.6 +/- 1.8% maximum, p < 0.05) and had a greater decline during the early and late sleep onset period (p < 0.05). During stable non-REM sleep, EMGgg remained below the wakeful baseline in all normal control subjects but increased above the baseline in four of the patients with OSAS. We speculate that the increased EMGgg activity during wakefulness represents a reflex-driven neuromuscular compensation for an anatomically compromised airway. Furthermore, the larger decline in EMGgg at sleep onset observed in patients with OSAS is consistent with the relative loss of this reflex. Finally, the return of EMGgg activity above baseline in patients with severe OSAS suggests that some chemical or mechanical compensatory mechanisms remain active during stable non-REM sleep in children.     

Impact of sleep apnea on sympathetic nervous system activity in heart failure

OBJECTIVES: To compare and establish the relevance of the relative degree of sympathetic nervous system activity (SNSA) in groups of patients with congestive heart failure (CHF) and obstructive sleep apnea (OSA), and in a control group. BACKGROUND: Elevated SNSA is a characteristic feature of CHF, as well as of OSA and nonhypercapnic central sleep apnea (CSA). OSA and CSA commonly occur with CHF; however, the relative contribution of apnea-related hypoxemia and sleep fragmentation to the SNSA of patients with CHF is not known. METHODS: This was a prospective, controlled, observational trial in which the overnight urinary norepinephrine (UNE) level, which is a measure of integrated overnight SNSA while asleep, was measured in 15 healthy male volunteers, 15 male OSA patients who did not have CHF, and 90 CHF patients (77 men). CHF patients also had right heart pressure measurements and then were grouped by the presence of sleep apnea. RESULTS: Compared with healthy individuals, the mean (+/- SD) UNE level was significantly elevated in the OSA group and was even further elevated in the CHF group (13.4 +/- 5.6 vs 19.7 +/- 12.3 vs 32.2 +/- 20.2 nmol/mmol creatinine, respectively; p < 0.001 [by analysis of variance]). Within the CHF group, the mean UNE levels were greatest in the CHF-CSA group compared with the CHF-OSA group and the CHF nonapnea group (43.9 +/- 24.1 vs 24.0 +/- 10.8 vs 22.4 +/- 8.9 nmol/mmol creatinine, respectively; p < 0.001). Using a multivariate regression model, the variance of the UNE level in the CHF group was predicted, in descending order, by pulmonary capillary wedge pressure (14% variance), rapid eye movement sleep (8%), and the mean sleep pulse oximetry level (7%). CONCLUSIONS: Overnight SNSA is significantly greater in CHF patients than in OSA patients. Moreover, the hemodynamic severity of CHF contributes to the elevation of SNSA in CHF patients to a greater degree than apnea-related hypoxemia.     

Muscle sympathetic nerve activity in patients with acromegaly

Muscle sympathetic nerve activity was measured in nine acromegalic patients (age, 35 +/- 4 yr; body mass index, 28 +/- 2 kg/m2) and eight healthy subjects (age, 32 +/- 3 yr; body mass index, 25 +/- 2 kg/m2) by combining the forearm arterial-venous difference technique with the tracer method [infusion of tritiated norepinephrine (NE)]. Muscle NE release was quantified both at rest and during physiological hyperinsulinemia while maintaining euglycemia (approximately 90 mg/dL) by means of the euglycemic clamp. Arterial plasma NE was similar in the two groups at rest (197 +/- 28 and 200 +/- 27 pg/mL (-1) and slightly increased during insulin infusion. Forearm NE release was 2.33 +/- 0.55 ng x liter(-1) x min(-1) in healthy subjects and 2.67 +/- 0.61 ng x liter(-1) x min(-1) in acromegalic subjects in the basal state and increased to a similar extent during insulin infusion in both groups (3.13 +/- 0.71 and 3.32 +/- 0.75 ng x L(-1) x min(-1), P < 0.05 vs. basal), indicating a normal stimulatory effect of insulin on muscle sympathetic activity. In contrast, insulin-stimulated forearm glucose uptake was markedly lower in acromegalic patients (2.3 +/- 0.4 mg x L(-1) x min(-1)) than in control subjects (7.9 +/- 1.3 mg x L(-1) x min(-1), P < 0.001), indicating the presence of severe insulin resistance involving glucose metabolism. Our data demonstrate that patients with long-term acromegaly have normal sympathetic activity in the skeletal muscle in the basal, postabsorptive state and normal increments in NE spillover in response to the sympatho-excitatory effect of insulin. Thus, the presence of severe insulin resistance in acromegaly is not accounted for by adrenergic mechanisms.     

Central sleep apnea in patients with congestive heart failure

Central apnea during sleep represents a manifestation of breathing instability in many clinical conditions of varied etiologies. Central apnea is the result of transient cessation of ventilatory motor output, which represents that inhibitory influences favoring instability predominate over excitatory influence favoring stable breathing. This article will review the determinants of central apnea, the specific features of CHF-related central apnea, and outline a management approach     

Abnormal breathing during sleep and chemical control of breathing during wakefulness in patients with sleep apnea syndrome

The possible role of ventilatory control in relation to sleep apnea has not yet been clarified. We investigated the relationship between awake ventilatory drives to hypoxia and hypercapnia and sleep-disordered breathing in 21 subjects with sleep apnea syndrome. The awake hypoxic ventilatory drive, which was evaluated by occlusion pressure responses, was inversely correlated with the magnitude of maximal oxygen desaturation during sleep as well as the ratio of duration with more than 4 and 10% oxygen desaturation to total sleep time. On the other hand, the awake hypercapnic ventilatory drive was not correlated with these parameters of sleep desaturation. Apnea index and duration were not correlated with the degree of hypoxic or hypercapnic ventilatory drive, respectively. Our study concluded that sleep desaturation is better correlated with hypoxic ventilatory drive than with hypercapnic ventilatory drive in patients with sleep apnea syndrome. These results are different from the results obtained in the patients with COPD in our previous study.     

Exercise training reduces sympathetic nerve activity in heart failure patients treated with carvedilol

BACKGROUND: Evidence suggests that carvedilol decreases muscle sympathetic nerve activity (MSNA) in patients with heart failure (HF) but carvedilol fails to improve forearm vascular resistance and overall functional capacity. Exercise training in HF reduces MSNA and improves forearm vascular resistance and functional capacity. AIMS: To investigate whether the beneficial effects exercise training on MSNA are maintained in the presence of carvedilol. METHODS AND RESULTS: Twenty seven HF patients, NYHA Class II-III, EF <35%, peak VO(2) <20 ml/kg/min, treated with carvedilol were randomly divided into two groups: exercise training (n=15) and untrained (n=12). MSNA was recorded by microneurography. Forearm blood flow (FBF) was measured by venous occlusion plethysmography. The four-month training program consisted of three 60-min exercise/week on a cycloergometer. Baseline parameters were similar between groups. Exercise training reduced MSNA (-14+/-3.3 bursts/100 HB, p=0.001) and increased forearm blood flow (0.6+/-0.1 mL/min/100 g, p<0.001) in HF patients on carvedilol. In addition, exercise training improved peak VO(2) in HF patients (20+/-6%, p=0.002). MSNA, FBF and peak VO(2) were unchanged in untrained HF patients on carvedilol. CONCLUSION: Exercise training reduces MSNA in heart failure patients treated with carvedilol. In addition, the beneficial effects of exercise training on muscle blood flow and functional capacity are still realized in patients on carvedilol.     

Accuracy of respiratory inductive plethysmography during wakefulness and sleep in patients with obstructive sleep apnea.

To assess the accuracy of the respiratory inductive plethysmograph (RIP) during sleep in obese patients with obstructive sleep apnea (OSA), we monitored 13 patients with OSA during wakefulness and nocturnal sleep with simultaneous measurements of tidal volume from RIP and integrated airflow. Patients wore a tightly fitting face mask with pneumotachograph during wakefulness and sleep. Calibrations were performed during wakefulness prior to sleep and compared with subsequent wakeful calibrations at the end of the study. Patients maintained the same posture during sleep (supine, 11; lateral, two) as during calibrations. There were no significant differences in calibrations before sleep and after awakening. The mean error in 13 patients undergoing RIP measurements of tidal volume during wakefulness was -0.7 +/- 3.4 percent while that during sleep was 2.1 +/- 14.9 percent (p < 0.001). The standard deviation (SD) of the differences between individual breaths measured by RIP and integrated airflow was 9.8 +/- 5.5 percent during wakefulness and 25.5 +/- 18.6 percent during sleep (p < 0.001). During both wakefulness and sleep, errors in RIP tidal volume were not significantly correlated with body mass index. In 12 patients with at least 10 percent time in each of stages 1 and 2 sleep, SD was greater in stage 2 sleep compared with wakefulness and stage 1 (p < 0.001). In three patients who manifested all stages of sleep, SD was greater in REM sleep than in wakefulness and all stages of non-REM sleep (p < 0.001). In three patients who manifested all stages of sleep, SD was greater in REM sleep than in wakefulness and all stages of non REM sleep (p < 0.001). This was associated with paradoxic motion of the rib cage in two patients during REM. We conclude that, despite increased errors in individual breath measurements during sleep, more marked during stages 2 and REM sleep, RIP is clinically useful to measure ventilation quantitatively in obese patients with sleep apnea. The criterion of a decrease of 50 percent in tidal volume assessed by RIP is appropriate to define hypopneas in such patients.     

Cheyne-stokes respiration during wakefulness in patients with chronic heart failure

Sleep and Breathing - Cheyne-Stokes respiration (CSR) during sleep has been studied extensively in patients with chronic heart failure (CHF). Prevalence and prognostic significance of CSR during...     

Sleepiness and sleep in patients with both systolic heart failure and obstructive sleep apnea

BACKGROUND: Adverse effects of obstructive sleep apnea (OSA), including sleep deprivation, can contribute to the progression of heart failure. The usual indication to diagnose and treat sleep apnea is subjective sleepiness. Previous studies suggest that patients with both heart failure and obstructive sleep apnea often do not complain of sleepiness, albeit their sleep time may be reduced. Therefore, we tested the hypothesis that patients with heart failure have less sleepiness and sleep less compared with subjects without heart failure for a given severity of OSA. METHODS: Sleepiness assessed with the Epworth Sleepiness Scale and sleep structure measured with polysomnography were compared among 155 consecutive patients with heart failure and from a random community sample (n = 1139) according to categories of the apnea-hypopnea index (<5, no OSA; 5-14, mild OSA; and > or =15, moderate to severe OSA). RESULTS: Compared with the community sample, for any given severity of OSA, patients with heart failure had lower mean +/- SE Epworth Sleepiness Scale scores (7.1 +/- 0.4 vs 8.3 +/- 0.2 [P = .005]; 6.7 +/- 0.7 vs 9.2 +/- 0.3 [P < .001]; and 7.8 +/- 0.7 vs 9.8 +/- 0.4 [P = .01]), indicating less sleepiness despite sleeping less (total sleep time mean +/- SE [in minutes]: 306 +/- 7 vs 384 +/- 2, 295 +/- 19 vs 384 +/- 5, and 285 +/- 13 vs 359 +/- 7 for no, mild, and moderate to severe OSA, respectively; P < .001 for all comparisons). CONCLUSIONS: Patients with heart failure have less subjective daytime sleepiness compared with individuals from a community sample, despite significantly reduced sleep time, whether or not they have OSA. In patients with heart failure, the absence of subjective sleepiness is not a reliable means of ruling out OSA.     

The effects of transcutaneous electrical stimulation during wakefulness and sleep in patients with obstructive sleep apnea.

Upper airway (UA) collapse in obstructive sleep apnea (OSA) is considered in part to result from the decrease in UA dilator muscle tone that occurs during sleep. We hypothesized that augmentation of UA muscle function by transcutaneous electrical stimulation (TES) might function to enlarge UA size during wakefulness and/or prevent UA collapse during sleep in patients with OSA. Eight male patients with OSA were studied both awake and asleep, with TES administered to the submental region in two patients and to both the submental and subhyoid regions in six patients. Fast-CT scans obtained at FRC and end-inspiration (VTei) demonstrated increased UA size with tidal breathing, p less than or equal to 0.05. The active generation of -10 cm H2O pressure at FRC substantially decreased UA size, p less than or equal to 0.001. However, no changes in UA size were detected at either FRC or VTei with TES applied at 50 and 100% of the maximal tolerated intensity. The collapsibility of the UA in response to the generation of -10 cm H2O pressure was also unchanged by TES. In contrast to the lack of effect of TES on UA size, voluntary protrusion of the tongue increased cross-sectional area (CSA) of the orohypopharyngeal (OHP) segment of the UA, p less than 0.05, and to a lesser extent the CSA of the distal velopharyngeal segment, p = 0.06. When applied during sleep, TES failed to prevent or improve either sleep-disordered breathing or sleep architecture.(ABSTRACT TRUNCATED AT 250 WORDS)