Mark Eric Dyken

Sympathetic neural mechanisms in obstructive sleep apnea.

Blood pressure, heart rate, sympathetic nerve activity, and polysomnography were recorded during wakefulness and sleep in 10 patients with obstructive sleep apnea. Measurements were also obtained after treatment with continuous positive airway pressure (CPAP) in four patients. Awake sympathetic activity was also measured in 10 age- and sex-matched control subjects and in 5 obese subjects without a history of sleep apnea. Patients with sleep apnea had high levels of nerve activity even when awake (P < 0.001). Blood pressure and sympathetic nerve activity did not fall during any stage of sleep. Mean blood pressure was 92 +/- 4.5 mmHg when awake and reached peak levels of 116 +/- 5 and 127 +/- 7 mmHg during stage II sleep (n = 10) and rapid eye movement (REM) sleep (n = 5), respectively (P < 0.001). Sympathetic activity increased during sleep (P = 0.01) especially during stage II (133 +/- 9% above wakefulness; P = 0.006) and REM (141 +/- 13%; P = 0.007). Peak sympathetic activity (measured over the last 10 s of each apneic event) increased to 299 +/- 96% during stage II sleep and to 246 +/- 36% during REM sleep (both P < 0.001). CPAP decreased sympathetic activity and blood pressure during sleep (P < 0.03). We conclude that patients with obstructive sleep apnea have high sympathetic activity when awake, with further increases in blood pressure and sympathetic activity during sleep. These increases are attenuated by treatment with CPAP.

Sympathetic-nerve activity during sleep in normal subjects

BACKGROUND The early hours of the morning after awakening are associated with an increased frequency of events such as myocardial infarction and ischemic stroke. The triggering mechanisms for these events are not clear. We investigated whether autonomic changes occurring during sleep, particularly rapid-eye-movement (REM) sleep, contribute to the initiation of such events. METHODS We measured blood pressure, heart rate, and sympathetic-nerve activity (using microneurography, which provides direct measurements of efferent sympathetic-nerve activity related to muscle blood vessels) in eight normal subjects while they were awake and while in the five stages of sleep. RESULTS The mean (+/- SE) amplitude of bursts of sympathetic-nerve activity and levels of blood pressure and heart rate declined significantly (P < 0.001), from 100 +/- 9 percent, 90 +/- 4 mm Hg, and 64 +/- 2 beats per minute, respectively, during wakefulness to 41 +/- 9 percent, 80 +/- 4 mm Hg, and 59 +/- 2 beats per minute, respectively, during stage 4 of non-REM sleep. Arousal stimuli during stage 2 sleep elicited high-amplitude deflections on the electroencephalogram (called K complexes), which were frequently associated with bursts of sympathetic-nerve activity and transient increases in blood pressure. During REM sleep, sympathetic-nerve activity increased significantly (to 215 +/- 11 percent; P < 0.001) and the blood pressure and heart rate returned to levels similar to those during wakefulness. Momentary restorations of muscle tone during REM sleep (REM twitches) were associated with cessation of sympathetic-nerve discharge and surges in blood pressure. CONCLUSIONS REM sleep is associated with profound sympathetic activation in normal subjects, possibly linked to changes in muscle tone. The hemodynamic and sympathetic changes during REM sleep could play a part in triggering ischemic events in patients with vascular disease.

Investigating the Relationship Between Stroke and Obstructive Sleep Apnea

BACKGROUND AND PURPOSE We aimed to prospectively determine whether the incidence of obstructive sleep apnea in patients with recent stroke was significantly different from that of a sex- and age-matched control group with no major medical problems. METHODS We prospectively performed overnight polysomnography in 24 patients with a recent stroke (13 men and 11 women; mean age [+/- SD], 64.6 +/- 10.4 years) and 27 subjects without stroke (13 men and 14 women; mean age, 61.6 +/- 8.8 years). Patients with either ischemic or hemorrhagic stroke were entered into this study. Polysomnographic evaluations were performed within approximately 2 to 5 weeks after each patients stroke. RESULTS Obstructive sleep apnea was found in 10 of 13 men with stroke (77%) and in only 3 of 13 male subjects without stroke (23%) (P=.0169). Seven of 11 women with stroke (64%) had obstructive sleep apnea, while only 2 of 14 female subjects without stroke (14%) had obstructive sleep apnea (P=.0168). For men with stroke, the mean apnea/hypopnea index (+/- SE) was 21.5 +/- 4.2 events per hour, while for male subjects without stroke it was 4.8 +/- 1.8 events per hour (P=.0014). For women with stroke the mean apnea/hypopnea index was 31.6 +/- 8.8 events per hour, while for female subjects without stroke it was 2.9 +/- 1.6 events per hour (P=.0024). The 4-year mortality for patients with stroke was 20.8%. All patients with stroke who died had obstructive sleep apnea. CONCLUSIONS Patients with stroke have an increased incidence of obstructive sleep apnea compared with normal sex- and age-matched control subjects. Hypoxia and hemodynamic responses to obstructive sleep apnea may have predisposed these patients to stroke.

Altered cardiovascular variability in obstructive sleep apnea

BACKGROUND Altered cardiovascular variability is a prognostic indicator for cardiovascular events. Patients with obstructive sleep apnea (OSA) are at an increased risk for cardiovascular disease. We tested the hypothesis that OSA is accompanied by alterations in cardiovascular variability, even in the absence of overt cardiovascular disease. METHODS AND RESULTS Spectral analysis of variability of muscle sympathetic nerve activity, RR interval, and blood pressure were obtained during undisturbed supine rest in 15 patients with moderate-to-severe OSA, 18 patients with mild OSA, and 16 healthy control subjects in whom sleep disordered breathing was excluded by complete overnight polysomnography. Patients with OSA were newly diagnosed, never treated for OSA, and free of any other known diseases. Patients with moderate-to-severe OSA had shorter RR intervals (793+/-27 ms) and increased sympathetic burst frequency (49+/-4 bursts/min) compared with control subjects (947+/-42 ms; 24+/-3 bursts/min; P=0.008 and P<0.001, respectively). In these patients, total variance of RR was reduced (P=0.01) and spectral analysis of RR variability showed an increase in low frequency normalized units, a decrease in high frequency normalized units, and an increase in the ratio of low to high frequency (all P<0.05). Even though blood pressure was similar to that of the control subjects, blood pressure variance in patients with moderate-to-severe OSA was more than double the variance in control subjects (P=0.01). Patients with mild OSA also had a reduction in RR variance (P=0.02) in the absence of any significant difference in absolute RR interval. For all patients with OSA, linear regression showed a positive correlation (r=0.40; P=0.02) between sleep apnea severity and blood pressure variance. CONCLUSIONS Cardiovascular variability is altered in patients with OSA. This alteration is evident even in the absence of hypertension, heart failure, or other disease states and may be linked to the severity of OSA. Abnormalities in cardiovascular variability may be implicated in the subsequent development of overt cardiovascular disease in patients with OSA.

Sympathetic Activity in Obese Subjects With and Without Obstructive Sleep Apnea

BACKGROUND Obese humans are reported to have increased muscle sympathetic nerve activity (MSNA). Obstructive sleep apnea (OSA) may also be accompanied by increased MSNA. Because there is a high prevalence of OSA in obese humans, it is possible that high MSNA reported in obese subjects may in fact reflect the presence of OSA in these subjects. We tested the hypothesis that obesity, per se, in the absence of OSA, is not accompanied by increased MSNA. METHODS AND RESULTS We measured MSNA in 25 healthy normal-weight subjects and 30 healthy sedentary obese subjects. All subjects were screened by history and examination to exclude subjects with OSA or hypertension. OSA was further excluded by overnight polysomnographic studies. Despite careful screening, polysomnography revealed that 1 of 25 normal-weight subjects and 9 of 30 obese subjects had occult OSA (P=0.015). MSNA was similar in normal-weight subjects (41+/-3 bursts per 100 heartbeats) and obese subjects without sleep apnea (42+/-3 bursts per 100 heartbeats, P=0.99). MSNA in the 9 obese subjects with occult OSA was 61+/-8 bursts per 100 heartbeats, which was higher than MSNA in normal-weight subjects without sleep apnea (P=0.02) and higher than MSNA in obese subjects without sleep apnea (P=0.02). CONCLUSIONS Obesity alone, in the absence of OSA, is not accompanied by increased sympathetic activity to muscle blood vessels.

Selective Potentiation of Peripheral Chemoreflex Sensitivity in Obstructive Sleep Apnea

BACKGROUND The chemoreflexes are an important mechanism for regulation of both breathing and autonomic cardiovascular function. Abnormalities in chemoreflex mechanisms may be implicated in increased cardiovascular stress in patients with obstructive sleep apnea (OSA). We tested the hypothesis that chemoreflex function is altered in patients with OSA. METHODS AND RESULTS We compared ventilatory, sympathetic, heart rate, and blood pressure responses to hypoxia, hypercapnia, and the cold pressor test in 16 untreated normotensive patients with OSA and 12 normal control subjects matched for age and body mass index. Baseline muscle sympathetic nerve activity (MSNA) was higher in the patients with OSA than in the control subjects (43+/-4 versus 21+/-3 bursts per minute; P<0. 001). During hypoxia, patients with OSA had greater increases in minute ventilation (5.8+/-0.8 versus 3.2+/-0.7 L/min; P=0.02), heart rate (10+/-1 versus 7+/-1 bpm; P=0.03), and mean arterial pressure (7+/-2 versus 0+/-2 mm Hg; P=0.001) than control subjects. Despite higher ventilation and blood pressure (both of which inhibit sympathetic activity) in OSA patients, the MSNA increase during hypoxia was similar in OSA patients and control subjects. When the sympathetic-inhibitory influence of breathing was eliminated by apnea during hypoxia, the increase in MSNA in OSA patients (106+/-20%) was greater than in control subjects (52+/-23%; P=0.04). Prolongation of R-R interval with apnea during hypoxia was also greater in OSA patients (24+/-6%) than in control subjects (7+/-5%) (P=0.04). Autonomic, ventilatory, and blood pressure responses to hypercapnia and the cold pressor test in OSA patients were not different from those observed in control subjects. CONCLUSIONS OSA is associated with a selective potentiation of autonomic, hemodynamic, and ventilatory responses to peripheral chemoreceptor activation by hypoxia.

Effects of obstructive sleep apnea on endothelin-1 and blood pressure

OBJECTIVE To evaluate blood pressure and humoral vasoconstrictor responses to recurrent episodes of obstructive sleep apnea and the effects of therapy by means of continuous positive airway pressure. PATIENTS AND METHODS We prospectively evaluated overnight changes in hemodynamics, oxygen saturation, the apnea-hypopnea index, circulating endothelin-1, norepinephrine and plasma renin activity in 22 patients with severe obstructive sleep apnea before and after successful therapy using continuous positive airway pressure therapy (three measurements). Measurements of endothelin-1 and blood pressure were also obtained on three occasions, at similar times, in 12 healthy control subjects without sleep disturbances. RESULTS Mean arterial pressure and endothelin-1 concentrations increased significantly after 4 h of untreated obstructive sleep apnea, and decreased after 5 h of continuous positive airway pressure. Changes in endothelin-1 levels were correlated with changes in mean arterial pressure (r = 0.44, P < 0.02) and with changes in oxygen saturation (r = 0.37, P < 0.05). Norepinephrine levels and plasma renin activity did not change significantly in patients with obstructive sleep apnea, and were not correlated with changes in blood pressure or oxygen saturation. In controls, blood pressure measurements at similar times during the night showed changes directionally opposite to that seen in obstructive sleep apnea, while endothelin-1 levels remained unchanged. CONCLUSIONS Sleep apnea elicits increases in blood pressure and endothelin-1, with reductions in both after treatment. Vasoconstrictor and mitogenic effects of endothelin-1 may be implicated in increased cardiovascular risk in patients with obstructive sleep apnea.

Contribution of tonic chemoreflex activation to sympathetic activity and blood pressure in patients with obstructive sleep apnea

BACKGROUND Muscle sympathetic nerve activity (MSNA) is increased in patients with obstructive sleep apnea (OSA). We tested the hypothesis that tonic activation of excitatory chemoreceptor afferents contributes to the elevated sympathetic activity in OSA. METHODS AND RESULTS Using a double-blind, randomized, vehicle-controlled design, we examined the effects of chemoreflex deactivation (by comparing effects of breathing 100% oxygen for 15 minutes with effects of breathing room air for 15 minutes) on MSNA, heart rate, blood pressure, and minute ventilation in 14 untreated patients with OSA and in 12 normal subjects matched for age and body mass index. All control subjects underwent overnight polysomnography to exclude the existence of occult OSA. Baseline MSNA was markedly elevated in the patients with OSA compared with the control subjects (44+/-4 versus 30+/-3 bursts per minute; P=.01). In both control subjects and patients with OSA, heart rate decreased during administration of 100% oxygen but did not change during administration of room air. By contrast, both MSNA (P=.008) and mean arterial pressure (P=.02) were significantly reduced during chemoreflex deactivation by 100% oxygen only in patients with OSA but not in control subjects. CONCLUSIONS Tonic activation of excitatory chemoreflex afferents may contribute to increased efferent sympathetic activity to muscle circulation in patients with OSA.

Recent weight gain in patients with newly diagnosed obstructive sleep apnea

OBJECTIVE Patients with obstructive sleep apnea are often obese. Obesity may contribute to both sleep apnea itself and to the cardiovascular risk associated with sleep apnea. Weight loss in obese patients with sleep apnea may alleviate symptoms and decrease the severity of sleep apnea. Whether patients with obstructive sleep apnea are indeed predisposed to recent weight gain, as compared with similarly obese subjects without sleep apnea, is not known. PATIENTS AND METHODS We compared 1-year weight histories in 53 male and female patients newly diagnosed with obstructive sleep apnea, compared with 24 controls matched for gender, age, body mass index, and percent body fat. Sleep apnea patients had never been treated. Control subjects were proven to be free of sleep-disordered breathing by overnight polysomnography. RESULTS Patients with obstructive sleep apnea (n = 53) had a significant recent weight gain of 7.4 +/- 1.5 kg compared with a weight loss of 0.5 +/- 1.7 kg (P = 0.001) in similarly obese controls (n = 24). Male patients with obstructive sleep apnea (n = 28) had a history of significant weight gain (6.8 +/- 2.3 kg) over the year preceding the study compared with male control subjects (n = 13), in whom average weight fell by 0.58 +/- 2.4 kg (P = 0.03). Female patients (n = 25) with obstructive sleep apnea had an 8.0 +/- 1.9 kg weight gain compared with female controls (n = 11) who had a history of weight loss of 0.46 +/- 2.6 kg (P = 0.02). CONCLUSION These findings support the concept that patients with obstructive sleep apnea may be susceptible to increasing obesity in the period preceding the diagnosis of obstructive sleep apnea.

Autonomic and hemodynamic responses and interactions during the Mueller maneuver in humans

We compared the responses to a Mueller maneuver maintained for 20 s to effects of an equal period of end expiratory apnea. We measured heart rate, mean blood pressure (BP), central venous pressure (CVP), and sympathetic nerve activity (SNA) in 9 normal humans. The Mueller maneuver was accompanied by a fall in CVP from 5 +/- 1.2 to -13 +/- 3.2 mmHg (P < 0.05). During the first 10 s of Mueller, BP fell from 95 +/- 4.2 to 81 +/- 5.5 mmHg and SNA fell as low as 16 +/- 6% of control (P < 0.05). For the 5 s prior to release SNA increased to 236 +/- 36% (P < 0.05), and BP began to increase. Release of the Mueller resulted in a surge in BP to 104 +/- 5.8 mmHg and suppression of SNA to 61 +/- 48% (P < 0.05). By contrast, there was no fall in BP or CVP during apnea and SNA increased to 188 +/- 24% for the first 5 s. Between 16 and 20 s of apnea SNA was 231 +/- 52% and BP increased from 92 +/- 3.1 to 96 +/- 3.6 mmHg (P < 0.05). Release of apnea resulted in a surge in BP to 105 +/- 3.0 mmHg and suppression of SNA to 30 +/- 12% (P < 0.05). Oscillations in BP and SNA during the Mueller maneuver may contribute to similar oscillations, and hence cardiovascular consequences, in patients with sleep apnea.