(Circulation. 1999;99:1183-1189.)
© 1999 American Heart Association, Inc.
Clinical Investigation and Reports |
Selective Potentiation of Peripheral Chemoreflex Sensitivity in Obstructive Sleep Apnea
From the Cardiovascular Division, Department of Internal Medicine (K.N., P.J.H.v.d.B., C.A.P., V.K.S.) and Department of Neurology (M.E.D.), University of Iowa College of Medicine, Iowa City, and Centro L.I.T.A. Vialba, Centro Ricerche Cardiovascolari, CNR, Medicina Interna II, Ospedalè L. Sacco, Universitá degli Studi di Milano, Italy (N.M.).
Correspondence to Virend Somers, MD, PhD, Cardiovascular Division, Department of Internal Medicine, University of Iowa, 200 Hawkins Dr, Iowa City, IA 52242. E-mail virend-somers{at}uiowa.edu
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Abstract |
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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.
Key Words: nervous system • sleep • blood pressure • heart rate • hypoxia
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Introduction |
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Peripheral chemoreceptors, located in the carotid bodies, respond primarily to hypoxia.1 2 Central chemoreceptors, located on the ventral surface of the medulla, respond primarily to hypercapnia.3 Peripheral and central chemoreceptors are the dominant reflex control mechanisms regulating ventilatory responses to changes in arterial oxygen and carbon dioxide content.4
Both sets of chemoreceptors also have powerful effects on neural circulatory control.5 6 7 8 9 Peripheral chemoreceptors elicit increases in sympathetic nerve traffic, with consequent increases in blood pressure.10 11 12 Peripheral chemoreflex activation in the absence of breathing (the diving reflex) increases sympathetic vasoconstrictor activity to peripheral blood vessels and also simultaneously increases cardiac vagal activity, causing bradycardia.13 14 15 Central chemoreceptor activation increases sympathetic nerve traffic and blood pressure.11 Increased blood pressure and increased minute ventilation both inhibit the sympathetic response to chemoreflex activation.11 12 16
Patients with obstructive sleep apnea (OSA) experience repeated prolonged episodes of cessation of breathing during sleep due to upper airway occlusion during inspiration.17 These patients also have high sympathetic activity, even during normoxic wakefulness.18 19 20 The chemoreflexes are an important mechanism for regulation of both breathing and autonomic cardiovascular function. Abnormalities in chemoreflex mechanisms may therefore be implicated in increased cardiovascular stress in patients with OSA.21
Chemoreflex activation elicits a number of cardiorespiratory responses, with complex interactions between the responses themselves. Therefore, to define any abnormalities in chemoreflex function, it is important that key components of the integrated chemoreflex response be considered. Previous studies examining chemoreflex responses in patients with OSA have examined primarily the ventilatory responses to hypoxia. These studies have reported conflicting results, showing either decreased,22 23 increased,24 25 or normal responses26 to hypoxia in patients with OSA. Hypertension,27 obesity,28 and age29 significantly influence chemoreflex sensitivity. Furthermore, the effects of treatment with medications and/or continuous positive airway pressure on chemoreflex function are unpredictable. Thus, the absence of control for these variables may be implicated in the inconsistency in the literature. In addition, even asymptomatic obese individuals have a high incidence of occult significant OSA.30 Thus, undiagnosed OSA in apparently normal control subjects may inadvertently obscure any distinctive chemoreflex abnormalities in OSA per se.
We tested the hypothesis that chemoreflex function is altered in OSA, independent of factors such as hypertension, obesity, and age. We measured autonomic, ventilatory, and hemodynamic responses to peripheral chemoreceptor activation by hypoxia and to central chemoreceptor activation by hypercapnia in newly diagnosed, never-treated patients with OSA who were free of any other known disease and were on no medications. These responses were compared with those obtained in normal control subjects closely matched for age and body mass index, in whom occult OSA was excluded by complete overnight polysomnographic study. To ensure that any abnormalities in chemoreflex function were specific to the chemoreflexes and did not represent a nonspecific generalized abnormality in response to excitatory stimuli, we also compared the responses to the cold pressor test, which served as an internal control.31
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Methods |
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Subjects
To avoid the confounding effects of comorbidities and treatment, we studied only patients with newly diagnosed OSA who were normotensive, free of any other diseases, and on no medications and had never been treated for OSA. Of
200 sleep apneic patients screened,
16 (13 men) fulfilled the criteria and agreed to participate in the
study (mean age, 42±2 years; mean body mass index, 33±2
kg/m2). Severity of OSA was defined on the basis
of the apnea-hypopnea index, indicating the number of respiratory
irregularities per sleep-hour. The 16 sleep apneic patients had an
apnea-hypopnea index of 38±8 events per hour. We also studied 12 healthy control subjects (9 men) matched for age and body mass index (mean age, 40±3 years; mean body mass index, 33±2 kg/m2). Sleep disordered breathing was excluded in control subjects by complete overnight polysomnographic studies.
Informed written consent was obtained from all subjects. The study was approved by the Institutional Human Subjects Review Committee.
Measurements
Heart rate was measured continuously by an ECG. Blood pressure
was measured each minute by an automatic sphygmomanometer (Life Stat
200, Physio-Control Corp). Oxygen saturation was monitored with a pulse
oximeter (Nellcor Inc). End-tidal CO2 was
monitored with a Hewlett-Packard 47210A Capnometer. Minute ventilation
was determined with a KL Engineering S430 monitor. Breathing was via a
mouthpiece with a nose clip to ensure exclusive mouth
breathing.
Sympathetic nerve activity to muscle was recorded continuously by multiunit recordings of postganglionic sympathetic activity to muscle circulation, measured from a nerve fascicle in the peroneal nerve posterior to the fibular head, as described previously.32
Protocol and Procedures
Subjects were studied in the supine position. The protocol used
to determine chemoreflex responses to isocapnic hypoxia and
hyperoxic hypercapnia was identical to that used in previous
studies.11 12 16 Subjects were exposed to a hypoxic gas
mixture to induce peripheral chemoreflex activation (10%
O2 in N2 with
CO2 titrated to maintain isocapnia) and a
hypercapnic gas mixture to induce central chemoreflex activation (7%
CO2 /93% O2). During
hypoxic stimulation of peripheral chemoreceptors,
perturbation of central chemoreceptors was minimized by the
maintenance of isocapnia.12 During hypercapnic
stimulation of central chemoreceptors, perturbation of
peripheral chemoreceptors was minimized by
hyperoxia.11 The sequence of hypoxic and hypercapnic
interventions was randomized. At least 15 minutes separated the end of
one intervention from the beginning of the next.
Baseline measurements were taken during a 5-minute period of stable ventilation while subjects breathed room air with a mouthpiece. Then, by use of a 3-way valve, the subjects were exposed to either the hypoxic or hypercapnic stressors for 3 minutes. Average values for the 3-minute period of gas exposure were used in comparison to measurements obtained at baseline. At the end of the gas exposure, the subjects underwent a brief period of voluntary end-expiratory apnea to examine the sympathetic responses to chemoreflex activation in the absence of the inhibitory influence of the thoracic afferents. Two patients with OSA were unable to comfortably tolerate the stress of hypoxia and/or hypercapnia. Consequently, we completed studies examining the effects of hypoxia in 15 patients with OSA and the effects of hypercapnia in 14 patients with OSA. Ten control subjects and 12 patients with OSA underwent a subsequent cold pressor test. The cold pressor test is a stimulus for ventilation and sympathetic excitation and involves immersing the subject's hand into ice water for 2 minutes.31 33
Analyses
Sympathetic bursts were identified by a careful inspection of
the voltage neurogram. The amplitude of each burst was determined, and
sympathetic activity was calculated as bursts per minute multiplied by
mean burst amplitude and expressed as units per minute. The
intraobserver and interobserver variabilities in our laboratory are
4.3±0.3%34 and 5.4±0.5%,35 respectively.
Measurement of nerve activity at baseline before each intervention was
expressed as 100%. For the apneas, the first 10 seconds were
analyzed, because all patients and control subjects were able
to maintain apnea for at least 10 seconds at the end of the hypoxic and
hypercapnic exposures. Changes in sympathetic nerve activity and
maximal R-R prolongation during apnea were expressed as a percentage
increase from the preceding minute (eg, last minute of hypoxia
or hypercapnia).
Demographic data and baseline characteristics were compared by an unpaired t test. Responses to hypoxia, hypercapnia, and the cold pressor test were analyzed by repeated-measures ANOVA with time (baseline versus intervention) as the within factor and group (the control subjects versus the patients with OSA) as the between factor. The key variable was the group-by-time interaction. Data are presented as mean±SEM. A value of P<0.05 was considered significant.
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Results |
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Resting Values
Table 1
shows baseline
characteristics of the patients with OSA and control subjects during
free breathing of room air. Oxygen saturation, mean
arterial pressure (MAP), and heart rate in patients with
OSA were similar to those observed in the normal obese subjects without
OSA. Baseline muscle sympathetic nerve activity (MSNA) was markedly
elevated in the patients with OSA compared with the control subjects
(43±4 versus 21±3 bursts per minute; P<0.001).
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Effects of Hypoxia
The change in oxygen saturation during hypoxia was similar
in patients with OSA and in control subjects (Table 2, Figures 1 and 2).
The control subjects and the patients with OSA both showed increases in
minute ventilation and heart rate during hypoxia. However, the
increase in heart rate (P=0.03) and minute ventilation
(P=0.02) was significantly greater in patients with OSA
(Table 2, Figures 1 and 2). MAP in the control
subjects did not increase during hypoxia (Table 2,
Figure 2). By contrast, MAP increased by 7.1±1.6 mm Hg
during hypoxia in patients with OSA, and the group-by-time
interaction was highly significant (P=0.001) (Table 2, Figure 2).
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) in oxygen saturation (O2
sat), minute ventilation (VE), MAP, and MSNA during
hypoxia in control subjects (
) and in patients with OSA
(
). Similar degrees of oxygen desaturation induced greater increases
in minute ventilation and MAP in patients with OSA. Despite higher
VE and MAP in OSA patients, MSNA response in OSA patients
was still comparable to that seen in control subjects.
*P<0.05 for group-by-time interaction. Data are
mean±SEM.
Despite higher minute ventilation and higher blood pressure during
hypoxia in the OSA patients, hypoxia induced similar
percentage increases in MSNA in the control subjects and in the
patients with OSA (Figure 1
, Figure 3). The magnitude of these increases
during breathing was not significantly different between the 2 groups
(Table 2, Figure 2).
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Effects of Apnea During Hypoxia
When the inhibitory influence of breathing during
hypoxia was eliminated by apnea, the increase in sympathetic
nerve activity in patients with OSA was greater than in the control
subjects (Figures 1 and 3). Sympathetic nerve activity
during apnea increased by 52±23% in the normal subjects and by
106±20% in the patients with OSA (P=0.04). Prolongation of
R-R interval during apnea was greater in the patients with OSA
(24±6%) than in the control subjects (7±5%; P=0.04)
(Figure 3).
Effects of Hypercapnia
The magnitude of the ventilatory, heart rate, blood
pressure, and MSNA responses to hypercapnia was similar in the control
subjects and patients with OSA (Table 3).
Changes in MSNA and R-R interval in response to apnea during
hypercapnia were also similar in the 2 groups (data not shown).
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Effects of the Cold Pressor Test
Autonomic, ventilatory, and blood pressure changes during the cold
pressor test in patients with OSA were not significantly different from
those observed in the control subjects (Figure 4).
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Discussion |
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The novel findings of this study are, first, that the peripheral chemoreflex response to hypoxia is potentiated in patients with OSA. This is evident in the increased ventilatory, pressor, and heart rate responses to hypoxic breathing. Because the ventilatory response to hypoxia inhibits and may therefore obscure the autonomic chemoreflex responses, it is only during apnea that the potentiated sympathetic response (to peripheral blood vessels) and vagal response (to the heart) become evident. Second, this chemoreflex abnormality is selective for the peripheral chemoreflex. There is preservation of the normal responses to both central chemoreflex activation and the cold pressor test.
During hypoxic breathing, ventilation and blood pressure
increased substantially in OSA patients compared with normal control
subjects. Both of these act as powerful restraints on the sympathetic
response to hypoxia.12 16 When blood pressure in
normal subjects is increased (by intravenous
phenylephrine) to levels similar to the increase observed
in sleep apneic patients exposed to hypoxia, the sympathetic
response to hypoxia is eliminated in normal
subjects.16 Nevertheless, in the present study, the
increase in sympathetic activity in OSA patients during hypoxia
was still comparable to that seen in control subjects, despite the
higher blood pressures and higher ventilation. Thus, in OSA patients,
the chemoreflex appears to be a potent mechanism for sympathetic
activation, overriding the combined restraining influences of increased
blood pressure and increased ventilation. This suggests, but does not
prove, that not only the ventilatory but also the chemoreflex-mediated
sympathetic autonomic response to hypoxia is augmented in OSA.
The proof is evident during apnea, when the vagolytic and
sympathetic-inhibitory influences of breathing are
eliminated.5 During apnea, an enhanced
peripheral sympathetic response and an enhanced vagal
bradycardic response are manifest. Thus, there is a global potentiation
of the peripheral chemoreflex response in OSA, affecting
both the ventilatory and autonomic efferent limbs of the reflex.
Potentiated ventilatory27 and sympathetic36
responses to hypoxia were demonstrated previously in patients
with hypertension. However, the enhanced chemoreflex responses we
report are evident in the absence of higher blood pressure in the
OSA patients (Figure 1).
Previous studies examining the pressor response to hypoxia in OSA have yielded conflicting results.24 26 37 Our data show clearly that the blood pressure increase during hypoxia is markedly exaggerated in OSA patients. These findings are important in understanding the absence of any nocturnal blood pressure decline in untreated sleep apneics, in whom repetitive apneic episodes elicit surges in blood pressure throughout the night.20 Furthermore, pressor responses and consequent baroreflex resetting to a higher set point may be implicated in the development of sustained hypertension in these patients.37 38 The exaggerated pressor response to hypoxia in OSA is explained in part by the greater increase in heart rate. However, other factors, such as impaired hypoxic vasodilator effects, cannot be excluded. The absence of any increased pressor response to the cold pressor test suggests that that the increased pressor response to hypoxia in OSA is not explained by any nonspecific exaggeration of the pressor response to excitatory stimuli generally.
Important strengths of this study include, first, that both ventilatory and cardiovascular responses to hypoxia were studied and that both these responses were shown to be potentiated in OSA patients. Second, all OSA patients were newly diagnosed, never treated, and free of any other known disease. Third, control subjects were closely matched for age and body mass index. Control subjects also underwent complete overnight polysomnographic study to exclude occult undiagnosed OSA, which is highly prevalent even in asymptomatic, seemingly normal, obese subjects.30 Fourth, all participants in this study were on no medications. Thus, the potential influence of confounding variables, such as hypertension, age, obesity, treatment (either with continuous positive airway pressure or medications), and occult OSA, in control subjects was eliminated.
Possible limitations of our study include, first, that chemoreflex measurements were obtained during daytime wakefulness. Nevertheless, the autonomic chemoreflex responses we report are very similar to those observed during nighttime sleep in patients with OSA. During sleep, these patients experience sympathetic activation in response to oxygen desaturation, with consequent surges in blood pressure.20 Patients with OSA also demonstrate a cyclical variation of nocturnal heart rate, with progressive bradycardia and often bradyarrhythmias.39 40 The pattern of heart rate during sleep apneic events correlates very closely with changes seen with apnea during hypoxia while awake.41 Second, we did not address the possible influence of familial aggregation of OSA42 43 44 on chemoreflex function. There may be a subset of patients with familial OSA who have a reduced ventilatory response to hypoxia.44 Third, our data do not address the question of whether an enhanced peripheral chemoreflex sensitivity to hypoxia is implicated in the pathogenesis of OSA. Increased chemoreflex sensitivity may be merely an adaptive response to repetitive apneas during sleep.
A recent study by Kimoff and colleagues45 speaks directly to this question. These investigators devised a dog model closely simulating OSA in humans.46 47 They induced repetitive nocturnal airway obstructions in previously normal dogs, closely mimicking the OSA syndrome. After 3 months of simulated OSA, the chemoreflex responses to hypoxia in these dogs were strikingly reduced during wakefulness and were also reduced significantly during sleep.45 Therefore, OSA would be expected to result in a reduction in chemoreflex sensitivity. The findings of enhanced chemoreflex sensitivity in our patients are therefore unlikely to be explained as an adaptive response to repetitive apneic events.
In conclusion, these data demonstrate a specific potentiation of autonomic and ventilatory responses to peripheral chemoreceptor activation in OSA. By contrast, responses to central chemoreceptor activation and responses to the nonspecific excitatory cold pressor stimulus are preserved. We speculate that this abnormality in the peripheral chemoreceptor response may be implicated in increased cardiovascular stress and morbidity in patients with OSA.
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Acknowledgments |
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Dr Narkiewicz, a visiting research scientist from the Department of Hypertension and Diabetology, Medical School of Gdansk, Poland, is a recipient of an International Research John E. Fogarty Fellowship (NIH 3F05-TW-05200) and a Perkins Memorial Award from the American Physiological Society. These studies were also supported by an American Heart Association Established Investigator Grant, National Institutes of Health grant HL-14388, and a Sleep Academic Award from the National Institutes of Health (Dr Somers). We thank Diane Davison, RN, MA, for technical assistance.
Received July 28, 1998; revision received October 28, 1998; accepted November 23, 1998.
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 J. H. Mateika and G. Narwani Intermittent hypoxia and respiratory plasticity in humans and other animals: does exposure to intermittent hypoxia promote or mitigate sleep apnoea? Exp Physiol, March 1, 2009; 94(3): 279 - 296. [Abstract] [Full Text] [PDF]
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 F. H. Sert Kuniyoshi, A. Garcia-Touchard, A. S. Gami, A. Romero-Corral, C. van der Walt, S. Pusalavidyasagar, T. Kara, S. M. Caples, G. S. Pressman, E. C. Vasquez, et al. Day-Night Variation of Acute Myocardial Infarction in Obstructive Sleep Apnea J. Am. Coll. Cardiol., July 29, 2008; 52(5): 343 - 346. [Abstract] [Full Text] [PDF]
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S. W. Mifflin NO and CO have got to GO for enhanced chemoreceptor sympathoexcitation in heart failure J Appl Physiol, July 1, 2008; 105(1): 1 - 2. [Full Text] [PDF]
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Z. Dujic, V. Ivancev, K. Heusser, G. Dzamonja, I. Palada, Z. Valic, J. Tank, A. Obad, D. Bakovic, A. Diedrich, et al. Central chemoreflex sensitivity and sympathetic neural outflow in elite breath-hold divers J Appl Physiol, January 1, 2008; 104(1): 205 - 211. [Abstract] [Full Text] [PDF]
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U. A. Leuenberger, C. S. Hogeman, S. Quraishi, L. Linton-Frazier, and K. S. Gray Short-term intermittent hypoxia enhances sympathetic responses to continuous hypoxia in humans J Appl Physiol, September 1, 2007; 103(3): 835 - 842. [Abstract] [Full Text] [PDF]
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S.-E. Genest, N. Balon, S. Laforest, G. Drolet, and R. Kinkead Neonatal maternal separation and enhancement of the hypoxic ventilatory response in rat: the role of GABAergic modulation within the paraventricular nucleus of the hypothalamus J. Physiol., August 15, 2007; 583(1): 299 - 314. [Abstract] [Full Text] [PDF]
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P. M. de Paula, G. Tolstykh, and S. Mifflin Chronic intermittent hypoxia alters NMDA and AMPA-evoked currents in NTS neurons receiving carotid body chemoreceptor inputs Am J Physiol Regulatory Integrative Comp Physiol, June 1, 2007; 292(6): R2259 - R2265. [Abstract] [Full Text] [PDF]
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 V. A. Imadojemu, Z. Mawji, A. Kunselman, K. S. Gray, C. S. Hogeman, and U. A. Leuenberger Sympathetic Chemoreflex Responses in Obstructive Sleep Apnea and Effects of Continuous Positive Airway Pressure Therapy Chest, May 1, 2007; 131(5): 1406 - 1413. [Abstract] [Full Text] [PDF]
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M. Gujic, A. Houssiere, O. Xhaet, J.-F. Argacha, N. Denewet, A. Noseda, P. Jespers, C. Melot, R. Naeije, and P. van de Borne Does Endothelin Play a Role in Chemoreception During Acute Hypoxia in Normal Men? Chest, May 1, 2007; 131(5): 1467 - 1472. [Abstract] [Full Text] [PDF]
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S. Ryan, S. Ward, C. Heneghan, and W. T. McNicholas Predictors of Decreased Spontaneous Baroreflex Sensitivity in Obstructive Sleep Apnea Syndrome Chest, April 1, 2007; 131(4): 1100 - 1107. [Abstract] [Full Text] [PDF]
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R. Wolk and V. K. Somers Sleep Apnoea & Hypertension: Physiological bases for a causal relation: Sleep and the metabolic syndrome Exp Physiol, January 1, 2007; 92(1): 67 - 78. [Abstract] [Full Text] [PDF]
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M. L. Smith and C. F. Pacchia Sleep Apnoea & Hypertension: Physiological bases for a causal relation: Sleep apnoea and hypertension: role of chemoreflexes in humans Exp Physiol, January 1, 2007; 92(1): 45 - 50. [Abstract] [Full Text] [PDF]
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G. E. Foster, M. J. Poulin, and P. J. Hanly Sleep Apnoea & Hypertension: Physiological bases for a causal relation: Intermittent hypoxia and vascular function: implications for obstructive sleep apnoea Exp Physiol, January 1, 2007; 92(1): 51 - 65. [Abstract] [Full Text] [PDF]
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N. R. Prabhakar, T. E. Dick, J. Nanduri, and G. K. Kumar Sleep Apnoea & Hypertension: Physiological bases for a causal relation: Systemic, cellular and molecular analysis of chemoreflex-mediated sympathoexcitation by chronic intermittent hypoxia Exp Physiol, January 1, 2007; 92(1): 39 - 44. [Abstract] [Full Text] [PDF]
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Y.-J. Peng, G. Yuan, D. Ramakrishnan, S. D. Sharma, M. Bosch-Marce, G. K. Kumar, G. L. Semenza, and N. R. Prabhakar Heterozygous HIF-1{alpha} deficiency impairs carotid body-mediated systemic responses and reactive oxygen species generation in mice exposed to intermittent hypoxia J. Physiol., December 1, 2006; 577(2): 705 - 716. [Abstract] [Full Text] [PDF]
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S.-J. C. Lusina, P. M. Kennedy, J. T. Inglis, D. C. McKenzie, N. T. Ayas, and A. W. Sheel Long-term intermittent hypoxia increases sympathetic activity and chemosensitivity during acute hypoxia in humans J. Physiol., September 15, 2006; 575(3): 961 - 970. [Abstract] [Full Text] [PDF]
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L. Spicuzza, L. Bernardi, R. Balsamo, N. Ciancio, R. Polosa, and G. Di Maria Effect of treatment with nasal continuous positive airway pressure on ventilatory response to hypoxia and hypercapnia in patients with sleep apnea syndrome. Chest, September 1, 2006; 130(3): 774 - 779. [Abstract] [Full Text] [PDF]
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K. D. Monahan, U. A. Leuenberger, and C. A. Ray Effect of repetitive hypoxic apnoeas on baroreflex function in humans J. Physiol., July 15, 2006; 574(2): 605 - 613. [Abstract] [Full Text] [PDF]
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C. J. Lai, C. C. H. Yang, Y. Y. Hsu, Y. N. Lin, and T. B. J. Kuo Enhanced sympathetic outflow and decreased baroreflex sensitivity are associated with intermittent hypoxia-induced systemic hypertension in conscious rats J Appl Physiol, June 1, 2006; 100(6): 1974 - 1982. [Abstract] [Full Text] [PDF]
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 R. Mehra, E. J. Benjamin, E. Shahar, D. J. Gottlieb, R. Nawabit, H. L. Kirchner, J. Sahadevan, and S. Redline Association of Nocturnal Arrhythmias with Sleep-disordered Breathing: The Sleep Heart Health Study Am. J. Respir. Crit. Care Med., April 15, 2006; 173(8): 910 - 916. [Abstract] [Full Text] [PDF]
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K. Narkiewicz, P. van de Borne, N. Montano, D. Hering, T. Kara, and V. K. Somers Sympathetic Neural Outflow and Chemoreflex Sensitivity Are Related to Spontaneous Breathing Rate in Normal Men Hypertension, January 1, 2006; 47(1): 51 - 55. [Abstract] [Full Text] [PDF]
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S. M. Caples, R. Wolk, and V. K. Somers Influence of cardiac function and failure on sleep-disordered breathing: evidence for a causative role J Appl Physiol, December 1, 2005; 99(6): 2433 - 2439. [Abstract] [Full Text] [PDF]
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M. J. Campen, L. A. Shimoda, and C. P. O'Donnell Acute and chronic cardiovascular effects of intermittent hypoxia in C57BL/6J mice J Appl Physiol, November 1, 2005; 99(5): 2028 - 2035. [Abstract] [Full Text] [PDF]
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 S. M. Caples, A. S. Gami, and V. K. Somers Obstructive Sleep Apnea Focus, October 1, 2005; 3(4): 557 - 567. [Full Text] [PDF]
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C. Hinojosa-Laborde and S. W. Mifflin Sex Differences in Blood Pressure Response to Intermittent Hypoxia in Rats Hypertension, October 1, 2005; 46(4): 1016 - 1021. [Abstract] [Full Text] [PDF]
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G. Grassi, A. Facchini, F. Q. Trevano, R. Dell'Oro, F. Arenare, F. Tana, G. Bolla, A. Monzani, M. Robuschi, and G. Mancia Obstructive Sleep Apnea-Dependent and -Independent Adrenergic Activation in Obesity Hypertension, August 1, 2005; 46(2): 321 - 325. [Abstract] [Full Text] [PDF]
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 A. S. Gami, D. E. Howard, E. J. Olson, and V. K. Somers Day-Night Pattern of Sudden Death in Obstructive Sleep Apnea N. Engl. J. Med., March 24, 2005; 352(12): 1206 - 1214. [Abstract] [Full Text] [PDF]
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 S. M. Caples, A. S. Gami, and V. K. Somers Obstructive Sleep Apnea Ann Intern Med, February 1, 2005; 142(3): 187 - 197. [Full Text] [PDF]
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A. Vovk, W. D. F Smith, N. D Paterson, D. A Cunningham, and D. H Paterson Peripheral chemoreceptor control of ventilation following sustained hypoxia in young and older adult humans Exp Physiol, November 1, 2004; 89(6): 647 - 656. [Abstract] [Full Text] [PDF]
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M. J. Cutler, N. M. Swift, D. M. Keller, W. L. Wasmund, J. R. Burk, and M. L. Smith Periods of intermittent hypoxic apnea can alter chemoreflex control of sympathetic nerve activity in humans Am J Physiol Heart Circ Physiol, November 1, 2004; 287(5): H2054 - H2060. [Abstract] [Full Text] [PDF]
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S. Rey, R. Del Rio, J. Alcayaga, and R. Iturriaga Chronic intermittent hypoxia enhances cat chemosensory and ventilatory responses to hypoxia J. Physiol., October 15, 2004; 560(2): 577 - 586. [Abstract] [Full Text] [PDF]
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G. J. Gates, S. E. Mateika, R. C. Basner, and J. H. Mateika Baroreflex Sensitivity in Nonapneic Snorers and Control Subjects Before and After Nasal Continuous Positive Airway Pressure Chest, September 1, 2004; 126(3): 801 - 807. [Abstract] [Full Text] [PDF]
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V. L. Cooper, C. M. Bowker, S. B. Pearson, M. W. Elliott, and R. Hainsworth Effects of simulated obstructive sleep apnoea on the human carotid baroreceptor-vascular resistance reflex J. Physiol., June 15, 2004; 557(3): 1055 - 1065. [Abstract] [Full Text] [PDF]
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M. J. Cutler, N. M. Swift, D. M. Keller, W. L. Wasmund, and M. L. Smith Hypoxia-mediated prolonged elevation of sympathetic nerve activity after periods of intermittent hypoxic apnea J Appl Physiol, February 1, 2004; 96(2): 754 - 761. [Abstract] [Full Text] [PDF]
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N. R. Prabhakar and Y.-J. Peng Peripheral chemoreceptors in health and disease J Appl Physiol, January 1, 2004; 96(1): 359 - 366. [Abstract] [Full Text] [PDF]
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J. A. Neubauer and J. Sunderram Oxygen-sensing neurons in the central nervous system J Appl Physiol, January 1, 2004; 96(1): 367 - 374. [Abstract] [Full Text] [PDF]
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N. Muenter Swift, M. J. Cutler, P. J. Fadel, W. L. Wasmund, S. Ogoh, D. M. Keller, P. B. Raven, and M. L. Smith Carotid baroreflex function during and following voluntary apnea in humans Am J Physiol Heart Circ Physiol, December 1, 2003; 285(6): H2411 - H2419. [Abstract] [Full Text] [PDF]
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 A. S. M. Shamsuzzaman, B. J. Gersh, and V. K. Somers Obstructive Sleep Apnea: Implications for Cardiac and Vascular Disease JAMA, October 8, 2003; 290(14): 1906 - 1914. [Abstract] [Full Text] [PDF]
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 J. A. S. Barreto-Filho, F. M. Consolim-Colombo, G. M. Guerra-Riccio, R. D. Santos, A. P. Chacra, H. F. Lopes, S. H. Teixeira, T. Martinez, J. E. Krieger, and E. M. Krieger Hypercholesterolemia Blunts Forearm Vasorelaxation and Enhances the Pressor Response During Acute Systemic Hypoxia Arterioscler. Thromb. Vasc. Biol., September 1, 2003; 23(9): 1660 - 1666. [Abstract] [Full Text] [PDF]
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J. A L Calbet Chronic hypoxia increases blood pressure and noradrenaline spillover in healthy humans J. Physiol., August 15, 2003; 551(1): 379 - 386. [Abstract] [Full Text] [PDF]
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S. Velez-Roa, B. Kojonazarov, A. Ciarka, P. Godart, R. Naeije, V. K. Somers, and P. van de Borne Dobutamine potentiates arterial chemoreflex sensitivity in healthy normal humans Am J Physiol Heart Circ Physiol, August 7, 2003; 285(3): H1356 - H1361. [Abstract] [Full Text] [PDF]
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T. Saaresranta and O. Polo Sleep-disordered breathing and hormones Eur. Respir. J., July 1, 2003; 22(1): 161 - 172. [Abstract] [Full Text] [PDF]
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J. Hansen and M. Sander Sympathetic neural overactivity in healthy humans after prolonged exposure to hypobaric hypoxia J. Physiol., February 1, 2003; 546(3): 921 - 929. [Abstract] [Full Text] [PDF]
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F. Garcia-Rio, J.M. Pino, T. Ramirez, D. Alvaro, A. Alonso, C. Villasante, and J. Villamor Inspiratory neural drive response to hypoxia adequately estimates peripheral chemosensitivity in OSAHS patients Eur. Respir. J., September 1, 2002; 20(3): 724 - 732. [Abstract] [Full Text] [PDF]
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M. R. Bonsignore, G. Parati, G. Insalaco, O. Marrone, P. Castiglioni, S. Romano, M. Di Rienzo, G. Mancia, and G. Bonsignore Continuous Positive Airway Pressure Treatment Improves Baroreflex Control of Heart Rate during Sleep in Severe Obstructive Sleep Apnea Syndrome Am. J. Respir. Crit. Care Med., August 1, 2002; 166(3): 279 - 286. [Abstract] [Full Text] [PDF]
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M. Elam, D. McKenzie, and V. Macefield Mechanisms of sympathoexcitation: single-unit analysis of muscle vasoconstrictor neurons in awake OSAS subjects J Appl Physiol, July 1, 2002; 93(1): 297 - 303. [Abstract] [Full Text] [PDF]
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R. S. T. LEUNG and T. DOUGLAS BRADLEY Sleep Apnea and Cardiovascular Disease Am. J. Respir. Crit. Care Med., December 15, 2001; 164(12): 2147 - 2165. [Full Text] [PDF]
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 M. G. Hennersdorf, S. Hillebrand, C. Perings, and B.-E. Strauer Chemoreflexsensitivity in chronic heart failure patients Eur J Heart Fail, December 1, 2001; 3(6): 679 - 684. [Abstract] [Full Text] [PDF]
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H. TESCHLER, J. DOHRING, Y.-M. WANG, and M. BERTHON-JONES Adaptive Pressure Support Servo-Ventilation . A Novel Treatment for Cheyne-Stokes Respiration in Heart Failure Am. J. Respir. Crit. Care Med., August 15, 2001; 164(4): 614 - 619. [Abstract] [Full Text] [PDF]
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S. Mahamed and J. Duffin Repeated hypoxic exposures change respiratory chemoreflex control in humans J. Physiol., July 15, 2001; 534(2): 595 - 603. [Abstract] [Full Text] [PDF]
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M.F. Hilton, M.J. Chappell, W.A. Bartlett, A. Malhotra, J.M. Beattie, and R.M. Cayton The sleep apnoea/hypopnoea syndrome depresses waking vagal tone independent of sympathetic activation Eur. Respir. J., June 1, 2001; 17(6): 1258 - 1266. [Abstract] [Full Text] [PDF]
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T. L. Clanton and P. F. Klawitter Physiological and Genomic Consequences of Intermittent Hypoxia: Invited Review: Adaptive responses of skeletal muscle to intermittent hypoxia: the known and the unknown J Appl Physiol, June 1, 2001; 90(6): 2476 - 2487. [Abstract] [Full Text] [PDF]
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T. L. Clanton, V. P. Wright, P. J. Reiser, P. F. Klawitter, and N. R. Prabhakar Physiological and Genomic Consequences of Intermittent Hypoxia: Selected Contribution: Improved anoxic tolerance in rat diaphragm following intermittent hypoxia J Appl Physiol, June 1, 2001; 90(6): 2508 - 2513. [Abstract] [Full Text] [PDF]
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I. Wilcox, S. G. McNamara, K. Narkiewicz, C. A. Pesek, P. J.H. van de Borne, M. Kato, and V. K. Somers Abnormal Breathing During Sleep and Increased Central Chemoreflex Sensitivity in Congestive Heart Failure Response Circulation, September 12, 2000; 102 (11): e91 - e91. [Full Text] [PDF]
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