(Circulation. 2000;102:2607.)
© 2000 American Heart Association, Inc.
Clinical Investigation and Reports |
Impairment of Endothelium-Dependent Vasodilation of Resistance Vessels in Patients With Obstructive Sleep Apnea
From the Division of Clinical and Administrative Pharmacy, University of Iowa Colleges of Medicine and Pharmacy (M.K., B.G.P.), and the Department of Internal Medicine, University of Iowa College of Medicine (P.R.-T., W.G.H.), Iowa City; and the Divisions of Hypertension and Cardiovascular Disease, Department of Internal Medicine, Mayo Clinic, Rochester, Minn (M.W., V.A., V.K.S.).
Correspondence to Virend K. Somers, MD, PhD, Divisions of Hypertension and Cardiovascular Disease, Department of Internal Medicine, Mayo Clinic, 200 First St SW, Rochester, MN 55905. E-mail somers.virend{at}mayo.edu
 |
Abstract |
|---|
 Top Abstract IntroductionMethodsResultsDiscussionReferences |
|---|
Background—Patients with obstructive sleep apnea (OSA) experience repetitive episodic hypoxemia with consequent sympathetic activation and marked blood pressure surges, each of which may impair endothelial function. We tested the hypothesis that patients with OSA have impaired endothelium-dependent vasodilation, even in the absence of overt cardiovascular disease.
Methods and Results—We studied 8 patients with OSA (age 44±4 years) and 9 obese control subjects (age 48±3 years). Patients with OSA were newly diagnosed, never treated for OSA, on no medications, and free of any other known diseases. All obese control subjects underwent complete overnight polysomnographic studies to exclude occult OSA. Resistance-vessel function was tested by use of forearm blood flow responses to intra-arterial infusions of acetylcholine (a vasodilator that stimulates endothelial release of nitric oxide), sodium nitroprusside (an exogenous nitric oxide donor), and verapamil (a calcium channel blocker). Conduit-vessel function was also evaluated by ultrasonography. Brachial artery diameter was measured under baseline conditions, during reactive hyperemia (with flow increase causing endothelium-dependent dilatation), and after sublingual administration of nitroglycerin (an endothelium-independent vasodilator). Patients with OSA had a blunted vasodilation in response to acetylcholine (P<0.007), but responses to sodium nitroprusside and verapamil were not significantly different from those of control subjects. No significant difference in conduit-vessel dilation was evident between OSA patients and obese control subjects.
Conclusions—Patients with OSA have an impairment of resistance-vessel endothelium-dependent vasodilation. This may be implicated in the pathogenesis of hypertension and heart failure in this condition.
Key Words: sleep • obesity • endothelium
|
Introduction |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Obstructive sleep apnea (OSA) has been linked to hypertension,1 heart failure,2 and stroke3 and to increased mortality.4 5 The mechanisms underlying the association between OSA and cardiovascular disease are not fully understood. Patients with OSA have a heightened sympathetic drive during wakefulness, which may increase even further during sleep. During sleep, these patients experience severe repetitive hypoxemic stress, with reflex sympathetic activation and consequent marked increases in blood pressure. Hypoxemia, sympathetic activation, and increased arterial pressure may impair endothelial function,6 7 suggesting a possible mechanism for the development of cardiovascular disease in OSA patients.
Endothelial dysfunction is characterized by an imbalance of endothelium-derived relaxing and contracting factors. It may contribute to the progression and complications of hypertension, atherosclerosis, and chronic heart failure.8 9 10 11 12 13 We tested the hypothesis that patients with OSA have impaired endothelial function compared with closely matched normal obese subjects shown to be free of OSA and independent of the presence of other disease states. We studied endothelium-dependent and -independent vasodilation in both resistance and conduit vessels.
|
Methods |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Subjects
We studied 8 male patients with OSA (age 44±4 years) and 9 male obese subjects without OSA (age 48±3 years). Patients with OSA were newly diagnosed, never treated for OSA, and free of any other known diseases. None of the subjects was taking medications. The studies were approved by the Institutional Review Board for Human Investigation, and written informed consent was obtained from all subjects before the study.
Measurements
Heart rate was measured continuously by ECG. Forearm
blood flow (FBF) was measured bilaterally by venous occlusion
plethysmography (EC4, Hokanson). Blood pressure was measured on the
noninfused arm with an automatic sphygmomanometer (Life Stat 200,
PhysioControl) for 2 minutes after each FBF measurement.
Respiration was monitored with a strain-gauge
pneumotachometer.
Protocol
Resistance-Vessel Dilation
The schematic of the randomized study design is shown
in
Figure 1
. All subjects abstained from the use of alcohol or
caffeine for 
24 hours before the study. Subjects were studied in the
supine position. A fine metal catheter was placed into the brachial
artery for arterial infusion of acetylcholine (ACh; a vasodilator that
stimulates endothelial release of nitric oxide [NO]), sodium
nitroprusside (SNP; an exogenous NO donor), and verapamil (VER; a
calcium channel blocker). Subjects then received intra-arterial
infusions of ACh, SNP, and VER
(Figure 1). The order of ACh and SNP was randomized between
subjects. VER was always infused last because of its longer-lasting
effect. Each infusion was preceded by a rest period of 20 minutes,
during which time saline (0.9% NaCl) was infused intra-arterially at a
constant rate of 1 mL/min.
|
Endothelium-dependent vasodilation was induced by infusing ACh intra-arterially in incremental doses of 3, 10, and 30 µg/min for 6 minutes each. Endothelium-independent vasodilation was induced by infusing SNP intra-arterially in incremental doses of 1, 3, and 10 µg/min for 6 minutes each. Calcium channel blocker vasodilation was induced by infusing VER intra-arterially in incremental doses of 30, 100, and 300 µg/min for 6 minutes each. FBF was measured at baseline and during the last 3 minutes of infusion of each dose.
Conduit-Vessel Dilation
Conduit-vessel dilation was studied in 16 subjects, 8
with OSA and 8 matched control subjects. Fourteen of these subjects
also underwent studies of resistance-vessel function. Subjects
underwent ultrasound evaluation of vasodilator function of the brachial
artery 1 hour after completion of resistance-vessel evaluation. The
ultrasound method for measuring endothelium-dependent and
endothelium-independent arterial dilation has been described
previously.14
Brachial artery diameter was measured by B-mode ultrasound images with
a 5.0-MHz linear-array transducer (Ultramark 9, Advanced Technology
Laboratories). The scans were obtained with the subject at rest and
after sublingual administration of nitroglycerin. Subjects lay quietly
for 30 minutes before the first scan. The brachial artery was scanned
in longitudinal section 5 cm above the elbow, and the center of the
artery was identified when the clearest picture of the anterior and
posterior intimal layers was obtained. When a satisfactory transducer
position was found, the skin was marked, and the arm remained in the
same position throughout the study. A resting scan was obtained, and
the Doppler velocity of arterial flow was measured with a
pulsed-Doppler signal at a 70° angle to the vessel in the center of
the artery. Reactive hyperemia was then induced by the inflation of a
blood pressure cuff placed around the forearm to a pressure of 220
mm Hg for 5 minutes, followed by release. The artery was scanned
continuously for 1 minute before and 2 minutes after deflation of the
cuff, including a repeated recording of flow velocity for the first 10
seconds after the cuff was released. Thereafter, 15 minutes was allowed
for recovery of the vessel, after which an additional resting scan was
performed. Sublingual nitroglycerin spray (400 µg) was then
administered, and the vessel was scanned continuously for 5
minutes.
The diameter of the vessel was measured by 3 observers unaware of the intervention being used. Measurements were taken at end diastole (peak of R wave of the ECG). Five cardiac cycles and 5 points across the vessel in each frame were analyzed, and measurements were averaged. Flow-mediated dilatation was calculated as percent increase in arterial diameter during hyperemia compared with the corresponding resting value. Nitroglycerin-induced dilation was calculated similarly. Reactive hyperemia was calculated as maximum velocity during the first 10 seconds after cuff deflation divided by the corresponding rest velocity.
Analyses
All analyses were conducted by observers unaware of
whether or not subjects had OSA. ECG, FBF, and respiration were
recorded simultaneously on a computerized data acquisition system
(MacLab, AD Instruments Inc) in combination with a Macintosh Quadra 950
Computer (Apple Computer Inc). FBF was expressed as mL/min per 100 mL
forearm volume. To avoid any systemic effects, changes in FBF were
expressed as the percent change from baseline in the ratio between the
infused-arm FBF and noninfused-arm FBF.
Results are expressed as mean±SEM. Differences in resistance-vessel dilation in response to ACh, SNP, and VER infusions were determined by 2-way ANOVA with repeated measures (SAS Institute Inc). Differences in baseline characteristics and conduit-vessel parameters (diameter, vasodilation, and flow) between OSA and control subjects were determined by an unpaired Student’s t test. Statistical significance was defined as P<0.05.
|
Results |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
FBF Studies
Baseline Measurements
The clinical characteristics of the subjects in the 2 study groups are indicated in Table 1
. There were no significant differences
between the 2 groups in age, body mass index, percent body fat, plasma
lipids, or plasma glucose. The apnea hypopnea index was significantly
different (OSA, 52±22; control subjects, 1±0;
P=0.03).
|
Vascular Responses to ACh, SNP, and VER
ACh infusion induced a dose-dependent increase in FBF
in both groups
(Figure 2). The percent change in infused/noninfused-arm FBF
was significantly reduced in the patients with OSA compared with
control subjects (P=0.007). The impairment in
responsiveness to ACH did not correlate with apnea hypopnea index or
oxygen desaturation.
|
Administration of increasing doses of SNP and VER increased FBF in both groups, but there was no significant difference between patients with OSA and control subjects (P=0.2 and P=0.5, respectively).
Brachial Artery Diameter Studies
Vascular Response to Reactive Hyperemia
The degree of reactive hyperemia produced by cuff
inflation and release was similar in OSA patients and control subjects
(P=0.7)
(Table 2). Arterial dilation increased by 3.7±0.7% in the
patients with OSA and 4.7±1.4% in the control subjects after cuff
release (P=0.54). Nitrate-induced dilation was
9.7±0.8% in OSA and 12.8±2.3% in control subjects
(P=0.22)
(Table 2).
|
Vascular Response to Sublingual
Administration of Nitroglycerin
Nitroglycerin-induced dilation was 9.7±0.8% in
patients with OSA and 12.8±2.3% in the control subjects
(Table 2
).
|
Discussion |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
In the present study, the vasodilation in response to intra-arterial infusion of ACh (an endothelium-dependent vasodilator) was significantly blunted in patients with OSA compared with closely matched normal control subjects. By contrast, the vasodilation responses to intra-arterial infusions of SNP (an endothelium-independent vasodilator) were not significantly different, and responses to VER (a calcium channel blocker) were very similar. Brachial artery conduit-vessel dilation, in response to both reactive hyperemia and nitroglycerin, was not significantly different in OSA patients and control subjects.
The important and novel finding in our study is therefore the attenuated endothelium-dependent vasodilation of resistance vessels demonstrated in patients with OSA compared with matched normal subjects. There is preservation of VER-mediated dilation, which is independent of NO bioactivity or smooth muscle responsiveness to NO. Thus, our finding cannot be explained by a nonspecific generalized vascular abnormality in OSA patients and is evident even in the absence of overt cardiovascular disease.
Patients with hypertension,8 9 10 11 hypercholesterolemia,15 16 congestive heart failure,12 13 and diabetes mellitus17 18 have impaired endothelial function. Our study suggests that OSA is associated with impaired resistance-vessel endothelial function, even in the absence of hypertension or other illnesses. OSA has been identified as an independent and additive risk factor for the development of systemic hypertension.19 The mechanisms responsible for the development of sustained hypertension are unclear. Endothelial dysfunction may be implicated.
To the best of our knowledge, only one previous study has studied endothelial function in OSA patients. Carlson et al20 showed abnormalities in both endothelium-dependent and -independent vasodilation of resistance vessels. Differences in our results are probably due to differences in subject selection and methodology. Impaired endothelium-dependent dilation was observed only at the highest doses of intra-arterial infusion of ACh in their patients with OSA, higher than doses used for the present study. Unlike our study, FBF was measured in only 1 arm, nonobese control subjects were used, some of the OSA patients had been treated with antihypertensive medications, and conduit-vessel endothelial function was not assessed.
Potential Mechanisms of Endothelial Dysfunction
in Patients With OSA
Apnea-induced hypoxemia may contribute to endothelial
damage.21
Biosynthesis of NO from L-arginine is an
oxygen-dependent process, and hypoxia might influence NO formation in
vascular beds
directly.22 23
The endothelial cell response to hypoxic stress can result in 2
different consequences in surrounding tissues, depending on the
duration of the
exposure24 : first,
short-term exposure causes physiological and reversible modulation of
vascular tone and blood flow; second, chronic hypoxic stress results in
irreversible remodeling of the vasculature and surrounding tissues,
with smooth muscle proliferation and fibrosis. The abnormality we
describe is suggestive that the former mechanism may be involved,
because structural vessel abnormalities would be likely to manifest as
impaired endothelium-dependent and -independent dilation.
Important strengths of our study are, first, that all participants were free of medications. Second, control subjects were matched for age and body mass index, thus ruling out any potential confounding influence of age or obesity on our data. Third, all patients with OSA were free of other known diseases, were newly diagnosed, and had never been treated for sleep apnea. Fourth, the study design was randomized, and data analysis was blinded. Fifth, FBF was measured in both arms, ruling out confounding systemic effects of the vasodilators used, because the infused-arm flow was standardized by flow in the noninfused arm. Last, we obtained complete overnight polysomnographic recordings in patients with OSA and obese subjects, excluding any effects of occult sleep apnea25 in our obese control subjects.
Limitations include the relatively small number of subjects studied, a consequence of the rigid and stringent selection criteria used for this study. It is possible that with substantially larger numbers of patients, significant differences might have emerged in the responses to SNP and/or conduit-vessel responsiveness to changes in flow or nitroglycerin. Thus, we cannot exclude a generalized impairment in responsiveness to NO, whether from the endothelium or from an NO donor, at the conduit artery and microcirculation level. Therefore, although our data demonstrate a clear impairment of endothelium-dependent resistance-vessel vasodilation, we cannot state with certainty that this impairment is selective. Nevertheless, our results imply that resistance-vessel endothelium may be more susceptible than conduit-vessel endothelium to damage by repetitive nocturnal hypoxia.
In conclusion, we observed a blunted resistance-vessel endothelium-dependent dilation in patients with OSA compared with matched control subjects. This is evident in the absence of other diseases, suggesting that OSA is an independent cause of endothelial dysfunction. We speculate that abnormalities in resistance-vessel endothelial function may precede, and possibly predispose to, hypertension and heart failure in sleep apnea patients.
|
Acknowledgments |
|---|
Dr Kato, a visiting scientist from the First Department of Internal Medicine, Tottori University, Japan, was the recipient of a Perkins Memorial Award from the American Physiological Society. Dr Roberts-Thomson was supported by a Ralph Reader Fellowship of the National Heart Foundation of Australia and a Neil Hamilton Fairley Fellowship of the National Health and Medical Research Council of Australia. Dr Haynes was supported by a Faculty Development Award from the Pharmaceutical Research Manufacturers of America Foundation. Dr Phillips is a Sleep Academic Awardee of the NIH, and Dr Somers is an Established Investigator of the AHA. These studies were also supported by NIH grants HL-65176, HL-61560 (Drs Somers and Phillips), and M01-RR00585. We thank Diane Davison, RN, MA, for her technical assistance.
Received May 19, 2000; revision received July 7, 2000; accepted July 13, 2000.
|
References |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
1. 1. Kales A, Cadieux RJ, Shaw LC, et al. Sleep apnoea in a hypertensive population. Lancet. 1984;2:1005–1008.[Medline] [Order article via Infotrieve]
2.
2. Tkacova
R, Rankin F, Fitzgerald FS, et al. Effects of continuous positive
airway pressure on obstructive sleep apnea and left ventricular
afterload in patients with heart failure. Circulation. 1998;98:2269–2275.
3.
3. Dyken
ME, Somers VK, Yamada T, et al. Investigating the relationship between
stroke and obstructive sleep apnea. Stroke. 1996;27:401–407.
4.
4. Bliwise
DL, Bliwise NG, Partinen M, et al. Sleep apnea and mortality in an age
cohort. Am J Public Health. 1988;78:544–547.
5.
5. He J,
Kryger MH, Zorick FJ, et al. Mortality and apnea index in obstructive
sleep apnea: experience in 386 male patients. Chest. 1988;94:9–14.
6. 6. Boulanger CM. Secondary endothelial dysfunction: hypertension and heart failure. J Mol Cell Cardiol. 1999;31:39–49.[Medline] [Order article via Infotrieve]
7. 7. Kourembanas S, Marsden PA, McQuillan LP, et al. Hypoxia induces endothelin gene expression and secretion in cultured human endothelium. J Clin Invest. 1991;88:1054–1057.
8. 8. Panza JA, Quyyumi AA, Brush JE Jr, et al. Abnormal endothelium-dependent vascular relaxation in patients with essential hypertension. N Engl J Med. 1990;323:22–27.[Abstract]
9.
9. Hirooka
Y, Imaizumi T, Masaki H, et al. Captopril improves impaired
endothelium-dependent vasodilation in hypertensive patients.
Hypertension. 1992;20:175–180.
10. Panza JA, Quyyumi AA, Callahan TS, et al. Effects of antihypertensive treatment on endothelium-dependent vascular relaxation in patients with essential hypertension. J Am Coll Cardiol. 1993;21:1145–1151.[Abstract]
11.
Creager
MA, Roddy MA. Effects of captopril and enalapril on endothelial
function in hypertensive patients. Hypertension. 1994;24:499–505.
12.
Kubo S,
Rector TS, Bank AJ, et al. Endothelium-dependent vasodilation is
attenuated in patients with heart failure.
Circulation. 1991;84:1589–1596.
13.
Hirooka
Y, Imaizumi T, Tagawa T, et al. Effects of
L-arginine on impaired acetylcholine-induced
and ischemic vasodilation of the forearm in patients with heart
failure. Circulation. 1994;90:658–668.
14. Celermajer DS, Sorensen KE, Gooch VM, et al. Non-invasive detection of endothelial dysfunction in children and adults at risk of atherosclerosis. Lancet. 1992;340:1111–1115.[Medline] [Order article via Infotrieve]
15. Creager MA, Cooke JP, Mendelsohn ME, et al. Impaired vasodilation of forearm resistance vessels in hypercholesterolemic humans. J Clin Invest. 1990;86:228–234.
16.
Gilligan
DM, Guetta V, Panza JA, et al. Selective loss of microvascular
endothelial function in human hypercholesterolemia.
Circulation. 1994;90:35–41.
17. Williams SB, Cusco JA, Roddy MA, et al. Impaired nitric oxide-mediated vasodilation in patients with non-insulin-dependent diabetes mellitus. J Am Coll Cardiol. 1996;27:567–574.[Abstract]
18.
Johnstone
MT, Creager SJ, Scales KM, et al. Impaired endothelium-dependent
vasodilation in patients with insulin-dependent diabetes mellitus.
Circulation. 1993;88:2510–2516.
19. Narkiewicz K, Somers VK. The sympathetic nervous system and obstructive sleep apnea implications for hypertension. J Hypertens. 1997;15:1613–1619.[Medline] [Order article via Infotrieve]
20. Carlson JT, Rangemark C, Hedner JA. Attenuated endothelium-dependent vascular relaxation in patients with sleep apnoea. J Hypertens. 1996;14:577–584.[Medline] [Order article via Infotrieve]
21. Dean RT, Wilcox I. Possible atherogenic effects of hypoxia during obstructive sleep apnea. Sleep. 1993;16:S15–S22.[Medline] [Order article via Infotrieve]
22.
Sprague
RS, Thiemermann C, Vane JR. Endogenous endothelium-derived relaxing
factor opposes hypoxic pulmonary vasoconstriction and supports blood
flow to hypoxic alveoli in anesthetized rabbits. Proc Natl Acad
Sci U S A. 1992;89:8711–8715.
23.
Leeman
M, Zegers de Beyl V, Biarent D, et al. Inhibition of cyclooxygenase and
nitric oxide synthase in hypoxic vasoconstriction and oleic
acid-induced lung injury. Am J Respir Crit Care
Med. 1999;159:1383–1390.
24. Faller DV. Endothelial cell responses to hypoxic stress. Clin Exp Pharmacol Physiol. 1999;26:74–84.[Medline] [Order article via Infotrieve]
25.
Vgontzas
AN, Tan TL, Bixler EO, et al. Sleep apnea and sleep disruption in obese
patients. Arch Intern Med. 1994;154:1705–1711.
This article has been cited by other articles:
 |
|
 |
|
  C. J. Leinum, J. M. Dopp, and B. J. Morgan Sleep-Disordered Breathing and Obesity: Pathophysiology, Complications, and Treatment Nutr Clin Pract, December 1, 2009; 24(6): 675 - 687. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. J. Reichmuth, J. M. Dopp, S. R. Barczi, J. B. Skatrud, P. Wojdyla, D. Hayes Jr., and B. J. Morgan Impaired Vascular Regulation in Patients with Obstructive Sleep Apnea: Effects of Continuous Positive Airway Pressure Treatment Am. J. Respir. Crit. Care Med., December 1, 2009; 180(11): 1143 - 1150. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. A Chami, M. J Keyes, J. A Vita, G. F Mitchell, M. G Larson, S. Fan, R. S Vasan, G. T O'Connor, E. J Benjamin, and D. J Gottlieb Brachial artery diameter, blood flow and flow-mediated dilation in sleep-disordered breathing Vascular Medicine, November 1, 2009; 14(4): 351 - 360. [Abstract] [PDF]
|
|
|
|
 |
|
 R. L. Verrier and M. E. Josephson Impact of Sleep on Arrhythmogenesis Circ Arrhythm Electrophysiol, August 1, 2009; 2(4): 450 - 459. [Full Text] [PDF]
|
|
|
|
 |
|
 L. Lavie and P. Lavie Molecular mechanisms of cardiovascular disease in OSAHS: the oxidative stress link Eur. Respir. J., June 1, 2009; 33(6): 1467 - 1484. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 U. Kuhlmann, F. G. Bormann, and H. F. Becker Obstructive sleep apnoea: clinical signs, diagnosis and treatment Nephrol. Dial. Transplant., January 1, 2009; 24(1): 8 - 14. [Full Text] [PDF]
|
|
|
|
 |
|
 F. Urbano, F. Roux, J. Schindler, and V. Mohsenin Impaired cerebral autoregulation in obstructive sleep apnea J Appl Physiol, December 1, 2008; 105(6): 1852 - 1857. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 F. Valham, T. Mooe, T. Rabben, H. Stenlund, U. Wiklund, and K. A. Franklin Increased Risk of Stroke in Patients With Coronary Artery Disease and Sleep Apnea: A 10-Year Follow-Up Circulation, August 26, 2008; 118(9): 955 - 960. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. Moro, C. Pedone, S. Scarlata, V. Malafarina, F. Fimognari, and R. Antonelli-Incalzi Endothelial Dysfunction in Chronic Obstructive Pulmonary Disease Angiology, July 1, 2008; 59(3): 357 - 364. [Abstract] [PDF]
|
|
|
|
 |
|
 M D Cross, N L Mills, M Al-Abri, R Riha, M Vennelle, T W Mackay, D E Newby, and N J Douglas Continuous positive airway pressure improves vascular function in obstructive sleep apnoea/hypopnoea syndrome: a randomised controlled trial Thorax, July 1, 2008; 63(7): 578 - 583. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. V. Serebrovskaya, E. B. Manukhina, M. L. Smith, H. F. Downey, and R. T. Mallet Intermittent Hypoxia: Cause of or Therapy for Systemic Hypertension? Experimental Biology and Medicine, June 1, 2008; 233(6): 627 - 650. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Jelic, M. Padeletti, S. M. Kawut, C. Higgins, S. M. Canfield, D. Onat, P. C. Colombo, R. C. Basner, P. Factor, and T. H. LeJemtel Inflammation, Oxidative Stress, and Repair Capacity of the Vascular Endothelium in Obstructive Sleep Apnea Circulation, April 29, 2008; 117(17): 2270 - 2278. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 F. Lopez-Jimenez, F. H. Sert Kuniyoshi, A. Gami, and V. K. Somers Obstructive Sleep Apnea: Implications for Cardiac and Vascular Disease Chest, March 1, 2008; 133(3): 793 - 804. [Full Text] [PDF]
|
|
|
|
 |
|
 J. M. Golbin, V. K. Somers, and S. M. Caples Obstructive Sleep Apnea, Cardiovascular Disease, and Pulmonary Hypertension Proceedings of the ATS, February 15, 2008; 5(2): 200 - 206. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. Gozal and L. Kheirandish-Gozal Cardiovascular Morbidity in Obstructive Sleep Apnea: Oxidative Stress, Inflammation, and Much More Am. J. Respir. Crit. Care Med., February 15, 2008; 177(4): 369 - 375. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Dematteis, C. Julien, C. Guillermet, N. Sturm, S. Lantuejoul, M. Mallaret, P. Levy, and E. Gozal Intermittent Hypoxia Induces Early Functional Cardiovascular Remodeling in Mice Am. J. Respir. Crit. Care Med., January 15, 2008; 177(2): 227 - 235. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
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]
|
|
|
|
|
|
L. F. Drager, L. A. Bortolotto, A. C. Figueiredo, E. M. Krieger, and G. Lorenzi-Filho Effects of Continuous Positive Airway Pressure on Early Signs of Atherosclerosis in Obstructive Sleep Apnea Am. J. Respir. Crit. Care Med., October 1, 2007; 176(7): 706 - 712. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 W. T. McNicholas Cardiovascular outcomes of CPAP therapy in obstructive sleep apnea syndrome Am J Physiol Regulatory Integrative Comp Physiol, October 1, 2007; 293(4): R1666 - R1670. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. Parati, C. Lombardi, and K. Narkiewicz Sleep apnea: epidemiology, pathophysiology, and relation to cardiovascular risk Am J Physiol Regulatory Integrative Comp Physiol, October 1, 2007; 293(4): R1671 - R1683. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Foresi, C. Leone, D. Olivieri, and G. Cremona Alveolar-Derived Exhaled Nitric Oxide Is Reduced in Obstructive Sleep Apnea Syndrome Chest, September 1, 2007; 132(3): 860 - 867. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. N. Ainslie, C. Murrell, K. Peebles, M. Swart, M. A. Skinner, M. J. A. Williams, and R. D. Taylor Early morning impairment in cerebral autoregulation and cerebrovascular CO2 reactivity in healthy humans: relation to endothelial function Exp Physiol, July 1, 2007; 92(4): 769 - 777. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. A. Smith, M. Vennelle, R. S. Gardner, T. A. McDonagh, M. A. Denvir, N. J. Douglas, and D. E. Newby Auto-titrating continuous positive airway pressure therapy in patients with chronic heart failure and obstructive sleep apnoea: a randomized placebo-controlled trial Eur. Heart J., May 2, 2007; 28(10): 1221 - 1227. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. N. Ainslie, A. Barach, K. J. Cummings, C. Murrell, M. Hamlin, and J. Hellemans Cardiorespiratory and cerebrovascular responses to acute poikilocapnic hypoxia following intermittent and continuous exposure to hypoxia in humans J Appl Physiol, May 1, 2007; 102(5): 1953 - 1961. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. J. Cummings, M. Swart, and P. N. Ainslie Morning attenuation in cerebrovascular CO2 reactivity in healthy humans is associated with a lowered cerebral oxygenation and an augmented ventilatory response to CO2 J Appl Physiol, May 1, 2007; 102(5): 1891 - 1898. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. Haentjens, A. Van Meerhaeghe, A. Moscariello, S. De Weerdt, K. Poppe, A. Dupont, and B. Velkeniers The Impact of Continuous Positive Airway Pressure on Blood Pressure in Patients With Obstructive Sleep Apnea Syndrome: Evidence From a Meta-analysis of Placebo-Controlled Randomized Trials Arch Intern Med, April 23, 2007; 167(8): 757 - 764. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
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]
|
|
|
|
|
|
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]
|
|
|
|
|
|
A. Tarasiuk, S. Greenberg-Dotan, T. Simon, A. Tal, A. Oksenberg, and H. Reuveni Low socioeconomic status is a risk factor for cardiovascular disease among adult obstructive sleep apnea syndrome patients requiring treatment. Chest, September 1, 2006; 130(3): 766 - 773. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N T Ayas, G B J Mancini, and J Fleetham Does CPAP delay the development of cardiovascular disease in patients with obstructive sleep apnoea hypopnoea? Thorax, June 1, 2006; 61(6): 459 - 460. [Full Text] [PDF]
|
|
|
|
|
|
J L Lattimore, I Wilcox, M Skilton, M Langenfeld, and D S Celermajer Treatment of obstructive sleep apnoea leads to improved microvascular endothelial function in the systemic circulation Thorax, June 1, 2006; 61(6): 491 - 495. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. A. El Solh, R. Saliba, T. Bosinski, B. J. B. Grant, E. Berbary, and N. Miller Allopurinol improves endothelial function in sleep apnoea: a randomised controlled study. Eur. Respir. J., May 1, 2006; 27(5): 997 - 1002. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. A. Phillips, E. B. Olson, J. H. Lombard, and B. J. Morgan Chronic intermittent hypoxia alters NE reactivity and mechanics of skeletal muscle resistance arteries J Appl Physiol, April 1, 2006; 100(4): 1117 - 1123. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. Yinon, L. Lowenstein, S. Suraya, R. Beloosesky, O. Zmora, A. Malhotra, and G. Pillar Pre-eclampsia is associated with sleep-disordered breathing and endothelial dysfunction Eur. Respir. J., February 1, 2006; 27(2): 328 - 333. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. K. Yaggi, J. Concato, W. N. Kernan, J. H. Lichtman, L. M. Brass, and V. Mohsenin Obstructive Sleep Apnea as a Risk Factor for Stroke and Death. N. Engl. J. Med., November 10, 2005; 353(19): 2034 - 2041. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. F. Drager, L. A. Bortolotto, M. C. Lorenzi, A. C. Figueiredo, E. M. Krieger, and G. Lorenzi-Filho Early Signs of Atherosclerosis in Obstructive Sleep Apnea Am. J. Respir. Crit. Care Med., September 1, 2005; 172(5): 613 - 618. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. E. Foster, D. C. McKenzie, W. K. Milsom, and A. W. Sheel Effects of two protocols of intermittent hypoxia on human ventilatory, cardiovascular and cerebral responses to hypoxia J. Physiol., September 1, 2005; 567(2): 689 - 699. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. Lavie, L. Lavie, and P. Herer All-cause mortality in males with sleep apnoea syndrome: declining mortality rates with age Eur. Respir. J., March 1, 2005; 25(3): 514 - 520. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Svatikova, R. Wolk, M. J Magera, A. S Shamsuzzaman, B. G Phillips, and V. K Somers Plasma homocysteine in obstructive sleep apnoea Eur. Heart J., August 1, 2004; 25(15): 1325 - 1329. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Svatikova, R. Wolk, H. H. Wang, M. E. Otto, K. A. Bybee, R. J. Singh, and V. K. Somers Circulating free nitrotyrosine in obstructive sleep apnea Am J Physiol Regulatory Integrative Comp Physiol, August 1, 2004; 287(2): R284 - R287. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. M. Parish and V. K. Somers Obstructive Sleep Apnea and Cardiovascular Disease Mayo Clin. Proc., August 1, 2004; 79(8): 1036 - 1046. [Abstract] [PDF]
|
|
|
|
|
|
A. S. Gami, A. Svatikova, R. Wolk, E. J. Olson, C. J. Duenwald, A. S. Jaffe, and V. K. Somers Cardiac Troponin T in Obstructive Sleep Apnea Chest, June 1, 2004; 125(6): 2097 - 2100. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. E. Otto, A. Svatikova, R. B. d. M. Barretto, S. Santos, M. Hoffmann, B. Khandheria, and V. Somers Early Morning Attenuation of Endothelial Function in Healthy Humans Circulation, June 1, 2004; 109(21): 2507 - 2510. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
O. Milleron, R. Pilliere, A. Foucher, F. de Roquefeuil, P. Aegerter, G. Jondeau, B. G Raffestin, and O. Dubourg Benefits of obstructive sleep apnoea treatment in coronary artery disease: a long-term follow-up study Eur. Heart J., May 1, 2004; 25(9): 728 - 734. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G J Gibson Sleep disordered breathing and the outcome of stroke Thorax, May 1, 2004; 59(5): 361 - 363. [Full Text] [PDF]
|
|
|
|
|
|
T. Altay, E. R. Gonzales, T. S. Park, and J. M. Gidday Cerebrovascular inflammation after brief episodic hypoxia: modulation by neuronal and endothelial nitric oxide synthase J Appl Physiol, March 1, 2004; 96(3): 1223 - 1230. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Javaheri, W. T. Abraham, C. Brown, H. Nishiyama, R. Giesting, and L. E. Wagoner Prevalence of obstructive sleep apnoea and periodic limb movement in 45 subjects with heart transplantation Eur. Heart J., February 1, 2004; 25(3): 260 - 266. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. J. Nieto, D. M. Herrington, S. Redline, E. J. Benjamin, and J. A. Robbins Sleep Apnea and Markers of Vascular Endothelial Function in a Large Community Sample of Older Adults Am. J. Respir. Crit. Care Med., February 1, 2004; 169(3): 354 - 360. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. S. M. Ip, H.-F. Tse, B. Lam, K. W. T. Tsang, and W.-K. Lam Endothelial Function in Obstructive Sleep Apnea and Response to Treatment Am. J. Respir. Crit. Care Med., February 1, 2004; 169(3): 348 - 353. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. A. Phillips, E. B. Olson, B. J. Morgan, and J. H. Lombard Chronic intermittent hypoxia impairs endothelium-dependent dilation in rat cerebral and skeletal muscle resistance arteries Am J Physiol Heart Circ Physiol, January 1, 2004; 286(1): H388 - H393. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. Wolk, A. S.M. Shamsuzzaman, and V. K. Somers Obesity, Sleep Apnea, and Hypertension Hypertension, December 1, 2003; 42(6): 1067 - 1074. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. V. Chobanian, G. L. Bakris, H. R. Black, W. C. Cushman, L. A. Green, J. L. Izzo Jr, D. W. Jones, B. J. Materson, S. Oparil, J. T. Wright Jr, et al. Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure Hypertension, December 1, 2003; 42(6): 1206 - 1252. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. von Kanel and J. E. Dimsdale Hemostatic Alterations in Patients With Obstructive Sleep Apnea and the Implications for Cardiovascular Disease Chest, November 1, 2003; 124(5): 1956 - 1967. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 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]
|
|
|
|
|
|
L. Dyugovskaya, P. Lavie, and L. Lavie Phenotypic and Functional Characterization of Blood {gamma}{delta} T Cells in Sleep Apnea Am. J. Respir. Crit. Care Med., July 15, 2003; 168(2): 242 - 249. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A.G. Logan, R. Tkacova, S.M. Perlikowski, R.S. Leung, A. Tisler, J.S. Floras, and T.D. Bradley Refractory hypertension and sleep apnoea: effect of CPAP on blood pressure and baroreflex Eur. Respir. J., February 1, 2003; 21(2): 241 - 247. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. F. Becker, A. Jerrentrup, T. Ploch, L. Grote, T. Penzel, C. E. Sullivan, and J. H. Peter Effect of Nasal Continuous Positive Airway Pressure Treatment on Blood Pressure in Patients With Obstructive Sleep Apnea Circulation, January 7, 2003; 107(1): 68 - 73. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. A. Dart, J. R. Gregoire, D. D. Gutterman, and S. H. Woolf The Association of Hypertension and Secondary Cardiovascular Disease With Sleep-Disordered Breathing Chest, January 1, 2003; 123(1): 244 - 260. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 V. Thongboonkerd, E. Gozal, L. R. Sachleben Jr., J. M. Arthur, W. M. Pierce, J. Cai, J. Chao, M. Bader, J. B. Pesquero, D. Gozal, et al. Proteomic Analysis Reveals Alterations in the Renal Kallikrein Pathway during Hypoxia-Induced Hypertension J. Biol. Chem., September 13, 2002; 277(38): 34708 - 34716. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K Otake, K Delaive, R Walld, J Manfreda, and M H Kryger Cardiovascular medication use in patients with undiagnosed obstructive sleep apnoea Thorax, May 1, 2002; 57(5): 417 - 422. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. DYUGOVSKAYA, P. LAVIE, and L. LAVIE Increased Adhesion Molecules Expression and Production of Reactive Oxygen Species in Leukocytes of Sleep Apnea Patients Am. J. Respir. Crit. Care Med., April 1, 2002; 165(7): 934 - 939. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
V. A. IMADOJEMU, K. GLEESON, S. A. QURAISHI, A. R. KUNSELMAN, L. I. SINOWAY, and U. A. LEUENBERGER Impaired Vasodilator Responses in Obstructive Sleep Apnea Are Improved with Continuous Positive Airway Pressure Therapy Am. J. Respir. Crit. Care Med., April 1, 2002; 165(7): 950 - 953. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
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]
|
|
|
|
|
|
L. Lavie, A. Perelman, and P. Lavie Plasma Homocysteine Levels in Obstructive Sleep Apnea : Association With Cardiovascular Morbidity Chest, September 1, 2001; 120(3): 900 - 908. [Abstract] [Full Text] [PDF]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||