Circadian variability of fibrinolytic markers and endothelial function in patients with obstructive sleep apnea.
OBJECTIVE
Obstructive sleep apnea (OSA) is strongly associated with cardiovascular disease, including stroke and acute coronary syndromes. Plasminogen activator inhibitor-1 (PAI-1), the principal inhibitor of tissue-type plasminogen activator (t-PA), has a pronounced circadian rhythm and is elevated in both OSA and cardiovascular disease and may be an important link between the two conditions. Endothelial dysfunction is one of the underlying pathophysiological mechanisms of cardiovascular disease, and may be altered in OSA. Our primary aim was to compare circadian variability of PAI-1 and t-PA in patients with OSA and normal controls by determining the amplitude (peak level) and mesor (rhythm adjusted mean) of PAI-1 and t-PA in serial blood samples over a 24-h period. The secondary aim was to measure markers of endothelial function (brachial and radial artery flow) in patients with OSA compared with normal controls.


METHODS
Cross-sectional cohort study.


METHODS
Subjects age 18 y or older, with a body mass index of 25-45 kg/m(2), with or without evidence of untreated OSA.


METHODS
Plasma samples were collected every 2 h, in OSA patients and matched controls, over a 24-h period. PAI-1 and t-PA antigen and activity were measured. The presence or absence of OSA (apnea-hypopnea index of 5 or greater) was confirmed by overnight polysomnography. Endothelial function was measured via brachial artery flow mediated vasodilatation and computerized arterial pulse waveform analysis.


RESULTS
The rhythm-adjusted mean levels of PAI-1 antigen levels in the OSA group (21.8 ng/mL, 95% confidence level [CI], 18 to 25.7) were significantly higher as compared to the non-OSA group (16 ng/mL, 95% CI, 12.2 to 19.8; P = 0.03). The rhythm-adjusted mean levels of PAI-1 activity levels in the OSA group (23.9 IU/mL, 95% CI, 21.4 to 26.5) were also significantly higher than in the non-OSA group (17.2 IU/ mL, 95% CI, 14.6 to 19.9; P < 0.001).There were strong correlations between amplitude of PAI-1 activity and severity of OSA as measured by AHI (P = 0.02), and minimum oxygen levels during sleep (P = 0.04). Endothelial function parameters did not differ significantly between the two groups.


CONCLUSIONS
The presence of obstructive sleep apnea adversely affects circadian fibrinolytic balance with higher mean plasminogen activator inhibitor-1 activity and antigen, and significantly lower mean tissue-type plasminogen activator activity compared with controls. This perturbation may be an important mechanism for increased cardiovascular events in patients with obstructive sleep apnea. Intermittent hypoxia and changes in circadian clock gene activity in obstructive sleep apnea may be responsible for these findings and warrant further study. Favorable changes in fibrinolytic balance may underlie the reduction in cardiovascular events observed with the treatment of obstructive sleep apnea.
Department of Neurology, Vanderbilt University, Nashville, TN.
Kanika
K
Bagai
Department of Medicine, Vanderbilt University, Nashville, TN.
James A S
JA
Muldowney
Department of Biostatistics, Vanderbilt University, Nashville, TN.
Yanna
Y
Song
Department of Biostatistics, Vanderbilt University, Nashville, TN.
Lily
L
Wang
Department of Medicine, Vanderbilt University, Nashville, TN.
Jayant
J
Bagai
Department of Neurology, Vanderbilt University, Nashville, TN.
Kay J
KJ
Artibee
Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL.
Douglas E
DE
Vaughan
Department of Neurology, Vanderbilt University, Nashville, TN.
Beth A
BA
Malow
D015415:Biomarkers / Q000097:blood; D015992:Body Mass Index; D002318:Cardiovascular Diseases / Q000097:blood / Q000150:complications / Q000503:physiopathology; D016022:Case-Control Studies; D002940:Circadian Rhythm / Q000502:physiology*; D003430:Cross-Sectional Studies; D042783:Endothelial Cells / Q000502:physiology; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D017395:Plasminogen Activator Inhibitor 1 / Q000097:blood; D017286:Polysomnography; D012890:Sleep / Q000502:physiology; D020181:Sleep Apnea, Obstructive / Q000097:blood* / Q000150:complications / Q000503:physiopathology*; D010959:Tissue Plasminogen Activator / Q000037:antagonists & inhibitors / Q000097:blood
D015415:Biomarkers; D017395:Plasminogen Activator Inhibitor 1; D010959:Tissue Plasminogen Activator
OSA; endothelial function; fibrinolytic activity