Circadian variability of fibrinolytic markers and endothelial function in patients with obstructive sleep apnea

Abstract

Study objectives: 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.

Setting: Cross-sectional cohort study.

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

Interventions: 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.

Measurements and 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.

Conclusion: 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.

Keywords: OSA; endothelial function; fibrinolytic activity.

Figure 1

Twenty-four-hour variability of PAI-1 and t-PA activity in patients with OSA and normal controls. PAI-1 and t-PA oscillations were evaluated by fitting nonlinear mixed-effect models y = (M + μ₁) + (A + μ₂) sin(2π ÷ 24hr × time + B + μ₃), where M was the rhythm-adjusted mean, A was the amplitude, and B was the acrophase. The solid line is based on the model and it is an estimator of population mean PAI-1 or t-PA activity along the time. OSA, obstructive sleep apnea; PAI-1, plasminogen activator inhibitor-1; t-PA, tissue-type plasminogen activator.

Figure 2

Twenty-four-hour variability of PAI-1 and t-PA antigen in patients with OSA and normal controls. PAI-1 and t-PA circadian variations (oscillations) were evaluated by fitting non- linear mixed-effect models y = (M + u₁) + (A + u₂) sin(2π ÷ 24hr × t + B + u₃), where M was the rhythm-adjusted mean, A was the amplitude, and B was the acrophase. In the above formula, the peak time (time of the day at which the maximum level of the variable was reached) was calculated by setting sin [(2*π / 24hr) * time + B] = sin [0.5 π] = 1. The solid line is based on the model and it is an estimator of population mean PAI-1 or t-PA antigen along the time. The mean amplitude of PAI-1 antigen in the OSA group was 3.3 units higher than that of the non-OSA group (P = 0.03). Shaded portion shows circadian night. OSA, obstructive sleep apnea; PAI-1, plasminogen activator inhibitor-1; t-PA, tissue-type plasminogen activator.