Increased urinary leukotriene E₄ excretion in obstructive sleep apnea: Effects of obesity and hypoxia

Background

Low-grade inflammation may potentially explain the relationship between obstructive sleep apnea syndrome (OSA) and cardiovascular events. However, the respective contribution of intermittent hypoxia and confounders, such as obesity, is still debated.

Objectives

To monitor urinary leukotriene E₄ (U-LTE₄), a validated marker of proinflammatory cysteinyl leukotriene production, in OSA; to determine the influence of obesity and other confounders on U-LTE₄ concentrations; to examine the mechanisms involved through transcriptional profiling of the leukotriene pathway in peripheral blood mononuclear cells (PBMCs); and to investigate the effect of continuous positive air pressure (CPAP) on U-LTE₄ concentrations.

Methods

We measured U-LTE₄ by liquid chromatography–tandem mass spectrometry.

Results

The U-LTE₄ concentrations were increased (P = .019) in 40 nonobese patients with OSA carefully matched for age, sex, and body mass index (BMI) to 25 control subjects, and correlated (r = 0.0312; P = .017) to the percentage of time spent with mean oxygen saturation (SaO₂) less than 90%. In a larger cohort of patients with OSA (n = 72), U-LTE₄ increased as a function of BMI (r = 0.445; P = .0002). In those patients, the expression levels of 5-lipoxygenase activating protein mRNA in mononuclear cells exhibited a similar pattern. A stepwise multiple linear regression analysis performed in this cohort identified BMI (P = .001; regression coefficient, 3.33) and percentage of time spent with SaO₂ <90% (P = .001; regression coefficient, 1.01) as independent predictors of U-LTE₄ concentrations. Compared with baseline, CPAP reduced by 22% (P = .006) U-LTE₄ concentrations only in patients with OSA with normal BMI.

Conclusion

Obesity, and to a lesser extent hypoxia severity, are determinant of U-LTE₄ production in patients with OSA.

Key words: Leukotriene E₄, obstructive sleep apnea syndrome, nocturnal oxygen desaturation, obesity

Abbreviations used: AHI, Apnea-hypopnea index, BMI, Body mass index, CPAP, Continuous positive air pressure, CRP, C-reactive protein, cysLT, Cysteinyl leukotriene, 11-DehydroTXB₂, 11-Dehydro thromboxane B₂, FLAP, 5-Lipoxygenase activating protein, hsCRP, High sensitive CRP, 5-LOX, 5-Lipoxygenase, LT, Leukotriene, OSA, Obstructive sleep apnea syndrome, RDI, Respiratory disturbance index, SaO₂, Oxygen saturation, U-LTE₄, Urinary leukotriene E₄