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Published ahead of print on July 13, 2006, doi:10.1164/rccm.200601-066OC

Am. J. Respir. Crit. Care Med., Volume 174, Number 7, October 2006, 824-830

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Submitted on January 16, 2006
Accepted on July 12, 2006

Predictors of Elevated Nuclear Factor kappa B - dependent Genes in Obstructive Sleep Apnea Syndrome

Silke Ryan1, Cormac T Taylor2, and Walter T McNicholas1*

1 Sleep Research Laboratory, St. Vincent's University Hospital, Dublin, Ireland; University College Dublin, The Conway Institute, School of Medicine and Medical Science, Dublin, Ireland, 2 University College Dublin, The Conway Institute, School of Medicine and Medical Science, Dublin, Ireland

* To whom correspondence should be addressed. E-mail: walter.mcnicholas{at}ucd.ie.

Background: Circulating nuclear factor kappa-B (NF-{kappa}B) dependent genes, particularly tumor necrosis factor-alpha (TNF-{alpha}), are elevated in Obstructive Sleep Apnea Syndrome (OSAS) and likely contribute to cardiovascular disease. Furthermore, TNF-{alpha} is associated with excessive daytime sleepiness (EDS). We investigated the predictors of TNF-{alpha} and related genes in large, well-selected OSAS patient and control cohorts. Methods: We performed a prospective study of 30 non-OSAS (22 non-sleepy normal controls and 8 sleepy non-apneic snorers), 36 mild-moderate OSAS and 31 severe OSAS male subjects. Groups were matched for age, BMI, and other relevant variables. Subjects had no other disease and were not taking regular medication. All had serum for TNF-{alpha} and related assays drawn after polysomnography (PSG). 49 suitable patients were treated with CPAP and sleep studies together with serum assays were repeated 6 weeks later. Results: TNF-{alpha} levels were higher in OSAS patients than controls (p<0.001). In multivariate analysis, TNF-{alpha} was independently associated with the desaturation index (r=0.399, p<0.001), Epworth Sleepiness Score (ESS; r=0.243, p=0.005) and cholesterol (r=0.216, p=0.018). Furthermore, levels were higher in sleepy non-apneic snorers than normal controls (p=0.002) but lower than OSAS patients (p=0.03). CPAP therapy lowered TNF-{alpha} levels (p=0.004). Another NF-{kappa}B dependent cytokine, interleukin-8 (IL-8), showed similar differences between groups and after CPAP therapy but a range of other inflammatory mediators, including IL-1, IL-6, IL-10 and IL-12, showed no differences. Conclusion: Intermittent hypoxia is the strongest predictor of TNF-{alpha} levels supporting a role for inflammation in the cardiovascular pathophysiology of OSAS. Furthermore, TNF-{alpha} levels are independently associated with EDS.
Key words: Obstructive sleep apnea syndrome, nuclear factor kappa B, tumor necrosis factor - {alpha}, cardiovascular diseases, excessive daytime sleepiness




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