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Depts of 1 Geriatric Medicine, and 2 Urology, Graduate School of Medicine, University of Tokyo, and 3 Dept of Respiratory Medicine, Nippon Medical School, Tokyo, Japan.
To the Editors:
In a recent issue of the European Respiratory Journal, El Solh et al. 1 demonstrated that allopurinol improves endothelial dysfunction in patients with moderate-to-severe obstructive sleep apnoea (OSA). Because xanthine oxidase inhibition with allopurinol prevents the formation of superoxide free radicals, which leads to better endothelial function, El Solh et al. 1 speculated that excess activity of xanthine oxidase contributes significantly to vasodilatory impairment in patients with OSA.
The study was a sophisticated prospective, randomised, crossover design, minimising the presence of confounding variables and eliminating inherent individual variations in terms of the generation of free radicals, hyperaemic vascular reactivity or response to treatment. However, a number of arguable assumptions were made in the article of El Solh et al. 1.
First, endothelial function assessment using hyperaemia-induced flow-mediated vasodilation (FMD) is not always suitable for the assessment of endotheloial function in female obese patients with sleep apnoea. There is a significant relationship between FMD and brachial artery size; therefore, as males have larger arterial diameters, smaller FMD is noted in males 2. Thus, the changes in FMD in males before and after therapeutic intervention are usually larger than those in females. As the current study did not examine the FMD results of females and males separately, the sex difference may exist in the study. Inversely, the FMD improvement after allopurinol treatment may be clearly indicated, when the males’ results were analysed separately from the females' results.
Secondly, FMD of the brachial artery diminished with age 2. Thus, the age distribution of the study sample affects the results of the FMD alterations after intervention. Because the authors examined subjects aged 29–60 yrs, this wide range of the population may not represent the genuine effects of allopirinol on the FMD in association with oxidative stress due to sleep apnoea itself.
Thirdly, obesity without sleep apnoea also causes endothelial dysfunction 3. The FMD results should be standardised by the body mass index (BMI) or metabolic variables, when the FMD results are properly assessed. In the study by El Solh et al. 1, BMI ranged 23–67. We speculate that the FMD results in patients with a normal BMI of 24 might be very different from the extraordinarily obese patients with a BMI of 67. It has also been reported that FMD is associated with systemic inflammation and glucose homeostasis in obese patients, independent of obesity 4. Because both obesity and sleep apnoea cause systemic inflammation 5, 6, the association of the inflammatory markers and insulin sensitivity with FMD should be further examined.
Fourthly, the menopause and menstrual cycle significantly affect sleep apnoea and endothelial function 7, 8. The menopausal transition is significantly associated with an increased likelihood of having sleep-disordered breathing, independent of known confounding factors 7. FMD increases in menstrual phase, when serum oestradiol level is low and the value is comparable to that in male subjects 8. Because endothelium-dependent vasodilatation varies during the menstrual cycle, the timing of FMD measurements of female subjects is critical for the precise assessment of allopinol effects.
The incidence of cardiovascular disease is lower in pre-menopausal females compared with males in the same age group; following menopause, the risk of mortality from cardiovascular disease increases in females 9. FMD-induced vasodilatation is lower in females aged 55 yrs than those aged 35 yrs 10. The lower FMD in females aged 55 yrs, compared with those aged 35 yrs, could be due to postmenopausal hormonal changes.
It has been suggested that endothelial function assessment using hyperaemia-induced FMD is adequately reproducible in healthy middle-aged males and females 2. However, there are many confounding factors including age, sex, obesity, smoking, elevated blood lipids, high blood pressure and systemic inflammation. Thus, FMD measurement may not be an appropriate method for the assessment of the endothelial function in female obese patients with sleep apnoea.
Further study using a large sample size should be carefully assessed by age, obesity and sex differences. The improvement of endothelial function by allopurinol effects on the vascular function in patients with sleep apnoea will then be adequately realised.
REFERENCES
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  S. Teramoto, Y. Yamaguchi, H. Yamamoto, Y. Hanaoka, M. Ishii, S. Hibi, T. Ishii, H. Kume, and Y. Ouchi Cardiovascular and metabolic effects of CPAP in obese obstructive sleep apnoea patients Eur. Respir. J., January 1, 2008; 31(1): 223 - 225. [Full Text] [PDF]
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