Sex differences in the association between obstructive sleep apnea and hypertension—what’s next?

We thank the editor for inviting both editorials on our recent publication in Chest and we also thank Freitas et al. and Fuchs et al. and appreciate their interest in our work (1). As the readership of Journal of Thoracic Disease is aware, most of the evidence on the cardiovascular impact of obstructive sleep apnea (OSA) comes from studies with a small proportion of women. However, over the last decade some studies have assessed the sex-related impact of OSA on cardiovascular outcomes, especially hypertension, with conflicting results (2-5). Along this line, we evaluated the relationship between OSA and incident hypertension in a previous analysis of the Vitoria Sleep Cohort and we did not find an independent association in men or in women (6). Subsequently, we performed a post hoc analysis to explore the relationship between OSA and incident stage 2 hypertension (blood pressure ≥160/100 mmHg) and we found an association in men but not in women.

We decided to explore the association between OSA and the risk of developing moderate to severe hypertension (stage 2) and not stage 1 hypertension because, as we used office blood pressure measurements, it allowed us to reduce the number of false-positive results for hypertension, and also because of the potential benefit of treating OSA patients to prevent the cardiovascular consequences of moderate to severe hypertension. As interestingly pointed out by Fuchs et al. (7), the findings of our study (OSA being a risk factor only for stage 2 hypertension and not for stage 1) as well as studies that have evaluated the positive OSA-resistant hypertension association, support the concept of a risk gradient. Future studies need to address this biological plausibility.

With regard to the sex differences found in the OSA-hypertension association, most studies (including ours) have been limited by sample size, which may reflect low statistical power rather than a lack of statistical significance. Supporting this, in our study the risk of incident hypertension for women with OSA was not so different from men, but in women it was not significant. However, we have to take into account that our population reflects the community-based nature of our study and, although the sample size was large and we included a similar proportion of men and women, patients with severe OSA were not well represented. This is especially relevant in the case of women, due to the lower prevalence of hypertension and OSA in premenopausal women compared to men (8) (67% of women included in our study were premenopausal). This leads us to highlight the essential role of female hormones in the OSA-hypertension relationship. In fact, when we analyzed the different clinical subgroups identified by the recursive partitioning method, although the majority of women in our sample (81%) belonged to the lowest-risk subgroup for stage 2 hypertension incidence (young and non-obese), there was a subgroup of women (3.8%) (over the age of 56 years and with a neck circumference diameter >35.3 cm) who were all postmenopausal and had the highest stage 2 hypertension incidence of our sample (28.0%). This last subgroup may present similar characteristics to women with clinical suspicion of OSA usually seen in sleep-disorders clinics. All these data emphasize the importance of studying the role of the menopause in the OSA-hypertension association and raise the question of whether women require a longer exposure time than men for the expression of hypertension.

In summary, larger longitudinal studies with longer follow-up, especially in women, are needed in order to identify all the clinical variables, biomarkers and intermediary pathways that may play a role in the OSA-hypertension association and to determine if OSA management should differ according to sex and age. Moreover, further investigation should be undertaken into whether the OSA phenotype remains static throughout life or whether it changes with time and under different environmental conditions. Use of dense mapping of candidate genes would provide a better approach for identifying genotype-phenotype correlations for OSA and hypertension.

Acknowledgements

Funding: The authors were supported by Fondo de Investigaciones Sanitarias, Ministerio de Sanidad y Consumo (FIS 01/1577), Departamento de Sanidad del Gobierno Vasco (2001 1037) and Spanish Respiratory Foundation (FEPAR 2001).

Footnote

Conflicts of Interest: The authors have no conflicts of interest to declare.

References

1. Cano-Pumarega I, Barbé F, Esteban A, et al. Sleep Apnea and Hypertension: Are There Sex Differences? The Vitoria Sleep Cohort. Chest 2017;152:742-50. [Crossref] [PubMed]
2. Hedner J, Bengtsson-Boström K, Peker Y, et al. Hypertension prevalence in obstructive sleep apnoea and sex: a population-based case-control study. Eur Respir J 2006;27:564-70. [Crossref] [PubMed]
3. Mokhlesi B, Ham SA, Gozal D. The effect of sex and age on the comorbidity burden of OSA: an observational analysis from a large nationwide US health claims database. Eur Respir J 2016;47:1162-9. [Crossref] [PubMed]
4. O'Connor GT, Caffo B, Newman AB, et al. Prospective study of sleep-disordered breathing and hypertension: the Sleep Heart Health Study. Am J Respir Crit Care Med 2009;179:1159-64. [Crossref] [PubMed]
5. Gaines J, Vgontzas AN, Fernandez-Mendoza J, et al. Gender differences in the association of sleep apnea and inflammation. Brain Behav Immun 2015;47:211-7. [Crossref] [PubMed]
6. Cano-Pumarega I, Durán-Cantolla J, Aizpuru F, et al. Obstructive sleep apnea and systemic hypertension: longitudinal study in the general population: the Vitoria Sleep Cohort. Am J Respir Crit Care Med 2011;184:1299-304. [Crossref] [PubMed]
7. Fuchs FD, Fuchs SC, Martinez D. Obstructive sleep apnea—Hypertension link: almost there? J Thorac Dis 2017;9:3537-40. [Crossref] [PubMed]
8. Young T, Finn L, Austin D, et al. Menopausal status and sleep-disordered breathing in the Wisconsin Sleep Cohort Study. Am J Respir Crit Care Med 2003;167:1181-5. [Crossref] [PubMed]