Gender and cardiovascular impact of obstructive sleep apnea: work in progress!

In the last decades, obstructive sleep apnea (OSA) has gained substantial attention due to the high prevalence and multiple consequences not limited to sleep quality and quality of life (1). Particularly, the cardiovascular impact of OSA has been consistently suggested by multiple, basic (2), translational (2) and clinical studies (3-10). However, because OSA is at least twice more common in men than in women (11) much of this evidence comprised basically only men or a small proportion of women that prevented us to have substantial data stratified by sex. However, considering the current burden of OSA (12), the amount of women with significant OSA is by far relevant. Therefore, there is an obvious interest in exploring whether the cardiovascular impact of OSA is potentially true regardless of gender. This notion has been extensively explored in other cardiovascular research areas, and not surprisingly has been recently addressed in the sleep medicine field.

One of the examples of sex-related impact of OSA on cardiovascular diseases came out from the Victoria Sleep Cohort study (13), an adult cohort designed to assess the prevalence and natural history of OSA in residents of Vitoria-Gasteiz, Spain. In this study, Cano-Pumarega and colleagues explored the association of untreated OSA and incident stage 2 hypertension (blood pressure ≥160/100 mmHg) based on gender differences in 1,155 normotensive subjects (650 of them women, 56%) at baseline. The presence of moderate to severe OSA was higher in men than in women (18.6% vs. 8.6%). After a mean follow-up of 7.5 years, the authors found that 23% of the hypertensive patients developed stage 2 hypertension and they found a significant difference between men and women (13.7% vs. 3.2%, P<0.001). A respiratory disturbance index (RDI) ≥14/h (comprising moderate and severe OSA) was independently associated with incident stage 2 hypertension in men (OR 2.54, 95% CI: 1.09‡5.95) but not in women. Interestingly, no significant association was observed in the baseline RDI between the subjects who developed stage 1 hypertension and the subjects who remained normotensive.

How to interpret these provocative and interesting prospective findings? Are women really protected from the cardiovascular effects of OSA, including clinical, relevant hypertension? Or the relative small sample of moderate to severe OSA women (n=48) may prevent us any definitive conclusion? Supporting the last, the OR for women with OSA to develop stage 2 hypertension was not so different from men (2.14, 95% CI: 0.40–11.36).

Putting the Victoria Sleep Cohort in context (Table 1), the next question is: how consistent are these results in comparison to recent evidence addressing surrogate markers, intermediary pathways and cardiovascular events in women with OSA? As described on Table 1, there are more questions than answers regarding this important research area. However, it is important to note that the majority of the evidence suggests that the presence of OSA in women were associated with significant impairment in arterial stiffness, coronary calcium, and higher cardiovascular risk (Table 1). Some of these studies pointed to the opposite direction: only women with OSA but not men are on risk! For instance, Faulx et al. found that the impact of OSA on endothelial function was only significant in women (16).

Table 1 Summary of the recent evidence addressing surrogate markers, intermediary pathways and cardiovascular events in women with obstructive sleep apnea (OSA)
Full table

So, what is the take-home message so far: work in progress (22)! Particularly, future investigations addressing several endpoints with significant amount of women and men with similar OSA severity may help to clarify whether the apparently differences in women and men with OSA is justified by differences in frequency and severity of OSA. In addition, intervention studies addressing the effects of OSA treatment is highly desired. For instance, a recent randomized controlled trial investigation addressed the effects of CPAP or conservative treatment for 12 weeks on blood pressure levels and the glucose and lipid profile in 307 women with moderate-to-severe OSA. Compared with the control group, the CPAP group achieved a significantly greater decrease in diastolic blood pressure (−2.04 mmHg), and a non-significant greater decrease in systolic blood pressure (−1.54 mmHg) and mean blood pressure (−1.90 mmHg). CPAP therapy did not change any of the metabolic variables assessed (23). New studies with direct comparisons of men and women are warranted. Finally, despite the recent neutral results of OSA treatment in the second prevention scenario of coronary artery disease and stroke (24), there is still too much to respond in the primary prevention and in patients with established cardiovascular diseases.

Acknowledgements

Funding: Dr. Drager is supported by a research fellowship Grant (2012/02953-2) from Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) and Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq).

Footnote

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

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