Cardiovascular impact of obstructive sleep apnea: does gender matter?

Abstract

Obstructive sleep apnea (OSA) is a common disease characterized by recurrent upper airway obstruction, intermittent hypoxemia and sleep fragmentation. OSA is considered to be predominantly a disease of obese middle-aged men, and it is generally accepted that this disorder is at least twice more common in men than in women. Consistent evidence suggests that OSA is independently associated with cardiovascular risk; however, a significant proportion of the evidence relates to men with OSA. In this brief editorial, we will discuss if markers of cardiovascular risk and cardiovascular events observed in OSA are modulated by gender. We will then examine the evidence regarding the impact of OSA treatment on cardiovascular events in men and women.

Keywords::

• cardiovascular disease
• female
• gender
• obstructive sleep apnea
• treatment

Obstructive sleep apnea (OSA) is a common disease characterized by recurrent upper airway obstruction, intermittent hypoxemia and sleep fragmentation. OSA has been considered to be predominantly a disease of obese middle-aged men, and it is generally accepted that this disorder is at least twice more common in men than in women [1]. Several studies have tried to provide potential explanations for the male predominance in the prevalence of OSA, including differences in the anatomic size of the airway [2], greater collapsibility of the upper airway [3], greater increase in upper airway resistance in men [4], gender differences in ventilatory responses during and following hypoxic challenges [5] or an apparent protective effect of estrogens in women [6]. Indeed, a previous investigation found that the prevalence of OSA was quite low in premenopausal women as well as postmenopausal women with hormone replacement therapy. By contrast, the prevalence of OSA in postmenopausal women without hormone replacement therapy was nearly four-times higher than the aforementioned groups [6].

More than a local phenomenon, there is growing evidence that OSA is independently associated with surrogate markers of cardiovascular risk and cardiovascular events including myocardial infarction and stroke. Several pathways seem to be triggered by OSA and its components including sympathetic overactivity, insulin resistance, vascular inflammation, oxidative stress, endothelial dysfunction and atherosclerosis [7]. We will discuss if markers of cardiovascular risk and cardiovascular events observed in OSA are modulated by gender. We will also examine the evidence regarding the impact of OSA treatment on cardiovascular events in men and women.

Is the cardiovascular impact of OSA modulated by gender?

Surrogate markers of cardiovascular risk

Autonomic dysfunction

It is well established that OSA promotes significant sympathetic activation not only during sleep but also extending during the wakefulness [8]. However, it is not entirely clear whether markers of sympathetic activation are increased in both males and females with OSA. Macey and colleagues studied heart rate responses to autonomic challenges (cold pressor, handgrip and Valsalva maneuver) in both genders with and without OSA patients [9]. OSA patients presented impaired heart rate response compared with healthy controls: lower amplitude, delayed onset and slower rate changes. However, females with OSA had had worse pattern of heart rate response when compared with men counterparts [9].

Endothelial dysfunction

Consistent evidence pointed that OSA is associated with endothelial dysfunction and impaired endothelium repair capacity [10]. Faulx et al. [11] have studied endothelial function by brachial artery ultrasonography in both genders with OSA and demonstrated that solely moderate-to-severe OSA women had impaired endothelial function when compared with men. On the contrary, no difference among moderate-to-severe OSA and mild-normal OSA men were observed [11]. More recently, another study enrolling middle-aged population found that OSA was associated with impaired vascular function (evaluated by digital peripheral arterial tonometry) only in women, independent of menopausal status [12]. Hormone replacement therapy and hormonal contraceptives did not change the results. Therefore, females seem to be more susceptible for developing endothelial dysfunction in patients with OSA.

Inflammation

There is consistent evidence suggesting that low-grade inflammation is associated with OSA [7]. Moreover, treatment with continuous positive airway pressure (CPAP) is associated with significant decrease in inflammatory markers such as C-reactive protein (CRP) [13]. The influence of gender on inflammatory markers has been explored only recently. Studying 1422 males and 2466 females from a Japanese community residents aged 40–69 years, Muraki and colleagues found that the presence of nocturnal intermittent hypoxia (a hallmark of OSA) was associated with raised serum CRP levels in both genders [14]. More recently, Yardim-Akaydin and colleagues explored the impact of gender on CRP, fibrinogen and erythrocyte sedimentation rate in 139 apparently healthy subjects with newly diagnosed OSA and 27 control subjects. In this study, fibrinogen and erythrocyte sedimentation rate were significantly higher in the female patients than in the male patients with OSA [15]. Interestingly, another study found that 3 months of OSA treatment with CPAP promoted a significant reduction of CPR only in men [16]. After 6 months of treatment, CPAP decreased CRP in both genders. Therefore, women seem to have a delay in the CRP normalization, which may indicate a refractory inflammatory process despite effective CPAP therapy [16]. The precise reasons for these findings are not clear but the authors speculated that gender-related hormonal and genetic factors may influence the above CRP evolution pattern [16]. Despite this evidence, definitive evidence regarding the impact of gender of inflammatory markers in OSA is still needed.

Cardiovascular events

Severe OSA is independently associated with increased non-fatal and fatal cardiovascular events in men [17]. Exploring the potential impact of gender, data from Sleep and Heart Health Study showed that severe OSA was an independent predictor of incident coronary heart disease, only in 40–70 years old men [18]. Similarly, severe OSA was a predictor of heart failure in men but not in women (independent of age). However, there were relatively few women with severe OSA and outcomes incidence was very low (only three events of coronary heart disease and eight events of heart failure), indicating that this study probably had low power to detect the impact of OSA in women [18]. Recently, Campos-Rodrigues et al. [19]. published a prospective observational cohort study in women devoted to explore cardiovascular mortality in OSA. After a median follow-up of 72 months, the authors found that females with severe OSA were independently associated with cardiovascular death.

The impact of OSA treatment in men & women on cardiovascular end points

Using an observational study design, Marin and colleagues reported for the first time that severe OSA treatment with CPAP promoted a significant reduction of cardiovascular mortality in men [17]. The cardiovascular impact of CPAP on females with OSA has been explored only recently. In the aforementioned manuscript, Campos-Rodrigues et al. [19] found that the cardiovascular mortality observed among women with severe OSA treated with CPAP was similar to that of women without OSA. However, the CPAP benefits was observed only in women with acceptable CPAP compliance (>4 h per night). CPAP did not reduce mortality in mild-to-moderate OSA group compared with no OSA patients [19].

Conclusions

So far, there is no definitive evidence to address if the cardiovascular impact of OSA is modulated by gender. Because OSA is much more common in men, it is a real challenge to have enough study power to detect potential differences in cardiovascular events in men and women with OSA. Another explanation for this gap in the literature is the exclusion of females in a significant proportion of the studies. The current evidence suggests that surrogate markers of cardiovascular risk seem to be much more impaired in females than males with OSA. However, there is conflicting evidence regarding the impact of OSA on future cardiovascular events. Despite the data from the Sleep and Heart Health Study suggesting that males but not females with severe OSA presented higher rates of total mortality [20] and cardiovascular events [18], recent report from Spain suggested that women are not protected from the cardiovascular consequences of OSA [19]. The importance of studying gender-specific aspects of OSA and cardiovascular disease may have direct implications for risk stratification and treatment of OSA patients. Future investigations should focus on adequately powered studies to provide a better description of the natural history of OSA and differential cardiovascular risk factor profiles. In addition, large interventional trials such as the Sleep Apnea cardioVascular End points trial, [21], may have sufficient power to accurately assess the gender-specific impact of the treatment of OSA.

Financial & competing interest disclosure

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending or royalties.

No writing assistance was utilized in the production of this manuscript.