Comorbid obstructive sleep apnea is associated with adverse cardiovascular outcomes in female patients with acute coronary syndrome complicating metabolic syndrome

Abstract Background Obstructive sleep apnea (OSA) and metabolic syndrome (MetS) are each increasingly common in patients with acute coronary syndrome (ACS). Whether OSA increases cardiovascular consequences in ACS patients with MetS has not been investigated. Hypothesis OSA increases cardiovascular risk in ACS patients with MetS. We aimed to examine the association between OSA and cardiovascular consequences in ACS patients with MetS. Methods In this prospective cohort study, we consecutive recruited 2160 ACS patients who underwent portable sleep breathing monitoring. OSA is defined as an apnea‐hypopnea index (AHI) ≥ 15 events/h. The primary endpoint was major adverse cardiovascular and cerebrovascular events (MACCE), including cardiovascular death, myocardial infarction, stroke, ischemia‐driven revascularization, or hospitalization for unstable angina or heart failure. Results A total of 1927 patients with ACS were enrolled. Among them, 1486 (77.1%) had MetS and 1014 (52.6%) had OSA. During 2.9 years of follow‐up, the cumulative incidence of MACCE was similar between OSA and non‐OSA groups in patients with MetS (21.9% vs. 17.9%, adjusted hazard ratio [HR] = 1.29 95% confidence interval [CI]: 0.99–1.67, p = .06) and patients without MetS (24.4% vs. 17.3%, adjusted HR = 1.21 95% CI: 0.73–2.03, p = .46). Patients with MetS and OSA had a significantly higher risk of MACCE than patients with MetS and without OSA in women (27.8% vs. 18.1%, adjusted HR = 1.70, 95% CI: 1.01–3.09, p = .04) but not in men (21.0% vs. 17.9%, adjusted HR = 1.19, 95% CI: 0.91–1.59, p = .21). Conclusions In hospitalized ACS patients with MetS, comorbid OSA was associated with increased risk of cardiovascular consequences among women.

group of metabolic abnormalities, including hypertriglyceridemia, hypertension, impaired glucose metabolism, central obesity, and low high-density lipoprotein cholesterol (HDL-C). 7 Moreover, current studies have identified several metabolic disturbances that cause and exacerbate OSA, the mechanisms include anatomical and neurological effects on the upper airway. 8,9 Existing data have suggested that the pathophysiology mechanisms of OSA and MetS interact with each other and that both have adverse effects on the prognosis of patients with ACS. [10][11][12][13][14][15] In addition, both OSA and MetS have gender differences in the pathogenesis, clinical symptoms, prevalence of comorbidities, and cardiovascular consequences. 16,17 However, whether OSA increases the risk of recurrent cardiovascular events in ACS patients with MetS has not been directly investigated. Therefore, based on a large prospective cohort study, we elucidated the association between OSA and subsequent cardiovascular events in ACS patients according to MetS and stratified by gender.

| Study design and participants
This is an auxiliary study of OSA-ACS study (NCT03362385), a large, prospective study designed to elucidate the association between OSA and subsequent cardiovascular events of hospitalized ACS patients. This study protocol has been described in previous studies. 12,18 Briefly, we consecutively recruited ACS patients aged This study conformed to the STROBE (Strengthening the Reporting of Observational studies in Epidemiology) guidelines and was conducted in accordance with the Declaration of Helsinki. 19,20 The Ethics Committee of Beijing Anzhen Hospital, Capital Medical University approved this study (2013025). All patients provided written informed consent.

| MetS diagnosis
The criteria for diagnosis of MetS are three or more risk factors based on the criteria established in the Joint Scientific Statement 21 : (1) Elevated waist circumference ≥90 cm for males and ≥80 cm for females; (2) triglycerides ≥ 1.7 mmol/L, or treatment for elevated triglycerides; (3) HDL-C < 1.0 mmol/L in males, <1.3 mmol/L in females, or treatment for HDL-C; (4) systolic blood pressure (SBP) ≥ 130 mmHg and/or diastolic blood pressure (DBP) ≥ 85 mmHg, or with a history of treatment for hypertension; and (5) fasting blood glucose level ≥ 5.6 mmol/L or treatment of elevated glucose.

| Procedures and management
All patients received standard medical care in line with current clinical practice guidelines. 22,23 At discharge, all patients were receiving aspirin (100 mg daily) plus clopidogrel (75 mg daily) or ticagrelor (90 mg twice daily) for at least 1 year unless clinically contraindicated.
Participants who had a diagnosis of moderate-to-severe OSA (AHI ≥ 15), particularly those with severe excessive daytime sleepiness, were referred to the sleep centers for further evaluation.

| Follow-up and outcomes
Patients' follow-up visits were scheduled at baseline,1, 3, 6, and 12 months and then every 6 months thereafter. Clinical cardiovascular and cerebrovascular events were evaluated with data collected during clinic visits, telephone calls, or medical record review by investigators who was blinded to the patients' results of the sleep study. Recurrent cardiovascular events were recorded at each follow-up visit and adjudicated by an independent clinical event committee.
All endpoints were defined per standardized cardiovascular trial protocol. 24 A composite of the major adverse cardiovascular and cerebrovascular events (MACCE) is the primary outcome for our study, defined as a composite of cardiovascular death, myocardial infarction (MI), stroke, ischemic-driven revascularization, or hospitalization for unstable angina or heart failure. Other outcomes included the 6 individual components of the primary outcome, also all-cause death, all repeat revascularization, a composite of major adverse cardiovascular events (including cardiovascular death, nonfatal myocardial infarction, and stroke), and a composite of adverse cardiac events (cardiovascular death, ischemia-driven revascularization, nonfatal MI, unstable angina, or hospitalization for heart failure). 18

| Statistical analyses
We used counts and percentages (%) to describe qualitative variables and mean ± SD or medians with interquartile ranges (    the composite of a cardiac event ( Figure S1 and Table S3). The crude numbers of events between MetS and non-MetS are listed in ( Figure S2 and Table 2). There was no significant difference  Note: Data are presented as mean ± SD, median (IQR), n (%), or n (%).  (Figure 2A), -but not in men (21.0% vs.
Previous studies have shown that ACS has gender differences in coronary artery anatomy, baseline risk factors, symptoms, treatment effects, comorbidities, and outcomes. 29 A recent intravascular imaging study showed differences between women and men, with women exhibiting coronary plaque features such as reduced overall plaque burden, calcification, and reduced signs of necrosis in the plaque core. 30 In addition, for ACS patients, gender also has different effects on their clinical manifestations and prognosis, such as a lower incidence of chest pain in young women, a higher incidence of other symptoms, and a higher mortality rate during hospitalization. 31 It's worth noting that both OSA and MetS have sex differences, such as OSA is often seen as a male disease, while MetS may be more prevalent in females. 17 Given that sex affects on the association among ACS, OSA, and MetS, it is fundamental to discuss and evaluate the relationship between OSA comorbid in MetS and adverse cardiovascular outcomes in ACS patients by sex. Interestingly, our study first found that ACS patients comorbid with MetS and OSA were associated with an increased risk of subsequent cardiovascular events only in women but not in men, suggesting that female ACS patients with OSA and MetS should be paid enough attention in diagnosis and treatment.
Specifically, comorbid OSA increased recurrent cardiovascular risk in female ACS patients with MetS, and this might be explained by gender differences in the pathophysiology, clinical symptoms, and disease manifestations of OSA. OSA is known to be more prevalent in men than women, but its prevalence increases in postmenopausal women, mainly due to loss of sex hormone protection in women and a similar disruption of insulin secretion and action. 32 Postmenopausal estrogen loss is associated with obesity, cardiovascular disease, and elevated markers of inflammation. 32 In addition, endocrine dysfunction such as hypothyroidism is very common in women, which itself may induce OSA. 33 Moreover, insulin sensitivity is different in gender that systemic insulin sensitivity is higher in women than men. 7 Women with OSA typically manifest as a clustering of apnea during rapid eye movement (REM) sleep, which may be associated with nocturnal ischemia and increased nocturnal sympathetic activity, resulting in a higher risk of cardiovascular events. 34 The phenotype of female OSA is closely related to age, hypertension, and abdominal  obesity. 35 Women also had a higher risk of high-sensitivity troponin T, endothelial dysfunction, and heart failure or death associated with OSA compared with men. 6,36 Currently, data from controlled trials failed to find a positive effect of CPAP treatment on cardiovascular outcomes. 37 41 In addition, a most recent study also demonstrated that 6 months of CPAP therapy in patients with OSA promoted a higher chance of MetS reversal as compared with a placebo. 42 However, several studies found that CPAP is unlikely to have a major effect on metabolic health. 43,44 Gender difference is also associated with the effectiveness of CPAP, as men with the same severity of OSA require more OSA treatment than women. 45

| CONCLUSIONS
In hospitalized ACS patients with MetS, comorbid OSA was associated with an increased risk of subsequent events among women. In response to the call for attention to cardiovascular disease in women, OSA screening should not be ignored in ACS patients, especially when combined with MetS.