Association of obstructive sleep apnea with cardiometabolic diseases and cardiovascular mortality

Abstract Background Obstructive sleep apnea (OSA) is one of the leading respiratory disorders, increasing the risk of cardiometabolic diseases. In the study, we investigated the association between OSA and the risk of cardiometabolic diseases and all‐cause and cardiovascular mortality in adults. Methods Participants were enrolled in the National Health and Nutrition Examination Survey. The baseline covariates were compared between participants with and without OSA status. Multivariable logistic regression was performed to explore the association between OSA and cardiometabolic diseases, while Cox proportional regression was performed for all‐cause and cardiovascular mortality. Results OSA status was positively associated with higher risks of cardiometabolic diseases, including hypertension (odds ratio [OR] 1.28, 95% confidence interval [CI] 1.14–1.45; p < 0.001), diabetes (OR 1.46, 95% CI 1.22–1.76; p < 0.001), and cardiovascular diseases (OR 1.29, 95% CI 1.08–1.54; p = 0.006) after adjusting for numerous covariates. However, no associations of OSA with all‐cause or cardiovascular mortality were observed. Conclusion OSA was associated with a higher risk of hypertension, diabetes, and cardiovascular diseases, but had no significant association with all‐cause or cardiovascular mortality in adults.

to determine the diagnosis and severity classification of OSA, 2 as well as the associations between OSA and comorbidities. 3 According to an epidemiological review by Franklin and Lindberg, the prevalence of OSA was estimated to be 22% in men and 17% in women. 4 It is well-known that OSA is a cause of hypertension. 5 Several studies have emphasized that OSA is an independent risk factor for coronary heart disease, 6,7 arrhythmia, 8,9 and stroke. 10,11 Metabolic disorders, including diabetes and impaired lipid metabolism, are also associated with OSA. 12,13 Additionally, more and more evidence has shown that OSA, independent of hypertension, could induce heart failure 14 and other lifethreatening incidents. 15 Therefore, OSA may be a detrimental co-morbidity that severely impacts all-cause and cardiovascular mortality.
Previous studies found that OSA was reported to be associated with all-cause and cardiovascular mortality in patients with chronic obstructive pulmonary disease, 16 acute coronary syndrome, 17 and chronic kidney disease. 18 However, data on the link between OSA and mortality in the general population was limited. In the present study, we aimed to examine the association between OSA and all-cause and cardiovascular mortality in general adults. It will improve our insights into the prevention and management of OSA.

| Study population
We made a secondary analysis based on the National Health and Nutrition Examination Survey (NHANES) 2005-2008, a nationwide multistage-sampling survey. Firstly, participants with missing data on OSA (n = 8310) and cardiometabolic diseases (n = 1715) were excluded. Participants with cancer and pregnancy (n = 1279) and unavailable mortality status (n = 11) were also excluded because pregnancy and cancer could have a cofounding effect on sleep status and mortality, respectively. A total of 9076 respondents were analyzed in this study. The study was approved by the Review Board of National Center of Health Statistics (protocol #2005-06), and the written consent was obtained from the participants.

| Exposure and outcomes
The presence of OSA was determined through a questionnaire that was administered by trained interviewers. Subjects who answered yes to the question "Have you ever been told by a doctor or other health professional that you have a sleep disorder?" and reported sleep apnea to "What was the sleep disorder?" were defined as having OSA. 19 Cardiovascular diseases consisting of congestive heart failure, coronary heart disease, angina pectoris, heart attack, and stroke were obtained from the self-reports. The questions included "Has a doctor or other health professional ever told you that you have congestive heart failure/coronary heart disease/angina pectoris/heart attack/stroke?". Hypertension was diagnosed as previous hypertension, systolic blood pressure ≥140 mmHg, diastolic blood pressure ≥90 mmHg, or taking antihypertensive drugs. Diabetes was diagnosed as previous diabetes, fasting glucose >7 mmol/L, HBA1c >6.5%, or use of hypoglycemic drugs.

| Survey and measurement
A standard questionnaire was used to collect demographic information, including age, sex, race, educational level, poverty income ratio (PIR), body mass index (BMI), drinking and smoking status, history of diseases (hypertension, diabetes, and cardiovascular disease), and history of medication (antihypertensive drug, hypoglycemic drug, and lipid-lowering drug). Smoking was categorized into current, former, and never. Race/ethnicity was divided into four groups: non-Hispanic White or Black, Mexican American, and others. Education level included four categories: less than or equivalent to high school, college, or above. Height and weight were measured by physical examinations, and BMI was calculated as body weight divided by height squared. Serum levels of cholesterol, triglycerides, high-density lipoprotein cholesterol (HDL-C), and low-density lipoprotein cholesterol (LDL-C) were measured using an enzymatic assay. The estimated glomerular filtration rate (eGFR) was calculated based on the chronic kidney disease epidemiology collaboration (CKD-EPI) equation.

| Statistical analysis
Numeric parameters were expressed as the mean ± standard deviation, and categorical variables were presented as numbers (percentages). Differences between groups were compared using the analysis of variance for quantitative values and the chi-squared test for qualitative parameters. A multivariable logistic regression analysis was used to explore the cross-sectional relationship T A B L E 1 Baseline variables of the study participants according to OSA status.

| RESULTS
A total of 9076 individuals were included in our study. Compared with participants without OSA, the population with OSA tends to be older and male and has a higher percentage of diabetes, hypertension, and cardiovascular disease (Table 1).

| DISCUSSION
Our study concluded that OSA was associated with the presence of cardiometabolic diseases, including diabetes, hypertension, and cardiovascular diseases, but had no significant relationship with all-cause or cardiovascular mortality.
Punjabi et al. showed that severe hypopneas were independently associated with cardiovascular diseases. 20 Appleton et al. conducted a longitudinal study showing that hypertension was related to OSA in communitydwelling men. 21 The prevalence of OSA in people with type 2 diabetes mellitus was higher than the general  population. 22 Besides, OSA was associated with atherosclerosis 23 and coronary plaque, 24 which all laid the foundations for increased risk of cardiovascular diseases. Our studies confirmed these associations among a survey-based general population. Increased sympathetic nervous system activity, oxidative stress, and systemic inflammation [25][26][27] may be the mechanisms underlying the association between OSA and cardiometabolic diseases. Another important factor was hypoxia-inducible factors (HIFs). 28 Intermittent hypoxia increased the expression of HIFs, which activated the burst of reactive oxygen species (ROS). ROS, in turn, stimulates the sympathetic nervous system and insulin resistance. 29 Recent study showed that hypoxemic burden because of sleep apnea was strongly predictive of cardiovascular diseases related mortality. 30 Lavie et al. conducted a large prospective cohort study and concluded that severe OSA increased the risk of all-cause mortality in middle-aged male patients. 31 Marin et al. also concluded that those with severe OSA were at higher risk for both fatal and non-fatal cardiovascular events. 5 Besides, a multitude of studies reported that OSA increased the all-cause mortality of patients with lung cancer, 32 asthmatics, 33 and metabolic syndrome. 34 However, using a nationwidely general population enrolled in NHANES, no associations between OSA and all-cause and cardiovascular mortality was observed. The difference could be because OSA diagnosis was based on self-reports rather than objective tests and lack of severity evaluation. The general population enrolled in our study may have a higher proportion of mild OSA, and mild hypoxia may be protective against cardiovascular mortality. Besides, short-duration and low-intensity intermittent hypoxia may provide a degree of protection against ischemic events, which may explain no predictive value in cardiovascular mortality, 35 which may weaken the associations. The underlying reasons need further investigation.
Some limitations existed in our study. First, the main limitation of this study is the lack of an objective assessment of OSA. Some data, including the diagnosis of OSA and cardiovascular diseases, were obtained from self-reported interviews. This may have overestimated the true burden of OSA. Second, even though we excluded individuals with cancer and pregnancy, other chronic conditions, like COPD, autoimmune disease, and chronic kidney disease, were not all excluded, which are linked to worse outcomes and poorer survival. Finally, there is a lack of knowledge regarding the treatment of OSA or not, such as adequate control or good compliance with CPAP, which has an important effect on the mortality in OSA. 36,37 Further research should evaluate the association across the subgroup with or without CPAP treatment.

| CONCLUSION
In conclusion, we found that OSA was associated with the presence of cardiometabolic diseases, including diabetes, hypertension, and cardiovascular diseases. However, it could not predict mortality in the general population.

AUTHOR CONTRIBUTIONS
Xuanfeng Zhu and Jiannan Liu designed the study. Jia Gao wrote the manuscript. Licheng Shi performed the statistical analysis. All authors approved the final manuscript.