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Vol. 182, No. 1 DOI: 10.1093/aje/kwv004 Advance Access publication: May 13, 2015

Original Contribution Association of Sleep Apnea and Snoring With Incident Atrial Fibrillation in the Multi-Ethnic Study of Atherosclerosis

* Correspondence to Dr. Gen-Min Lin, Department of Preventive Medicine, Feinberg School of Medicine, Northwestern University, 680 North Lake Shore Drive, Suite 1400, Chicago, IL 60611 (e-mail: [email protected]).

Initially submitted June 27, 2014; accepted for publication January 7, 2015.

The association between sleep apnea and atrial fibrillation (AF) has not been examined in a multiethnic adult population in prospective community-based studies. We prospectively (2000–2011) investigated the associations of physician-diagnosed sleep apnea (PDSA), which is considered more severe sleep apnea, and self-reported habitual snoring without PDSA (HS), a surrogate for mild sleep apnea, with incident AF in white, black, and Hispanic participants in the Multi-Ethnic Study of Atherosclerosis (MESA) who were free of clinical cardiovascular disease at baseline (2000–2002). Cox proportional hazards models were used to assess the associations, with adjustment for socioeconomic status, traditional vascular disease risk factors, race/ethnicity, body mass index, diabetes, chronic kidney disease, alcohol intake, and lipid-lowering therapy. Out of 4,395 respondents to a sleep questionnaire administered in MESA, 181 reported PDSA, 1,086 reported HS, and 3,128 reported neither HS nor PDSA (unaffected). Over an average 8.5-year follow-up period, 212 AF events were identified. As compared with unaffected participants, PDSA was associated with incident AF in the multivariable analysis, but HS was not (PDSA: hazard ratio = 1.76, 95% confidence interval: 1.03, 3.02; HS: hazard ratio = 1.02, 95% confidence interval: 0.72, 1.44). PDSA, a marker of more severe sleep apnea, was associated with higher risk of incident AF in this analysis of MESA data. atrial fibrillation; longitudinal studies; sleep apnea; snoring

Abbreviations: AF, atrial fibrillation; CHD, coronary heart disease; CVD, cardiovascular disease; HF, heart failure; HR, hazard ratio; HS, habitual snoring [without PDSA]; LAE, left atrial enlargement; MESA, Multi-Ethnic Study of Atherosclerosis; MRI, magnetic resonance imaging; OSA, obstructive sleep apnea; PDSA, physician-diagnosed sleep apnea.

Atrial fibrillation (AF) is prevalent in the elderly population (1), and the occurrence of AF is related to many comorbid clinical conditions such as cigarette smoking, excessive alcohol consumption, hypertension, diabetes mellitus, obesity, chronic kidney disease, structural heart disease, heart failure (HF), coronary heart disease (CHD), inflammation, and sleep apnea (2–7). Most of the current evidence for the association between sleep apnea and AF comes from patients with multiple comorbidities and established cardiovascular disease (CVD) in cross-sectional, retrospective, or hospital-based studies (8– 12). Central sleep apnea is the most common sleep apnea

subtype in persons with HF, and it is reported to be associated with an increased risk of AF, especially in elderly populations (13, 14). Across the population, obstructive sleep apnea (OSA) is the major form of sleep apnea, affecting about 15 million US adults (15). A previous observational study found that half of patients with OSA and AF had recurrent AF after electrical cardioversion (7). In addition, treatment of OSA reduces recurrent AF after pulmonary vein isolation (12). In a clinic-based study, some risk factors for incident AF were identified retrospectively in patients with OSA, such as obesity and nocturnal oxygen desaturation, in addition to CHD and HF (11). 49

Am J Epidemiol. 2015;182(1):49–57

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Gen-Min Lin*, Laura A. Colangelo, Donald M. Lloyd-Jones, Susan Redline, Joseph Yeboah, Susan R. Heckbert, Saman Nazarian, Alvaro Alonso, David A. Bluemke, Naresh M. Punjabi, Moyses Szklo, and Kiang Liu

50 Lin et al.

METHODS Study population and data collection

We used data from the Multi-Ethnic Study of Atherosclerosis (MESA), a longitudinal cohort study designed to investigate the prevalence, correlates, and progression of subclinical CVD in persons without clinical CVD at baseline. The study design for MESA has been described in detail elsewhere (17). The cohort includes 6,814 women and men aged 45–84 years recruited from 6 US communities (Baltimore, Maryland; Chicago, Illinois; Forsyth County, North Carolina; Los Angeles County, California; northern Manhattan, New York City; and St. Paul-Minneapolis, Minnesota). At baseline, the participants were 38% white, 28% black, 22% Hispanic, and 12% Chinese. This study was approved by the institutional review board at each study site, and written informed consent was obtained from all participants. Demographic, medical history, anthropometric, and laboratory data for the present analysis were obtained from the first examination of the MESA cohort (July 2000–August 2002). Body mass index was calculated as weight (kg)/height (m)2. Smoking status was defined as current, former, or never smoking. Alcohol consumption was classified into current and noncurrent (never and former) drinking. Blood pressure was ascertained as the mean of the last 2 of 3 seated measurements. Diabetes mellitus was defined as fasting glucose concentration ≥126 mg/dL or the use of hypoglycemic medication. Chronic kidney disease was defined as an estimated glomerular filtration rate less than 60 mL/minute/1.73 m2 based on the Chronic Kidney Disease Epidemiology Collaboration equation (19). Total cholesterol and high-density lipoprotein cholesterol were measured from blood samples obtained after a 12-hour fast. Medication use was assessed by reviewing participants’ medication containers. Serum levels of interleukin-6 were measured as a marker of systemic inflammation. Levels of interleukin-6 were determined by ultrasensitive enzyme-linked immunosorbent assay (Quantikine HS Human Interleukin-6 Immunoassay; R&D Systems, Minneapolis, Minnesota).

Participants were evaluated at baseline with 12-lead electrocardiography and magnetic resonance imaging (MRI). Novacode 6.1 was used to define left ventricular hypertrophy, Novacode 7.1 for left atrial enlargement (LAE), Novacode 8.1 for right ventricular hypertrophy, and Novacode 9.1 for right atrial enlargement on 12-lead electrocardiography (20). In addition, left and right ventricular mass were measured in participants who agreed to undergo cardiac MRI at study entry. The MRI protocol and analysis methods have been previously described (21). Collection of data on PDSA and self-reported snoring

During the second MESA examination (September 2002– February 2004), a self-administered sleep history questionnaire was completed by participants. Among the questions included were 1) “Have you ever snored (now or at any time in the past)?” and (if yes) “How frequently and loudly do you snore?”; and 2) “Have you ever been told by a doctor that you had sleep apnea (a condition in which breathing stops briefly during sleep)?” Participants were provided with 3 potential responses to each question: “yes,” “no,” and “don’t know.” Participants with HS were defined as those who did not report PDSA and reported snoring at least 3–5 days/week. Participants who did not report sleep apnea or habitual snoring were classified as “unaffected.” Among the 6,814 MESA participants, 594 did not participate in the sleep history study, and 882 responded “don’t know” to either the sleep apnea question or the snoring questions and were excluded from this analysis, yielding a sample size of 5,338 (17). Of this sample, there were only 9 Chinese participants with PDSA (18). Therefore, the Chinese participants were excluded (n = 630). Non-Chinese participants found by the Centers for Medicare and Medicaid Services (through events ascertainment) to have AF prior to entry into MESA or evidence of AF at baseline electrocardiography (n = 36) and those with missing data on covariates (n = 277) were also excluded, resulting in 4,395 participants in the following analysis. Figure 1 shows the process used for selection of the eligible MESA sleep cohort. Ascertainment of incident AF events

Current self-reported AF was an exclusion criterion for recruitment in MESA, and participants underwent electrocardiography at baseline. Incident AF was identified from hospital discharge diagnosis codes for AF or atrial flutter (International Classification of Diseases, Ninth Revision, diagnosis codes 427.31 and 427.32) as ascertained by the MESA events detection protocol or from inpatient Medicare claims data. A validation substudy reviewing a random sample of 45 of 185 MESA participants with hospital discharge diagnosis codes for AF showed that AF was confirmed in 93% of the hospitalizations, implying a high positive predictive value for the diagnosis (22). Statistical analysis

Demographic characteristics of participants in each of the 3 groups—PDSA, HS, and unaffected (neither sleep apnea nor snoring)—were compared using either analysis of variance or χ2 analysis. Results are reported as mean values with standard Am J Epidemiol. 2015;182(1):49–57

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To the best of our knowledge, there have been no prospective longitudinal community-based studies to date that have compared the incidence of AF in persons with and without sleep apnea and none which have had the ability to evaluate confounding by an extensive array of CVD risk factors and cardiovascular function. Furthermore, given the known racial/ ethnic differences in AF burden (16), it is unclear whether sleep apnea may have similar associations with incident AF in diverse racial/ethnic groups. To further address the longitudinal associations between sleep apnea and incident AF in community-based samples, we prospectively assessed the associations of physician-diagnosed sleep apnea (PDSA), which is considered a marker of more severe sleep apnea, and selfreported habitual snoring without PDSA (HS), a surrogate for mild sleep apnea, with incident AF in a multiethnic adult population (17, 18). In addition, we explicitly compared models using PDSA and HS to explore the consistency of the associations across racial/ethnic groups. Given prior research, we also explored differences by age and sex as well as by obesity.

Sleep Apnea and Incident Atrial Fibrillation 51

Total MESA Cohort (n = 6,814) Participants Excluded: No sleep history (n = 594) Reported “don’t know” to the questions on snoring or sleep apneain MESA examination 2 (n = 882) MESA Sleep Cohort (n = 5,338)

Eligible for Inclusion in MESA Sleep Cohort (n = 4,395)

Participants With Physician-Diagnosed Sleep Apnea (n = 181)

Participants With SelfReported Habitual Snoring (n = 1,086)

Unaffected Participants (n = 3,128)

Figure 1. Selection of the overall cohort for the sleep study, Multi-Ethnic Study of Atherosclerosis (MESA), 2000–2011.

deviations for continuous variables and percentages for categorical variables. Since PDSA and HS referred to conditions or symptoms that preceded MESA examination 2, follow-up started at MESA examination 1 and continued until the first occurrence of incident AF, death, loss to follow-up, or the end of follow-up (December 31, 2011). Kaplan-Meier analysis was used to assess the associations between the 3 groups and incident AF. Cox proportional hazards regression analyses were used to assess the multivariable association of each group with incident AF, adjusting for potential confounders. In model 1, covariates included age, sex, race/ethnicity, study site, health insurance status, educational attainment, body mass index, diabetes, systolic blood pressure, total cholesterol, high-density lipoprotein cholesterol, chronic kidney disease, smoking status, alcohol intake status, and use of antihypertensive and lipid-lowering agents, which we defined as conventional risk factors. In model 2, covariates included log interleukin-6 and conventional risk factors. In model 3, covariates included electrocardiographic LAE and the model 2 covariates. In model 4, covariates included interim HF or CHD, which was defined as myocardial infarction or definite or probable angina pectoris (if followed by coronary artery bypass grafting or percutaneous coronary intervention) (17), Am J Epidemiol. 2015;182(1):49–57

and the covariates in model 3. These potential confounders or mediators were chosen on the basis of prior published associations with AF or sleep disorders. We conducted another stepwise multivariable analysis in participants who had available data on MRI-measured left and right ventricular mass, as a sensitivity analysis for the overall cohort. Stratified analyses exploring the association between PDSA and AF within racial/ethnic, age, sex, and body mass index groups, as well as formal testing for multiplicative interactions, were performed. In addition, mediation analyses were conducted to evaluate the potential mediating effects of log interleukin-6 and electrocardiographic LAE on the associations in the overall cohort (23). A 2-tailed P value less than 0.05 was considered significant. All statistical analyses were performed using SAS, version 9.4 (SAS Institute, Inc., Cary, North Carolina). RESULTS

In the overall cohort, 181 participants (4.1%) reported PDSA, 1,086 (24.7%) reported HS, and 3,128 (71.2%) reported neither PDSA nor HS. As compared with unaffected participants and those with HS, participants with PDSA were more obese, were more likely to be male, and had higher proportions of chronic kidney disease and use of medication for

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Participants Excluded: Chinese population (n = 630) Evidence of atrial fibrillation at baseline (n = 36) Missing covariates (n = 277)

52 Lin et al.

Table 1. Demographic Characteristics of Participants With Physician-Diagnosed Sleep Apnea, Participants With Self-Reported Habitual Snoring, and Unaffected Participants in the Multi-Ethnic Study of Atherosclerosis, 2000–2011 Variable

Sleep Apnea (n = 181) No.

%

Age, years Female sex

Mean (SD)

Habitual Snoring (n = 1,086) No.

%

59.9 (9.4)

Mean (SD)

Unaffected (n = 3,128) No.

%

59.3 (9.3)

Mean (SD)

62.1 (10.2)

P Value

Association of Sleep Apnea and Snoring With Incident Atrial Fibrillation in the Multi-Ethnic Study of Atherosclerosis.

The association between sleep apnea and atrial fibrillation (AF) has not been examined in a multiethnic adult population in prospective community-base...
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