CARDIOVASCULAR RISK FACTORS IN COMORBID INSOMNIA AND SLEEP APNEA http://dx.doi.org/10.5665/sleep.3506

Traditional and Nontraditional Cardiovascular Risk Factors in Comorbid Insomnia and Sleep Apnea Faith S. Luyster, PhD1; Kevin E. Kip, PhD2; Daniel J. Buysse, MD3; Aryan N. Aiyer, MD4; Steven E. Reis, MD5; Patrick J. Strollo, Jr, MD6

School of Nursing, University of Pittsburgh, Pittsburgh, PA; 2College of Nursing, University of South Florida, Tampa, FL; 3Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA; 4Division of Cardiology, University of Pittsburgh Medical Center, Pittsburgh, PA; 5Department of Medicine, University of Pittsburgh, Pittsburgh, PA; 6Division of Pulmonary, Allergy, and Critical Care, University of Pittsburgh, PA 1

Objectives: Insomnia and sleep apnea frequently co-occur and are independently associated with an increased risk of cardiovascular disease, but little is known about cardiovascular disease risk among individuals with comorbid insomnia and sleep apnea. The current study examined traditional risk factors and a physiologic biomarker of cardiovascular risk in comorbid insomnia and sleep apnea. Design: Community-based participatory research study. Participants: The sample comprised 795 participants without preexisting cardiovascular disease from the Heart Strategies Concentrating On Risk Evaluation (Heart SCORE) study. Measurements and Results: Participants were assessed for symptoms of insomnia and sleep apnea risk, as well as for presence of obesity, smoking, a sedentary lifestyle, hypertension, dyslipidemia, and diabetes. Baseline resting brachial artery diameter was measured by B-mode ultrasonography. A total of 138 participants (17.4%) met criteria for insomnia syndrome alone, 179 (22.5%) were at high risk for sleep apnea alone, 95 (11.9%) reported both insomnia syndrome and high sleep apnea risk, and 383 (48.2%) reported having neither insomnia nor sleep apnea symptoms Both high sleep apnea risk alone and comorbid insomnia and high sleep apnea risk groups had greater frequencies of obesity, sedentary lifestyle, hypertension, and three or more traditional cardiovascular risk factors and significantly larger brachial artery diameters than the insomnia alone group and those without insomnia or sleep apnea symptoms. No differences in traditional cardiovascular risk factors or brachial artery diameter were found between the high sleep apnea risk and comorbid groups. Conclusions: These findings suggest that sleep apnea is a major contributor to cardiovascular risk and co-occurring insomnia does not appear to add to this risk. Keywords: Cardiovascular diseases, hypertension, insomnia, risk factors, sleep apnea Citation: Luyster FS; Kip KE; Buysse DJ; Aiyer AN; Reis SE; Strollo PJ. Traditional and nontraditional cardiovascular risk factors in comorbid insomnia and sleep apnea. SLEEP 2014;37(3):593-600.

INTRODUCTION Insomnia and obstructive sleep apnea (OSA) are the two most common sleep disorders in adults. Over the past decade, growing evidence from clinical and research samples has suggested a high rate of comorbidity between these two sleep disorders. Prevalence rates of comorbid insomnia and sleep apnea vary widely due to variations in operational definitions across studies, with up to 84% of sleep apnea patients reporting insomnia symptoms.1,2 Both disorders are associated with significant and overlapping health consequences including sleep disturbances, psychological symptoms, occupational impairments, and decreased quality of life; when co-occurring they may have additional negative effects.3 Individuals with comorbid insomnia and sleep apnea have worse sleep,4,5 more daytime sleepiness,5,6 worse cognitive impairment,7 greater mood disturbances,5,8,9 and more dysfunctional beliefs about sleep10 compared to those with only one of the disorders. With growing recognition of the comorbidity between insomnia and sleep apnea, it is important to understand the health risks associated with each

Submitted for publication April, 2013 Submitted in final revised form June, 2013 Accepted for publication June, 2013 Address correspondence to: Faith S. Luyster, PhD, University of Pittsburgh School of Nursing, 3500 Victoria Street, Room 360E, Pittsburgh, PA 15261; Tel: (412) 624-7910; Fax: (412) 624-1201; E-mail: luysterfs@ upmc.edu SLEEP, Vol. 37, No. 3, 2014 593 Downloaded from https://academic.oup.com/sleep/article-abstract/37/3/593/2595987 by guest on 20 February 2018

condition separately and in combination, and ultimately, how treatment may affect these risks. Both sleep apnea11-13 and insomnia14,15 have been independently associated with an increased risk of cardiovascular disease, although the relationship between insomnia and cardiovascular disease has been less consistent.16,17 Thus, cardiovascular disease risk may theoretically be additive for individuals with comorbid insomnia and sleep apnea. Little is known about cardiovascular disease risk among individuals with co-occurring insomnia and sleep apnea and the few available studies have primarily focused on patient-reported cardiovascular diseases. No differences in frequencies of self-reported hypertension, myocardial infarction, and congestive heart failure have been reported between individuals with comorbid insomnia and sleep apnea and individuals with sleep apnea alone.18-20 A greater frequency of stroke has been reported among comorbid insomnia and sleep apnea19; however, after adjusting for confounders, no significant difference in odds of stroke was found between individuals with comorbid insomnia and sleep apnea and individuals with sleep apnea alone.20 Although these studies suggest that the presence of cardiovascular disease may not differ between those with comorbid insomnia and sleep apnea and those with sleep apnea alone, cardiovascular risk factor profiles of individuals with co-occurring insomnia and sleep apnea without preexisting cardiovascular disease have yet to be examined and could have important implications for cardiovascular prevention strategies in this patient population. Traditional cardiovascular risk factors including cigarette smoking,21 obesity,22,23 diabetes,24 hypertension,25 Comorbid Insomnia and Sleep Apnea—Luyster et al

Table 1—Demographic and clinical characteristics of participants with and without insomnia syndrome and high sleep apnea risk in the Heart SCORE study

Characteristic Age, mean (SD)

Comorbid Controls without insomnia insomnia or Insomnia High sleep syndrome and sleep apnea syndrome alone apnea risk alone high sleep apnea symptoms (n = 138) (n = 179) risk (n = 95) (n = 383) Total (n = 795) 57.1 ± 7.2 60.2 ± 7.1 56.2 ± 6.2 57.6 ± 7.6 58.0 ± 7.4

Heart SCORE subjects excluded (n = 1,178) 59.9 ± 7.5

Pa < 0.001

Sex, (%) Male Female

12.3 87.7

73.7 26.3

57.9 42.1

35.7 64.3

36.1 63.9

33.9 66.1

< 0.001

Race, (%) White Other

59.4 40.6

55.9 44.1

40.0 60.0

59.3 40.7

58.5 41.5

52.5 47.5

< 0.001

Education, (%) Less than HS HS diploma Some college, college degree, advanced degree

0.7 10.1 89.1

2.8 12.9 84.3

1.1 22.3 76.6

2.0 15.8 82.1

1.6 14.6 83.7

2.8 18.4 78.8

0.142

Framingham risk strata, (%) Low Intermediate/high

73.2 26.8

27.9 72.1

44.7 55.3

63.6 36.4

60.7 39.3

54.1a 45.9

< 0.001

CESD, mean (SD)

11.3 ± 10.4

4.6 ± 6.4

13.5 ± 10.5

4.9 ± 5.7

7.0 ± 8.3

6.9 ± 7.8

< 0.001

P values are based on analysis of variance or Pearson χ2 test. an = 113 missing data on Framingham risk strata. CESD, Center for Epidemiologic Studies Depression Scale; Heart SCORE, Heart Strategies Concentrating On Risk Evaluation; HS, high school; SD, standard deviation.

a

hyperlipidemia,26 and lack of physical activity27 have been established as independent predictors of cardiovascular disease, and modification of these risk factors with pharmacological therapy and/or lifestyle modification reduces the risk of future cardiac events.28 Brachial artery diameter, a surrogate marker of coronary atherosclerosis, has been found to be associated with cardiovascular risk factors.29-31 A larger brachial artery diameter is significantly correlated with greater body mass index (BMI), hypertension, smoking, dyslipidemia, and diabetes,29-31 and mean resting diameter tends to increase with number of risk factors.30 Brachial artery diameter has been proposed as a useful tool in the prediction of cardiovascular risk. Prior studies have shown that a larger brachial artery diameter is an independent predictor of cardiovascular disease.29,30,32 An association between an increasing apnea-hypopnea index (AHI) and larger mean brachial artery diameter has previously been reported in large community-based samples of middle-aged and older adults,33-35 which suggests compromised vascular function as a possible underlying mechanism linking sleep apnea and cardiovascular disease. Brachial artery diameter has not been examined in individuals with insomnia. Two studies that have investigated the relationship between insomnia and subclinical atherosclerosis assessed by intima-media thickness (IMT) produced conflicting results.36,37 The potential additive effect of insomnia co-occurring with sleep apnea on brachial artery diameter, a novel cardiovascular disease risk, has not been previously explored. The current study examined traditional risk factors (smoking, obesity, sedentary lifestyle, hypertension, dyslipidemia, and diabetes) and a physiologic biomarker (brachial artery diameter) of cardiovascular risk among individuals with comorbid insomnia and high risk of sleep apnea, high sleep apnea risk SLEEP, Vol. 37, No. 3, 2014 594 Downloaded from https://academic.oup.com/sleep/article-abstract/37/3/593/2595987 by guest on 20 February 2018

alone, insomnia alone, and a reference group with no insomnia and low risk of sleep apnea in a large community-based cohort without preexisting cardiovascular disease. METHODS Study Population Participants were recruited from the Heart Strategies Concentrating On Risk Evaluation (Heart SCORE) community-based participatory research study (n = 1,973) designed to evaluate whether a culturally sensitive multidisciplinary risk modification intervention can reduce racial, socioeconomic, and geographic disparities in cardiovascular risk.38,39 Eligibility criteria for Heart SCORE included age 45-75 y, residence in the Pittsburgh metropolitan area, ability to undergo baseline and annual follow-up visits, and absence of a known comorbidity expected to limit life expectancy to less than 5 y. Participants identified as having preexisting cardiovascular disease (prior myocardial infarction, coronary revascularization, or stroke) at study entry were not enrolled in the intervention study, but were prospectively followed and received usual care. For the current analysis, we examined baseline data and excluded those who were missing data on sleep (n = 1,057) or cardiovascular risk factor (n = 70), or who were identified at study entry as having preexisting cardiovascular disease (n = 51). A response of “do not know” on any of the sleep items was scored as missing and many participants reported “do not know” for the three sleep apnea items. Thus, the final sample consisted of 795 participants who met study eligibility criteria and had data on the key variables of interest. The participants excluded from the current analyses are similar to the sample included in the current study (Table 1). The institutional review board at the University of Comorbid Insomnia and Sleep Apnea—Luyster et al

Pittsburgh approved the study protocol, and all study participants provided written informed consent. Measures

questionnaire was used to assess smoking history (current/ past smoker versus never smoked) and current overall level of physical activity that was categorized as sedentary versus nonsedentary lifestyle.

Sleep Disorder Symptoms

Brachial Artery Diameter

The Insomnia Symptom Questionnaire (ISQ) was used to assess the presence and frequency of specific insomnia symptoms and related daytime impairments in the past mo. The ISQ has been validated using classical test theory and item response theory as a screening instrument for sleep complaints and associated daytime consequences consistent with diagnostic criteria for primary insomnia.40 Individuals who reported experiencing at least one of three insomnia symptoms (difficulty falling asleep, difficulty staying asleep, or unrefreshing sleep) as “frequently” (defined as three to four times per w) or “always” (defined as five to seven times per w) and rated at least one symptom of daytime impairment as moderate to extremely severe were categorized as having insomnia syndrome. The Multivariable Apnea Prediction Questionnaire (MAP),41 a validated screening tool for sleep apnea, was used to assess sleep apnea risk by calculation of the MAP index.41 It incorporates data on sleep apnea symptoms (loud snoring, gasping, and choking or pauses in breathing during sleep) during the past mo, BMI, age, and sex to derive a value between 0-1 (i.e., estimated probability of having sleep apnea). Individuals with a MAP index ≥ 0.5 were categorized as having high sleep apnea risk and those with a MAP index < 0.5 were categorized as having low sleep apnea risk. Participants with both insomnia syndrome and high sleep apnea risk were categorized as having comorbid insomnia syndrome and high sleep apnea risk. Participants without the insomnia syndrome and who had low sleep apnea risk were categorized as controls. Traditional Cardiovascular Risk Factors

Assessment of traditional cardiovascular risk factors including smoking history, obesity, sedentary lifestyle, hypertension, dyslipidemia, and diabetes took place at study entry. During the baseline visit, demographic information and detailed medical histories were collected and classification of cardiovascular risk using the Framingham risk score was determined.42 Additionally, a physical examination was conducted and included measurement of blood pressure, waist/hip circumferences, and a 12-h fasting blood draw. Measurement of fasting lipid levels (total and high-density lipoprotein (HDL) cholesterol, triglycerides, and calculated low-density lipoprotein (LDL) cholesterol) were performed using standard laboratory techniques (Cholestech LDX System, Hayward, CA). Dyslipidemia was defined as having blood lipid concentrations within the following parameters, HDL cholesterol ≤ 40 mg/ dL, total cholesterol ≥ 200 mg/dL, or self-reported treatment for dyslipidemia. Hypertension was defined as diastolic blood pressure (DBP) ≥ 90 mm Hg and/or systolic blood pressure (SBP) ≥ 140 mmHg, or self-reported usage of antihypertensive medication. Diabetes was defined as a self-reported diagnosis, current use of antidiabetic medication, or fasting glucose ≥ 110 mg/dL. BMI was calculated as body weight (in kilograms) divided by the square of height (in meters). The presence of obesity was defined as a BMI ≥ 30. A study-specific lifestyle SLEEP, Vol. 37, No. 3, 2014 595 Downloaded from https://academic.oup.com/sleep/article-abstract/37/3/593/2595987 by guest on 20 February 2018

Resting brachial artery diameter was measured by B-mode ultrasonography using a 10 MHz probe with digital recording of images. Off-line quantitative analysis was performed by investigators blinded to subject identifiers. Images were digitized, and calibrated electronic calipers were used to measure brachial artery diameter using the intima-media interface to define arterial borders. Three measurements were made in each analyzed frame and averaged. The intraclass correlation coefficient between two independent observers was 0.94. Statistical Analyses Differences in demographic characteristics were compared between the four groups (insomnia alone, high sleep apnea risk alone, comorbid insomnia, and high sleep apnea risk and controls) using χ2 test for categorical variables and analysis of variance with post hoc comparison for continuous variables. To evaluate the relationships between demographic variables and number of cardiovascular risk factors, correlation analyses and Student t-tests were used. Frequencies of the individual cardiovascular risk factors were calculated among the four groups. Multivariate logistic regression controlling for age, sex, and race was used to calculate the odds ratio of the traditional cardiovascular risk factors among individuals with insomnia alone, high sleep apnea risk alone, comorbid insomnia and high sleep apnea risk, and controls (last group representing the reference group). To determine if individuals with comorbid insomnia and high sleep apnea risk had a potentially different cardiovascular risk factor profile in comparison with individuals with sleep apnea alone, multivariate logistic regression was used to calculate the odds ratio of the traditional cardiovascular risk factors among individuals with high sleep apnea risk alone compared to comorbid insomnia and high sleep apnea risk adjusting for age, sex, and race. Because seven outcome measures were tested in four group comparisons, a Bonferroni-adjusted significance level of 0.002 was used to define statistical significance to account for multiple comparisons. Correlation analyses were conducted to examine the relationship between number of traditional cardiovascular risk factors and brachial artery diameter. For the analysis of brachial artery diameter, analysis of covariance was performed with number of traditional cardiovascular risk factors as a covariate to compare differences between the four groups. SPSS statistical software (SPSS Inc, Chicago, IL) for Windows 20 was used for all statistical analyses. RESULTS Study Population and Traditional Cardiovascular Risk Factors Of the 795 participants included in the analyses, 138 (17.4%) met criteria for insomnia syndrome only, 179 (22.5%) were at high risk for sleep apnea only, 95 (11.9%) reported both insomnia syndrome and high sleep apnea risk, and 383 (48.2%) reported having neither insomnia nor sleep apnea symptoms Comorbid Insomnia and Sleep Apnea—Luyster et al

(Table 1). The high sleep apnea risk alone group were older and had a greater percentage of males than the other three groups (comorbid insomnia and high sleep apnea risk, insomnia alone, and controls). Those with comorbid insomnia and high sleep apnea risk had a greater percentage of nonwhites than those with insomnia alone, high sleep apnea risk alone, and controls. No differences in education level were found between the groups. As compared to the insomnia alone group and controls, both the comorbid insomnia and high sleep apnea risk and high sleep

Figure 1—Frequencies of traditional cardiovascular risk factors among individuals with comorbid insomnia syndrome and high sleep apnea risk, insomnia syndrome alone, high sleep apnea risk alone, and controls. *Bonferroni-corrected P < 0.002 versus controls (reference group). Multivariate logistic regressions were adjusted for age, sex, and race. BMI, body mass index; CVD, cardiovascular disease.

apnea risk alone groups had greater percentage of participants with intermediate/high cardiovascular risk according to their Framingham risk score. Both the insomnia alone and comorbid insomnia and high sleep apnea risk groups had greater levels of depressive symptoms than those with high sleep apnea risk alone and controls. Of the 795 participants, only 2.8% had no cardiovascular risk factors, 71.9% had a clustering of one to three risk factors, and 25.3% had four to six risk factors. The median number of traditional cardiovascular risk factors was three (possible range = zero to six). The most common cardiovascular risk factor was dyslipidemia (82.1%), followed by hypertension (58.4%), smoking (53.3%), obesity (41.1%), diabetes (18.1%), and the least common cardiovascular risk factor, sedentary lifestyle (9.7%). There was no significant relationship between number of traditional cardiovascular risk factors and age (r = 0.06, P = 0.07) and sex (t = -0.28, P = 0.78). Nonwhites had a greater number of cardiovascular risk factors than whites (t = 7.00, P < 0.001). Traditional Cardiovascular Risk Factors Between Groups Using the median number of cardiovascular risk factors for the total sample, number of cardiovascular risk factors was dichotomized into those with less than three cardiovascular risk factors and those with three or more cardiovascular risk factors. Figure 1 presents the frequencies of individual cardiovascular risk factors and cardiovascular risk factor group categorization among the four groups. No differences in cardiovascular risk factors were found between those with insomnia alone and controls. The frequency of obesity, sedentary lifestyle, hypertension, and having three or more cardiovascular risk factors was significantly greater in both the high sleep apnea risk alone and comorbid insomnia and high sleep apnea risk groups compared to controls (Table 2). Diabetes was significantly more frequent among individuals with sleep apnea alone as compared to controls. We also evaluated differences in cardiovascular risk factors among those with high sleep apnea risk alone compared to those with comorbid insomnia and high sleep apnea risk (Table 2). No significant differences in cardiovascular risk factors were found between high sleep apnea risk alone and comorbid insomnia and high sleep apnea risk groups.

Table 2—Adjusted odds ratios of traditional cardiovascular risk factors among individuals with comorbid insomnia syndrome and high sleep apnea risk, insomnia syndrome alone, and high sleep apnea risk alone versus controls Insomnia syndrome alone (n = 138) Current/past smoker BMI ≥ 30 Sedentary lifestyle Hypertension Dyslipidemia Diabetes CVD risk factors ≥ 3

OR (95% CI)a 1.22 (0.82 -1.82) 1.07 (0.67-1.70) 1.40 (0.68-2.87) 1.53 (1.02-2.31) 1.49 (0.84-2.63) 1.52 (0.87-2.67) 1.48 (0.99-2.26)

High sleep apnea risk alone (n = 179) OR (95% CI)a 0.91 (0.61-1.37) 39.14 (18.81-81.49) 4.65 (2.27-9.54) 3.43 (2.16-5.44) 1.35 (0.80-2.28) 2.71 (1.65-4.47) 6.13 (3.79-9.91)

Comorbid insomnia syndrome and high sleep apnea risk (n = 95) OR (95% CI)a 1.34 (0.82-2.17) 25.50 (11.80 -55.11) 4.88 (2.37-10.05) 5.05 (2.81-9.08) 1.08 (0.60-1.93) 1.58 (0.85-2.94) 5.80 (3.30-10.20)

OR (95% CI)b 1.47 (0.88-2.47) 0.65 (0.35-1.22) 1.05 (0.51-2.16) 1.47 (0.79-2.76) 0.80 (0.43-1.50) 0.58 (0.32-1.07) 0.95 (0.52-1.71)

Reference group: controls without insomnia or sleep apnea symptoms (n = 383). bReference group: high sleep apnea risk alone (n = 179). Adjusted for age, sex, and race. Bolded odds ratios and confidence intervals = Bonferroni-corrected P < 0.002. BMI, body mass index; CI, confidence interval; CVD, cardiovascular disease; OR, odds ratio. a

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Comorbid Insomnia and Sleep Apnea—Luyster et al

Nontraditional Cardiovascular Risk Factor, Brachial Artery Diameter A greater number of traditional cardiovascular risk factors was associated with larger brachial artery diameter (r = 0.22, P < 0.001). After adjusting for number of traditional cardiovascular risk factors, which was a significant covariate (P = 0.01), group mean differences were observed for brachial artery diameter (F(3, 794) = 47.03, P < 0.001). Both high sleep apnea risk alone (4.01 ± 0.77) and comorbid insomnia and high sleep apnea risk (3.97 ± 0.80) groups had significantly larger mean brachial artery diameters than the insomnia alone group (3.23 ± 0.60) and controls (3.37 ± 0.66). No difference in brachial artery diameter was found between the high sleep apnea risk and comorbid groups. DISCUSSION Sleep apnea and insomnia have been independently linked with an increased risk of cardiovascular disease; however, cardiovascular disease risk in comorbid insomnia and sleep apnea has not been fully explored. This is the first study to evaluate both traditional risk factors and a novel nontraditional risk factor, brachial artery diameter, in a large community-based cohort of individuals with comorbid insomnia and sleep apnea symptoms without preexisting cardiovascular disease. A greater proportion of individuals with comorbid insomnia and high sleep apnea risk and with high sleep apnea risk alone had Framingham risk scores indicating intermediate or high cardiovascular risk as compared to those with insomnia alone and controls. The two groups with sleep apnea symptoms (both alone and with co-occurring insomnia) were more likely to be obese, be sedentary, have hypertension, have a greater number of traditional cardiovascular risk factors, and have larger brachial artery diameters than both the insomnia alone group and controls. However, the high sleep apnea risk alone group and the comorbid insomnia and high sleep apnea risk group had similar cardiovascular risk factor profiles. These findings suggest that insomnia co-occurring with sleep apnea does not produce an additive effect on risk of cardiovascular disease as evidenced by the presence of traditional cardiovascular risk factors and large brachial artery diameter, a surrogate marker of subclinical atherosclerosis. Traditional cardiovascular risk factors in comorbid insomnia and sleep apnea have been indirectly assessed in several previous studies.18-20 Two large population-based studies reported conflicting findings for BMI,19,20 with one study reporting higher BMI in individuals with comorbid insomnia and sleep apnea and the other reporting higher BMI in those having sleep apnea only. No difference in BMI was found in a group of untreated sleep apnea patients with and without insomnia.18 Contrasting results have also been found for frequency of current and former smokers.19,20 Consistent with our findings, no differences in frequencies of diabetes, elevated total cholesterol, and hypertension have been found between those with comorbid insomnia and sleep apnea and those with sleep apnea only.18-20 Cross-sectional43-47 and prospective studies48,49 and treatment trials with continuous positive airway pressure (CPAP)50,51 provide strong evidence that hypertension is a direct consequence of sleep apnea. The few studies that have examined the association between insomnia and hypertension reported inconsistent and modest SLEEP, Vol. 37, No. 3, 2014 597 Downloaded from https://academic.oup.com/sleep/article-abstract/37/3/593/2595987 by guest on 20 February 2018

results that may be partly explained by potential confounding of comorbid sleep apnea.16,17,52-54 Additionally, recent studies suggest risk for adverse health outcomes, including hypertension,55 diabetes,56 and mortality,57 that may be greatest among a severe insomnia phenotype of chronic insomnia with objective short sleep duration. As compared to normal sleepers who slept 6 h or longer, those with chronic insomnia who slept fewer than 6 h are 3.8 times more likely to develop hypertension, whereas no increased risk for incident hypertension was found for chronic insomniacs who slept 6 h or longer.58 It is important to note that incident hypertension was based on self-report and not blood pressure measurements and that short sleep duration was determined during 1 night of polysomnography, which may not be representative of an individual’s habitual sleep duration. In a recent study using data from the National Health and Nutrition Examination Surveys, insomnia with self-reported short sleep duration was not found to be associated with objectively measured hypertension.59 The underlying mechanisms linking insomnia to hypertension and cardiovascular disease are not fully understood; however, chronic activation of the stress system resulting in increased cortisol secretion, increased catecholaminergic activity, and increased heart rate and decreased heart rate variability have been proposed as potential mechanisms and are associated with insomnia with short sleep duration.30-62 The absence of short sleep duration in the criteria for insomnia in our study and previous studies examining cardiovascular risk in comorbid insomnia and sleep apnea may have contributed to the lack of additive effect. Thus, further research is needed to explore the association between cardiovascular risk and comorbid insomnia with short sleep duration and sleep apnea. Mean brachial artery diameters were not significantly different between the high sleep apnea risk alone and comorbid insomnia and high sleep apnea risk groups, but were larger in both the insomnia alone group and controls even after controlling for number of traditional cardiovascular risk factors. These findings suggest that co-occurring insomnia does not produce a synergistic effect with sleep apnea on vascular health. Several studies have reported an association between sleep apnea and baseline brachial artery diameter.33-35 After adjusting for age, sex, and race, mean brachial artery diameter was shown to be progressively larger with increasing AHI in two studies.33,35 As compared to the mean brachial artery diameters found in our study, the mean brachial artery diameters from these previous studies are larger, with mean brachial artery diameters of 4.6633 and 4.6135 for AHI = 15-29.9 and 4.6733 and 4.7435 for AHI ≥ 30. The discrepancy between mean brachial artery diameter between our study and previous studies is likely explained by the low burden of OSA in the Heart SCORE cohort as suggested by previous objective measurement of AHI with ApneaLINK (ResMed Corporation) in a subpopulation of this cohort.63 In a sample of patients with OSA recruited as part of a Norwegian population-based study, mean baseline brachial artery diameter was 4.0, which is consistent with our high sleep apnea risk alone group (4.0), and was found to be significantly larger than a control group without OSA.34 The mechanisms underlying the association between sleep apnea and larger arterial diameter are unclear. Increased brachial artery diameter may be the consequence of arterial remodeling resulting from Comorbid Insomnia and Sleep Apnea—Luyster et al

oxidative stress and inflammation due to elevated blood pressure and recurrent episodes of hypoxemia.64,65 Vascular changes related to insomnia have not been extensively investigated. The current study evaluated a novel biomarker of subclinical atherosclerosis, brachial artery diameter, and found no difference in brachial artery diameter between individuals with insomnia alone and individuals without insomnia or high sleep apnea risk. This corroborates previous findings that suggest insomnia may not play a role in promotion of atherosclerosis.37,66 A large population-based cohort study of middle-aged and older adults found no significant association between insomnia complaints and increased carotid IMT after adjustment for demographics and cardiovascular risk factors including BMI, LDL and HDL cholesterol, hypertension, diabetes, smoking status, and history of cardiac disease.37 Insomnia symptoms were not associated with endothelial dysfunction measured by flow-mediated dilation after controlling for demographics, lifestyle factors, and self-reported sleep disordered breathing and snoring in a large sample of adults without cardiovascular disease or hypertension.66 Conversely, IMT was significantly greater in a sample of older adults with insomnia and total sleep time of 5 h or less as compared to those without insomnia and total sleep time greater than 5 h.36 This finding is consistent with previous reports that insomnia with short sleep duration is associated with high risk for adverse medical outcomes,55-58 thus suggesting that the joint effect of insomnia and short sleep duration may have the greatest effect on health. Limitations The strengths of our study include a large community-based cohort, evaluation of insomnia complaints consistent with standard American Academy of Sleep Medicine’s Research Diagnostic Criteria67 and Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition68 diagnostic criteria for insomnia, and assessment of a physiologic biomarker of cardiovascular risk. Despite the strengths, several important limitations to this study warrant caution in interpreting the findings. First, a large number of participants were excluded from the analyses due to missing data that may limit generalizability to the Heart SCORE cohort and the broader population of community-dwelling adults. However, participants excluded from the analyses had demographic and clinical characteristics similar to the sample included in the current study. Another limit to generalizability concerns the fact that participants from Heart SCORE were all middle-aged and older adults (age 45-75 y); thus, results from this study cannot be generalized to younger adults. Second, results are based on cross-sectional data; thus, causation cannot be determined. Third, a clinical diagnosis of sleep apnea based on polysomnography was not used for classification of sleep apnea in the current study. We used a validated screening tool for sleep apnea, the MAP, which has been shown to have acceptable sensitivities and specificities at respiratory disturbance index cutoffs of ≥ 5 and ≥ 30.69 None of the participants included in the analyses reported using CPAP. Another limitation is potential recall bias associated with the use of self-report measures for sleep apnea and insomnia symptoms, which may have led to misclassification of individuals with and without insomnia and high sleep apnea risk. Other limitations SLEEP, Vol. 37, No. 3, 2014 598 Downloaded from https://academic.oup.com/sleep/article-abstract/37/3/593/2595987 by guest on 20 February 2018

of the current study include a single assessment for determining objective cardiovascular risk factors, and that the results were not adjusted for cardiovascular pharmacotherapy. CONCLUSION These findings suggest that in a community-based cohort, sleep apnea is a major contributor to cardiovascular risk and co-occurring insomnia does not appear to add to this risk. Prospective studies using objective assessment of sleep apnea are needed to more precisely determine the potential additive effect of comorbid insomnia and sleep apnea on cardiovascular risk. Additionally, investigations exploring the association between cardiovascular diseases and comorbid insomnia with short sleep duration and sleep apnea are warranted. DISCLOSURE STATEMENT This was not an industry supported study. This study was funded by the Pennsylvania Department of Health (ME-02-384) and National Institutes of Health (R01HL089292). Support for Dr. Luyster was provided by the National Heart, Lung, and Blood Institute (NHLBI) K23HL105887. Dr. Strollo has received research support from ResMed, Philips-Respironics, ResMed Foundation, Inspire Medical, and the National Football League. Dr. Strollo has served as a paid consultant for Apnicure and PimMed. Dr. Buysse has served as a paid consultant on scientific advisory boards for the following companies: Merck, Philips Respironics, Purdue Pharma. Dr. Buysse has also spoken at single-sponsored educational meetings for Servier. He has also spoken at a single-sponsored lecture for Astellas. The other authors have indicated no financial conflicts of interest. REFERENCES

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Comorbid Insomnia and Sleep Apnea—Luyster et al

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