Fibrinogen may mediate the association between long sleep duration and coronary heart disease

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<ul><li><p>Fibrinogen may mediate the association between long sleepduration and coronary heart disease</p><p>LAUREN HALE 1 , V I C TOR I A PARENTE 2 , J ENN I F ER BEAM DOWD 3 ,MEGAN SANDS 4 , J E F FREY S . BERGER 5 , Y I Q I NG SONG 6 , L I S A W . MART I N 7</p><p>and MATTHEW A . A L L I SON 81Stony Brook University, Stony Brook, NY, USA, 2Childrens Health Center, Duke University, Durham, NC, USA, 3CUNY School of Public Healthat Hunter College, New York,NY, USA, 4Center for Sleep and Circadian Neurobiology, University of Pennsylvania Perelman School of Medicine,Philadelphia, PA, USA, 5Divisions of Cardiology and Hematology, New York University Medical Center, New York University, New York, NY,USA, 6Division of Preventive Medicine, Brigham Womens Hospital, Brigham and Womens Hospital, Boston, MA, USA, 7Cardiology, GeorgeWashington University School of Medicine and Health Sciences, George Washington University, Washington, DC, USA, 8University ofCalifornia, San Diego, La Jolla, CA, USA</p><p>Keywordscoagulation, coronary heart disease, fibrinogen,long sleep, mortality, sleep duration</p><p>CorrespondenceLauren Hale, PhD, HSC Level 3, Room 071,Stony Brook, NY 11794-8338, USA.Tel.:631 444 1007;fax : 631 444 3480;e-mail: Lauren.Hale@stonybrook.edu</p><p>Accepted in revised form 24 October 2012;received 11 July 2012</p><p>DOI: 10.1111/jsr.12020</p><p>SUMMARYLong sleep duration has been associated with increased risk ofcardiovascular disease (CVD) and all-cause mortality. Inflammationand coagulation have been hypothesized as possible physiologicalpathways to explain this association, although specific biomarkers havenot been studied. Using longitudinal data from 3942 postmenopausalwomen in the Womens Health Initiative observational study and clinicaltrials, we investigated whether fibrinogen, an acute-phase inflammatoryprotein involved in blood clotting, mediates the associations betweensleep duration and coronary heart disease (CHD) and mortality amongwomen. Fibrinogen levels were associated positively with self-reportedlong sleep duration (9+ h per night), CHD and all-cause mortality, evenafter adjustment for a range of sociodemographic characteristics,cardiovascular risk factors and comorbidities.Compared with self-reported 78 h per night sleep duration, self-reported long sleep durationwas associated with increased odds of CHD [odds ratio (OR) = 2.05,95% confidence interval (CI): 1.024.11]. Adjustment for fibrinogen levelsreduced the increased odds of CHD associated with long sleep byapproximately 8 percentage points (OR = 1.97, 95% CI: 0.983.97).A similar reduction in the OR was observed with mortality. For bothoutcomes there is support for partial mediation of 67%, suggesting thatfibrinogen may be a mechanism through which long sleep duration isassociated with CHD and mortality.</p><p>INTRODUCTION</p><p>Long sleep duration has been associated with increasedcardiovascular disease (CVD) and all-cause mortality inwomen (Ayas et al., 2003; Cappuccio et al., 2010; Gallicchioand Kalesan, 2009; Grandner et al., 2009; Knutson andTurek, 2006; Kripke et al., 2002; Stamatakis and Punjabi,2007; Stranges et al., 2008; Tamakoshi and Ohno, 2004;Youngstedt and Kripke, 2004). The physiological pathwaysthrough which these associations occur have not beenelucidated fully (Grandner et al., 2009; Youngstedt andKripke, 2004). Inflammation and coagulation, which areinvolved in the pathophysiology of cardiovascular disease</p><p>through inflammation of arteries and clot formation onplaques, have been hypothesized as possible mediatingmechanisms, particularly among women (Miller et al., 2009;Opp, 2009; Patel et al., 2009; Simpson and Dinges, 2007;Suarez, 2008). However, as recently as, Cappuccio et al.,2010 stated that: no studies published to date havedemonstrated a possible mechanism mediating the effectof long duration of sleep as a cause of morbidity andmortality.A more recent study has shown that longer self-reported</p><p>sleep durations were associated with increased odds ofintima-media thickness (IMT) greater than 1.2 mm, even afteradjustment for demographic factors (e.g. age, sex), health</p><p> 2012 European Sleep Research Society 305</p><p>J Sleep Res. (2013) 22, 305314 Extending sleep and the heart</p></li><li><p>behaviors (e.g. alcohol intake, smoking history) and otherbiomarkers (e.g. lipid profile, fasting plasma glucose) (Abeet al., 2011). Among various potential markers of inflamma-tion and coagulation, prior research has indicated consis-tently that fibrinogen is associated positively with IMT(Martinez-Vila et al., 2003; Temelkova-Kurktschiev et al.,2002) and both sleep duration and quality (Matthews et al.,2010; Suarez, 2008; Wessendorf et al., 2000). Thus, in thisanalysis, we looked specifically at the potential explanatoryrole of fibrinogen in the association between long sleepduration and cardiovascular health. Fibrinogen has been anunderstudied mechanism of the association between longsleep duration and poor CVD health.Fibrinogen, an acute phase inflammatory protein produced</p><p>in the liver, promotes blood clotting and is associatedpositively with increased risks of mortality and incident CVD(Danesh et al., 1998, 2001; Ernst and Resch, 1993; Kannelet al., 1987). Fibrinogen was associated with more difficultyfalling asleep and longer sleep duration among 95 women ina sample of adults in North Carolina (Suarez, 2008). In across-sectional study of multi-ethnic women, however, therewere positive associations between sleep-disordered breath-ing and fibrinogen, but no association between fibrinogenand sleep duration (Matthews et al., 2010). That study,however, treated sleep duration as a continuous variable anddid not separate out categories of sleep duration, whichwould have allowed for a non-linear association betweensleep duration and fibrinogen (Matthews et al., 2010). In asample of more than 1000 Taiwanese adults age 53 yearsand over, there was a positive association between longsleep duration (&gt;8 h per night) and higher levels of severalinflammatory markers (Dowd et al., 2011). With regard tofibrinogen, the study found that long sleepers had fibrinogenlevels 21.8 mg dL1 (P &lt; 0.01) higher than 68-h sleepers,even after adjustment for potential health conditions includingself-reported diabetes, arthritis, heart disease, waist circum-ference, depressive symptoms and health decline since theprevious wave. Consistent with the findings from the multi-ethnic sample (Matthews et al., 2010), no associationbetween fibrinogen and sleep duration was found whensleep duration was treated linearly. The potential mechanismlinking long sleep duration to increased fibrinogen levels maybe due directly to the act of long sleeping or indirectly throughincreased sleep fragmentation, which is more commonamong long sleepers (Grandner and Drummond, 2007).Given these prior findings, we investigated the possible</p><p>mediating role of fibrinogen, a marker of inflammation andcoagulation, in the associations between sleep duration andincident coronary heart disease (CHD) and all-cause mortal-ity in a longitudinal sample of post-menopausal women.Specifically, we hypothesized that long sleep duration wouldbe associated positively with fibrinogen and adverse healthoutcomes (CHD and all-cause mortality), even after adjust-ment for a range of demographic and health covariates. Inaddition, we expected to find that adjustment for fibrinogenattenuated the associations between long sleep duration,</p><p>subsequent CHD and mortality. Fig. 1 provides a heuristicdiagram of the hypothesized relationships.</p><p>METHODS</p><p>Sample</p><p>Data are from a subsample of the Womens Health Initiative(WHI) clinical trial (CT) and observational study (OS).Descriptions of the study population, recruitment methodsand measurement protocols have been published previously(Matthews et al., 1997). The study enrolled postmenopausalwomen between 1993 and 1998 from 40 geographicallydiverse clinical centers throughout the United States, aged5079 years. In total, 161 808 women met the WHI eligibilitycriteria and were enrolled into the study. All participants werefollowed to August 2009 for outcomes for these analyses. Allparticipants provided informed consent, which was approvedby the Institutional Review Boards of the participating studysites.Of this large sample, only a subset of women had serum</p><p>studies performed at baseline; fibrinogen measurementswere part of the core blood analytes and were measuredprospectively in a 6% random subsample of CT participantsat baseline and in a 1% random subsample of OS partic-ipants at baseline. A total of 5016 women had baselinefibrinogen levels recorded. Women with a history of CHD atbaseline were removed from this sample, to leave a remain-ing sample size of 4206. Of these women, approximately 6%were missing information on variables to be included inregression analyses, and were removed from the sample fora final sample size of 3942 for complete case analysis. Therewere no statistically significant differences in long sleepduration among those who were included in the studycompared to those who were not (both around 4% of the</p><p>Sleep duration</p><p>Fibrinogen</p><p>CovariatesAge</p><p>Race/ethnicityEducation</p><p>IncomeCVD risk factors</p><p>Comorbidities</p><p>Health outcomesCHD</p><p>All-cause mortality</p><p>Figure 1. A heuristic diagram of the hypothesized relationships.</p><p> 2012 European Sleep Research Society</p><p>306 Lauren Hale et al.</p></li><li><p>population). There were, however, sociodemographic differ-ences between those who were included in the study. Forexample, the included sample were more likely to be black,Hispanic and Asian, and slightly less likely to be married,compared to the full WHI sample.</p><p>Outcome variables</p><p>Our primary endpoints were incident CHD and all-causemortality during follow-up. Incident CHD was defined by theWHI study as the first occurrence of clinical myocardialinfarction (MI), definite silent MI or a death due to CHD(defined before October 1999), definite CHD or possibleCHD. Overall mortality was defined as death from any cause.All outcomes were determined by a physician, and wereidentified initially through annual follow-up contacts and thenverified through medical records and death certificates.</p><p>Key predictor variables</p><p>Self-reported sleep duration at study baseline was theprimary predictor of interest. As part of the baseline exam-ination, each WHI participant was asked to report hours ofsleep on a typical night during the past 4 weeks ( 5, 6, 7, 8,9, 10). In our study sample, 450 (11.4%) women slept 5 h, 1189 (30.2%) women slept 6 h, 1381 (35.0%) slept7 h, 770 (19.5%) slept 8 h, 133 (3.4%) slept 9 h and 19(0.5%) slept 10 h or more. Due to the very small number ofwomen at the longest sleep duration category, we combinedthe top two sleep durations and labeled the categories basedon typical descriptions in the literature: long sleepers (9+ h),mid-range sleepers (7 or 8 h), short sleepers (6 h) andvery short sleepers ( 5 h).Fibrinogen levels at screening were evaluated as both a</p><p>predicting and mediating variable. The average fibrinogenlevel in the sample was 304.45 mg dL1, with a standarddeviation of 61.68 mg dL1. Fibrinogen levels were stan-dardized for ease of interpreting values such that the meanwas 0 and a standard deviation was 1 [standardizedlevel = (fibrinogen level: 304.45)/61.68]. The standardizedfibrinogen level was used for all multivariable modelspresented in the results.</p><p>Other pertinent covariates</p><p>Demographic covariates</p><p>All demographic characteristics were determined at the initialscreening visit and were based on self-report questionnaire.Age was treated as a continuous variable. Education wascategorized as less than high school, high school diploma orgeneral education diploma (GED), some college or voca-tional training and college degree or more. Annual householdincome was classified into the groups 140 mm Hg and/or diastolic blood pressurewas &gt;90 mm Hg, and/or were taking antihypertensive med-ication. Individuals with diabetes included those participantswith physician-diagnosed diabetes who were taking diabetesmedications. Depression was measured at baseline amongthe WHI-OS participants using the Burnam screening algo-rithm, a measure that includes six items from the 20-itemCenter for Epidemiologic Studies-Depression Scale (CES-D)and two items from the National Institute of Mental HealthsDiagnostic Interview Schedule (DIS). The Burnam screenwas developed initially for the Medical Outcomes Study anduses a logistic regression algorithm to develop a compositescore between 0 and 1. A cutoff point of 0.06 was used toidentify current depressive symptomatology. This instrumenthas shown good sensitivity (74%) and specificity (87%) fordetecting depressive disorder (major depressive disorder anddysthymia) in both primary care and mental health settingsamong postmenopausal women (Tuunainen et al., 2001).We also included covariates of self-rated health (In</p><p>general, would you say your health is: excellent, very good,good, fair or poor?) and a measure of life satisfaction. Self-rated health was grouped into a dichotomous variable withexcellent and very good (=1) compared to all else. The lifesatisfaction variable came from the question: Overall, howwould you rate your quality of life? based on a scale of 110</p><p> 2012 European Sleep Research Society</p><p>Long Sleep, Fibrinogen, and CHD 307</p></li><li><p>with 10 being the best. We dichotomized this variable at nineor better (=1), compared to all those scores at eight or below.</p><p>Statistical analyses</p><p>First, we tested the association between fibrinogen and self-reported sleep duration using nested ordinary least-squaresregression models. In the crude model, we utilized a four-level categorical variable for sleep duration (reference group78 h) to predict continuous fibrinogen (in mg dL1), unad-justed for other covariates. The next model added adjustmentfor demographic variables (age, education, income andethnicity) and other risk factors and comorbidities.We then investigated two sets of nested logistic regression</p><p>models with fibrinogen predicting incident CHD and all-causemortality, respectively. Crude and adjusted models wereestimated as described above.Finally, we estimated two different sets of nested models</p><p>for incident CHD and all-cause mortality. In model A, weadjusted only for sleep duration and demographic factors toidentify the baseline association of long sleep duration (9+ h)on the outcome variables. In model B, we included fibrinogento test whether the odds ratio for long sleep duration wasreduced with the addition of fibrinogen. Model C includedadjustment for cardiovascular risk factors and comorbidities.Finally, we conducted tests of mediation using thebinary_mediation command in STATA, which is used forassessing mediation dichotomous outcomes (MacKinnonand Dwyer, 1993; Sobel, 1982). All analyses were conductedin STATA version 11.0 (STATA Corp., College Station, TX,USA).</p><p>RESULTS</p><p>Descriptive statistics of the analytical sample are shown inTable 1, stratified by sleep duration category. The all-femalesample was primarily white, age 60 or older, with at least wit...</p></li></ul>

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