CLINICAL RESEARCH STUDY

Persistent Insomnia is Associated with Mortality Risk Sairam Parthasarathy, MD,a,b Monica M. Vasquez, MPH,b Marilyn Halonen, PhD,b,c Richard Bootzin, PhD,d Stuart F. Quan, MD,b,e Fernando D. Martinez, MD,b,c Stefano Guerra, MD, PhDa,b,f a Department of Medicine, bArizona Respiratory Center, cBIO5 Institute, and dDepartment of Psychology and Psychiatry, University of Arizona, Tucson; eDivision of Sleep Medicine, Harvard Medical School, Boston, Mass; fCREAL Centre and Universitat Pompeu Fabra, Barcelona, Spain.

ABSTRACT BACKGROUND: Insomnia has been associated with mortality risk, but whether this association is different in subjects with persistent vs intermittent insomnia is unclear. Additionally, the role of systemic inflammation in such an association is unknown. METHODS: We used data from a community-based cohort to determine whether persistent or intermittent insomnia, defined based on persistence of symptoms over a 6-year period, was associated with death during the following 20 years of follow-up. We also determined whether changes in serum C-reactive protein (CRP) levels measured over 2 decades between study initiation and insomnia determination were different for the persistent, intermittent, and never insomnia groups. The results were adjusted for confounders such as age, sex, body mass index, smoking, physical activity, alcohol, and sedatives. RESULTS: Of the 1409 adult participants, 249 (18%) had intermittent and 128 (9%) had persistent insomnia. During a 20-year follow-up period, 318 participants died (118 due to cardiopulmonary disease). In adjusted Cox proportional-hazards models, participants with persistent insomnia (adjusted hazards ratio [HR] 1.58; 95% confidence interval [CI], 1.02-2.45) but not intermittent insomnia (HR 1.22; 95% CI, 0.86-1.74) were more likely to die than participants without insomnia. Serum CRP levels were higher and increased at a steeper rate in subjects with persistent insomnia as compared with intermittent (P ¼ .04) or never (P ¼ .004) insomnia. Although CRP levels were themselves associated with increased mortality (adjusted HR 1.36; 95% CI, 1.01-1.82; P ¼ .04), adjustment for CRP levels did not notably change the association between persistent insomnia and mortality. CONCLUSIONS: In a population-based cohort, persistent, and not intermittent, insomnia was associated with increased risk for all-cause and cardiopulmonary mortality and was associated with a steeper increase in inflammation. Ó 2015 Elsevier Inc. All rights reserved.  The American Journal of Medicine (2015) 128, 268-275 KEYWORDS: Cardiovascular; Chronic insomnia; Mortality; Sleep

Insomnia is a common medical complaint that affects 20% of US adults, but persistent (or chronic) insomnia is estimated to occur in only half (10%) of such individuals.1-5 Although insomnia has been associated with death,6-17 whether this association holds true both for persistent Funding: See last page of article. Conflicts of Interest: See last page of article. Authorship: See last page of article. Requests for reprints should be addressed to Sairam Parthasarathy, MD, Department of Medicine, University of Arizona, 1501 N. Campbell Avenue, AHSC Rm 2342D, Tucson, AZ 85724. E-mail address: [email protected] 0002-9343/$ -see front matter Ó 2015 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.amjmed.2014.10.015

and intermittent insomnia remains unknown. An enhanced understanding of the association between persistence of insomnia and death would inform treatment of the “at-risk” population. We hypothesized that insomnia that was persistent over 8 yearserather than intermittent insomniaewas associated with death independent of the effects of sedatives, opportunity for sleep (to distinguish it from sleep deprivation), and other confounding factors in a representative sample of the general adult community. The mechanistic basis for the association between insomnia and increased risk of death is unclear. Systemic inflammation has been posited as a potential mechanism

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because sleep curtailment leads to, or is associated with, up too early in the morningeaccompanied by at least one elevation in biomarkers of inflammation.17-20 Such systemic symptom of impaired daytime function (concern about not inflammation, measured as circulating levels of C-reactive getting enough sleep or daytime sleepiness).23 Adequate protein (CRP), has in turn been independently associated opportunity to sleep was gauged by at least 7 hours spent with increased risk for cardiovascular disease and death.21 sleeping or reclining on a typical weekday and on a typical weekend day.24 The persistence of insomnia was assessed We hypothesized that persistent insomnia is associated with elevated circulating levels of CRP. based upon whether insomnia was We tested the above hypothepresent in both the 1984-1985 and CLINICAL SIGNIFICANCE ses by assessing the persistence of 1990-1992 surveys (persistent insomnia complaints in 1409 adult insomnia), in either but not both  Persistent insomnia, but not intermitparticipants from the Tucson (intermittent insomnia), or in tent insomnia, was associated with Epidemiological Study of Airway neither of the 2 surveys (never mortality. Obstructive Disease (TESAOD) insomnia).  Systemic inflammation rose at a steeper and linking such information to the temporal trajectories of their rate in those with persistent insomnia CRP Measurements serum CRP levels and to their than in others. mortality risk over 38 years of CRP was measured using the  Mortality in those with persistent follow-up. enzymatic solid-phase chemilumiinsomnia was cardiovascular- rather than nescent immunometric assay supcancer-related. ported by Immulite 2000 (Siemens METHODS Diagnostics, Tarrytown, NY)25 in 722 available cryopreserved serum Study Population samples that were collected either at the 1990-1992 survey The community-based, prospective cohort study (TESAOD) or at the previous survey (completed in 1988-1989; median was conducted on a multistage, stratified cluster sample of time interval between the 2 surveys: 1.75 years). Of these non-Hispanic white households in Tucson, Arizona. As a 722 subjects, 389 were already 21 years old and had population-based study aimed at studying risk for obstructive available serum samples at the initial survey in 1972-1973, airway disease, study entry did not require the presence of and their enrollment samples were also assayed for respiratory symptoms but was based upon door-to-door CRP levels. campaigning and recruitment of community-dwelling participants. The study methodology and population have been described previously.22 Briefly, the study commenced in 1972 with multiple follow-up surveys up to 1996 and continuous mortality follow-up data up to 2011.22 Blood was collected and serum samples cryopreserved at baseline in 1972 and subsequently at multiple time points. At each survey, weight and height were measured by study nurses and questions about demographic data, medical history, medication history (consumption of hypnotics), smoking history, pulmonary symptoms, and social and environmental information were posed through questionnaires (Appendix, available online). Questions about sleep and related habits were inserted in the 2 surveys completed between 1984 and 1985 (hereafter, survey 1984-1985) and between 1990 and 1992 (hereafter, survey 1990-1992) (Appendix, available online). The present study included 1409 adult participants who completed sleep-related questions in both surveys and were 21 to 75 years old at the time of completion of the 19901992 survey. The study received approval by the University of Arizona Institutional Review Board and written informed consent was obtained from all participants.

Insomnia Definition Insomnia definition was derived from the International Classification of Sleep Disorders criteria, specifically by the presence of any of the following symptomsepersistent symptoms of trouble falling asleep, staying asleep, or waking

Outcomes, Covariates, and Statistical Analysis A thorough review of participants’ vital status as of January 1, 2011 was completed through direct contact with the family or designated next of kin and linkage with the National Death Index.26 The main causes of death were obtained directly from death certificates for events that occurred up to 1978 and from National Death Index records for events that occurred after 1978. We evaluated all-cause mortality (318 events) and death due to each of the 3 main causes of death: heart disease (95 events), cancer (78 events), and chronic obstructive pulmonary disease (COPD, 23 events). Because the number of deaths due to COPD was relatively small, these events were combined with death due to heart disease into the category of cardiopulmonary mortality. Cox proportional hazard models with household clustered sandwich estimators of standard errors were used to calculate the hazard ratios (HRs) for mortality with 95% confidence intervals (CIs) for persistent and intermittent insomnia as compared with never insomnia. Multivariable Cox models included important confounders such as age, sex, body mass index (BMI; categorized as underweight [BMI

Persistent insomnia is associated with mortality risk.

Insomnia has been associated with mortality risk, but whether this association is different in subjects with persistent vs intermittent insomnia is un...
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