Insomnia With Objective Short Sleep Duration and Incident Hypertension

 
 
Insomnia With Objective Short Sleep Duration and
                        Incident Hypertension
                                                  The Penn State Cohort
          Julio Fernandez-Mendoza, Alexandros N. Vgontzas, Duanping Liao, Michele L. Shaffer,
                           Antonio Vela-Bueno, Maria Basta, Edward O. Bixler

Abstract—Insomnia with objective short sleep duration appears to be a biologically more severe phenotype of the disorder.
  No longitudinal study to date has examined the association of this type of insomnia with incident hypertension using
  polysomnography. From a random, general population sample of 1741 adults of the Penn State Cohort, 1395 were
  followed-up after 7.5 years, and 786 did not have hypertension at baseline. Hypertension was determined by a self-
  report of receiving treatment for high blood pressure. Chronic insomnia was defined as a complaint of insomnia lasting
  ≥1 year, whereas poor sleep was defined as moderate-to-severe sleep difficulties. All of the subjects underwent 8-hour
  polysomnography. Sleep-disordered breathing (SDB) was defined as an obstructive apnea/hypopnea index ≥5. We used
  the median polysomnographic percentage of sleep time to define short sleep duration (ie,
930  Hypertension  October 2012


of chronic insomnia and incident hypertension is enhanced by               subjects’ sleep laboratory visit. Furthermore, BP was measured in
objective short sleep duration.                                            the evening, ≈2 hours before the start of the sleep recording, using
                                                                           a pneumoelectric microprocessor-controlled instrument with the
                                                                           appropriate-sized cuffs. The accuracy of this monitor is reported to be
                             Methods                                       ±3 mm Hg; in addition, internal calibration was performed before
Participants                                                               each use, and the machine was checked against a mercury sphyg-
                                                                           momanometer at least annually. The recorded BP was the average
The data presented here were collected as part of a population-
                                                                           of 3 consecutive readings during a 5-minute period after 10 minutes
based study of sleep disorders, which used a 2-phase protocol to
                                                                           of rest in the supine position. Based on these baseline BP measure-
recruit participants from various age groups.10,18–21 In the first phase
                                                                           ments, a normal BP status was defined as systolic BP (SBP)
Fernandez-Mendoza et al   Insomnia, Sleep, Duration, and Hypertension   931


Table 1. Demographic, Clinical, and Sleep Characteristics of            Table 1.      Continued
Study Population at Baseline
                                                                                                                         Hypertension Incidence
                                           Hypertension Incidence
                                                                        Characteristics             All (N=786)      No (N=595)       Yes (N=191)
Characteristics         All (N=786)    No (N=595)       Yes (N=191)
                                                                        Sleep difficulty
Sex                                                                       Normal sleep, %              74.3             83.3              16.7
  Women, %                 51.3            79.5             15.1          Poor sleep, %                20.2             82.4              17.6
  Men, %                   48.7            84.9            20.5*          Chronic insomnia, %           5.5             68.9              31.1†
Race
                                                                        Sleep duration, h            6.0 (1.1)        6.0 (1.1)         5.7 (1.1)†
  White, %                 94.2            82.9             17.1
                                                                          ≥6, %                        59.4             85.0              15.0
  Nonwhite, %               5.8            71.9            28.1*
932  Hypertension  October 2012


Table 2. Multivariable Adjusted Odds Ratio (95% CI) of                                      1.80 (95% CI, 1.04–3.12; P=0.036), however, this association
Incident Hypertension and Insomnia or Objective Sleep Duration                              became marginally significant after controlling for obesity (OR,
                         Model 1                 Model 2                Model 3             1.62 [95% CI, 0.92–2.83]; P=0.09). In contrast, in subjects with
   Predictors           OR (95% CI)             OR (95% CI)            OR (95% CI)          chronic insomnia or poor sleep who slept objectively ≥6 hours,
                                                                                            the risk for hypertension was not significantly increased (see
Sleep difficulty
                                                                                            Table 3). The results remained significant and the ORs very
   Normal sleep              1.0               1.0               1.0
                                                                                            similar to those reported in Table 3 after we adjusted for hyp-
   Poor sleep        1.19 (0.78–1.79) 1.02 (0.66–1.57) 1.01 (0.65–1.55)
   Chronic           2.66 (1.45–4.88)† 2.29 (1.22–4.27)† 2.24 (1.19–4.19)†                  notic use and periodic limb movements at baseline.
   insomnia
Sleep duration                                                                                                            Discussion
   ≥6 h                      1.0                     1.0                    1.0             This is the first study to demonstrate that chronic insomnia
Fernandez-Mendoza et al   Insomnia, Sleep, Duration, and Hypertension   933


association found in these latter studies between insomnia             In our previous studies, PSG-measured sleep duration
and hypertension may be explained by the addition of severity       was a strong predictor of hypothalamic-pituitary-adrenal
and/or chronicity in their definition of insomnia. However, in      axis hyperactivity and medical morbidity among insom-
these studies, no polysomnographic measures were obtained,          niacs.12–17 However, PSG involves significant expense
and, therefore, the potential confounder of SDB was not con-        and efforts, tends to disturb a subject’s sleep (“first-night
trolled for and the role of objective short sleep duration as       effect”), and, because of night-to-night variability of the
a marker of the biological severity of the disorder was not         subject’s sleep, multiple night recordings are required to
examined.                                                           obtain a representative sample of an individual’s typical
   In our study, the group with chronic insomnia, that is, a        habitual sleep duration and pattern.33–35 More recently,
complaint of insomnia ≥1 year, was associated with a sig-           night-to-night variability assessed with actigraphy for 1 to
nificant risk for incident hypertension (OR, 2.2), whereas          2 weeks has been indicated as a very useful marker of the
the group with poor sleep, that is, moderate-to-severe              severity of insomnia, that is, there is significant increase
insomnia symptoms, was not associated with an increased             in the night-to-night variability among chronic insomni-
risk for hypertension. When we introduced the criterion of          acs than among the controls.36 There was also a significant
objectively measured short sleep duration in the definition         adverse association between intraindividual variability in
of insomnia, we showed a strong and significant joint effect        sleep duration and fragmentation and psychosocial and
on the association of insomnia with the incidence of hyper-         physiological indices of stress, reflected as increased night-
tension. Chronic insomniacs who slept
934  Hypertension  October 2012


subjects’ habitual sleep duration. However, in our previous                        Heart Disease and Stroke Statistics: 2012 update–a report from the
                                                                                   American Heart Association. Circulation. 2012;125:e2–e220.
studies, the association between objective sleep duration and
                                                                              2.   Young T, Peppard P, Palta M, Hla KM, Finn L, Morgan B, Skatrud J.
hypercortisolemia was based on a 4-consecutive-night sleep                         Population-based study of sleep-disordered breathing as a risk factor for
laboratory protocol, which should represent better the typi-                       hypertension. Arch Intern Med. 1997;157:1746–1752.
cal sleep profile of the subjects.16,17 The consistency of the                3.   Bixler EO, Vgontzas AN, Lin HM, Ten Have T, Leiby BE, Vela-Bueno A,
                                                                                   Kales A. Association of hypertension and sleep-disordered breathing.
findings on the role of objective sleep duration in predicting
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insomnia severity between these physiological studies with                    4.   Nieto FJ, Young TB, Lind BK, Shahar E, Samet JM, Redline S,
multiple night recordings and the current epidemiological                          D’Agostino RB, Newman AB, Lebowitz MD, Pickering TG. Association
study based on a single night recording increases our con-                         of sleep-disordered breathing, sleep apnea, and hypertension in a large
                                                                                   community-based study. JAMA. 2000;283:1829–1836.
fidence about the replicability and generalizability of the
                                                                              5.   National Institutes of Health. NIH state of the science statement on mani-
present findings. Future studies should explore the asso-                          festations and management of chronic insomnia in adults. J Clin Sleep
ciation among insomnia, sleep duration, and hypertension                           Med. 2005;1:412–421.
using multiple night recordings. Finally, we performed fur-                   6.   Phillips B, Mannino DM. Do insomnia complaints cause hypertension or
                                                                                   cardiovascular disease? J Clin Sleep Med. 2007;3:489–494.
ther analyses to address the question of whether receiving
                                                                              7.   Phillips B, Bùzková P, Enright P, for the Cardiovascular Health Study
treatment for hypertension at follow-up relatively improved                        Research Group. Insomnia did not predict incident hypertension in older
the sleep of chronic insomniacs and perhaps decrease their                         adults in the cardiovascular health study. Sleep. 2009;32:65–72.
insomnia-related cardiovascular risk (see the online-only                     8.   Suka M, Yoshida K, Sugimori H. Persistent insomnia is a predic-
                                                                                   tor of hypertension in Japanese male workers. J Occup Health.
Data Supplement for details). In fact, we found that a higher                      2003;45:344–350.
percentage of those who persisted with chronic insomnia                       9.   Janson C, Lindberg E, Gislason T, Elmasry A, Boman G. Insomnia
reported being treated for hypertension, which reinforces our                      in men: a 10-year prospective population based study. Sleep. 2001;
findings that severe, persistent insomnia is a premorbid risk                      24:425–430.
                                                                             10.   Bixler EO, Vgontzas AN, Lin HM, Vela-Bueno A, Kales A. Insomnia in
factor for incident hypertension.                                                  central Pennsylvania. J Psychosom Res. 2002;53:589–592.
                                                                             11.   Gangwisch JE, Malaspina D, Posner K, Babiss LA, Heymsfield SB,
Perspectives                                                                       Turner JB, Zammit GK, Pickering TG. Insomnia and sleep duration as
In summary, insomnia with short sleep duration is associ-                          mediators of the relationship between depression and hypertension inci-
                                                                                   dence. Am J Hypertens. 2010;23:62–69.
ated with a high risk for the development of hypertension to a               12.   Vgontzas AN, Liao D, Bixler EO, Chrousos GP, Vela-Bueno A. Insomnia
degree comparable with the other most common sleep disor-                          with objective short sleep duration is associated with a high risk for hyper-
der, that is, SDB.2–4 Given the high prevalence of insomnia in                     tension. Sleep. 2009;32:491–497.
the general population and the widespread misconception of                   13.   Vgontzas AN, Liao D, Pejovic S, Calhoun S, Karataraki M, Bixler EO.
                                                                                   Insomnia with objective short sleep duration is associated with type 2 dia-
a disorder of the “worried well,” its detection and diagnosis                      betes: a population-based study. Diabetes Care. 2009;32:1980–1985.
should become the target of public health policy. It appears                 14.   Fernandez-Mendoza J, Calhoun S, Bixler EO, Pejovic S, Karataraki M,
that insomnia with objective short sleep duration may repre-                       Liao D, Vela-Bueno A, Ramos-Platon MJ, Sauder KA, Vgontzas AN.
sent a biologically more severe phenotype of insomnia that                         Insomnia with objective short sleep duration is associated with deficits
                                                                                   in neuropsychological performance: a general population study. Sleep.
may respond differentially to treatment. Finally, because poly-                    2010;33:459–465.
somnographic measures of sleep are inconvenient and expen-                   15.   Vgontzas AN, Liao D, Pejovic S, Calhoun S, Karataraki M, Basta M,
sive, there is a need for validation of practical, easy to use,                    Fernández-Mendoza J, Bixler EO. Insomnia with short sleep duration and
inexpensive methods to measure sleep duration outside of the                       mortality: the Penn State cohort. Sleep. 2010;33:1159–1164.
                                                                             16.   Vgontzas AN, Tsigos C, Bixler EO, Stratakis CA, Zachman K, Kales A,
sleep laboratory.                                                                  Vela-Bueno A, Chrousos GP. Chronic insomnia and activity of the stress
                                                                                   system: a preliminary study. J Psychosom Res. 1998;45:21–31.
                      Acknowledgments                                        17.   Vgontzas AN, Bixler EO, Lin HM, Prolo P, Mastorakos G, Vela-Bueno A,
The work was performed at the Sleep Research and Treatment Center                  Kales A, Chrousos GP. Chronic insomnia is associated with nyctohemeral
at the Penn State University Milton Hershey Hospital, and the staff                activation of the hypothalamic-pituitary-adrenal axis: clinical implica-
(C. Criley, P. Cain, S. George, and T. Miksiewicz) is especially com-              tions. J Clin Endocrinol Metab. 2001;86:3787–3794.
mended for their efforts.                                                    18.   Bixler EO, Vgontzas AN, Ten Have T, Tyson K, Kales A. Effects of age
                                                                                   on sleep apnea in men: I–prevalence and severity. Am J Respir Crit Care
                                                                                   Med. 1998;157:144–148.
                     Sources of Funding�                                     19.   Bixler EO, Vgontzas AN, Lin HM, Ten Have T, Rein J, Vela-Bueno A,
This research was in part funded by the National Institutes of Health              Kales A. Prevalence of sleep-disordered breathing in women: effects of
grants R01 51931, R01 40916, and R01 64415.                                        gender. Am J Respir Crit Care Med. 2001;163:608–613.
                                                                             20.   Waksberg J. Sampling methods for random digit dialing. J Am Stat Assoc.
                           Disclosures�                                            1978;73:40–46.
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                                                                                   Techniques and Scoring System for Sleep Stages of Human Subjects.
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                                                                   Novelty and Significance
                                  What Is New?                                      • Physicians should become aware that patients with hypertension may
  • Although insomnia is a highly prevalent sleep disorder, it has not been con-      experience untreated severe chronic insomnia.
    sistently associated with significant cardiovascular morbidity.
  • There is a lack of longitudinal studies examining the association between                                       Summary
    insomnia and incident hypertension, and none has included objective mea-
                                                                                    Insomnia with short sleep duration is associated with a high risk
    sures of sleep to evaluate the biological severity of insomnia.
                                                                                    for the development of hypertension to a degree comparable with
                               What Is Relevant?                                    the other most common sleep disorder, sleep apnea. Given the high
  • Insomnia is highly prevalent in the outpatient practice of general practitio-   prevalence of insomnia in the general population, its early diagno-
    ners, such as family doctors, internists, and cardiologists.                    sis and appropriate management should become a target of public
  • Severe chronic insomnia is a risk factor for new-onset hypertension.            health policy in the prevention of hypertension.




                                    Downloaded from http://hyper.ahajournals.org/ by guest on October 11, 2015
ONLINE DATA SUPPLEMENTS

INSOMNIA WITH OBJECTIVE SHORT SLEEP DURATION AND INCIDENT
HYPERTENSION: THE PENN STATE COHORT

Julio Fernandez-Mendoza, PhD;1 Alexandros N. Vgontzas, MD;1 Duanping Liao, MD;2 Michele
L. Shaffer, PhD;2 Antonio Vela-Bueno, MD;3 Maria Basta, MD;4 Edward O. Bixler, PhD1
1
    Sleep Research & Treatment Center, Department of Psychiatry, Pennsylvania State University
    College of Medicine, Hershey, PA
2
    Department of Public Health Sciences, Pennsylvania State University College of Medicine,
    Hershey, PA
3
    Department of Psychiatry, School of Medicine, Autonomous University, Madrid, Spain
4
    Department of Psychiatry, School of Medicine, University of Crete, Crete, Greece
Insomnia, Objective Sleep Duration, and Incident Hypertension                                     1


ONLINE SUPPLEMENTAL METHODS

Participants
        The data presented here were collected as part of a population-based study of sleep
disorders, which used a two-phase protocol in order to recruit participants from various age
groups.1-3 In the first phase of the study, a sample of adult men and women (age ≥20 years) was
randomly selected from local telephone households in two counties of Central Pennsylvania
(Dauphin and Lebanon) using the Mitofsky-Waksberg two-stage random digit dialing
procedure.4 A within-household selection procedure described by Kish5 was used to select the
specific man or woman to be interviewed. Telephone interviews were conducted with 4,364 age-
eligible men and 12,219 age-eligible women residing in the sample households, for a total
sample of 16,583 with response rates of 73.5% and 74.1%, respectively. The questionnaire
employed in this interview included basic demographic and sleep information. In the second
phase of this study, a subsample of 741 men and 1,000 women, selected randomly from those
subjects previously interviewed by telephone, were studied in our sleep laboratory. The response
rates for this phase were 67.8% and 65.8% for men and women, respectively. After giving a
complete description of the study to the subjects, written informed consent was obtained. We
contrasted those subjects who were recorded in the laboratory with those who were selected but
not recorded in terms of age, BMI, and prevalence of sleep disorders. There were no significant
differences between these two groups on any of these variables.
        Of the 1741 subjects who completed the comprehensive sleep lab evaluation, 1395
subjects were followed up after an average duration of 7.5 years (mean duration of 4.5 years for
women and 10.5 years for men) via telephone interview. In the Penn State Cohort Study, men
were recruited first and women 5 years later. This explains the five-year difference in the follow-
up period between men and women. The response rate of the follow-up study was 79.7%.
However, if one considers that 215 subjects died between baseline and follow-up, then the
response rate of those alive was 90.9%. After complete description of the follow-up study to the
subjects, verbal informed consent was obtained. The whole study procedure was approved by the
University’s Institutional Review Board. Figure S1 shows the participant flow in the study.

Definition of Incident Hypertension
        For the purpose of this study, the presence of hypertension at baseline was defined by a
self-report of receiving treatment for high blood pressure, based on a standardized questionnaire
completed by the subjects on the evening of their sleep laboratory visit. Commensurate with the
baseline definition, hypertension at follow-up was defined by a self-report of receiving treatment
for high blood pressure. Of the 1395 subjects who were followed-up, 786 did not have
hypertension at baseline and were selected for the present study. A total of 191 subjects were
incident cases of hypertension while 595 did not have hypertension at follow-up. Twenty
subjects had missing data on hypertension at follow-up.

Sleep Laboratory Evaluation
       Each subject selected for laboratory evaluation completed a comprehensive sleep history
and physical examination. All subjects were evaluated for one night in the sleep laboratory in
sound-attenuated, light- and temperature-controlled rooms. During this evaluation, each subject
was continuously monitored for eight hours (fixed-time period) using 16-channel
polysomnography (PSG) including electroencephalogram, electrooculogram, and
Insomnia, Objective Sleep Duration, and Incident Hypertension                                      2


electromyogram. Bedtimes were adjusted to conform to subjects’ usual bedtimes, and subjects
were recorded between 22:00-23:00 and 06:00-07:00. The sleep recordings were subsequently
scored independently, according to Rechtschaffen and Kales criteria.6 Percent of sleep time is
total sleep time divided by recorded time in bed and multiplied by 100. From the objectively
recorded sleep time data, we regrouped the entire study sample into two ordinal groups: the top
50% of persons above the median percent of sleep time (“longer sleep duration group”), and the
50% of persons in the bottom half (“short sleep duration group”). We then rounded the cutoff
point to meaningful numbers and thus created the following two sleep duration groups: the
“longer sleep duration group” consisted of those who slept ≥6 h (i.e., percent of sleep time
≥75%), and the “short sleep duration group” of those who slept
Insomnia, Objective Sleep Duration, and Incident Hypertension                                      3


you have difficulty staying asleep?”), early final awakening (“Do you wake up in the morning
earlier than desired?”), or non-restorative sleep (“Do you still feel groggy and unrefreshed after
morning awakening?”). Finally, normal sleep was defined as the absence of either of these two
categories. In order to create three mutually exclusive categories, none in the poor sleep group
reported having chronic insomnia and none in the normal sleeping group reported either chronic
insomnia or poor sleep. Table S1 presents the characteristics of normal sleepers, poor sleepers,
and chronic insomniacs at baseline.
        Additional information obtained from the standardized questionnaire included assessing
other physical health conditions, depression, and substance use. The presence of diabetes at
baseline was defined as a self-report of receiving treatment for diabetes or having a fasting blood
sugar ≥126 mg/dl from blood drawn the morning after the subject’s PSG. We also ascertained at
baseline whether the respondent was currently treated for depression, including a history of
suicidal thoughts or attempts. Participants’ daily consumption of caffeine (number of cups/day),
tobacco (number of cigarettes/day), and alcohol (number of drinks/day) was also assessed at
baseline.
        Follow-up measures taken through telephone interview included the standardized
questionnaire that subjects completed at baseline during their sleep laboratory visit. Physical
health questions were used to establish the presence of hypertension at follow-up.

Statistical Analyses
        The design of this study included oversampling of those at higher risk for SDB and
women with markedly higher BMI to increase the precision of the risk estimates. Because of this
sampling strategy, numeric sampling weights were developed for the analysis so that the
estimates could be inferred to the original target population.2,3,11 Specifically, to improve the
efficiency of subject identification and screening, compensatory weights were developed for the
analysis to obtain estimates for the original target population of men and women in the two-
county study area. Specifically, three weights were created for the men. First, in the telephone
sample, 32 of the 963 clusters of phone numbers in the first stage were “exhausted” before the
target sample size was obtained. A compensatory weight was computed which corrected for this
problem. A second weight was computed because the within-household screening deliberately
introduced unequal probabilities of selection across the three age groups in order to oversample
the middle age group. The final weight for men was computed to account for the oversampling
of subjects for the sleep laboratory study (Phase II); those with larger counts of the four possible
risk factors, i.e., snoring, daytime sleepiness, obesity, and hypertension, had substantially higher
probability of being selected. For women, the only weight required was to account for the
oversampling of subjects for the sleep laboratory study. To eliminate any suggestion of possible
sample bias, we calculated 32 unique weights for the women and 16 unique weights for the men
corresponding to all possible combinations of the five risk factors for the women (menopause
was the fifth risk factor) and four for the men. Any individual weight that had a cell size that was
too small was combined with adjacent cells, so that
Insomnia, Objective Sleep Duration, and Incident Hypertension                                        4


population. Therefore, we adjusted for the sampling weight in all of our statistical analyses,
including those estimating the rate of incident hypertension.
        Logistic regression models were used to assess the independent associations of the three-
level sleep complaints and objective sleep duration with incident hypertension. The covariables
we adjusted for included major confounding factors expected to affect this relation (i.e., gender,
race, age, caffeine, cigarettes, and alcohol consumption, depression, SDB, diabetes, and obesity).
We further tested the interaction between sleep complaints and objective sleep duration using the
likelihood ratio test in logistic regression models. Because of the significant interaction between
sleep complaints and objective sleep duration, we performed final logistic regression models to
include five dummy variables to represent all six possible combinations of sleep complaints and
objective sleep duration; we used normal sleepers with objective sleep duration ≥ 6 h as a
common reference group. We calculated the odds ratios (OR) and the 95% confidence intervals
(95%CI) from this model to estimate the risk of hypertension incidence associated with different
combinations of sleep complaints and objective sleep duration, simultaneously adjusting for
gender, race, age, caffeine, cigarettes, and alcohol consumption, depression, SDB, diabetes, and
obesity. Because incident hypertension was ascertained by self-report, we further adjusted for
baseline SBP/DBP status, i.e., normal BP (SBP < 120 mm Hg and DBP < 80 mm Hg), pre-
hypertensive BP (SBP ≥ 120 and < 140 mm Hg and/or DBP ≥ 80 and < 90 mm Hg), and
hypertensive BP (SBP ≥ 140 mm Hg and/or diastolic BP ≥ 90 mm Hg). Moreover, two
sensitivity analyses were performed. First, we entered SBP and DBP in two separate models as
continuous variables and, secondly, we excluded individuals with baseline SBP ≥ 140 and/or
DBP ≥ 90. The pattern of associations remained very similar to that reported in Table 3, Model 3
in the manuscript. All analyses were conducted with IBM SPSS version 20.0 for Windows.


ONLINE SUPPLEMENTAL RESULTS

Change in Sleep Difficulty from Baseline to Follow-up

        In order to address the question whether individuals who started treatment for
hypertension during the follow-up period have better subjective sleep compared with their
baseline than did the control group (i.e., whether receiving treatment for hypertension at follow-
up relatively improved their sleep and perhaps decrease their insomnia-related cardiovascular
risk), Table S2 presents data on the association of incident hypertension with change in sleep
difficulty status at follow-up in normal sleepers, poor sleepers, and chronic insomniacs.

        In summary, when compared to those who did not report being treated for hypertension at
follow-up, insomniacs who did report being treated for hypertension over the follow-up did not
have better subjective sleep at follow-up, i.e., normal sleep (20% vs. 35.7%) or poor sleep (20%
vs. 21.4%). In fact, a higher percent of those who persisted with insomnia reported being treated
for hypertension (60.0% vs. 42.9%), which reinforces our findings that severe, persistent
insomnia is a premorbid risk factor for incident hypertension.
Insomnia, Objective Sleep Duration, and Incident Hypertension                                    5


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3. Bixler EO, Vgontzas AN, Lin HM, Ten Have T, Rein J, Vela-Bueno A, Kales A. Prevalence
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5. Kish L. Survey sampling. New York: John Wiley & Sons, Inc, 1965.
6. Rechtschaffen A, Kales A. A manual of standardized terminology, techniques and scoring
      system for sleep stages of human subjects. Bethesda, MD: National Institutes of Health,
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7. Vgontzas AN, Liao D, Bixler EO, Chrousos GP, Vela-Bueno A. Insomnia with objective short
      sleep duration is associated with a high risk for hypertension. Sleep. 2009;32:491-497.
8. Vgontzas AN, Liao D, Pejovic S, Calhoun S, Karataraki M, Bixler EO. Insomnia with
      objective short sleep duration is associated with type 2 diabetes: A population-based study.
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9. Fernandez-Mendoza J, Calhoun S, Bixler EO, Pejovic S, Karataraki M, Liao D, Vela-Bueno
      A, Ramos-Platon MJ, Sauder KA, Vgontzas AN. Insomnia with objective short sleep
      duration is associated with deficits in neuropsychological performance: a general
      population study. Sleep. 2010;33:459-465.
10. Vgontzas AN, Liao D, Pejovic S, Calhoun S, Karataraki M, Basta M, Fernández-Mendoza J,
      Bixler EO. Insomnia with short sleep duration and mortality: the Penn State cohort. Sleep.
      2010;33:1159-1164.
11. U.S. Department of Health and Human Services (DHHS), National Center for Health
      Statistics. Third National Health and Nutrition Examination Survey, 1988-1994. NHANES
      III laboratory data file. Hyattsville, MD: Centers for Disease Control and Prevention,
      1996.
Insomnia, Objective Sleep Duration, and Incident Hypertension                              6


Table S1. Demographic, Clinical, and Sleep Characteristics of Sleep Difficulty groups

                               Normal Sleep            Poor Sleep       Chronic Insomnia
Baseline characteristics         (n = 474)              (n = 236)           (n = 76)
Sex
  Male, %                           53.0                  40.4                22.6
  Female, %                         47.0                  59.6†               77.4†
Race
  Caucasian, %                       93.6                  97.7                 90.2
  Non-Caucasian, %                    6.4                  2.3*                 9.8
Age, years                        48.0 (12.9)          45.4 (12.2)*         49.5 (11.8)
  ≤ 40, %                            29.0                 40.4*                 16.4
  41-59, %                           52.2                  44.4                 67.2
  ≥ 60, %                            18.8                  15.2                 16.4
BMI, kg/m2                         26.5 (4.3)          28.6 (5.5)†          29.1 (6.0)†
  < 30, %                            83.4                  68.5                 57.4
  ≥ 30, %                            16.6                 31.5†                42.6†
SBP, mm Hg                       125.4 (14.6)          126.8 (16.2)        132.8 (16.6)†
  < 120, %                           31.7                  32.0                 19.7
  ≥ 120, %                           53.8                  50.5                 50.8
  ≥ 140, %                           14.5                  17.6                29.5†
DBP, mmHg                          78.4 (8.5)           79.6 (9.0)           81.0 (9.0)
  < 80, %                            51.4                  39.6                 30.6
  ≥ 80, %                            37.2                  45.0                56.5†
  ≥ 90, %                            11.4                  15.3                 12.9
SDP/DBP status
  Normal, %                         24.9                   28.3                16.4
  Pre-hypertensive, %               54.5                   47.5                52.5
  Hypertensive, %                   20.5                   24.2               31.1*
Diabetes
  No, %                             90.6                   87.4                93.4
  Yes, %                             9.4                   12.6                 6.6
Depression
  No, %                              91.9                  71.2                62.3
  Yes, %                              8.1                 28.8†               37.7†
OHI, events/h                      2.0 (6.6)             2.3 (6.9)           1.7 (7.1)
 OHI < 5, %                          90.0                  89.6                93.4
 OHI ≥ 5, %                          10.0                  10.4                 6.6
Caffeine, cup/day                  2.3 (2.8)            3.0 (3.6)†          1.8 (2.3)
  None, %                            34.2                  23.4                42.6
   1-2 cups/day, %                   31.2                  34.7                29.5
   ≥ 3 cups/day, %                   34.6                  41.9                27.9
Cigarettes, n/day                 4.2 (11.3)            4.8 (10.3)          5.0 (10.5)
   None, %                           78.6                  74.8                77.0
   1-20 /day, %                       9.9                   9.9                 6.6
   ≥ 20/day, %                       11.5                  15.3                16.4
Insomnia, Objective Sleep Duration, and Incident Hypertension                                  7


Alcohol, drink/day                  1.6 (7.5)              0.9 (2.3)              0.3 (0.7)
   None, %                            70.0                   78.8                   82.3
   1 drink/day, %                     12.1                    4.5                    9.7
   ≥ 2 drink/day, %                   17.8                   16.7                    8.1
Sleep Duration, hrs                 6.0 (1.1)              6.1 (1.1)              5.8 (1.2)
   ≥ 6 hrs, %                         59.8                   59.5                   52.5
   < 6 hrs, %                         40.2                   40.5                   47.5

All data are adjusted for sampling weight. Where appropriate the standard deviation is presented
in parenthesis. BMI, body mass index; SBP, systolic blood pressure; DBP, diastolic blood
pressure; Pre-hypertensive status, SBP ≥ 120 and < 140 mm Hg and/or DBP ≥ 80 and < 90 mm
Hg; Hypertensive status, SBP ≥ 140 mm Hg and/or DBP ≥ 90 mm Hg; OHI, obstructive
apnea/hypopnea index. *p < .05; †p < .01
Insomnia, Objective Sleep Duration, and Incident Hypertension                              8




Table S2. Association of Incident Hypertension with Change in Sleep Difficulty status at
Follow-up

                                                    Sleep Difficulty at Follow-up
  Incident   Sleep Difficulty at             Normal             Poor             Chronic
Hypertension Baseline                         Sleep             Sleep           Insomnia
    NO       Normal Sleep                     74.3               18.8              6.9
             Poor Sleep                       41.5               41.5             16.9
             Chronic Insomnia                 35.7               21.4             42.9
    YES
             Normal Sleep                      80.3               13.9            5.8
             Poor Sleep                        48.7               33.3           17.9
             Chronic Insomnia                  20.0               20.0          60.0†

All data are % adjusted for sampling weight. *p < .05; †p < .01
Insomnia, Objective Sleep Duration, and Incident Hypertension                               9


                                     Phase I: Telephone Survey
                                            (N = 16,583)




                                     Phase II: Sleep Lab Study
                                              Baseline
                                            (N = 1,741)




                                          Follow-Up Survey
                                              (N = 1,395)
                               Mean duration 7.5 years
                               215 cases deceased
                               131 cases could not be reached
                               20 cases missing hypertension data




       No Hypertension at Baseline                               Hypertension at Baseline
                Included                                                Excluded

                (n = 786)                                               (n = 609)




                                      No Hypertension at Follow-up

                                                (n = 595)




                                        Hypertension at Follow-up
                                          Incident Hypertension
                                                 (n = 191)




                            Figure S1. Participants’ flow in the study
Insomnia With Objective Short Sleep Duration and Incident Hypertension: The Penn
                                     State Cohort
   Julio Fernandez-Mendoza, Alexandros N. Vgontzas, Duanping Liao, Michele L. Shaffer,
                  Antonio Vela-Bueno, Maria Basta and Edward O. Bixler


         Hypertension. 2012;60:929-935; originally published online August 14, 2012;
                      doi: 10.1161/HYPERTENSIONAHA.112.193268
   Hypertension is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231
                    Copyright © 2012 American Heart Association, Inc. All rights reserved.
                              Print ISSN: 0194-911X. Online ISSN: 1524-4563




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