Sleep and Health

Patrick J. Strollo, Jr., M.D.University of Pittsburgh Medical

Center

PMBC SLEEP WORKSHOP 2006

Goals

• Review how disturbed sleep impacts physiology in healthy humans

• Examine the data relating disturbed sleep to morbidity and mortality

• Understand how a common sleep disorder (Sleep Apnea) may the contribute to cardiovascular risk

• Appreciate the complex interaction between disturbed sleep and physiologic risk in patient populations

Function of Sleep

• Consolidate memory• Improve

concentration• Improve mood• Enhance creativity

• Hormonal control of appetite

• Immune function & systemic inflammation

Brain Systemically

Sleep Medicine 2004 5:225-30Nature 2004 430:27-28J Am Coll Cardiol 2004 43:678-83J Clin Endocrinol Metab 2004 89:5762-71

NREM WAKE

Interaction between Sleep and Wake States

REM

Sleep Med2005 6:23-27

Effect of insufficient sleep on unadjusted prevalence rates for HRQOL among adults aged 18 or older (n = 79,625)

> 14 / 30 days insufficient sleep

< 14 / 30 days insufficient sleep

The Cumulative Cost of Additional Wakefulness: Dose-Response Effects on Neurobehavioral Functions and Sleep Physiology From Chronic Sleep Restriction and Total Sleep Deprivation

SLEEP 20032:117-126

Aim: Assess whether human sleep can be chronically reduced without consequencesDesign: The chronic sleep restriction experiment involved randomization to 1 of 3sleep doses (4 h, 6 h, or 8 h time in bed per night), which were maintained for 14 consecutive days. The total sleep deprivation experiment involved 3 nights without sleep (0 h time in bed). Each study also involved 3 baseline (pre-deprivation) days and 3 recovery days.Subjects: A total of n = 48 healthy adults (ages 21–38)Results: Chronic restriction of sleep periods to 4 h or 6 h per night over 14 consecutive days resulted in significant cumulative, dose-dependent deficits in cognitive performance on all tasks.Conclusion: Chronic restriction of sleep to 6 h or less per night produced cognitive performance deficits equivalent to up to 2 nights of total sleep deprivation,relatively moderate sleep restriction can seriously impair waking neurobehavioralfunction in healthy adults.

Sleepiness

Sympathovagal Balance

Evening cortisol concentrations

Time in Bed4 8 12

Impact of Sleep Debt on Metabolic And Endocrine FunctionLancet 1999 354:1435-39

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Aim: Examine the effect of sleep debton metabolic and hormonal function Subjects: 11 Males (18 -27 yrs)Design:• Baseline - 3 nights 8 hrs in bed• Sleep Debt - 6 nights 4 hrs in bed• Recovery – 7 nights 12 hrs in bedResults: In the Sleep Debt Condition• Glucose tolerance & thryrotropin concentrations were decreased• Evening cortisol concentrations were increased• Sympathetic nervous system activity was increased

p < 0.0001

p < 0.02

p < 0.007

After 2 d of

4-h sleep time

After 2 d of 10-h sleep time

After 2 d of 10-h sleep time

After 2 d of 10-h sleep time

After 2 d of4-h sleep time

After 2 d of4-h sleep time

After 2 d of4-h sleep time

After 2 d of 10-h sleep time

Sleep Curtailment in Healthy Young Men Is Associated with Decreased Leptin Levels, Elevated Ghrelin Levels, andIncreased Hunger and AppetiteAnn Intern Med 2004 141:846-850

Aim: To determine whether partial sleep curtailment, alters appetiteSubjects: 12 normal weight malesBMI 23.6 + 2.0 / Age 22 + 2 yrsDesign: Randomized, 2 period, 2 condition crossover clinical studyIntervention: 2 days of sleep restrictionand 2 days of sleep extensionResults: Sleep restriction was associatedwith – • Decreased Leptin (anorexigenic) 18%• Increased Ghrelin (orexigenic) 24%• Increased Hunger 24%• Increased appetite* 23% *calorie dense high carbohydrate food

Arch Intern Med. 2005165:25-30

Aim: Examine the association between restricted sleep and obesityin a heterogeneous adult primarycare populationDesign: Prospective cohort, involving questionnaires and measurement of BMI in 4 primary care offices (n = 1001)Conclusion: Reduced amountsof sleep are associated with overweight and obese status

The association between total sleep time and body weight in primary care

Results:

The Obesity Epidemic Worldwide

Nature 2000

Obesity and the Risk of Heart failure

NEJM 2002347:305-13

Men

Goals

• Review how disturbed sleep impacts physiology in healthy humans

• Examine the data relating disturbed sleep to morbidity and mortality

• Understand how a common sleep disorder (Sleep Apnea) may the contribute to cardiovascular risk

• Appreciate the complex interaction between disturbed sleep and physiologic risk in patient populations

Relative Risk of CHD across 10 Years according to Self-Reported Sleep Duration*: Nurses Health Study

1

1.05

1.11.15

1.2

1.25

1.31.35

1.4

1.45

1.5

6 7 8 > 9

N = 76,617* *

Covariates: shift work, depression, high cholesterol, diabetes, hypertension, BMI, smoking, snoring, exercise, alcohol consumption, aspirin use, postmenopausal hormone use, family history of MI.

Arch Int Med 2003 163:205-209

< 5

Impact of Sleep on Survival

Sleep Latency Sleep Efficiency

Latency < 30 min

Latency > 30 min

Efficiency > 80 %

Efficiency < 80 %

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rviv

al

Weeks Weeks

Psychosomatic Medicine 2003 65:63–73

Brain, Behavior, and Immunity2003 17: 350–364

Stress

JACC 200443:678–83

Effect of Partial Sleep Deprivation on C-Reactive Protein

(n = 5)(n = 4)

Sleep Complaints Heart Failure Patients vs. General Population

0 10 20 30 40 50 60

Trouble sleeping

Hypnotics

Sleep Maintenance

Difficulty Initiating Sleep

Early AM Awakening

RLS

Stop BreathingHeart Failure

General Population

Percentage AACN Clinical Issues2003 14:477-87

n = 84Male (59%)Age = 54.1 + 10.8NYHA = 2.8 + 0.8LVEF (%) = 21.7 + 6.3

*

****

*

Impact of Sleep Difficulties on the Minnesota Living with Heart Failure Questionnaire

J Cardiovasc Nurs 200419: 234–242

Aim: To describe self-assessed sleep difficulties, daytime sleepiness, and theirrelation to HRQOL in men and women with HF, as well as to make a comparisonto data from a norm population.Design: Cross-sectional design including 223 patients with HF, New York HeartAssociation classification II–IV, assessed using the Uppsala Sleep Inventory-ChronicHeart Failure, the Epworth Sleepiness Scale, Medical Outcomes Study 36-Item Short Form Health Survey, and Minnesota Living With Heart Failure Questionnaire.

Conclusion: Patients with HF have a reduced HRQOL especially if difficulties maintaining sleep, initiating sleep, and early morning awakenings are involved.

Results:

Goals

• Review how disturbed sleep impacts physiology in healthy humans

• Examine the data relating disturbed sleep to morbidity and mortality

• Understand how a common sleep disorder (Sleep Apnea) may the contribute to cardiovascular risk

• Appreciate the complex interaction between disturbed sleep and physiologic risk in patient populations

ROS

Xanthine Oxidase Mitochondrial Dysfunction Homocysteine

Activation of Transcription Factors

Monocyte Activation

Lymphcyte Activation

Endothelial cell Activation

Adhesion Molecule Expression

Monocyte Lymphocyte / Endothelial Adhesion

Endothelial Dysfunction

Vascular Disease

Intermittent Hypoxia

Sleep Med Rev2003 7:35-51

OSDB: Effect on Nocturnal BP and CO

Thorax 1998

53:416-418

Sympathetic Neural Activity OSA vs. Normals

J Clin Invest 199596:1897-1904

10 sec

Awake

Normal OSA

Effect of OSA on Inflammatory Markers

Circulation 2003107:1129-34

C-Reactive Protein IL-6

Effect of Activated Monocytes on the Endothelium

Nature 2002420: 868-74

ROS

Cytokines MMPs

Tissue Factor

Sleep Apnea Impacts on Insulin and Glucose Independent of Obesity

J Intern Med 2003254:32-44

Effect of Long-term Intermittent Hypoxia on

Brain Structure and Function • Adult male C57BL/6J mice• 8 week protocol: LTIH during

sleep period• Conditions

– Sham Intermittent Hypoxia– Intermittent Hypoxia

• MSLT performed after 2 weeks of recovery

• Basal forebrain and brainstem– Elevated isoprostane (22%)– Increased protein carbonylation

50%– Increased nitration 200%– Induction of antioxidant enzymes 0

2

4

6

8

10

12

14

LTIH(n =19)

Sham LTIH(n = 16)

Mean Sleep Latency

*

8.9 + 1.0

12.7 + 0.5

Significant oxidative injuries in the sleep-wakeregions of the brain after LTIH are associatedwith “residual hypersomnolence”

Day–Night Pattern of Sudden Death in Obstructive Sleep Apnea

N Engl J Med 2005352:1206-14.

< 5 5 -39 > 40

Apnea Hypopnea Index

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6:00 AM – 1:59 PM

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AIM: Observational study to compare incidence of fatal and non-fatal cardiovascular events in simple snorers, patients with untreated OSA,patients treated with CPAP, and healthy men recruited from the general population.Design: Prospective observational cohort. 264 healthy men, 377 simple snorers, 403 with untreated mild-moderate OSA (AHI 5-30), 235 with untreated severe OSA (AHI > 30), and 372 with OSA and treated with CPAP

Lancet 2005 365: 1046–53

MonthsMonths

.

Conclusion: In men, severe OSA significantly increases the risk of fatal and non-fatalcardiovascular events. CPAP treatment reduces this risk.

Long-term cardiovascular outcomes in men with OSA

Goals

• Review how disturbed sleep impacts physiology in healthy humans

• Examine the data relating disturbed sleep to morbidity and mortality

• Understand how a common sleep disorder (Sleep Apnea) may the contribute to cardiovascular risk

• Appreciate the complex interaction between disturbed sleep and physiologic risk in patient populations

Obesity

Sleep Apnea Diabetes

LV Hypertrophy

Pleiotrophic Effects of Adiopkines on Vascular Risk

Adipokines & Leptin

J Appl Physiol 98: 2226–2234, 2005.

Healthy Controls (n = 10)

OSA Subjects (n =16)

Arch Intern Med. 2006;166:1709-171

Proposed Model Integrating Sleep Disordered Breathing, Psychological Stress and Nocturnal Physiology as Predictors of CVD Risk Factors

Heart SCORESleep SCORE

Sleep Disordered Breathing

Nocturnal Physiology• Non SDB sleep Characteristics• Urinary catecholamines• Autonomic function• BP dipping status

Psychological stress• Acute & chronic life events• Ambient stress

Established CV Risk Factors• Cholesterol• Hyperglycemia• Blood Pressure • Smoking Cardiovascular

Morbidity & Mortality• Coronary calcification• Brachial artery size• Endothelial dysfunction• MI• Stroke • Death

Emerging CV Risk Factors• Inflammation• Metabolic Syndrome• Renal Insufficiency

Sleep

Heart Failure

Sympathetic Activation

Inflammation

CRT

Wake DriveSleep Drive

Sleep and Heart Failure: The role of Autonomic Activation and Inflammation

NREM WAKE

Interaction between Sleep and Wake States

REM

Summary

• Impaired sleep affects a number of physiologic parameters.

• Concomitant primary sleep disorders can “gain up” the stress response.

• Understanding the relative contribution of psychological stress vs. metabolic stress is crucial when investigating patient populations.

• A collaborative / translational approach is essential to understand mechanisms and advance the field.

• Think about sleep when caring for patients and planning research questions.

“Never, ever, think outside of the box.”