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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

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Sleep and health

Sleep and Health

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

PMBC SLEEP WORKSHOP 2006


Goals
Goals

  • Review how disturbed sleep impacts physiology in healthyhumans

  • 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

Function of Sleep

Brain

Systemically

Sleep Medicine 2004 5:225-30

Nature 2004 430:27-28

J Am Coll Cardiol 2004 43:678-83

J Clin Endocrinol Metab 2004 89:5762-71



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

Sleep Med

2005 6:23-27


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

Aim: Assess whether human sleep can be chronically reduced without consequences

Design: The chronic sleep restriction experiment involved randomization to 1 of 3

sleep 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 neurobehavioral

function in healthy adults.

SLEEP 2003

2:117-126


Impact of Sleep Debt on Metabolic Effects on Neurobehavioral Functions and Sleep Physiology From Chronic Sleep Restriction and Total Sleep Deprivation

And Endocrine Function

Lancet 1999 354:1435-39

Sleepiness

p < 0.0001

Stanford Sleepiness

Score 1000 – 1400 h

  • Aim: Examine the effect of sleep debt

  • on 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 bed

  • Results: In the Sleep Debt Condition

  • Glucose tolerance & thryrotropin

  • concentrations were decreased

  • Evening cortisol concentrations were

  • increased

  • Sympathetic nervous system activity

  • was increased

Sympathovagal Balance

p < 0.02

Sympathovagal

Balance 0900 -1400 h

Evening cortisol concentrations

p < 0.007

Saliva Free Cortisol

Mmol/L 1600 - 2000 h

8

12

4

Time in Bed


Sleep Curtailment in Healthy Effects on Neurobehavioral Functions and Sleep Physiology From Chronic Sleep Restriction and Total Sleep Deprivation

Young Men Is Associated with

Decreased Leptin Levels,

Elevated Ghrelin Levels, and

Increased Hunger and Appetite

Ann Intern Med 2004 141:846-850

After 2 d of

10-h sleep time

After 2 d of

4-h sleep time

After 2 d of

4-h sleep time

  • Aim: To determine whether partial

  • sleep curtailment, alters appetite

  • Subjects: 12 normal weight males

  • BMI 23.6 + 2.0 / Age 22 + 2 yrs

  • Design: Randomized, 2 period,

  • 2 condition crossover clinical study

  • Intervention: 2 days of sleep restriction

  • and 2 days of sleep extension

  • Results: Sleep restriction was associated

  • with –

  • Decreased Leptin (anorexigenic) 18%

  • Increased Ghrelin (orexigenic) 24%

  • Increased Hunger 24%

  • Increased appetite* 23%

  • *calorie dense high carbohydrate food

After 2 d of

10-h sleep time

After 2 d of

4-h sleep time

After 2 d of

10-h sleep time

After 2 d of

4-h sleep time

After 2 d of

10-h sleep time


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

Results:

Aim: Examine the association

between restricted sleep and obesity

in a heterogeneous adult primary

care population

Design: Prospective cohort,

involving questionnaires and

measurement of BMI in 4 primary

care offices (n = 1001)

Conclusion: Reduced amounts

of sleep are associated with

overweight and obese status

Arch Intern Med. 2005

165:25-30


The Obesity Epidemic Worldwide primary care

Nature 2000


Obesity and the risk of heart failure
Obesity and the Risk of Heart failure primary care

Men

NEJM 2002

347:305-13


Goals1
Goals primary care

  • Review how disturbed sleep impacts physiology in healthyhumans

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

*

N = 76,617

*

< 5

> 9

  • 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


Impact of sleep on survival
Impact of Sleep on Survival Self-Reported Sleep Duration*: Nurses Health Study

Sleep Efficiency

Sleep Latency

Efficiency > 80 %

Latency < 30 min

Survival

Efficiency < 80 %

Latency > 30 min

Weeks

Weeks

Psychosomatic Medicine 2003 65:63–73


Stress Self-Reported Sleep Duration*: Nurses Health Study

Brain, Behavior, and Immunity

2003 17: 350–364


Effect of Partial Sleep Deprivation on C-Reactive Protein Self-Reported Sleep Duration*: Nurses Health Study

(n = 5)

(n = 4)

JACC 2004

43:678–83


Sleep complaints heart failure patients vs general population
Sleep Complaints Heart Failure Patients vs. General Population

*

*

*

n = 84

Male (59%)

Age = 54.1 + 10.8

NYHA = 2.8 + 0.8

LVEF (%) = 21.7 + 6.3

*

*

*

AACN Clinical Issues

2003 14:477-87

Percentage


Impact of Sleep Difficulties on the Minnesota Living with Population

Heart Failure Questionnaire

Aim: To describe self-assessed sleep difficulties, daytime sleepiness, and their

relation to HRQOL in men and women with HF, as well as to make a comparison

to data from a norm population.

Design: Cross-sectional design including 223 patients with HF, New York Heart

Association classification II–IV, assessed using the Uppsala Sleep Inventory-Chronic

Heart Failure, the Epworth Sleepiness Scale, Medical Outcomes Study 36-Item

Short Form Health Survey, and Minnesota Living With Heart Failure Questionnaire.

Results:

Conclusion: Patients with HF have a reduced HRQOL especially if difficulties

maintaining sleep, initiating sleep, and early morning awakenings are involved.

J Cardiovasc Nurs 2004

19: 234–242


Goals2
Goals Population

  • Review how disturbed sleep impacts physiology in healthyhumans

  • 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


Intermittent Hypoxia Population

Xanthine Oxidase Mitochondrial Dysfunction Homocysteine

ROS

Activation of Transcription Factors

Monocyte

Activation

Lymphcyte

Activation

Endothelial cell

Activation

Adhesion Molecule Expression

Monocyte Lymphocyte / Endothelial Adhesion

Endothelial Dysfunction

Sleep Med Rev

2003 7:35-51

Vascular Disease


OSDB: Effect on Nocturnal BP and CO Population

Thorax 1998

53:416-418


Sympathetic neural activity osa vs normals
Sympathetic Neural Activity OSA vs. Normals Population

Awake

OSA

Normal

10 sec

J Clin Invest 1995

96:1897-1904


Effect of osa on inflammatory markers
Effect of OSA on Inflammatory Markers Population

IL-6

C-Reactive Protein

Circulation 2003

107:1129-34


Effect of activated monocytes on the endothelium
Effect of Activated Monocytes on the Endothelium Population

Tissue Factor

ROS

Cytokines

MMPs

Nature 2002

420: 868-74



Effect of long term intermittent hypoxia on brain structure and function
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

Mean Sleep Latency

*

12.7 + 0.5

8.9 + 1.0

Sham LTIH

(n = 16)

LTIH

(n =19)

Significant oxidative injuries in the sleep-wake

regions of the brain after LTIH are associated

with “residual hypersomnolence”


Day–Night Pattern of Sudden Death in Obstructive Sleep Apnea

Proportion of Sudden Death from

all Cardiac Causes (%)

Relative Risk of Sudden Death

from Cardiac Causes 12:00 – 6:00 AM

< 5

> 40

5 -39

10:00 PM –

5:59 AM

6:00 AM –

1:59 PM

2:00 PM –

9:59 PM

Apnea Hypopnea Index

N Engl J Med 2005

352:1206-14.


Long-term cardiovascular outcomes in men with OSA Apnea

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

Cumulative Incidence of Fatal CV Events

Cumulative Incidence of Non-fatal CV Events

Months

Months

Conclusion: In men, severe OSA significantly increases the risk of fatal and non-fatal

cardiovascular events. CPAP treatment reduces this risk.

Lancet 2005

365: 1046–53

.


Goals3
Goals Apnea

  • Review how disturbed sleep impacts physiology in healthyhumans

  • 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


Pleiotrophic Effects of Adiopkines on Vascular Risk Apnea

Obesity

Sleep Apnea

Diabetes

Adipokines &

Leptin

LV Hypertrophy


Healthy Controls (n = 10) Apnea

OSA Subjects (n =16)

J Appl Physiol 98: 2226–2234, 2005.



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

Sleep SCORE

Heart SCORE

  • Established CV

  • Risk Factors

  • Cholesterol

  • Hyperglycemia

  • Blood Pressure

  • Smoking

Sleep Disordered

Breathing

  • Cardiovascular

  • Morbidity & Mortality

  • Coronary calcification

  • Brachial artery size

  • Endothelial dysfunction

  • MI

  • Stroke

  • Death

  • Nocturnal Physiology

  • Non SDB sleep Characteristics

  • Urinary catecholamines

  • Autonomic function

  • BP dipping status

  • Emerging CV

  • Risk Factors

  • Inflammation

  • Metabolic Syndrome

  • Renal Insufficiency

  • Psychological stress

  • Acute & chronic life events

  • Ambient stress


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

Sleep Drive

Wake Drive

Sleep

Inflammation

Sympathetic

Activation

Heart Failure

CRT


Interaction between Sleep and Wake States and Inflammation

NREM

WAKE

REM


Summary
Summary and Inflammation

  • 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.



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