Sleep Deprivation and Chronic Disease

Francesco P Cappuccio MD MSc FRCP FFPH FAHA

Professor of Cardiovascular Medicine & Epidemiology Clinical Sciences Research Institute Warwick Medical School, Coventry, UK

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How many hours per night do you usually sleep?

50

1. 2. 3. 4. 5.

Less than 5h 6h 7h 8h 9h or more

0%
5h

0%
6h

0%
7h

0%
8h

0%

ss

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Le

9h

or m or e

th an

Sleep Duration Time Trends in US Adults

Hrs per night

10.0 9.0 8.0 7.0 6.0 5.0 4.0 3.0 2.0 1.0 0.0

9.0 7.5 6.8

1910
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1975

2005
National Sleep Foundation. Sleep in America Poll

Sleep duration in British Adults (1967/2003)

1967 2003

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Groeger JA et al. J Sleep Res. 2004; 13:359-71

How much did you score at the ESS questionnaire?

50

1. 10 or less 2. 11-16 3. 17 or more

0%
es s or l 11

0%
-1 6

0%
or m or e 17

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10

Insufficient Sleep (Sleep Deprivation)

Fragmented Sleep (Sleep Disruption)

Excessive Daytime Sleepiness (EDS)

Neurobehavioral deficits
cognitive/executive function attention/concentration

Performance deficits
errors/accuracy

Cardio-metabolic
appetite regulation high blood pressure

Increased Morbidity / Mortality Decreased Quality of Life

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Short Sleep Duration & Chronic Diseases

Cardio-Metabolic Risk Factors
Obesity/body fat distribution Type 2 Diabetes Mellitus

Hypertension

Total and Cause-Specific Mortality Coronary Heart Disease

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Cardio-Metabolic Risk Factors:

Obesity

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Obesity Epidemic and Sleep Duration

BMI in US adults
28.0 27.0 26.0 25.0 24.0 23.0 22.0 21.0 1910 1975 2005 23.0 25.2 26.9

Sleep duration in US adults 10.0 9.0

8.0 7.0 6.0 5.0 4.0 3.0 2.0 1.0 0.0

9.0 7.5 6.8

1910

1975

2005

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Short Sleep Duration and Metabolic Hormones Leptin Ghrelin

-15.5%

+14.9%

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Taheri S et al. PLoS Med. 2004; 1:210-7

Sleep Deprivation and Appetite Regulation

-18% leptin; +28% ghrelin +24% hunger/appetite

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Spiegel K et al. Ann Intern Med. 2004; 141:846-50

Short Sleep Duration (<10h) and Obesity Meta-analysis of Cross-Sectional Studies

Children, n=29,502
Locard (1992) BenSlama (2002) Sekine (2002) Von Kries (2002) Agras (2004) Giugliano (2004) Padez (2005) Reilly (2005) Chaput (2006) Chen (2006) Seicean (2007) Combined 0.72 1 1.89 Odds Ratio 11

OR & 95% CI 2.25 (1.27; 3.98) 11.00 (4.75; 25.49) 1.19 (1.00; 1.42) 2.17 (1.57; 3.00) 2.00 (0.80; 5.02) 5.63 (0.72; 44.06) 1.15 (0.93; 1.43) 1.45 (1.20; 1.76) 2.63 (1.24; 5.58) 1.75 (1.28; 2.39) 2.23 (0.87; 5.73)

1.89
(1.46-2.43)

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Cappuccio FP et al. Sleep 2008; in press

Short Sleep Duration (<5h) and Obesity Meta-analysis of Cross-Sectional Studies

Adults, n=603,519
Vioque (2000) Shigeta (2001) Kripke (2002) Cournot (2004) Hasler (2004) Bjorkelund (2005) Gangwisch1 (2005) Gangwisch2 (2005) Gangwisch3 (2005) Singh (2005) Moreno (2006) Vahtera (2006) Watari (men) (2006) Watari (women) (2006) Bjorvatn (2007) Chaput (men) (2007) Chaput (women) (2007) Ko (2007) Tuomilehto (2007) Fogelholm (men) (2007) Fogelholm (Women) (2007) Stranges (2008) Combined

OR & 95% CI 3.36 (2.24; 5.03) 1.98 (1.03; 3.81) 1.52 (1.46; 1.58) 1.38 (0.98; 1.95) 10.80 (0.99; 117.4) 1.52 (0.68; 3.41) 1.84 (1.40; 2.41) 1.38 (1.06; 1.79) 0.95 (0.67; 1.34) 1.70 (1.26; 2.29) 1.22 (1.07; 1.40) 1.43 (1.34; 1.52) 1.96 (1.19; 3.22) 2.98 (0.77; 11.57) 1.87 (1.22; 2.86) 4.01 (1.72; 9.34) 2.65 (1.27; 5.54) 1.30 (1.14; 1.48) 1.30 (1.06; 1.60) 1.46 (1.13; 1.88) 1.75 (1.36; 2.25) 2.02 (1.57; 2.60)

1.55
0.67 1 1.55
Odds Ratio

10

(1.43-1.68)

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Cappuccio FP et al. Sleep 2008; in press

Sleep Deprivation & Obesity: Potential Mechanisms

Sleep Deprivation

Obesity

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Patel SR et al. Obesity; 2008; in press

Short Sleep Duration and Obesity The Whitehall II Study/Cross-Sectional (n=5,021)

2 1.5 1

-0.35 (-0.57;-0.12)
P <0.001

0.5

BMI

0 -0.5

-1 -1.5

-2 <=5 6 7 8 9+

2.5 2

1.65
(1.22-2.24)

OR Obesity 1.5
1 0.5 0

<=5

7 Hours of sleep

9+

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Stranges S et al. Am J Epidemiol. 2008; 167: 321-9

Short Sleep Duration and Obesity

The Whitehall II Study/Prospective
0.6 0.4 0.2

0.03 (-0.03; 0.08)

P = 0.36

BMI

0 -0.2 -0.4 -0.6 <=5 6 7 8 9+

OR Obesity

2.5 2 1.5 1 0.5 0

1.05
(0.60-1.82)

<=5

7 Hours of sleep

9+

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Stranges S et al. Am J Epidemiol. 2008; 167: 321-9

Cardio-Metabolic Risk Factors:

Type 2 Diabetes

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Sleep Duration and Risk of Diabetes The Massachusetts Male Aging Study (n=1,139)
3.12
(1.53-6.37)

6 5

1.95
(0.95-4.01)

Relative Risk

4 3 2 1 0 <=5 6 7 Hours of Sleep 8 >8

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Yaggi HK et al. Diabetes Care 2006; 29:657-61

Sleep Duration and Risk of Diabetes The Nurses Health Study (n=70,026)

1.29 1.18
(1.05-1.59) (0.96-1.44)

1.5

Relative Risk

0.5

0 <=5 6 7 Hours of Sleep 8 >8

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Ayas NT et al. Diabetes Care 2003; 26:380-4

Sleep Deprivation & Diabetes: Potential Mechanisms

Elevation of evening cortisol levels predisposing to

insulin resistance
Increase in sympathetic tone, inhibiting pancreatic function and leading to increased glucose intolerance

Weight gain and reduction in leptin

Reduction of testosterone levels

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Cardio-Metabolic Risk Factors:

Hypertension

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Sleep duration and incident Hypertension NHANES-I

2.5 2
Hazard Ratio

1.60
(1.19-2.14)

Men & Women, 32-59 years, n=3,620

1.5 1 0.5 0 <=5 6 7 to 8 Hours of Sleep =>9

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Gangwish JE et al. Hypertension 2006; 47:833-9

Sleep duration and prevalent Hypertension The Whitehall II Study

1.72
(1.07-2.75)

2.0

Relative Risk

1.5 1.0 0.5 0.0

2.0

Women, n=1,567
0.92 1.0 0.74

P = 0.037
0.70

Relative Risk

Men, n=4,199
1.5 1.0 0.5 0.0

0.88

0.86

1.0

1.12 0.92

<=5

7 Hours sleep

>=9

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Cappuccio FP et al. Hypertension 2007:50:694-701

Sleep duration and incident Hypertension The Whitehall II Study

2.0

Relative Risk

1.5 1.0 0.5 0.0

2.0

1.31

1.42

Women, n=1,005
1.0 0.99 1.07

Relative Risk

Men, n=2,686
1.5 1.0 0.5

0.89

1.02

1.0

1.11

0.13
0.0

<=5

7 Hours sleep

>=9

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Cappuccio FP et al. Hypertension 2007:50:694-701

Sleep duration and prevalent Hypertension The Western New York Health Study
2.0

1.61
(1.08-2.41)

Relative Risk

1.5 1.0 0.5 0.0

2.0

Women, n=1,710
1.0 0.69

Men, n=1,317
Relative Risk
1.5 1.0 0.5 0.0

0.88

1.0

1.39

<6

6-8 Hours sleep

>8

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Stranges S et al. 2008; (under review)

Sleep Deprivation & Hypertension: Potential Mechanisms

Increased BP load resulting from prolongation of higher BP

whilst awake
Truncation of the BP dip during sleep Prolonged activation of sympathetic nervous system

Increased renal sodium retention

Gender-specific effects? Confounding?

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Total and cause-specific mortality

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The U-Shaped Association between Sleep Duration and Total Mortality

The Cancer Prevention Study II

Women, n=636,095

Men, n=480,841

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Kripke DF et al. Arch Gen Psychiatry 2002;59:131-136

All-Cause mortality by hours of sleep

The Whitehall II Study
Phase 1 (1985-88) n=9,781
4 Hazard Ratio (95% CI)

Phase 3 (1991-93) n=7,729

4 Hazard Ratio (95% CI)

Age-adjusted Fully adjusted

3 3

Age-adjusted Fully adjusted

0
< 5h (56 deaths) 6h 7h 8h (160 deaths) (256 deaths) (87 deaths) > 9h (7 deaths)

0
< 5h (29 deaths) 6h (61 deaths) 7h 8h (112 deaths) (74 deaths) > 9h (16 deaths)

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Ferrie JE et al. Sleep 2007; 30:1659-66

All-Cause mortality from Phase 3 by changes in hours sleep between Phase 1 and Phase 3
4
Hazard Ratio (95% CI) Age-adjusted Fully adjusted

0
Increase from 5 or 6h (55 deaths)

Ref

Decrease from 6, 7 or 8h (57 deaths)

Increase from 7 or 8h (58 deaths)

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Ferrie JE et al. Sleep 2007; 30:1659-66

CVD mortality from Phase 3 by changes in hours sleep between Phase 1 and Phase 3
4
Hazard Ratio (95% CI) Age-adjusted Fully adjusted

0
Increase from 5 or 6h (16 deaths)

Ref

Decrease from 6, 7 or 8h (24 deaths)

Increase from 7 or 8h (12 deaths)

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Ferrie JE et al. Sleep 2007; 30:1659-66

Non-CVD mortality from Phase 3 by changes in hours sleep between Phase 1 and Phase 3
4
Hazard Ratio (95% CI) Age-adjusted Fully adjusted

0
Increase from 5 or 6h (38 deaths)

Ref

Decrease from 6, 7 or 8h (33 deaths)

Increase from 7 or 8h (45 deaths)

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Ferrie JE et al. Sleep 2007; 30:1659-66

Summary
Either a decrease in sleep duration from a regular 6, 7 or 8h per night or an increase from a regular 7 or 8h per night predict all-cause mortality A decrease in sleep duration affects all-cause mortality via increases in cardiovascular deaths An increase in sleep duration affects overall mortality via an increase in non-cardiovascular deaths

Sleep changes over time may represent more reliable measures to assess the impact of sleep on health
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Coronary Heart Disease

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Coronary Heart Disease by hours of sleep The MONICA Study

2.98
(1.48-6.03)

3.0

Relative Risk

2.5 2.0 1.5 1.0 0.5 0.0

2.0

Women, n=3,388
1.34 1.05 1.0 1.40

Men, n=3,508
1.13 1.05 1.22 1.0 1.07

Relative Risk

1.5 1.0 0.5 0.0

<=5

7 Hours sleep

>=9

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Meisinger C et al. Sleep 2007; 30:1121-27

Coronary Heart Disease by hours of sleep The Nurses Health Study

Women, n=71,617
Relative Risk

2.0 1.5 1.0 0.5 0.0

1.45
(1.10-1.92)

1.38
(1.03-1.86)

1.18

1.09

1.0

<=5

7
Hours sleep

>=9

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Ayas NT et al. Arch Intern Med 2003; 163:205-9

Summary
Both short and long sleep duration may be associated with more detrimental effects on cardiovascular health in women than men The biological mechanisms underlying these associations are unclear High blood pressure may represent one mechanism linking short sleep duration with increased risk of CHD, at least in women

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Unresolved issues
Co-morbidities of sleep disorders (psychiatric/chronic conditions) Bidirectional relationship (reverse causality/temporality?) Confounding by other lifestyle behaviors

Sleep as marker of health status vs. risk factor

Biological plausibility Objective assessment of sleep changes over time

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SLEEP, HEALTH & SOCIETY

University of Warwick Medical School
sleepresearch@warwick.ac.uk
Leads:
Warwick Team:

FP Cappuccio & E Peile

MA Miller, S Stranges, N-B Kandala, FM Taggart, C Ji, A Currie, G Ward, A Bakewell, A Lowe, D Cooper

Collaborators: Warwick: RCP: UCL: Surrey: Harvard: Naples: Buffalo:

Funding:

S Williams, D Banejee, R Pounder MG Marmot, E Brunner, M Kumari, M Shipley, JE Ferrie D-J Djik, S Archer C Czeisler, S Lockley, C Landrigan P Strazzullo, G Barba JM Dorn, RP Donahue, M Trevisan Cephalon Inc., Wingate Foundation, Whitehall II, RDF University of Warwick, NHS Workforce
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Average sleep duration in a survey of ~2,000 British Adults

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Groeger JA et al. J Sleep Res. 2004; 13:359-71

Co-morbidities of Sleep Disorders

Sleep disorders
Insomnia

Co-morbidities
Psychiatric Disorders

Sleep Apnoea
Restless Legs Syndrome Short sleep duration (behavioural)

Cardiopulmonary Disease
Musculoskeletal Conditions Cancer

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Co-morbidities of Sleep Disorders

80 70 69 52 36.0

% Sleep problems

60 50 40 30 20 10 0 None

1 to 3

4 or more

Number of Medical Conditions

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Foley D et al. Psychosom Res. 2004; 56:497-502

Sleep Duration and BMI Meta-analysis of Cross-Sectional Studies

Adults, n=16,509
Vioque (2000) Cournot (2004) Hasler (2004) Bjorkelund (2005) Gangwisch1 (2005) Kohatsu (2006) Stranges (2008)

& 95% CI

-0.60 (-0.75; -0.45) -0.01 (-0.03; 0.00)

-0.45 (-0.71; -0.19)

-0.18 (-0.36; 0.00) -0.36 (-0.52;-0.20) -0.52 (-0.86; -0.18)

-0.39 (-0.51; -0.27)

-0.35 (-0.57;-0.12)

Combined -0.86 -0.57 -0.35 Regression coefficient: (unit of BMI per h sleep per night) -0.12 0

Equivalent to approx 1.4 kg per hour

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Cappuccio FP et al. Sleep 2008; in press

LACK OF SLEEP

less more

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Gale SM et al. J Nutr 2004; 134:295-8

Need for further research

Objective assessment of sleep changes over time More prospective evidence Better understanding of determinants of sleep duration Better control for confounders/co-morbidities Experimental evidence on biological plausibility

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Putative pathways
Low SES/Unhealthy lifestyle/ Poor general health status Co-Morbidities/Elderly

Short sleep duration

Appetite dysregulation/ Impaired glucose homeostasis Inflammatory/neurovegatative/ hormonal responses CVD/Metabolic alterations

Long sleep duration

Depression/ Poor general health status

Increased morbidity/mortality/ Reduced quality of life

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Sleep Deprivation & Diabetes: Potential Mechanisms

Acute sleep deprivation Chronic sleep deprivation

Diabetes

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Spiegel K et al. J Appl Physiol. 2005; 99: 2008-19