1. 8 th Hypertension Masterclass 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

2. 8 th Hypertension Masterclass How many hours per night do you usually sleep? 0 50 1.Less than 5h 2.6h 3.7h 4.8h 5.9h or more

3. 8 th Hypertension Masterclass Sleep Duration Time Trends in US Adults Hrs per night National Sleep Foundation. Sleep in America Poll

4. 8 th Hypertension Masterclass Sleep duration in British Adults (1967/2003) Groeger JA et al. J Sleep Res. 2004; 13:359-7119672003

5. 8 th Hypertension Masterclass How much did you score at the ESS questionnaire? 0 50 1.10 or less 2.11-16 3.17 or more

6. 8 th Hypertension Masterclass Fragmented Sleep (Sleep Disruption) Insufficient Sleep (Sleep Deprivation) Excessive Daytime Sleepiness (EDS) Neurobehavioral deficits cognitive/executive function attention/concentrationCardio-metabolic appetite regulation high blood pressure Increased Morbidity / Mortality Decreased Quality of Life Performance deficits errors/accuracy

7. 8 th Hypertension Masterclass Cardio-Metabolic Risk Factors Obesity/body fat distributionObesity/body fat distribution Type 2 Diabetes MellitusType 2 Diabetes Mellitus HypertensionHypertension Total and Cause-Specific Mortality Coronary Heart Disease Short Sleep Duration & Chronic Diseases

8. 8 th Hypertension Masterclass Cardio-Metabolic Risk Factors: Obesity

9. 8 th Hypertension Masterclass Obesity Epidemic and Sleep Duration Sleep duration in US adults BMI in US adults

10. 8 th Hypertension Masterclass Short Sleep Duration and Metabolic Hormones Taheri S et al. PLoS Med. 2004; 1:210-7 LeptinGhrelin -15.5% +14.9%

11. 8 th Hypertension Masterclass Sleep Deprivation and Appetite Regulation -18% leptin; +28% ghrelin +24% hunger/appetite Spiegel K et al. Ann Intern Med. 2004; 141:846-50

12. 8 th Hypertension Masterclass Short Sleep Duration (<10h) and Obesity Meta-analysis of Cross-Sectional Studies Cappuccio FP et al. Sleep 2008; in press 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) Children, n=29,502 1.89 (1.46-2.43)

13. 8 th Hypertension Masterclass Short Sleep Duration (<5h) and Obesity Meta-analysis of Cross-Sectional Studies Cappuccio FP et al. Sleep 2008; in press Adults, n=603,519 1.55 (1.43-1.68) 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)

14. 8 th Hypertension Masterclass Sleep Deprivation & Obesity: Potential Mechanisms Obesity Sleep Deprivation Patel SR et al. Obesity; 2008; in press

15. 8 th Hypertension Masterclass Stranges S et al. Am J Epidemiol. 2008; 167: 321-9 BMI OR Obesity Short Sleep Duration and Obesity The Whitehall II Study/Cross-Sectional (n=5,021) -0.35 (-0.57;-0.12) P <0.001 1.65 (1.22-2.24)

16. 8 th Hypertension Masterclass Stranges S et al. Am J Epidemiol. 2008; 167: 321-9 BMI OR Obesity Short Sleep Duration and Obesity The Whitehall II Study/Prospective 0.03 (-0.03; 0.08) P = 0.36 1.05 (0.60-1.82)

17. 8 th Hypertension Masterclass Cardio-Metabolic Risk Factors: Type 2 Diabetes

18. 8 th Hypertension Masterclass Sleep Duration and Risk of Diabetes The Massachusetts Male Aging Study (n=1,139) Yaggi HK et al. Diabetes Care 2006; 29:657-61 1.95 (0.95-4.01) 3.12 (1.53-6.37)

19. 8 th Hypertension Masterclass Sleep Duration and Risk of Diabetes The Nurses’ Health Study (n=70,026) Ayas NT et al. Diabetes Care 2003; 26:380-4 1.18 (0.96-1.44) 1.29 (1.05-1.59)

20. 8 th Hypertension Masterclass Elevation of evening cortisol levels predisposing to insulin resistanceElevation of evening cortisol levels predisposing to insulin resistance Increase in sympathetic tone, inhibiting pancreatic function and leading to increased glucose intoleranceIncrease in sympathetic tone, inhibiting pancreatic function and leading to increased glucose intolerance Weight gain and reduction in leptinWeight gain and reduction in leptin Reduction of testosterone levelsReduction of testosterone levels Sleep Deprivation & Diabetes: Potential Mechanisms

21. 8 th Hypertension Masterclass Cardio-Metabolic Risk Factors: Hypertension

22. 8 th Hypertension Masterclass Sleep duration and incident Hypertension NHANES-I Gangwish JE et al. Hypertension 2006; 47:833-9 Men & Women, 32-59 years, n=3,620 1.60 (1.19-2.14)

23. 8 th Hypertension Masterclass Cappuccio FP et al. Hypertension 2007:50:694-701 Sleep duration and prevalent Hypertension The Whitehall II Study Hours sleep Women, n=1,567 Men, n=4,199 1.72 (1.07-2.75) P = 0.037

24. 8 th Hypertension Masterclass Cappuccio FP et al. Hypertension 2007:50:694-701 Sleep duration and incident Hypertension The Whitehall II Study Hours sleep Women, n=1,005 Men, n=2,686

25. 8 th Hypertension Masterclass Stranges S et al. 2008; (under review) Sleep duration and prevalent Hypertension The Western New York Health Study Hours sleep Women, n=1,710 Men, n=1,317 1.61 (1.08-2.41) <66-8>8

26. 8 th Hypertension Masterclass Increased BP load resulting from prolongation of higher BP whilst awakeIncreased BP load resulting from prolongation of higher BP whilst awake Truncation of the BP dip during sleepTruncation of the BP dip during sleep Prolonged activation of sympathetic nervous systemProlonged activation of sympathetic nervous system Increased renal sodium retentionIncreased renal sodium retention Gender-specific effects?Gender-specific effects? Confounding?Confounding? Sleep Deprivation & Hypertension: Potential Mechanisms

27. 8 th Hypertension Masterclass Total and cause-specific mortality

28. 8 th Hypertension Masterclass Kripke DF et al. Arch Gen Psychiatry 2002;59:131-136 The U-Shaped Association between Sleep Duration and Total Mortality The Cancer Prevention Study II Women, n=636,095 Men, n=480,841

29. 8 th Hypertension Masterclass All-Cause mortality by hours of sleep The Whitehall II Study < 5h (56 deaths) 7h (256 deaths) 8h (87 deaths) Hazard Ratio (95% CI) Age-adjusted Fully adjusted 6h (160 deaths) > 9h (7 deaths) Phase 1 (1985-88) n=9,781 < 5h (29 deaths) 7h (112 deaths) 8h (74 deaths) Hazard Ratio (95% CI) Age-adjusted Fully adjusted 6h (61 deaths) > 9h (16 deaths) Phase 3 (1991-93) n=7,729 Ferrie JE et al. Sleep 2007; 30:1659-66

30. 8 th Hypertension Masterclass All-Cause mortality from Phase 3 by changes in hours sleep between Phase 1 and Phase 3 Increase from 5 or 6h (55 deaths) Decrease from 6, 7 or 8h (57 deaths) Increase from 7 or 8h (58 deaths) Hazard Ratio (95% CI) Age-adjusted Fully adjusted Ferrie JE et al. Sleep 2007; 30:1659-66

31. 8 th Hypertension Masterclass Increase from 5 or 6h (16 deaths) Decrease from 6, 7 or 8h (24 deaths) Increase from 7 or 8h (12 deaths) Hazard Ratio (95% CI) Age-adjusted Fully adjusted CVD mortality from Phase 3 by changes in hours sleep between Phase 1 and Phase 3 Ferrie JE et al. Sleep 2007; 30:1659-66

32. 8 th Hypertension Masterclass Increase from 5 or 6h (38 deaths) Decrease from 6, 7 or 8h (33 deaths) Increase from 7 or 8h (45 deaths) Hazard Ratio (95% CI) Age-adjusted Fully adjusted Non-CVD mortality from Phase 3 by changes in hours sleep between Phase 1 and Phase 3 Ferrie JE et al. Sleep 2007; 30:1659-66

33. 8 th Hypertension Masterclass 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 mortalityEither 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 deathsA 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 deathsAn 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 healthSleep changes over time may represent more reliable measures to assess the impact of sleep on health

34. 8 th Hypertension Masterclass Coronary Heart Disease

35. 8 th Hypertension Masterclass Coronary Heart Disease by hours of sleep The MONICA Study Hours sleep Women, n=3,388 Men, n=3,508 2.98 (1.48-6.03) Meisinger C et al. Sleep 2007; 30:1121-27

36. 8 th Hypertension Masterclass Coronary Heart Disease by hours of sleep The Nurses’ Health Study Hours sleep 1.45 (1.10-1.92) Ayas NT et al. Arch Intern Med 2003; 163:205-9 1.38 (1.03-1.86) Women, n=71,617

37. 8 th Hypertension Masterclass Summary Both short and long sleep duration may be associated with more detrimental effects on cardiovascular health in women than menBoth 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 unclearThe 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 womenHigh blood pressure may represent one mechanism linking short sleep duration with increased risk of CHD, at least in women

38. 8 th Hypertension Masterclass Co-morbidities of sleep disorders (psychiatric/chronic conditions) Co-morbidities of sleep disorders (psychiatric/chronic conditions) Bidirectional relationship (reverse causality/temporality?) Bidirectional relationship (reverse causality/temporality?) Confounding by other lifestyle behaviors Confounding by other lifestyle behaviors Sleep as marker of health status vs. risk factor Sleep as marker of health status vs. risk factor Biological plausibility Biological plausibility Objective assessment of sleep changes over time Objective assessment of sleep changes over time Unresolved issues

39. 8 th Hypertension Masterclass SLEEP, HEALTH & SOCIETY University of Warwick Medical School sleepresearch@warwick.ac.uk Leads: FP Cappuccio & E Peile Warwick Team:MA Miller, S Stranges, N-B Kandala, FM Taggart, C Ji, A Currie, G Ward, A Bakewell, A Lowe, D Cooper Collaborators: Warwick: S Williams, D Banejee, RCP: R Pounder UCL: MG Marmot, E Brunner, M Kumari, M Shipley, JE Ferrie Surrey:D-J Djik, S Archer Harvard: C Czeisler, S Lockley, C Landrigan Naples:P Strazzullo, G Barba Buffalo:JM Dorn, RP Donahue, M Trevisan Funding:Cephalon Inc., Wingate Foundation, Whitehall II, RDF University of Warwick, NHS Workforce

40. 8 th Hypertension Masterclass Groeger JA et al. J Sleep Res. 2004; 13:359-71 Average sleep duration in a survey of ~2,000 British Adults

41. 8 th Hypertension Masterclass Co-morbidities of Sleep Disorders Sleep disorders Co-morbiditiesInsomnia Psychiatric Disorders Sleep Apnoea Cardiopulmonary Disease Restless Legs Syndrome Musculoskeletal Conditions Short sleep duration () Short sleep duration (behavioural)Cancer

42. 8 th Hypertension Masterclass Co-morbidities of Sleep Disorders Foley D et al. Psychosom Res. 2004; 56:497-502

43. 8 th Hypertension Masterclass Sleep Duration and BMI Meta-analysis of Cross-Sectional Studies Cappuccio FP et al. Sleep 2008; in press Adults, n=16,509 β & 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) Equivalent to approx 1.4 kg per hour

44. 8 th Hypertension Masterclass Gale SM et al. J Nutr 2004; 134:295-8 LACK OF SLEEP less more

45. 8 th Hypertension Masterclass Objective assessment of sleep changes over time Objective assessment of sleep changes over time More prospective evidence More prospective evidence Better understanding of determinants of sleep duration Better understanding of determinants of sleep duration Better control for confounders/co-morbidities Better control for confounders/co-morbidities Experimental evidence on biological plausibility Experimental evidence on biological plausibility Need for further research…

46. 8 th Hypertension Masterclass Short sleep duration Long sleep duration Low SES/Unhealthy lifestyle/ Poor general health status Co-Morbidities/Elderly Appetite dysregulation/ Impaired glucose homeostasis CVD/Metabolic alterations Increased morbidity/mortality/ Reduced quality of life Inflammatory/neurovegatative/ hormonal responses Depression/ Poor general health status Putative pathways

47. 8 th Hypertension Masterclass Sleep Deprivation & Diabetes: Potential Mechanisms Spiegel K et al. J Appl Physiol. 2005; 99: 2008-19 Diabetes Acute sleep deprivation Chronic sleep deprivation