1. Sleep and Health Patrick J. Strollo, Jr., M.D. University of Pittsburgh Medical Center PMBC SLEEP WORKSHOP 2006

2. 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

3. Function of Sleep Consolidate memory Improve concentration Improve mood Enhance creativity Hormonal control of appetite Immune function & systemic inflammation Brain Systemically Sleep Medicine 2004 5:225-30 Nature 2004 430:27-28 J Am Coll Cardiol 2004 43:678-83 J Clin Endocrinol Metab 2004 89:5762-71

4. NREMWAKE Interaction between Sleep and Wake States REM

5. Sleep Med 2005 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

6. The Cumulative Cost of Additional Wakefulness: Dose- Response Effects on Neurobehavioral Functions and Sleep Physiology From Chronic Sleep Restriction and Total Sleep Deprivation SLEEP 2003 2:117-126 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.

7. Sleepiness Sympathovagal Balance Evening cortisol concentrations Time in Bed 4 8 12 Impact of Sleep Debt on Metabolic And Endocrine Function Lancet 1999 354:1435-39 Stanford Sleepiness Score 1000 – 1400 h Sympathovagal Balance 0900 -1400 h Saliva Free Cortisol Mmol/L 1600 - 2000 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 p < 0.0001 p < 0.02 p < 0.007

8. 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 of 4-h sleep time After 2 d of 4-h sleep time After 2 d of 4-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, and Increased Hunger and Appetite Ann Intern Med 2004 141:846-850 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

9. Arch Intern Med. 2005 165:25-30 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 The association between total sleep time and body weight in primary care Results:   

10. The Obesity Epidemic Worldwide Nature 2000

11. Obesity and the Risk of Heart failure NEJM 2002 347:305-13 Men

12. 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

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

14. Impact of Sleep on Survival Sleep Latency Sleep Efficiency Latency < 30 min Latency > 30 min Efficiency > 80 % Efficiency < 80 % Survival Weeks Psychosomatic Medicine 2003 65:63–73

15. Brain, Behavior, and Immunity 2003 17: 350–364 Stress

16. JACC 2004 43:678–83 Effect of Partial Sleep Deprivation on C-Reactive Protein (n = 5) (n = 4)

17. Sleep Complaints Heart Failure Patients vs. General Population Percentage AACN Clinical Issues 2003 14:477-87 n = 84 Male (59%) Age = 54.1 + 10.8 NYHA = 2.8 + 0.8 LVEF (%) = 21.7 + 6.3 * * * * * *

18. Impact of Sleep Difficulties on the Minnesota Living with Heart Failure Questionnaire J Cardiovasc Nurs 2004 19: 234–242 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. Conclusion: Patients with HF have a reduced HRQOL especially if difficulties maintaining sleep, initiating sleep, and early morning awakenings are involved. Results:

19. 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

20. 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 Rev 2003 7:35-51

21. OSDB: Effect on Nocturnal BP and CO Thorax 1998 53:416-418

22. Sympathetic Neural Activity OSA vs. Normals J Clin Invest 1995 96:1897-1904 10 sec Awake Normal OSA

23. Effect of OSA on Inflammatory Markers Circulation 2003 107:1129-34 C-Reactive Protein IL-6

24. Effect of Activated Monocytes on the Endothelium Nature 2002 420: 868-74 ROS Cytokines MMPs Tissue Factor

25. Sleep Apnea Impacts on Insulin and Glucose Independent of Obesity J Intern Med 2003 254:32-44

26. 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 LTIH (n =19) Sham LTIH (n = 16) Mean Sleep Latency * 8.9 + 1.0 12.7 + 0.5 Significant oxidative injuries in the sleep-wake regions of the brain after LTIH are associated with “residual hypersomnolence”

27. Day–Night Pattern of Sudden Death in Obstructive Sleep Apnea N Engl J Med 2005 352:1206-14. < 5 5 -39 > 40 Apnea Hypopnea Index Relative Risk of Sudden Death from Cardiac Causes 12:00 – 6:00 AM 10:00 PM – 5:59 AM 6:00 AM – 1:59 PM 2:00 PM – 9:59 PM Proportion of Sudden Death from all Cardiac Causes (%)

28. Cumulative Incidence of Fatal CV Events Cumulative Incidence of Non-fatal CV Events 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 Months. Conclusion: In men, severe OSA significantly increases the risk of fatal and non-fatal cardiovascular events. CPAP treatment reduces this risk. Long-term cardiovascular outcomes in men with OSA

29. 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

30. Obesity Sleep Apnea Diabetes LV Hypertrophy Pleiotrophic Effects of Adiopkines on Vascular Risk Adipokines & Leptin

32. J Appl Physiol 98: 2226–2234, 2005. Healthy Controls (n = 10) OSA Subjects (n =16)

33. Arch Intern Med. 2006;166:1709-171

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

35. Sleep Heart Failure Sympathetic Activation Inflammation CRT Wake Drive Sleep Drive Sleep and Heart Failure: The role of Autonomic Activation and Inflammation

36. NREMWAKE Interaction between Sleep and Wake States REM

37. 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.

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