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  • N=14 & 11 w/o MS% & EC5 Use For Paper
  • SLA & CONTROLS N = 14 & 10 w/o MS% & EC5 and those missing data Use For Paper
  • Transcript

    • 1.  
    • 2. Is Sleep Apnea a Systemic Disease?
      • Alexandros N. Vgontzas, M.D., Professor
      • Penn State College of Medicine
      • Department of Psychiatry
    • 3. Sleep Apnea Clinical Features
      • Snoring
      • Nocturnal breath cessation
      • Excessive daytime sleepiness
      • Obesity
      • Hypertension
      • Diabetes
    • 4. King ED et al., Am J Respir Crit Care Med; 161(6):1979-84, 2000 Obstructive Sleep Apnea … … in a Normal Subject on Negative Nasal Pressure
    • 5. Apnea Hypopnea Snoring Normal P CRIT (cmH 2 O) UPPER AIRWAY DISEASE STATUS Upper Airway Mechanical Loads and Neural Responses 5 0 -5 -10 -15 Compensatory Neuromuscular Responses Soft Tissue Properties Box Size Sleep Apnea Risk Factors ? ? ?
    • 6. Sleep Apnea is an Anatomic Disorder
      • Pros – R. Schwab
      • Cons – K. Strohl
      • Am J Respir Crit Care Med, 2003
      • Both views treated obesity as a purely anatomic/mechanical factor.
    • 7. Apnea is a Manifestation of a Metabolic Syndrome: Evidence from Clinical Data
      • Obesity
      • Male gender (android obesity)
      • Course of symptoms (snoring -> weight gain ->  snoring, apnea -> EDS -> weight gain)
      • Majority of adult apneics do not have structural abnormalities
      • Systemic effects, e.g., hypertension
      • Failure of mechanical treatments, e.g., surgery
      • “ Systemic illness” vs local abnormality
      Vgontzas et.al., 2005
    • 8. Insulin Resistance Syndrome
      • High levels of insulin in order to maintain glucose homeostasis (Reaven, 1967)
      • 25% of the general population
      • Visceral adiposity- stress system effects (Bj örntorp , 1983)
    • 9. ATP(ADULT TREATMENT PANEL III) III Criteria for Identification of the Metabolic Syndrome Diagnosis of Metabolic Syndrome is made when 3 or more of the risk determinants shown above are present JAMA, 2001 ≥ 110mg/dL Fasting Glucose ≥ 130 /≥85mmHg Blood Pressure <50mg/dL Women <40mg/dL Men HDL cholesterol ≥ 150 mg/dL Triglycerides >88cm Women >102cm Men Abdominal Obesity (waist circumference)
    • 10. IDF (INTERNATIONAL DIABETES FEDERATION CONSENCUS DEFINITION 2005) Criteria for Identification of the Metabolic Syndrome Alberti K.G., Lancet, 2005 Fasting Glucose Blood Pressure Women Men HDL cholesterol Triglycerides PLUS ANY TWO OF THE FOLLOWING Women
      • Abdominal Obesity (waist circumference)
      • ethnicity specific
      • for Europids: Men >94 cm
      ≥ 100mg/dL or Type II Diabetes ≥ 130 / ≥85mmHg <50 mg/dL <40 mg/dL ≥ 150 mg/dL >80 cm
    • 11. pg/mL A B Normal Obstructive Sleep Apnea Narcolepsy Idiopathic Hypersomnia TNF  IL-6 * * * Normal Obstructive Sleep Apnea Narcolepsy Idiopathic Hypersomnia Cytokines and disorders of EDS Vgontzas et.al., 1997
    • 12. r xy = .636
    • 13. Vgontzas et.al., 2000 IL-6 and TNF α in Sleep apneics, Obese Controls, and non-Obese Controls
    • 14. IL-6 (pg/ml) r = .790 p = .000 TNF  (pg/ml) r = .400 p = .014 BMI Both IL-6 and TNF  correlate with BMI
    • 15. Plasma levels (  g/ml) * * Insulin Glucose Sleep Apnea and Insulin Resistance Vgontzas et al., 2000
    • 16. Sleep Apnea, Sleep Loss, Insulin Resistance and Obesity
      • Insulin resistance is present even in non obese apneics
      • Ip, 2002
      • Insulin resistance is present even in mild forms of Sleep Apnea
      • Punjabi, 2002
      • Sleep loss leads to insulin resistance and obesity
      • Van Cauter, 1999, 2002
    • 17. * Abdominal Fat Distribution (cm 2 ) p < 0.05 Vgontzas et al., 2000
    • 18. Apnea/Hypopnea Index Visceral Fat (cm 2 ) % Minimum SaO 2 r = .70 p = .00 r = -.612 p = .001 Sleep Apnea and Visceral Fat Visceral Fat (cm 2 )
    • 19. Fang et.al., 2006 Visceral
    • 20. Is sleep apnea increased in disorders in which insulin resistance is a primary pathophysiologic abnormality?
    • 21. Polycystic Ovary Syndrome
      • Most common endocrine disorder of premenopausal women (5-10%)
      • Chronic hyperandrogenism, oligoanovulation
      • Insulin resistance
    • 22. % Sleep Apnea % EDS * * Vgontzas et al. 2001
    • 23. Sleep apnea in PCOS
      • 17% Vgontzas, 2001
      • 44% Fogel, 2001
      • 21% Gopal, 2002
      • 75% Tasali, 2006
      • 57% Erhman 2007 (personal communication)
      • OSA in PCOS is not explained by the presence of obesity alone
    • 24. IL-6 (pg/ml) a Plasma IL-6 Levels in PCOS Women, and Obese, and Normal-Weight Controls a P < 0.05; PCOS women versus normal-weight controls b P < 0.05; obese controls versus normal-weight controls b
    • 25. Prevalence Sleep Apnea Menopause Bixler, 2001
    • 26.  
    • 27. Effects of CPAP on Inflammation, Insulin Resistance and visceral fat in Patients with SA
      • Inflammation
        • TNF α – two positive studies
        • IL-6 – two studies, inconsistent
      • Insulin Resistance
        • 12 out of 15 are negative
        • A positive effect was observed in non-obese
      • Visceral fat
        • 1 study positive effect
      • Studies with positive effects conducted in non-obese apneics
    • 28. Effects of CPAP on Stress System & in Inflammation / Metabolic Abnormalities in Obese with SA
      • 16 obese middle-age men with Obstructive Sleep Apnea
      • 13 obese men without Obstructive Sleep Apnea
      • 16 normal weight controls
      • Vgontzas et al., 2004
    • 29. Cortisol levels pre & post CPAP
    • 30. IL-6 in OSA, obese & thin controls: CPAP effects
    • 31. TNFr in OSA, obese & thin controls: CPAP effects
    • 32. 0 20 40 60 80 100 120 1 Glucose Sleep Apneics CPAP Obese Controls Lean Controls
    • 33.  
    • 34. Vgontzas et al 2004
    • 35. *
    • 36. Abdominal fat distribution in OSA & obese control OB OSA
    • 37.  
    • 38. Summary
      • CPAP in obese OSA men improves:
        • EDS
        • Hypercortisolism
        • Blood pressure
      • Does not improve:
        • Low grade inflammation
        • Insulin resistance
        • Visceral fat
      • Inflammation/insulin resistance are primary in sleep apnea in obese vs. nonobese
      • Irreversible due to presence for many years
      • “ Ceiling” effect due to obesity
    • 39. Sleep Apnea Phenotypes - Heterogeneity
      • Clinical & Lab criteria vs Lab criteria only
      • Symptomatic (EDS and/or hypertension) vs. non-symptomatic sleep apnea: age distribution
    • 40. Bixler, 1998, 2001
    • 41. Prevalence Sleep Apnea Clinical (SDC) Bixler, 1998, 2001
    • 42. Age (years) Prevalence NHANES III (1988-1994) Metabolic Syndrome Park et al., 2003
    • 43. Sleep Apnea and Metabolic Syndrome
      • The age distribution of symptomatic sleep apnea and metabolic syndrome are similar.
      • Metabolic syndrome is stronger associated with symptomatic sleep apnea
    • 44. Cytokine Antagonists (etanercept) in Sleep Apnea
      • 8 obese men with symptomatic apnea (A/HI > 20 plus EDS and/or hypertension) in a placebo-controlled pilot study
      • 7-week study, 3 weeks of placebo followed by 3 weeks of Enbrel
      • Polysomnography, respiration, MSLT, IL-6, CRP, adiponectin, FBS, insulin
      • Vgontzas et al., 2004
    • 45.  
    • 46.  
    • 47. 0 0.5 1 1.5 2 2.5 3 3.5 4 4.5 5 PLACEBO ETANERCEPT IL-6 Plasma Levels pg/ml *
    • 48. Exercise and Sleep Apnea
      • 1104 men and women, 30-60 years
      • Sleep assessed in the sleep lab
      • Exercise assessed by questionnaire
      • Adjusting for BMI, age, sex and other
      • Apnea Hypopnea Index 5.3 - 0 hours of exercise
      • Apnea Hypopnea Index 2.8 - >7 hours of exercise
      Wisconsin Sleep Cohort Study Peppard and Young 2004
    • 49.  
    • 50. Metabolic Abnormalities and Upper Airway Collapse
      • Diabetes mellitus may lead to ventilatory depression in obesity during sleep
      • Leptin deficiency/resistance may lead to respiratory depression
      • Inflammation of upper airway tissues primarily related to obesity
    • 51.
      • Growth factors released by fat tissue/hyperinsulinemia may lead to soft tissue edema
      • Male type of obesity impacts more upper airway function
      • Metabolic abnormalities present in SA may lead to sleepiness/hypertension independent of the airway collapse
      Metabolic Abnormalities and Upper Airway Collapse (cont’d)
    • 52. Acknowledgements
      • Sleep Research and Treatment Center, Hershey
        • A. Vgontzas, M.D. M. Basta, M.D.
        • E.O. Bixler, Ph.D. B. Pejovic, M.D.
        • H-M Lin, Ph.D. M. Papaliaga, M.D.
        • A. Kales, M.D. A. Sarrigiannidis, M.D.
        • M. Tsaoussoglou, B.Sc.
      • PREB NIH, Bethesda
      • G. P. Chrousos, M.D. G. Mastorakos, M.D.
      • E. Zoumakis, Ph.D.
      • D. Papanicolaou, M.D.
      • P. Prolo, M.D.

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