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OSA & Oxidative Stress

OSA & Oxidative Stress. Patrick J. Strollo, Jr., M.D., FCCP, D,AASM Medical Director, UPMC Sleep Medicine Center. http://www.pitt.edu/~paccm/sleepmed.htm. Outline. Introduction What is “Oxidative Stress”? How does Oxidative Stress relate to Obstructive Sleep Apnea? Blood Brainstem

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OSA & Oxidative Stress

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  1. OSA & Oxidative Stress Patrick J. Strollo, Jr., M.D., FCCP, D,AASM Medical Director, UPMC Sleep Medicine Center http://www.pitt.edu/~paccm/sleepmed.htm

  2. Outline • Introduction • What is “Oxidative Stress”? • How does Oxidative Stress relate to Obstructive Sleep Apnea? • Blood • Brainstem • What evidence supports that reversal of Oxidative stress is beneficial? • Summary & Future challenges.

  3. “Oxidative stress is now understood to be the common denominator in many-indeed, most-pathologic processes. An antidote to oxidative damage has become the holy grail of medical research.” Am J Respir Cell Mol Biol 2002 27:8-16

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

  5. Oxidative Stress Free Radical Chemistry • “An imbalance between • oxidants and antioxidants • in favor of oxidants, • leading to damage” • Loss of oxidants • Consumption of anti- oxidants Superoxide Anion Formation Hydrogen Peroxide Formation Hydroxyl Radical Formation Free Radical Peroxynitrite Formation Any molecule that contains one or more unpaired electrons. Physiol Rev 2004 84:1381-1478

  6. Ischemia-Reperfusion: Generation of Reactive Oxygen Species Sleep Med Rev 2003 7:35-51

  7. Effect of ROS on Lipids and Proteins in the Cell Reactive Oxygen Species Lipid Peroxidation Protein Oxidation Unsaturated aldehydes Oxidized sulfhydryl groups Oxidized amino acid residues Malondialdehydes Membrane disturbance Protein inactivation Cellular disturbance J Hypertens 2000 18:655-73

  8. The Role of Monocytes in the Pathogenesis of Atherosclerosis ROS ROS Physiol Rev2004 84:1381–1478

  9. The Acute Physiologic Effects of OSA 20 sec J Clin Invest 1995 96 (4):1897-1904

  10. 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.

  11. Sleep Apnea is Associated with Significant Co-morbidities Cardiovascular Complications Neuro-cognitive Complications Metabolic Complications

  12. Intermittent Hypoxia in Obstructive Sleep Apnea Sleep Med Rev 2003 7:35-51

  13. Sleep Disordered Breathing and Cardiovascular Disease N = 5,250 Odds Ratio AJRCCM 2001 163:19-25 AHI (Quartiles)

  14. Effect of Sleep Apnea on Incident HTN 2.89 (1.46-5.64) 2.03 1.39-3.17 1.42 (1.13-1.78) Odds Ratio 1.0 NEJM 2000 342:1378-84

  15. Effect of Nocturnal Desaturationon ASCAD Severity CHEST 2003 124:936-941

  16. Long-term cardiovascular outcomes in men with OSA 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 .

  17. SOD Release from PMNs in OSA vs. Controls SOD Release after fLMP Stimulation OSA n = 18 Healthy Controls n = 10 Lung CA n = 10 AJRCCM 2000 162: 566–570

  18. 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) Significant oxidative injuries in the sleep-wake regions of the brain after LTIH are associated with “residual hypersomnolence” LTIH (n =19) Sleep 2004 27:194-201.

  19. INCREASED OXIDATIVE STRESS IS ASSOCIATED WITH CHRONIC INTERMITTENT HYPOXIA-MEDIATED BRAIN CORTICAL NEURONAL CELL APOPTOSIS IN A MOUSE MODEL OF SLEEP APNEA ROS Neuroscience 2004 126:313–323

  20. Effect of CPAP on SOD Release n = 18 SOD Release from PMNs S/P fMLP Baseline CPAP (Follow-up)* CPAP (2 nights) AJRCCM 2000 162: 566–570

  21. Effect of CPAP on Lipid Peroxidation PD (nmol/ml plasma) TBARS (nmol/ml plasma) Time (h) Time (h) OSA n = 9 Control n = 6 OSA on CPAP n = 5 SLEEP2004 27:123-8

  22. SLEEP APNEA (CIH) Lipids Sleep Deprivation Gender HTN CHF Diabetes Smoking Obesity Xanthine Oxidase NADPH Oxidase “Uncoupled” NOS O - • SOD O2 - • OONO• LOO • LO • OH • Oxidation H2O2 Oxidant Stress NO / CO ROS Bioavailable NO / CO Remodeling Endothelial Dysfunction SMC Growth Loss of Vasodilatation Platelet Aggregation Inflammation Circ Res 2000 87:84-844

  23. Intermittent Hypoxia Xanthine Oxidase Mitochondrial Dysfunction Homocysteine ROS Activation of Transcription Factors Lymphocyte Activation Monocyte Activation Endothelial cell Activation Adhesion Molecule Expression Monocyte Lymphocyte / Endothelial Adhesion Endothelial Dysfunction Sleep Med Rev 2003 7:35-51 Vascular Disease

  24. Summary & Current Challenges • Oxidative Stress in OSA adversely impacts: • Endothelial function • Neuronal function • Oxidative Stress can be favorably modified by treatment (Positive Pressure*) • The “Downstream” effects of ROS are linked to cytokine & neurohormonal activation* • Further research is needed to better define: • The mechanisms (signaling pathways) • Relative risk in individual OSA phenotypes

  25. Teşekkürler

  26. HeartSCORE Study Design Recruitment (n = 2000) Screening (n = 2000) Screening Visit: Hx, Exam, EKG, Psychosocial Questionnaires Lipids (LDL particle size), Glu, Creat, CRP, Inflammatory Markers, Brachial Artery Size, EndoPAT Low Risk (n =800) Intermediate Risk (n = 1,000) Electron Beam CT Preexisting Cardiovascular Disease (n = 200)

  27. 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

  28. Pulse Wave Amplitude Testing Normal CAD finger with cuff CAD contralateral finger Am Heart J 2003 146:168-74

  29. HIF 1alpha regulated gene expression in OSA Hypoxia Vasoconstriction Antiapoptosis Antioxidative stress Angiogenesis Glycolysis Bratisl Lek Listy 2003: 104:167-173

  30. Introduction • Obstructive Sleep Disordered Breathing (OSDB) and Cheyne-Stokes Respirations (CSR) are disease states characterized by intermittent hypoxemia • These conditions are associated with increased cardiovascular co morbidities • Oxygen sensing and homeostasis is of utmost importance

  31. Introduction • Hypoxia Inducible Factor (HIF-1) is essential for sensing hypoxia • Heme Oxygenase-1 (HO-1) and Nitric Oxide Synthase (iNOS) are produced in response to oxidative stress • The induction of HIF-1 has increased effects on the regulation of HO-1 and iNOS

  32. Hypotheses • The biologic impact of intermittent hypoxia is different from that of sustained hypoxia • intermittent hypoxia appears to induce an ischemic reperfusion injury which increases free radical oxygen species and mediators • there may be difference in adaptive mechanisms

  33. Objective • We sought to examine the induction of HO-1 and iNOS in states of intermittent versus chronic hypoxemia • We also sought to examine the regulation of HIF-1 in states of intermittent versus chronic hypoxemia

  34. Methods • Northern blot analysis was used to assess the expression of HO-1 and iNOS mRNA • Gel shift analysis was used for assessment of HIF-1 induction • Whole lung tissue samples were used from male Sprague-Dawley rats

  35. Methods • Control rats were maintained at room air (21% FiO2) • Chronically hypoxic rats were oxygenated using 10% FiO2 for set durations (from 1 hour to 30 days) • Intermittent hypoxia involved 90 seconds of 10% FiO2 alternating with room air, also for set periods

  36. Hypoxia HIF-1a stabilization HIF-1a/b DNA binding to consensus element Induction of VEGF gene iNOS and HO-1 EPO gene (Angiogenesis) (Vasodilation) (Erythropoiesis)

  37. iNOS 1hr 3d 14d 1hr 3d 14d Intermittent Hypoxia Chronic Hypoxia

  38. Heme Oxygenase -1 1hr 7d 14d 30d 1hr 7d 14d 30d Chronic Hypoxia Intermittent Hypoxia

  39. HIF-1 1d 7hr 1d 1hr 7hr 1hr Intermittent Hypoxia Chronic Hypoxia

  40. Conclusion • Adaptive responses to hypoxia are seen in states of both intermittent and chronic hypoxemia • HO-1, iNOS and HIF-1 are most significantly expressed under chronically hypoxic conditions

  41. Conclusion • Further investigation is needed in order to understand the risk of intermittent hypoxia associated with Obstructive Sleep Disordered Breathing (OSDB) and Cheyne-Stokes Respirations (CSR)

  42. The Cytokine Cascade Atherosclerotic plaque Adipose Tissue Coronary Artery Interleukin-1 TNF Interferon–gamma Interleukin-1 TNF Interleukin 6 Liver Acute Phase Reactants Serum Amyloid A CRP NEJM 2005 352:1685-95.

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

  44. Elevated CRP in OSA Circulation 2002 105:2462-2464

  45. Effect of treatment on CRP & IL-6 C-Reactive Protein Interleukin 6 Circulation 2003 107:1129-1134

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

  47. Molecular Immunology 41 (2004) 29–44

  48. Effect of OSA Rx on Cardiac Events • Design:Prospective observational study (86.5 + 39 months) • Patients: • N = 54 (53 M / 1 F) • Age 57.3 + 10.1 • CAD (> 70% stenosis) & AHI > 15 • Endpoints: • Cardiovascular death • Acute coronary artery syndrome • Hospitalization for CHF • Coronary Artery Revascularisation • Results: • Treated 6/25 (24%) • Untreated 17/29 (58%) Treated n = 25 p < 0.01 Event-free survival Untreated n = 29 Time (months) EHJ 2004 25:728-34

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

  50. Circulation2003 108:2041-2048

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