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Obstructive Sleep Apnea endothelial dysfunction and lipid metabolism

Obstructive Sleep Apnea endothelial dysfunction and lipid metabolism. Lena Lavie IIT, ISRAEL. TTS, april 27 th , 2007 Beldibi, Kemer - Antalia. Special Acknowledgements. Prof. Eyüp S Uçan  - President of TTS           Prof. Numan Ekim - Congress Chair                   

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Obstructive Sleep Apnea endothelial dysfunction and lipid metabolism

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  1. Obstructive Sleep Apnea endothelial dysfunction and lipid metabolism Lena Lavie IIT, ISRAEL TTS, april 27th, 2007 Beldibi, Kemer - Antalia

  2. Special Acknowledgements • Prof. Eyüp S Uçan  - President of TTS           • Prof. Numan Ekim - Congress Chair                    • Prof. Metin Görgüner - Scientific Committee Chair  • The panel chairs: Prof. Johan Verbraecken and Prof. Banu Salepçi

  3. Mechanisms that affect endothelial function and Atherosclerosis: • oxidative stress • inflammation • lipid metabolism

  4. Lecture outlines • Introduction: Sleep apnea and cardiovascular morbidity • Underlying mechanisms of atherosclerosis: oxidative stress inflammation and dyslipidemia in OSA • Activated monocytes and foam cell formation • Endothelial dysfunction

  5. Lecture outlines • Introduction: Sleep apnea and cardiovascular morbidity • Underlying mechanisms of atherosclerosis: oxidative stress inflammation and dyslipidemia in OSA • Activated monocytes and foam cell formation • Endothelial dysfunction

  6. Obstructive Sleep Apnea (OSA) Syndrome Is characterized by recurrent collapse of the upper airway during sleep leading to Chronic Intermittent Hypoxia (IH) and Sleep Fragmentation TIME (hr.) % O2Sat. IH responsible for many pathophysiological consequences

  7. Increasingly evident that the severity of Sleep Apnea is associated with • Increased CAD morbidity & mortality • Systemic hypertension • Pulmonary hypertension • IHD • Stroke

  8. Prospective study - 408 patients with chronic stable angina pectoris referred for coronary catheterization Conclusion: Worse long term prognosis and independent association with ceebrovascular events in OSA AJRCCM, 164 pp1910-1913, 2001

  9. Long-term cardiovascular outcomes in men with obstructive sleep apnoea-hypopnoea with or without treatment with continuous positive airway pressure: an observational study.Lancet. 2005 Mar 19-25;365(9464):1046-53. Incidence Fatal CVS A 10 year follow-up to determine fatal and non-fatal CVD on controls snorers mild sever and nCPAP treated OSA Conclusion: in men severe OSA significantly increases the risk of fatal and non-fatal cardiovascular events. nCPAP treatment reduces this risk. Non-Fatal Marin et al. Lancet, 2005; 365:1046-53

  10. All these studies and others point to OSA as an independent risk factor for various CAD morbidities. Although the underlying mechanisms are not fully elucidated atherosclerosis is a major component in these morbidities.

  11. Obsructive Sleep Apnoea Intermittent Hypoxia ROS NFB, AP-1: Inflammatory transcription factor activation Direct injury proteins DNA Lipids Adhesion molecules and inflammatory Cytokines Activation Monocytes Neutrophils Lymphocytes Adhesion Endothelial Cells Injury Foam cells Endothelial dysfunction Atherosclerosis Lavie L, Sleep Medicine Reviews 7:35-51, 2003 CAD

  12. Obsructive Sleep Apnoea Intermittent Hypoxia ROS Inflammation- NFB, AP-1 SREBP-lipid metabolism Direct injury proteins DNA Lipids Adhesion molecules and inflammatory Cytokines Activation Lipids Monocytes Neutrophils Lymphocytes Adhesion Endothelial Cells Injury Foam cells Endothelial dysfunction Atherosclerosis Lavie L, Sleep Medicine Reviews 7:35-51, 2003 SREBP- sterol regulatory element binding protein CAD

  13. Lecture outlines • Introduction: Sleep apnea and cardiovascular morbidity • Underlying mechanisms of atherosclerosis: oxidative stress inflammation anddyslipidemia in OSA • Activated monocytes and foam cell formation • Endothelial dysfunction

  14. Atherosclerosis • Hardening and thickening of the arterial walls - is a multifactorial disease with elements of oxidative stress, inflammation and lipid deposition. • An inflammatory/immune response to the injury of blood vessels starting in endothelial dysfunction – a subclinical condition of atherosclerosis and eventually resulting in vessel wall thickening. • Endothelial dysfunction – results from oxidative/inflammatory injury/lipid deposition Characteristic of many diseases - ischemia, hypercholesterolemia, diabetes, hyperhomocysteinemia, hypertension, inflammatory and neurological diseases, intermittent hypoxia - OSA Libby P,.Nature 2002;420:868-74

  15. Early signs of atherosclerosis in sleep apnea • Increased intima-media thickness Drager et al, 2005 • Arterial plaque formation Kaynak et al, 2003 • Calcified artery atheromas Friedlander et al, 1999 • Atherosclerotic lesions Aboyans et al, 1999 • Higher pulse wave velocity Drager et al, 2005

  16. OSA and Atherosclerosis – increased intima-media thikening

  17. OSA and AtherosclerosisDrager et al/AJRCCM 2005,172:613

  18. OSA and Dyslipidemia • Newman AB et al. Am J Epidemiol. 2001 Jul 1;154(1):50-59 • The Sleep Heart Health study found that the severity of Sleep Apnea correlates with: • An increase in serum total cholesterol and triglyceride levels independent of age and BMI • A decrease in serum HDL levels independent of age and BMI • Robinson et al. Thorax 2004; 59:777-782. • Therapeutic levels of CPAP for 1 month decrease serum total cholesterol levels by 10.8 mg/dl in patients with OSA

  19. OSA and Dyslipidemia Chin et al. Circulation . 1999; 100:706-712. Chin et al. Am J Med. 2000; 109:562-567

  20. OSA and Dyslipidemia McArdle et al. AJRCCM 2007; 175:190

  21. OSA and Dyslipidemia-HDL dysfunction Control – R=-0.04, NS OSA – R=0.53, p<0.001 Conclusion: HDL is dysfunctional in preventing the inactivation of oxidized lipids in OSA Tan et al. Atherosclerosis, 2006;184:377

  22. OSA and Dyslipidemia-HDL dysfunction and lipid peroxidation Tan, K. C et al. 2006. Atherosclerosis 184:377-382.

  23. Lipid peroxydation – in matched comorbidity- free OSA and controls PDs TBARS

  24. 114 consecutive patients – now over 700

  25. TBARS and PD in controls and OSA before and 9 months after nCPAP treatment MDA (nmol/ml pl) TBARS N=15 Control N=6 OSA N=9 CPAP N=5 AHI Control =7 OSA =55 CPAP =13 PD (nmol/ml pl) PD Lavie et al SLEEP 2004;27:123-8

  26. Obsructive Sleep Apnoea Intermittent Hypoxia ROS Inflammation- NFB, AP-1 SREBP-lipid metabolism Direct injury proteins DNA Adhesion molecules and inflammatory Cytokines Activation Lipids Monocytes Neutrophils Lymphocytes Adhesion Endothelial Cells Injury Foam cells Endothelial dysfunction Atherosclerosis Lavie L, Sleep Medicine Reviews 7:35-51, 2003 SREBP- sterol regulatory element binding protein CAD

  27. Intermittent Hypoxia in the Laboratory –A mouse model by Polotsky et al. Upregulation of SREBP, lipid metabolism, and genes responsible fore lipid metabolism and development of atherosclerosis in mice exposed to CIH

  28. A B G . . SREBP - 1 . SREBP - 2 * 250 IA IH IA IH 200 IH/ IA immature immature * (%) 150 protein protein 100 Active Active nuclear nuclear 50 isoform isoform C D . SCD - 1 . GPAT 0 IA IH IA IH nSREBP - 1 nSREBP - 2 SCD - 1 GPAT Intermittent Hypoxia Increases SREBP-1 and SCD-1 Protein Levels in the Liver Li et al. Circ Res. 2005;97:698-706

  29. Intermittent Air Control Intermittent Air Control Intermittent Hypoxia Intermittent Hypoxia Chronic Intermittent Hypoxia Up-regulates SREBP-1 and SCD-1 Gene Expression in mouse Liver phospholipids Li et al. J Appl Physiol. 2005 Nov;99(5):1643-8.

  30. Chronic Intermittent Hypoxia (CIH) and Atherosclerosis CIH IA En face preparation of thoracic aorta of C57BL/6J mice on a high cholesterol diet. Black wax surface, x 20. Sudan IV. Upper panel – CIH; Lower panel – Intermittent Air control. Arrows point at atherosclerotic lesions. Savransky et al. Am J Respir Crit Care Med. 2007 Mar 1; [Epub ahead of print]

  31. Chronic Intermittent Hypoxia (CIH) and Atherosclerosis CIH IA Representative sections of the aortic valve area in C57BL/6J mice on a high cholesterol diet. X 200. Oil red O – hematoxylin. Left panel – CIH; an atherosclerotic lesion with disruption of the intima; foam cells can be seen (arrows). Right panel – Intermittent Air Control; intact aorta.

  32. Chronic Intermittent Hypoxia (CIH) and Atherosclerosis CIH IA Cross sections of the ascending aorta of C57BL/6J mice on a high cholesterol diet. X 100. Oil red O – hematoxylin. Left panel – CIH; atherosclerotic lesions(arrows); Right panel – Intermittent Air Control; intact aorta. Savransky et al. Am J Respir Crit Care Med. 2007 Mar 1; [Epub ahead of print]

  33. Lecture outlines • Introduction: Sleep apnea and cardiovascular morbidity • Underlying mechanisms of atherosclerosis: oxidative stress inflammation and dyslipidemia in OSA • Activated monocytes and foam cell formation in OSA • Endothelial dysfunction

  34. Complementary Studies on Human Monocytes The atherosclerotic process is also characterized by the accumulation of cholesterol deposits in monocytes which become macrophages in large- and medium-sized arteries. • Participate/ accumulate in atherosclerotic plaques • Release inflammatory Mediators/ Cytokines and ROS • Exert cytotoxic activity and damage Endothelial cells causing Endothelial dysfunction

  35. Index of ROS production by blood monocytes bearing CD11c and CD64 molecules p<0.0005 p<0.004 p<0.03 Dyugovskaya Lavie & Lavie AJRCCM 2002;165:934-9

  36. % CD11c Monocytes participating in ROS production in patients with and without CPAP (two consecutive nights) and controls nCPAP treatment lowers basal ROS production in monocytes Dyugovskaya Lavie & Lavie AJRCCM 2002;165:934-9

  37. Expression of CD11b, CD11c and CD15 on PBMS from OSA patients and controls p<.05 p<.001 p<.0001 17 21 C3b-R R forfor ICAMselectins C3b-R for ICAM

  38. The involvement of OxLDL in the development of atherosclerotic plaque OxLDL is a potent chemoattractant for monocytes & promotes the differentionof monocytes to tissue macrophages. OxLDL induces the expression of macrophage scavenger receptor (SR-A,CD36) & thus promotes the formation of foam cells. The uptake of OxLDL by macrophages is a stimulant for the release of cytokines & initiates an inflammatory response. What is the involvement of ox-LDL in foa

  39. What is the involvement of ox-LDL in foam cell formation in OSA?

  40. oxLDL uptake and CD36 expression in co-morbidity free OSA patients and controls P<0.03 P<0.04

  41. Expression of the scavenger receptor CD36 increases with oxLDL uptake r=0.57, P<0.01

  42. Foam cell formation (Oil Red o) in co-morbidity free OSA patients and controls P<0.009 P<0.07

  43. 77-nonOSA 77-nonOSA-oxLDL 74-OSA 74-OSA-oxLDL

  44. 77-ox-non

  45. 74ox OSA

  46. 89c

  47. Obsructive Sleep Apnoea Intermittent Hypoxia ROS Inflammation- NFB, AP-1 SREBP-lipid metabolism Direct injury proteins DNA Lipids Adhesion molecules and inflammatory Cytokines Activation Lipids Monocytes Neutrophils Lymphocytes Adhesion Endothelial Cells Injury Foam cells Endothelial dysfunction Atherosclerosis Lavie L, Sleep Medicine Reviews 7:35-51, 2003 SREBP- sterol regulatory element binding protein CAD

  48. Thank You • Dyugovskaya L. • Polyakov A. • Vishnevsky A. • Tsabary Z. • Golan O. • Leder E. • Itzhaki S. • Lavie P • The staff of the Sleep Lab. in the Technion

  49. Lecture outlines • Introduction: Sleep apnea and cardiovascular morbidity • Underlying mechanisms of atherosclerosis: oxidative stress inflammation and dyslipidemia • Monocytes and foam cell formation • Endothelial dysfunction

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