1. Aspectos fisiopatólogicos del SAHS Ferran Barbé Novembre, 2007

3. Definitions APNEA: Airflow cessation longer than 10 seconds Obstructive: with respiratory effort Central: without respiratory effort HYPOPNEA: Airflow reduction that induce a oxigen desaturation and/or arousal AHI: Nº of apneas + nº of hypopneas by hour slept.

4. Obstructive apnea No airflow Increased effort Desaturation 30 s

5. TRDS GENES relacionados con la etiología GENES que determinan la susceptibilidad Craneofacial Obesidad S.N.Central Control VAS HTA Cardiovascular Somnolencia Trans. cognitivos Otros Factores Etiológicos (20%)(4%) SAHS Consecuencias Clínicas

6. TRDS GENES relacionados con la etiología Craneofacial Obesidad S.N.Central Control VAS Factores Etiológicos (20%)

7. Genetics in SAHS SAHS: 1p, 2p, 12p, 19pSAHS: 1p, 2p, 12p, 19p Obesity: 2p, 7p, 12pObesity: 2p, 7p, 12p Candidate chromosomes: Palmer et al, Am J Hum Genet 2003

8. Genetics in SAHS SAHS: 8qSAHS: 8q Obesity: 4q, 8qObesity: 4q, 8q Candidate chromosomes in African-American: Palmer et al, AJRCCM 2004

9. TRDS GENES que determinan la susceptibilidad HTA Cardiovascular Somnolencia Trans. Cognitivos Otros (20%) (4%) SAHS Consecuencias Clínicas

10. Genetics in OSAS Genetics in OSAS Positive association Apo E є 4. JAMA 2001 TNF alfa ERJ 2004 No association PAI-I (Barceló Res Med 2002) ACE (Barceló Eur Resp J 2001) NPS (Hussain 2007)

11. OSAHS and CV disease Potential Mechanisms Metabolic abnormalities (obesity)Metabolic abnormalities (obesity) Increased sympathetic toneIncreased sympathetic tone Oxidative stressOxidative stress Systemic inflammationSystemic inflammation Coagulation abnormalitiesCoagulation abnormalities Endothelial dysfunctionEndothelial dysfunction Genetic backgroundGenetic background

12. Metabolic abnormalities in OSAHS Obesity is a known cardiovascular risk factor often present in patients with OSAHSObesity is a known cardiovascular risk factor often present in patients with OSAHS Patients with OSAHS show metabolic abnormalities:Patients with OSAHS show metabolic abnormalities: –Insulin resistance Ip et al, Am J Respir Crit Care Med 02; 165:670-6 Ip et al, Am J Respir Crit Care Med 02; 165:670-6 Punjabi et al, Am J Respir Crit Care Med 02; 165: 677-82 Punjabi et al, Am J Respir Crit Care Med 02; 165: 677-82 Barceló et al, Am J Med 04 Barceló et al, Am J Med 04 –Increased plasma leptin levels Chin et al, Circulation 99; 100: 706-12 Chin et al, Circulation 99; 100: 706-12 Ip et al, Chest 00; 118: 580-6 Ip et al, Chest 00; 118: 580-6

13. Metabolic abnormalities in OSAHS Obesity is a known cardiovascular risk factor often present in patients with OSAHSObesity is a known cardiovascular risk factor often present in patients with OSAHS Patients with OSAHS show metabolic abnormalities:Patients with OSAHS show metabolic abnormalities: –Insulin resistance Ip et al, Am J Respir Crit Care Med 02; 165:670-6 Ip et al, Am J Respir Crit Care Med 02; 165:670-6 Punjabi et al, Am J Respir Crit Care Med 02; 165: 677-82 Punjabi et al, Am J Respir Crit Care Med 02; 165: 677-82 Barceló et al, Am J Med 04 Barceló et al, Am J Med 04 –Increased plasma leptin levels Chin et al, Circulation 99; 100: 706-12 Chin et al, Circulation 99; 100: 706-12 Ip et al, Chest 00; 118: 580-6 Ip et al, Chest 00; 118: 580-6

14. Metabolic abnormalities in OSAHS Obesity is a known cardiovascular risk factor often present in patients with OSAHSObesity is a known cardiovascular risk factor often present in patients with OSAHS Patients with OSAHS show metabolic abnormalities:Patients with OSAHS show metabolic abnormalities: –Insulin resistance Ip et al, Am J Respir Crit Care Med 02; 165:670-6 Ip et al, Am J Respir Crit Care Med 02; 165:670-6 Punjabi et al, Am J Respir Crit Care Med 02; 165: 677-82 Punjabi et al, Am J Respir Crit Care Med 02; 165: 677-82 Barceló et al, Am J Med 04 Barceló et al, Am J Med 04 –Increased plasma leptin levels Chin et al, Circulation 99; 100: 706-12 Chin et al, Circulation 99; 100: 706-12 Ip et al, Chest 00; 118: 580-6 Ip et al, Chest 00; 118: 580-6

15. Increased sympathetic activity in OSAHS Increased sympathetic activity in OSAHS Fletcher et al, Sleep 1987; 10:35-44Fletcher et al, Sleep 1987; 10:35-44 Carlson et al, Chest 1993; 103: 1763-8Carlson et al, Chest 1993; 103: 1763-8 Narkiewicz et al, Circulation 1999; 100: 2332-5Narkiewicz et al, Circulation 1999; 100: 2332-5 Heitmann et al, Eur Respir J 2004; 23: 255-62Heitmann et al, Eur Respir J 2004; 23: 255-62 Increased sympathetic activity in obesity Increased sympathetic activity in obesity Spraul et al, J Clin Invest 1993; 92: 1730-5Spraul et al, J Clin Invest 1993; 92: 1730-5 Scherrer et al, Circulation 1994; 89: 2634-40Scherrer et al, Circulation 1994; 89: 2634-40 Grassi et al, Hypertension 1995; 25: 560-3Grassi et al, Hypertension 1995; 25: 560-3 Alvarez et al, Circulation 2002; 106: 2533-6Alvarez et al, Circulation 2002; 106: 2533-6

16. SYMPATHETIC ACTIVITY MARKERS NOREPINEPHRINENOREPINEPHRINE NEUROPEPTIDE YNEUROPEPTIDE Y Gullestad et al, Circulation 2000

17. NEUROPEPTIDE Y NEUROPEPTIDE Y Schwartz and Seeley, N Engl J Med, 97; 336(25) Schwartz and Seeley, N Engl J Med, 97; 336(25)

18. Neuropeptide Y and Leptin in Patients with OSAHS: Role of Obesity Barcelo A et al. AJRCCM 2005; 171: 183-7

20. ROS Adhesion molecule expression VSMC growth Apoptosis Lipid oxidation Altered vasomotion MMP activation Oxidative stress and cardiovascular risk Harrison et al; Am J Cardiol 03, 91: 7A-11A OSA hypoxemia hypoxia-reoxigenation

21. Direct markers:Direct markers: Indirect markers:Indirect markers: Oxidative stress and OSA -Increased ROS production -Increased plasma lipid peroxidation - Activation of redox sensitive gene expression: VEGF, endothelin - Reduced NO availability - Hyperhomocysteinaemia - Reduced levels of antioxidants

22. Increased ROS production Schultz et al. AJRCCM 00; 162: 566-70 Schultz et al. AJRCCM 00; 162: 566-70 Dyugovskaya et al. AJRCCM 02; 165: 934-9 Dyugovskaya et al. AJRCCM 02; 165: 934-9 Lipoprotein oxidation Lipoprotein oxidation Saarelainen et al. Clin Chem Lab Med 99; 37:517-20 Saarelainen et al. Clin Chem Lab Med 99; 37:517-20 Barceló et al. Eur Respir J 00; 16: 644-47 Barceló et al. Eur Respir J 00; 16: 644-47 Plasma homocistein levels Plasma homocistein levels Lavie et al. Chest 01; 120: 900-908 Lavie et al. Chest 01; 120: 900-908 Oxidative stress in OSAHS

23. Antioxidant status in patients with sleep apnoea and impact of continuous positive airway pressure treatment. A. Barceló, F. Barbé, M. de la Peña, M. Vila, G. Pérez, J. Piérola, J. Duran and A.G.N. Agustí´ Eur Respir J 2006; 27: 756–760

24. 1.40 0.02* 1.50 0.02 TAS (mmol/L) OSA(n=47) Controls Controls (n=37) (n=37) 10.8 0.6 11.8 1 Hcy (nmol/L) 501 81 474 51 Vit B12 (pg/mL) 10.1 0.5 9.5 0.6 Folic ac ( ng/mL) 1525 73* 1774 85 Vit E (ug/dL) 64 3* 74 3 Vit A (ug/dL) 42 3.3* 32 2.9 GGT (U/L) 844 19 798 19 GPX (U/L) OXIDATIVE STRESS

26. EDS n = 24 No EDS n = 21 p value TST (min)401 ± 41379 ± 61ns Sleep latency (min) 11 ± 1618 ± 160.03 Sleep efficiency (%) 90 ± 783 ± 120.03 Awake (min)37 ± 2963 ± 510.04 Arousal index64±2160±23ns Respiratory arousals 58 ± 2053 ±23ns Phase 1 + 2 (%) 80±1375±12ns Phase 3 + 4 (%) 7±99±6ns REM (%)13 ± 615 ± 7ns Min Sat (%)69 ± 1278 ± 100.007 Mean Sat (%)86 ± 690 ± 50.03 Somnolencia diurna y polisomnografia O Mediano ERJ 2007

27. Controls

28. Patients

29. Endothelial function in OSAHS and response to treatment Ip MS et al. AJRCCM 2004; 169: 348-53

30. Positive associationPositive association Shamsuzzaman et al. Circulation 2002; 105: 2462-4 Shamsuzzaman et al. Circulation 2002; 105: 2462-4 Yokoe et al. Circulation 2003; 107: 1129-34 Yokoe et al. Circulation 2003; 107: 1129-34 No associationNo association Chin K et al. Am J Med 2000; 109: 562-7 Chin K et al. Am J Med 2000; 109: 562-7 C-reactive protein and OSAHS Visser et al. JAMA 1999; 282: 2131-5Visser et al. JAMA 1999; 282: 2131-5 Frölich et al. Diabetes Care 2000; 3: 1835-9Frölich et al. Diabetes Care 2000; 3: 1835-9 Escobar et al. Diabetologia 2003; 46: 625-33Escobar et al. Diabetologia 2003; 46: 625-33 Aronson et al. Int J Obes Relat Metab 2004; 28: 674Aronson et al. Int J Obes Relat Metab 2004; 28: 674 C-reactive protein and obesity

31. Effects of obesity on C-reactive protein level and metabolic disturbances in male patients with OSAHS Barcelo A et al. Am.J Med 2004; 117: 118-21 * OSAHS

32. Endothelial dysfunction in OSAHS Nitric OxideNitric Oxide Ip et al. Am J Respir Crit Care Med 2000; 162: 2166-71 Ip et al. Am J Respir Crit Care Med 2000; 162: 2166-71 Schulz et al. Thorax 2000; 55: 1046-51 Schulz et al. Thorax 2000; 55: 1046-51 Lavie et al. J Mol Neurosci 2003; 21: 57-64 Lavie et al. J Mol Neurosci 2003; 21: 57-64 Endothelin-1Endothelin-1 Saarelainen et al. Endothelium 1997; 5: 115-8 Saarelainen et al. Endothelium 1997; 5: 115-8 Phillips et al. J Hypertens 1999; 17: 61-6 Phillips et al. J Hypertens 1999; 17: 61-6

33. Imagawa et al. Blood 2001; 98: 1255-7 Schulz et al. AJRCCM 2002; 165: 67-70 Gozal et al. Sleep 2002; 25: 59-65 Lavie et al. AJRCCM 2002; 165: 1624-8 Teramoto et al. Intern Med 2003; 42: 681-5 Increased circulating levels of VEGF in OSAHS

34. Szmitko et al. Circulation 03; 108: 1917-23

35. Areas denudadas del endotelio vascular Peinado et al. ERJ 2004;24:435s

36. Células progenitoras endoteliales (CD133 + ) (técnica de inmunogold) Peinado et al. ERJ 2004;24:435s

37. Endothelial progenitor cells in OSAHS

38. Agradecimientos H Univ Son DuretaH Univ Son Dureta –Antonia Barceló –Monica de la Peña –Antoni Ladaria –Margalida Bosch –Monica Castresana –Alvar Agustí H Univ Arnau de VilanovaH Univ Arnau de Vilanova –Olga Mediano –Marina Lumbierres –Silvia Gomez –Montse Pujol –Zahid Hussain