Sleep Apnea & Cardiovascular Disease: What Have We Learned Over The Last 25 Years

1. Sleep Apnea & Cardiovascular Disease: What Have We Learned Over The Last 25 Years Stuart F. Quan, M.D. Division of Sleep Medicine Harvard Medical School

2. Overview Obstructive sleep apnea-- a bit of history OSA and CVD: Biological plausibility/physiology Time machine to ~1970s-80s: What we knew then Present time: What we know now Current knowledge gaps Clinical Trials: Opportunities to Address Knowledge Gaps

3. Sleep Apnea in Antiquity • Dionysius……….. So his physicians prescribed he should get some fine needles, exceedingly long, which they thrust through his ribs and belly whenever he happened to fall into a deep sleep…then he would be thoroughly aroused.

4. Historical Medical Accountsof Sleep Apnea When a person, especially advanced in years, is lying on his back in heavy sleep and snoring loudly, it very commonly happens that every now and then the inspiration fails to overcome the resistance in the pharynx, of which stridor or snoring is the audible sign, and there will be perfect silence through two, three, or four respiratory periods, in which there are ineffectual chest movements; finally air enters with a loud snort, after which there are several compensatory deep inspirations….. Broadbent, WH Lancet, 1877

6. Burwell et al, Am J Med 1956

7. Why Might OSA be a Risk Factor for CVD?

8. Physiological Consequences Intrathoracic Pressure Changes Preload, afterload and transmural pressure Trigger baroreceptors Hypoxemia, hypercapnia, and arousal SNS overdrive Systemic and Pulmonary Vasoconstriction Abnormal HRV and increased HR

9. Negative Intrathoracic Pressure Swings • Increased preload • Increased LV afterload (increased transmural pressure) • Impaired diastolic function • Atrial and aortic enlargement Tracheal Pressure (mmHg) LV Pressure (mmHg) LV Transmural Pressure (mmHg) LV End Systolic Volume (mL) Parker Am J Respir Crit Care Med 1999; 160: 1888-96.

10. State of Affairs 1970’s-1980’s or otherwise “What I knew when I was an intern?”

11. 1970s and 1980s

13. Circa ~1980s Ann Intern Med. 1985 Aug;103(2):190-5.

14. Snoring and Hypertension in San Marino N=5713 Lugaresi et al, Sleep 1980; 3:221-4

15. Snoring and Hypertension:Finnish Twin Study N=3847 N=3664 KOSKENVUO et al, Lancet, 1985

16. Koskenvuo M, BMJ, 1987 N=4388 men

17. Boudoulas H, et al. J Med 1983:14:223-38

18. Effect of AI on Mortality He et al, Chest 94:9-14, 1988

19. Partinen et al Chest 1988

20. No Increase in Mortality in OSA PatientsCirca 1988 • 91 patients with treated and untreated OSA • 35 patients with symptoms of OSA, but negative PSG • Retrospective f/u for 7-98 months • Mortality • 4/35 (11.4%) Controls and 9/91 (9.8%) OSA patients Gonzalez-Rothi et al, Chest, 1988

21. Acute Hemodynamic Changes with OSA Cyclical increases in ABP Cyclical increases in PAP Apnea Schroeder et al, in Sleep Apnea Syndromes, 1978

22. Cardiovascular Pathogenesis of OSA--1976 Tilkian et al, Ann Intern Med 1976

23. State of Affairs 2011 or otherwise “What do wise men and women know now?”

24. SDB and Incident HypertensionAdjusted Odds Ratios for Hypertension at Follow-up Odds Ratio Peppard et al, N Engl J Med 2000; 342:1378

27. Gottlieb et al, Circulation 2010

28. Incident CHD and OSA Although there was an increased risk of incident CHD in clinic-derived samples, those who were treated with CPAP had the same risk as controls Treated with CPAP 12 year follow-up All Men N=1651 No CPAP Marin, Lancet 2005

29. Major Adverse Cardiovascular Events (MACE) In Patients with CAD and OSA • 407 consecutive patients with CAD • 38% with ODI >5 • Increased 5-year MACE • ♂ AHI ≥10: 28% vs. 16% • ♀ AHI ≥ 10: 20% vs. 14% Mooe T AJRCCM 2001:164

30. OSA Increases Risk of MACE and Re-stenosis After Percutaneous Coronary Intervention 89 consecutive pts with ACS followed for mean 227 days, 57% OSA (AHI>10) Higher CRP but otherwise comparable MACE in OSA vs non-OSA: 23.5% vs. 5.3% HR: 11.6 (2.2,62.2) Quantitative Coronary Arteriography Late Loss: 1.28 vs 0.69 mm MLD Binary restenosis: 37% vs 15% Yumino, D. AJC 2007:99

32. Gottlieb et al, Circulation 2010

33. All Cause Mortality: Busselton Health Study* RDI ≥15/hr, 6 deaths, HR = 6.24, 95% CL 2.01, 19.39 *N=380 Marshall et al, Sleep. 2008 August 1; 31(8): 1079–1085

34. All Cause Mortality: Wisconsin Sleep Cohort* *N=1496, CPAP Treated Excluded Young et al, Sleep. 2008 August 1; 31(8): 1071–1078

35. Sleep Apnea and All-Cause Mortality in SHHS 1.0 0.9 Survival Probability Apnea-hypopnea index (events/hr) 0.8 < 5.0 5.0 – 14.9 15.0 – 29.9 > 30.0 0.7 0 1 2 3 4 5 6 7 8 9 10 Years Numbers at risk: 6294 6205 6110 6001 5868 5732 5566 5411 4756 2357 300 Total Deaths: 0 59 143 241 359 478 616 757 875 989 1046 Punjabi et al, PLOS Med 2009

36. Nocturnal Predilection for Sudden Cardiac Death in OSA Gami AS NEJM 2005:352 N=112

37. Adjusted Odds Ratio of Nocturnal Arrhythmia By Sleep Apnea (AHI>30) In SHHS Adjusted OR 95% CI Atrial Fibrillation 4.5 1.2, 17 CVE or NSVT 1.8 1.2, 2.8 AF or NSVT 3.7 1.7, 8.0 Odds > 7.0 for those 50 to 60 years old MehraR AJRCCM 2006 Case-Cross-Over Study: Relative Risk of a Paroxysmal Arrhythmia Occurring After an Apnea/Hyponea:17 Monahan JAAC 2008

38. Absolute Risk of Nocturnal Arrhythmias In Association with Apneas in SHHS • 1 excess episode of PAF or NSVT for every 1000 hours of sleep or 40000 respiratory disturbances • For a person with moderate Sleep Apnea (AHI = 25 events/hour) sleeping 8 hours/night • 1 excess arrhythmia in 7 months

39. Recurrence of AFib (12 mo) P=0.013 P=0.009 Sleep apnea – CPAP (n=12) Sleep apnea – no CPAP (n=27) Controls – no sleep study 82 Pt (%) 53 42 Untreated pt – mean nocturnal fall in O2 sat • Recurrence – 18% • No recurrence – 8% P=0.034 Obstructive Sleep Apnea and Recurrence of AFib 118 pt – successful cardioversion Kanagala and Somers CP1073966-6

40. OSA and CVD Mechanistic Observations

41. OSA and Cardiac Morphology Chami et al. Circulation. 2008. 117:2599 • SHHS (n=2058), AHI < 5 vs AHI > 30 • Adjusted LVMI 7% higher: 41. 3 vs 44.1 g/m 2.7 • LVH: Odds Ratio: 1.78(1.14, 2.79, 95% CI) • Increased LVIDd • Eccentric Hypertrophy • Stronger associations with hypoxemia indices vs AHI

42. Impaired LV Diastolic Function • Cross-sectional Findings • 15 controls; 27 OSA (Avg AHI 44) • No co-morbidities • OSA: 56% abnormal LV • Longer IVRT and DT and lower E/A 41% Impaired Relaxation • 12 week intervention • CPAP vs sham • Improved E/A, IVRT, mitral DT • No change in BP, catecholamines Arias MA Circulation 2005:112:375

43. Prevalence of Metabolic Syndrome in OSA vs non OSA Patients * * * Parish et al, J Clin Sleep Med 2007;3: 467–472

46. Sleep Apnea and Oxidative Stress Recurrent hypoxia and reoxygenation Increase flux of free radicals Induce endothelin expression Suppress NO generation Induce local vasoconstriction and changes in vascular permeability Results in oxidative stress causing generation of ROS (superoxide) Prabhakar NR, JAP, 2001

47. Pro-Inflammatory and Atherogenic Effects Upregulation of inflammatory mediators IL6, sIL6R, IL-8, TNFα, CRP, (NF-Kappa B) Enhanced thrombotic potential PAI-1, P-selectin, fibrinogen, VEGF Oxidation of serum proteins and lipids Endothelial dysfunction Insulin Resistance and Dyslipidemia Hansson NEJM 352: 2005

48. SavranskyAJRCCM 2007: 177 SavranskyCirc Res 2008:103 Loresnzi-Filho AJRCCM 2007:175 Intermittent Hypoxia SREBP-1 ↑hepatic HIF-1 Hypoxic inducible factor 1 sterol regulatory element–binding protein-1 + high fat diet Dyslipidemia TNFα gene Atherosclerosis SCD-1 stearoyl-Coenzyme A desaturase 1 IA, Nldiet CIH, Nl diet Mice: CIH + fat diet> ↑ 70% SCD-1 mRNA, VLDL, atherosclerosis (reversed by blocking SCD-1) Est 12 wks CIH in M~1 yr HC Diet in F Humans: hepatic SCD-1 α overnight hypoxemia (r=.68) IA, H Fat CIH, H Fat

49. PHYSIOLOGIC PERTURBATIONS CLINICAL OUTCOMES INTERMEDIATE MECHANISMS Chronic Intermittent Hypoxia Ventilatory Overshoot Hyperoxia Increased Sympathetic Nervous System Activity Intrathoracic Pressure Swings Hypercapnia Increased Arousals Reduced Sleep Duration Increased Inflammation Increased Oxidative Stress Metabolic Dysfunction/ Insulin Resistance Hyper-coaguability Endothelial Dysfunction Autonomic Dysfunction Systemic Hypertension Atherosclerosis Diastolic Dysfunction Congestive Heart Failure Stroke Increased Mortality and Sudden Death Cardiac Arrhythmias SLEEP-Apnea Mehra R Curr Resp Med Rev 2007

50. OSA and CVD:Knowledge Gaps Hypertension Does treatment of OSA reduce incident hypertension? In whom does treatment of OSA significantly lower BP? Coronary Heart Disease/CHF/Stroke Does adverse impact of OSA affect only men? Does treatment of OSA decrease risk of CHD/CHF/Stroke? What treatments will be effective? Mortality Does treatment of OSA decrease mortality risk?