1. Sleep Disordered Breathing and Cardiovascular Disease
Sleep Disordered Breathing and Cardiovascular Disease Obstructive Sleep Apnea and Cardiovascular Risk
David P. White, MD, Chief Medical Officer, Philips Respironics
Professor of Medicine Harvard Medical School
September 10, 2009

2. Sleep and Cardiovascular Disease

4. OSA and Cardiovascular Disease
Intermediate Outcomes
Hypertension
Diabetes
Hard Outcomes
Myocardial infarction
Stroke
Congestive Heart Failure
Death

5. OSA and Cardiovascular Disease
Intermediate Outcomes
Hypertension
Diabetes
Hard Outcomes
Myocardial infarction
Stroke
Congestive Heart Failure
Death

6. Systemic Hypertension and Obstructive Sleep Apnea
Human/animal physiologic data
Human epidemiologic data
OSA treatment trials

7. Hedner et al J Hypertension, 1988
Muscle nerve sympathetic activity
Blood pressure
(mmHg)
Heart rate
(mine-1)
Respiratory
movements
Nose
Air flow
Mouth
Oxygen saturation
SaO2 (%)

8. Somers et al J Clin Invest, 1995
AWAKE
NORMAL
OSA
10 sec

9. J Clin Invest
Obstructive Sleep Apnea as a Cause of Systemic Hypertension
Evidence from a Canine Model
Dina Brooks, Richard L. Horner, Louise F. Kozar, Caroline L. Render-Teixeira, and Eliot A. Phillipson
Department of Medicine, University of Toronto, Toronto, Ontario, Canada, M5S 1A8

10. JCI 1997 Brooks et al Protocol 4 dogs studied.
Sleep apnea induced mechanically for 1-3 months.
Arousal induced to sound recurrently for 1-3 months.
Mean BP assessed frequently awake and asleep.

11. Mean Nighttime BP (% Control)
Brooks et al. JCI 1997
110
Mean Nighttime BP (% Control)
100 90
control
1-2 wk
>4 wk
First
Night

12. Mean Nighttime BP (% Control)
Brooks et al. JCI 1997
130
120
Mean Nighttime BP (% Control)
110
100 90
control
1-2 wk
2-5 wk
>5 wk
1-3 wk
>5 wk

14. New England Journal of Medicine, 2000 Peppard et al
The Apnea-Hypopnea Index at Base Line

15. 24 Hour BP Before and After 1 Month of CPAP, Therapeutic Versus Sub-therapeutic (Pepperell et al, Lancet 359:204, 2002)
Before Treatment
AfterTreatment
Mean blood pressure (mmHg)
Mean blood pressure (mmHg)
Time from wake and sleep onset (hours)
Time from wake and sleep onset (hours)

16. Results: Pooled Analysis Systolic Blood Pressure
-50
-40
-30
-20
-10 10
Usui 2005
Barnes 2004
Kaneko 2003
Becker 2002
Pepperell 2002
Barnes 2002
Barbe 2001
Monasterio 2001
Overall
Lung 2007
Point estimates and 95% confidence intervals of each study are shown.
A negative value indicates that CPAP reduced blood pressure compared to control.

17. Results: Pooled Analysis Diastolic Blood Pressure
-30
-20
-10 10
Usui 2005
Barnes 2004
Kaneko 2003
Becker 2002
Pepperell 2002
Barnes 2002
Barbe 2001
Monasterio 2001
Overall
Lung 2007
Point estimates and 95% confidence intervals of each study are shown.
A negative value indicates that CPAP reduced blood pressure compared to control.

18. Effect of CPAP on Blood Pressure
MAP
systolic
diastolic 15 10 * * * 5
mmHg -5
-10
-15
-20
-25
Figure 2. Changes in blood pressure with effective (closed bars) and subtherapeutic (open bars) nCPAP. “Significant difference. MAP indicates mean arterial blood pressure; systolic, systolic blood pressure; and diastolic, diastolic blood pressure. MAP, P=0.01: systolic blood pressure, P=0.04; diastolic blood pressure, P<0.005.
Becker et al, 2003

19. OSA and Cardiovascular Disease
Intermediate Outcomes
Hypertension
Diabetes
Hard Outcomes
Myocardial infarction
Stroke
Congestive Heart Failure
Death

20. Alterations in Glucose Disposal in Sleep-disordered Breathing
Naresh M. Punjabi1 and Brock A. Beamer1
1Department of Medicine, John Hopkins University School of Medicine, Baltimore, Maryland

21. Punjabi et al, AJRCCM 2009

22. Punjabi et al, AJRCCM 2009

23. Punjabi et al, AJRCCM 2009

24. Arch of Intern Med 2005
Type 2 Diabetes, Glycemic Control, and Continuous Positive Airway Pressure in Obstructive Sleep Apnea
Ambika R. Babu, MD; James Herdegen, MD; Leon Fogelfeld, MD; Susan Shott, PhD; Theodore Mazzone, MD

25. Babu et al Arch of Intern Med 2005

26. Thorax 2007
Effect of CPAP on insulin resistance and HbA1c in men with obstructive sleep apnoea and type 2 diabetes
Sophie D West, Debby J Nicoll, Tara M Wallace, David R Matthews, John R Stradling

27. West SD. et al Thorax 2007

28. West SD. et al Thorax 2007

29. OSA and Cardiovascular Disease
Intermediate Outcomes
Hypertension
Diabetes
Hard Outcomes
Myocardial infarction
Stroke
Congestive Heart Failure
Death

30. Sleep-disordered Breathing and Cardiovascular Disease
Cross-sectional Results of the Sleep Heart Health Study
EYAL SHAHAR, CORALYN W. WHITNEY, SUSAN REDLINE, ELISA T. LEE, ANNE B. NEWMAN, F. JAVIER NIETO, GEORGE T. O’CONNOR, LORI L. BOLAND, JOSEPH E. SCHWARTZ, and JONATHAN M. SAMET for the Sleep Heart Health Study Research Group

31. Am J Respir Crit Care Med - 2000
Adjusted* Relative Odds (95% Confidence Interval) of Prevalent Coronary Heart Disease, Heart Failure, or Stroke, According to Quartile of the Apnea-Hypopnea Index
Quartile I II
III IV
P Value*
Coronary heart disease Full Model
1.0
1.01 (0.77–1.32)
1.20 (0.92–1.57)
1.22 (0.93–1.59)
0.08
Coronary hear t disease Parsimonious Model
0.92 (0.71–1.20)
1.20 (0.93–1.54)
1.27 (0.99–1.62)
0.004
Heart Failure Full Model
1.19 (0.56–2.53)
1.96 (0.99–3.90)
2.20 (1.11–4.37)
0.008
Heart Failure Parsimonious Model
1.13 (0.54–2.39)
1.95 (0.99–3.83)
2.38 (1.22–4.62)
0.002
Stroke Full Model
1.24 (0.76–2.01)
1.38 (0.86–2.83)
1.55 (0.96–2.50)
0.06
Stroke Parsimonious Model
1.15 (0.72–1.83)
1.42 (0.91–2.21)
1.58 (1.02–2.46)
0.03

32. Lancet
Long-term cardiovascular outcomes in men with obstructive sleep apnoea-hypopnoea with or without treatment with continuous positive airway pressure: an observational study
Jose M Marin, Santiago J Carrizo, Eugenio Vicente, Alvar G N Agusti

33. Marin et al Lancet2005

34. Marin et al – Lancet, 2005

35. OSA and Cardiovascular Disease
Intermediate Outcomes
Hypertension
Diabetes
Hard Outcomes
Myocardial infarction
Stroke
Congestive Heart Failure
Death

36. Investigating the Relationship Between
Articles
Investigating the Relationship Between
Stroke and Obstructive Sleep Apnea
Mark E. Dyken, MD; Virend K. Somers, MD, DPhil;
Thoru Yamada, MD; Zong-Ying Ren, MD
M. Bridget Zimmerman, PhD

37. Dyken et al Stroke 1996 Stroke % with OSA All Subjects Men Women
Non- Stroke
Stroke
77%
71%
64%
% with OSA
23%
19%
14%
Stroke
All Subjects
Men
Women
Copyright ©1996 American Heart Association

38. Am J Respir Crit Care Med - 2000
Adjusted* Relative Odds (95% Confidence Interval) of Prevalent Coronary Heart Disease, Heart Failure, or Stroke, According to Quartile of the Apnea-Hypopnea Index
Quartile I II
III IV
P Value*
Coronary heart disease Full Model
1.0
1.01 (0.77–1.32)
1.20 (0.92–1.57)
1.22 (0.93–1.59)
0.08
Coronary hear t disease Parsimonious Model
0.92 (0.71–1.20)
1.20 (0.93–1.54)
1.27 (0.99–1.62)
0.004
Heart Failure Full Model
1.19 (0.56–2.53)
1.96 (0.99–3.90)
2.20 (1.11–4.37)
0.008
Heart Failure Parsimonious Model
1.13 (0.54–2.39)
1.95 (0.99–3.83)
2.38 (1.22–4.62)
0.002
Stroke Full Model
1.24 (0.76–2.01)
1.38 (0.86–2.83)
1.55 (0.96–2.50)
0.06
Stroke Parsimonious Model
1.15 (0.72–1.83)
1.42 (0.91–2.21)
1.58 (1.02–2.46)
0.03

39. Obstructive Sleep Apnea as a Risk Factor for Stroke and Death
H. Klar Yaggi, M.C., M.P.H., John Concato, M.D., M.P.H.,
Walter N. Kernan, M.D., Judith H. Lichtman, Ph.D., M.P.H.,
Lawrence M. Brass, M.D., and Vahid Mohsenin, M.D.

40. Yaggi et al – N Engl J Med, 2005

41. Yaggi et al – N Engl J Med, 2005

42. Yaggi et al – N Engl J Med, 2005

43. OSA and Cardiovascular Disease
Intermediate Outcomes
Hypertension
Diabetes
Hard Outcomes
Myocardial infarction
Stroke
Congestive Heart Failure
Death

44. Am J Respir Crit Care Med - 2000
Adjusted* Relative Odds (95% Confidence Interval) of Prevalent Coronary Heart Disease, Heart Failure, or Stroke, Accorindg to Quartile of the Apnea-Hypopnea Index
Quartile I II
III IV
P Value*
Coronary heart disease Full Model
1.0
1.01 (0.77–1.32)
1.20 (0.92–1.57)
1.22 (0.93–1.59)
0.08
Coronary hear t disease Parsimonious Model
0.92 (0.71–1.20)
1.20 (0.93–1.54)
1.27 (0.99–1.62)
0.004
Heart Failure Full Model
1.19 (0.56–2.53)
1.96 (0.99–3.90)
2.20 (1.11–4.37)
0.008
Heart Failure Parsimonious Model
1.13 (0.54–2.39)
1.95 (0.99–3.83)
2.38 (1.22–4.62)
0.002
Stroke Full Model
1.24 (0.76–2.01)
1.38 (0.86–2.83)
1.55 (0.96–2.50)
0.06
Stroke Parsimonious Model
1.15 (0.72–1.83)
1.42 (0.91–2.21)
1.58 (1.02–2.46)
0.03

45. OSA and Cardiovascular Disease
Intermediate Outcomes
Hypertension
Diabetes
Hard Outcomes
Myocardial infarction
Stroke
Congestive Heart Failure
Death

46. Marin et al – Lancet, 2005

47. Yaggi et al – N Engl J Med, 2005

48. Sleep 2008
Sleep Disordered Breathing and Mortality: Eighteen-Year Follow-up of the Wisconsin Sleep Cohort
Terry Young, PhD1; Laurel Finn, MS1; Paul E. Peppard, PhD1; Mariana Szklo-Coxe, PhD1; Diane Austin, MS1; F. Javier Nieto, PhD1; Robin Stubbs1, BS; K. Mae Hla, MD2

49. All-cause mortality Hazard Ratio Cardiovascular mortality
Young T et al Sleep 2008
Table 3—Mortality Risk with Sleep-Disordered Breathing
(n = 1522): Adjusted Hazard Ratios*
Baseline AHI
Category
All-cause mortality Hazard Ratio
(95% CI)
Cardiovascular mortality
Hazard Ratio
None: 0 - < 5
Reference
Mild: 5 - < 15
1.6 (0.9, 2.8)
1.8 (0.7, 4.9)
Moderate: 15 - < 30
1.4 (0.6, 3.3)
1.2 (0.3, 5.8)
Severe: > 30
3.0 (1.4, 6.3)
2.9 (0.8, 10.0)
P trend = 0.008
P trend = 0.12
*adjusted for age, age2, sex, body mass index, and body mass index2

50. PLoS Medicine 2009
Sleep-Disordered Breathing and Mortality: A Prospective Cohort Study
Naresh M. Punjabi1*, Brian S. Caffo1, James L. Goodwin2, Daniel J. Gottlieb3, Anne B. Newman4, George T.O’Connor5, David M. Rapoport6, Susan Redline7, Helaine E. Resnick8, John A. Robbins9, Eyal Shahar2,Mark L. Unruh4, Jonathan M. Samet10

51. Punjabi et al PLoS Medicine 2009

52. OSA and Cardiovascular Disease
Intermediate Outcomes
Hypertension
Diabetes
Hard Outcomes
Myocardial infarction
Stroke
Congestive Heart Failure
Death

53. Sleep Apnea CardioVascular End Points
5,000 patients with OSA plus documented:
- coronary artery disease
- cerebrovascular disease
100 sites (China, India, and Australia)
Patients randomized to either:
- Standard medical care
- Standard medical care + CPAP

54. Sleep Apnea CardioVascular End Points
Outcomes:
- Subsequent MI’s and strokes
- Survival

55. Sleep and Cardiovascular Disease