1. Pathophysiological Interactions between Sleep Apnea and Heart Failure T. Douglas Bradley, MD Director, Centre for Sleep Medicine and Circadian Biology, Toronto General Hospital and Toronto Rehabilitation Institute, University of Toronto

3. The prevalence of sleep apnea in HF patients Epidemiological study in Toronto 1997-2005 H Wang et al. JACC 2007 0 20 40 60 80 100 (%) 40% 37% 23% 20% 26% 54% CSA OSA No-SA AHI≥15AHI≥10

4. LEFT VENTRICULAR FAILURE:  CARDIAC OUTPUT  CARDIAC OUTPUT  LV FILLING PRESSURE LEFT VENTRICULAR FAILURE:  CARDIAC OUTPUT  CARDIAC OUTPUT  LV FILLING PRESSURE FatigueFatigue Pulmonary edema HypersomnolenceHypersomnolence PulmonaryafferentstimulationPulmonaryafferentstimulation HyperventilationHyperventilation CENTRAL APNEA  PaCO2 Sleep disruption  Cardiac O 2 supply supply  Cardiac O 2 demand demand  Cardiac O 2 supply supply  Cardiac O 2 demand demand ArousalArousal  Chemosensitivity  PaO 2  PaCO 2  PaO 2  PaCO 2  SNA  Catecholamines  HR  BP  SNA  Catecholamines  HR  BP

5. Lanfranchi et al. Circulation 1999 Mortality according to AHI and LA area

6. Pathophysiology of Non-hypercapnic CSA Respiratory control system instability: Hyperventilation and hypocapnia with PCO 2 close to apnea threshold Hyperventilation and hypocapnia with PCO 2 close to apnea threshold Central apnea occurs when PCO 2 falls below the apnea threshold (post-hyperventilation) Central apnea occurs when PCO 2 falls below the apnea threshold (post-hyperventilation) Increased chemosensitivity Increased chemosensitivity CNS state instability and arousals CNS state instability and arousals Pulmonary congestion and vagal irritant stimulation in CHF Pulmonary congestion and vagal irritant stimulation in CHF

7. Bradley and Phillipson. Clin Chest Med 1992 Effects of sleep on CO 2 responsiveness and set point and set point

8. Destabilizing Effect of State Changes and High Gain on Respiratory Control Bradley & Phillipson. Clin Chest Med 1992 High Gain (unstable) Low Gain (stable)

9. Xie et al. Am J Respir Crit Care Med 1994 Idiopathic CSA

10. Lorenzi-Filho G et al. Am J Respir Crit Care Med 1999

11. Lorenzi-Filho G et al. Am J Respir Crit Care Med 1999 AIR CO 2

12. Peripheral CO 2 Sensitivity Solin P et al. Am J Respir Crit Care Med 2001

13. Central CO 2 Sensitivity Solin P et al. Am J Respir Crit Care Med 2001

14. Lorenzi-Filho G et al. Am J Respir Crit Care Med 1999

15. RT Obstructive Sleep Apnea

16. Arousals Occurring After Onset of Ventilation in Patients with HF and CSA AS baseline

17. AK baseline

18. Baseline Subject AK

19. 3-Month Follow-up on CPAP (CSA suppressed) Subject AK

20. AS baseline

21. Xie et al. Am J Respir Crit Care Med 1994

22. Non-apneaOSACSAP PAP sys, mm Hg 31±2 32±248±2<0.001 PAP dias, mm Hg 13±213±121±1<0.001 PAP mean, mm Hg 20±220±133±2<0.001 PCWP, 12±112±123±1<0.001 CI, L/min/m 2 2.2±0.12.3±0.12.0±0.1NS Right Heart Catheter Data Solin et al. Circulation 1999

23. Lorenzi -Filho G et al. Eur Respir J 2002 PCWP (mm Hg)

24. Cheyne-Stokes Respiration with Central Sleep Apnea Definition: Central apneas alternating with hyperpneas in which there is a waxing and waning of V T Central apneas alternating with hyperpneas in which there is a waxing and waning of V T Waxing-waning V T and long periodic breathing cycle length originally described by Cheyne implies low cardiac output and distinguishes it from other forms of periodic breathing Waxing-waning V T and long periodic breathing cycle length originally described by Cheyne implies low cardiac output and distinguishes it from other forms of periodic breathing

25. Hall MJ et al. Am J Respir Crit Care Med 1996

29. Bradley and Floras. Circulation 2003 MSNA Oscillating in Time with Cheyne-Stokes Respiration

30. **** MSNA in Heart Failure with No Sleep Apnea, Obstructive or Central Sleep Apnea Spaak et al. Hypertension 2005

31. Leung RST et al. SLEEP 2004

35. CONCLUSIONS  VPBs occur more frequently during periods of CSR than during regular breathing in the same patients  VPBs occur preferentially during the hyperpneic phase of the CSR cycle  The frequency of VPBs is reduced by abolition of CSR but not by elimination of hypoxia  These effects are best explained by respiratory modulation of autonomic nervous system at the frequency of periodic breathing

36. Obstructive Sleep Apnea  Intrathoracic pressure  PO 2  PCO 2 ArousalArousal  Myocardial O 2 delivery O 2 delivery  Myocardial O 2 delivery O 2 delivery  SNA  Catechols  SNA  Catechols  BP  LV wall tension  Cardiac O 2 demand  LV wall tension  Cardiac O 2 demand Bradley & Floras. Lancet 2008 (on-line)  PNA Hypertension Hypertension Atherosclerosis Atherosclerosis Myocardial Ischemia Myocardial Ischemia LV hypertrophy and LV hypertrophy and failure failure Cardiac Arrhythmias Cardiac Arrhythmias Sudden death Sudden death Cerebrovascular disease Cerebrovascular disease Hypertension Hypertension Atherosclerosis Atherosclerosis Myocardial Ischemia Myocardial Ischemia LV hypertrophy and LV hypertrophy and failure failure Cardiac Arrhythmias Cardiac Arrhythmias Sudden death Sudden death Cerebrovascular disease Cerebrovascular disease  HR Oxidative stress Oxidative stress Dysglycemia Dysglycemia Inflammation Inflammation Endothelial Endothelial dysfunction dysfunction Oxidative stress Oxidative stress Dysglycemia Dysglycemia Inflammation Inflammation Endothelial Endothelial dysfunction dysfunction

37. Obstructive Sleep Apnea  Intrathoracic pressure  PO 2  PCO 2 ArousalArousal  Myocardial O 2 delivery O 2 delivery  Myocardial O 2 delivery O 2 delivery  SNA  Catechols  SNA  Catechols  BP  LV wall tension  Cardiac O 2 demand  LV wall tension  Cardiac O 2 demand Bradley & Floras. Lancet 2008 (on-line)  PNA Hypertension Hypertension Atherosclerosis Atherosclerosis Myocardial Ischemia Myocardial Ischemia LV hypertrophy and LV hypertrophy and failure failure Cardiac Arrhythmias Cardiac Arrhythmias Sudden death Sudden death Cerebrovascular disease Cerebrovascular disease Hypertension Hypertension Atherosclerosis Atherosclerosis Myocardial Ischemia Myocardial Ischemia LV hypertrophy and LV hypertrophy and failure failure Cardiac Arrhythmias Cardiac Arrhythmias Sudden death Sudden death Cerebrovascular disease Cerebrovascular disease  HR Oxidative stress Oxidative stress Dysglycemia Dysglycemia Inflammation Inflammation Endothelial Endothelial dysfunction dysfunction Oxidative stress Oxidative stress Dysglycemia Dysglycemia Inflammation Inflammation Endothelial Endothelial dysfunction dysfunction  CPAPCPAP

38. Brooks D et al. J Clin Invest 1997

39. Brooks D et al. J Clin Invest 1997

40. Parker JD et al. Am J Respir Crit Care Med 1999

41. 150 - 0 = 150 200 - 0 = 200 150 - (-50) = 200

42. RV IVS LV PW Leftward shift of the interventricular septum (IVS) during obstructed inspiration ( Shiomi T, et al Chest 1991) M-mode recording with esophageal pressure during obstructive apnea PES 

43. Prevalence of LVH (IVS or PW thickness > 12 mm) Non-OSAOSA 0 20 40 60 80100 P<0.016 15.4% 47.6% (%) Usui et al. Am J Respir Crit Care Med 2006

44. 0 2 4 6 8 10 12 14 0 2 4 6 8 10 1214IVSTPWT P<0.001 Non-OSA OSA Echocardiographic findings (mm)(mm) Usui et al. Am J Respir Crit Care Med 2006

45. Tkacova R et al. Circulation 1998 CONTROL CONTROLCPAPRECONTROL

46. HYPOTHESES In patients with CHF, treatment of coexisting OSA with CPAP will:  Reduce heart rate and systemic BP  Improve cardiac mechanics (LVEF)  Reduce sympathetic nervous system activity  Increase cardiac parasympathetic activity (i.e. high frequency heart rate variability [HF-HRV])  Improve baroreflex sensitivity (BRS)  Reduce ventricular ectopy  Improve quality of life

47. Characteristics of the subjects Control (n=12) CPAP (n=12) Control (n=12) CPAP (n=12) Age, yr 55.2±3.6 55.9±2.5 Sex, male:female 10:2 11:1 Body mass index, kg/m 2 32.3±2.5 30.4±1.8 Epworth Sleepiness Scale 5.7±0.9 6.8±0.7 Etiology, n Ischemic 6 6 Non- ischemic 6 6 Non- ischemic 6 6 NYHA Class 2.3±0.1 2.3±0.2 LVEF, % 28.5±1.8 25.0±2.8 Kaneko et al. NEJM 2003;348:1233-41

48. Blood Pressure and Heart Rate Control (n=12) CPAP (n=12) Control (n=12) CPAP (n=12) BL 1 mo p BL 1 mo p BL 1 mo p BL 1 mo p HR, bpm 67±4 67±4 ns 68±3 64±3.007* BPsys, mmHg 128±7 134±8 ns 126±6 116±5.020 † BPdi, mmHg 60±4 58±3 ns 62±4 59±2 ns * p=.089 and † p=.008 for between group comparisons * p=.089 and † p=.008 for between group comparisons Kaneko et al. NEJM 2003;348:1233-41

49. LVEF and Fractional Shortening Kaneko et al. NEJM 2003;348: 1233-41

50. SUBGROUP ANALYSES OF CPAP TREATED SUBJECTS Improvements in LVEF on CPAP were similar in:  subjects receiving (n=7) or not receiving (n=5)  -blockers (9.1  2.4%, P=0.008 and 8.5  2.1%, P=0.016, respectively).  subjects with ischemic (n=6) and non- ischemic dilated cardiomyopathy (n=6) (8.1  1.3%, P=0.022 and 9.7  3.0%, P=0.024, respectively). Kaneko et al. NEJM 2003;348:1233-41

51. Baseline 1 month later Control subject MSNAECG MSNAECG

52. Baseline 1 month later MSNAECG MSNAECG CPAP treated subject

53. MSNA bursts/min 0 30 50 70 90 Baseline1 monthBaseline1 month Control Group CPAP Group CPAP Group MSNA, bursts/min nsp < 0.001 p = 0.009 Usui et al. JACC 2005

54. Gilman et al. Clin Sci 2008

55. Control CPAP BRS Slope (ms/mm Hg) 0 5 10 15 20 NS p = 0.02 p = 0.008 Baseline 1 month Baseline 1 month BRS Slope 4.9 4.7 5.4 7.9

56. EEG ECG Ribcage Abdomen SUM SaO 2 % 100 1L Baseline On CPAP 1 month later Ryan et al. Thorax 2005 EEG ECG Ribcage Abdomen SUM SaO 2 % 1L 100 70

57. Ventricular Premature Beats/hr 0 1 2 3 Baseline 1 month Control Group CPAP Group CPAP Group Log 10 VPBs/hr ns p < 0.02 p < 0.04 Ryan et al. Thorax 2005

58. CONCLUSIONS In medically treated CHF patients with OSA, CPAP:  Reduces BPsys partly as a result of a decrease in sympathetic vasoconstrictor tone (MSNA)  Improves LV systolic function (LVEF)  Increase cardiac vagal activity (i.e. HF-HRV)  Improve baroreflex sensitivity (BRS)  Decreases the frequency of VPBs  OSA should be considered a therapeutic target in CHF

59. Hypotheses  CHF patients with untreated moderate to severe OSA (AHI≥15) will have a higher mortality rate than CHF patients with mild to no sleep apnea (AHI < 15; M-NSA)  CHF patients with treated OSA will have a lower mortality rate than HF patients with untreated OSA

60. 218 CHF Patients Underwent PSG From (1997-2005) 56 (26%) OSA (AHI  15) 45 (21%) CSA (AHI  15) ExcludedExcluded 117 (53%) M-NSA (AHI<15) 4 lost to follow-up 37 untreated OSA completed study 14 treated OSA completed study 113 M-NSA completed study 1 lost to follow-up 4 lost to follow-up 41 untreated OSA OSA 15 treated OSA OSA Wang et al JACC 2007

61. Results  During a mean and maximum follow-up period of 2.9  2.2 and 7.3 years, respectively, the mortality in the untreated OSA and M- NSA groups were 8.7 and 4.2 per 100 person yr, respectively (P = 0.029)  However, there were no deaths in the 14 treated OSA patients, and this was significantly lower than in the untreated OSA patients (P = 0.044) Wang et al JACC 2007

62. Treated OSA ( 0 deaths. 0%, P = 0.07 vs untreated OSA) M-NSA ( 14 deaths, 12% ) Untreated OSA ( 9 deaths, 24%, P= 0.029 vsM- NSA) Survival in HF Patients with Treated and Untreated OSA Wang et al. JACC 2007

64. Multivariable Hazards Ratios for Mortality Rate Wang et al JACC 2007

65. CONCLUSIONS  These findings suggest that OSA has adverse effects on survival in patients with CHF, that appear to be at least partially reversible with treatment by CPAP  However, because of the observational nature of the study, they fall short of proving mortality benefit in CHF patients with OSA

66. Is it scientifically, medically and ethically justifiable to test the effects of CPAP on morbidity and mortality in CHF patients with OSA in a RCT?

67. Subjects Inclusion Criteria:  Patients with chronic HF due to ischemic or nonischemic dilated cardiomyopathy, on optimal HF therapy for at least 6 months  Left ventricular ejection fraction (LVEF)  45% at rest  New York Heart association [NYHA] Class 2-4

68. Subjects Exclusion criteria:  Unstable angina, myocardial infarction or cardiac surgery within the previous 3 months  Prior history of sleep apnea  Presence of predominantly central sleep apnea on the sleep study

69. Methods  Prospective observational study  Eligible patients (LVEF  45%) from the Mount Sinai HF Clinic enrolled between Sept. 1, 1997 and Dec. 1, 2004 underwent polysomnography (PSG) and followed until Jan. 1, 2005  Patients divided into those with NSA and those with OSA defined as an AHI of  15 per hr of sleep of which  50 % were obstructive

70. Methods  Patients with OSA stratified into those who were untreated (did not receive CPAP or used it < 3 months), and those who were treated (used CPAP for  3 months)

71. Outcome  Cumulative mortality rate from the time of the PSG until January 1, 2005  The status of all subjects was ascertained from the patients’ medical records, or by a telephone call to them, their families, or their referring physicians

72. Results  During a mean and maximum follow-up period of 2.9  2.2 and 7.3 years, respectively, the mortality in the untreated OSA and NSA groups were 8.7 and 4.2 per 100 person yr, respectively (P = 0.029)  However, there were no deaths in the 14 treated OSA patients, and this was significantly lower than in the untreated OSA patients (P = 0.044) Wang et al JACC (In Press)

73. Tkacova R et al. Circulation 2001 PCO 2 = 41.2 mm Hg PCO 2 = 38.8 mm Hg 30 sec Overnight Shift from Obstructive to Central Apnea

74. Tkacova et al. Circulation 2000 Overnight Shift from Obstructive to Central Apnea

75. Overnight Changes in Transcutaneous PCO 2 Tkacova et al. Circulation 2000

76. Changes in Lung to Ear Circulation Time and Cycle Length from Obstructive to Central Apneas

77. CONCLUSIONS In CHF patients: Overnight shift from OSA to CSA is related to a fall in PCO 2Overnight shift from OSA to CSA is related to a fall in PCO 2 Overnight increase in periodic breathing cycle length and circulation time suggest a decrease in cardiac outputOvernight increase in periodic breathing cycle length and circulation time suggest a decrease in cardiac output Therefore a fall in PCO 2 is likely due to increasing pulmonary congestion 2 0 to increased venous return while recumbent and to decreased cardiac output due to cardiovascular stresses of OSATherefore a fall in PCO 2 is likely due to increasing pulmonary congestion 2 0 to increased venous return while recumbent and to decreased cardiac output due to cardiovascular stresses of OSA

78. Differences of BMI between HF patients and the GP according to the AHI ( † p<0.05, †† p<0.01) Body-mass index 20 25 30 35 40 AHI < 5 AHI  5-15AHI  15 HF GP †† Arzt M et al. Arch Int Med 2006

79. 0 10 20 30 40 50 60 70 3202802402001601208040040 Change in LFV (ml) AHI r = -0.802 p < 0.001 n = 23 Redolfi S et al. Am J Respir Crit Care Med 2008

80. AHI (no./hr) Change in LFV (ml) 0 10 20 30 40 50 60 70 100-0-100-200-300-400-500-600-700 CSA OSA NSA Correlation between change in LFV and AHI among types of sleep apnea In healthy men (AJRCCM, in Press) R = -0.88, p<0.001 R = -0.90, p<0.001 N = 48 Yumino D et al. AHA Abstract 2008

81. OSAOSA Proposed Interactions between OSA and CHF: A Two-Way Street

82. OSAOSA Hypoxia  BP,  SNA Hypoxia Proposed Interactions between OSA and CHF: A Two-Way Street

83. OSAOSA CHFCHF Hypoxia  BP,  SNA Hypoxia Proposed Interactions between OSA and CHF: A Two-Way Street

84. OSAOSA CHFCHF Hypoxia  BP,  SNA Hypoxia Recumbent UA Edema Recumbent Proposed Interactions between OSA and CHF: A Two-Way Street

85. OSAOSA CHFCHF Hypoxia  BP,  SNA Hypoxia Recumbent UA Edema Recumbent Proposed Interactions between OSA and CHF: A Two-Way Street

86. OSAOSA WorseningCHFWorseningCHF Hypoxia  BP,  SNA Hypoxia Proposed Interactions between OSA, CSA and CHF: A Shifting Spectrum

87. OSAOSA WorseningCHFWorseningCHF Hypoxia  BP,  SNA Hypoxia PulmonaryEdemaPulmonaryEdema Proposed Interactions between OSA, CSA and CHF: A Shifting Spectrum

88. OSAOSA WorseningCHFWorseningCHF Hypoxia  BP,  SNA Hypoxia PulmonaryEdemaPulmonaryEdema Proposed Interactions between OSA, CSA and CHF: A Shifting Spectrum VagalStimulationVagalStimulation

89. OSAOSA WorseningCHFWorseningCHF Hypoxia  BP,  SNA Hypoxia PulmonaryEdemaPulmonaryEdema Proposed Interactions between OSA, CSA and CHF: A Shifting Spectrum VagalStimulationVagalStimulationHyperventilation  PCO 2 Hyperventilation

90. CSACSA WorseningCHFWorseningCHF Hypoxia  BP,  SNA Hypoxia PulmonaryEdemaPulmonaryEdema Proposed Interactions between OSA, CSA and CHF: A Shifting Spectrum VagalStimulationVagalStimulationHyperventilation  PCO 2 Hyperventilation

91. Aknowledgments Colleagues  John Floras  Sandy Logan  John Parker  Gary Newton  Susanna Mak  Clodagh Ryan Fellows  Michael Arzt  Matthew Gilman  Yasuyuki Kaneko  Stefania Redolfi  Pimon Ruttanaumpawan  Kengo Usui  Hanqiao Wang  Dai Yumino