Pathophysiological Interactions Pathophysiological Interactions between Sleep Apnea and between Sleep Apnea and

Heart FailureHeart Failure

T. Douglas Bradley, MDT. Douglas Bradley, MDDirector, Centre for Sleep Medicine and Circadian Biology,Director, Centre for Sleep Medicine and Circadian Biology,

Toronto General Hospital and Toronto Rehabilitation Institute, Toronto General Hospital and Toronto Rehabilitation Institute, University of Toronto University of Toronto

The prevalence of sleep apnea in HF patients The prevalence of sleep apnea in HF patients Epidemiological study in Toronto 1997-2005 Epidemiological study in Toronto 1997-2005

H Wang et al. JACC 2007 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

LEFT VENTRICULAR FAILURE:LEFT VENTRICULAR FAILURE:

CARDIAC OUTPUTCARDIAC OUTPUT LV FILLING PRESSURELV FILLING PRESSURE

LEFT VENTRICULAR FAILURE:LEFT VENTRICULAR FAILURE:

CARDIAC OUTPUTCARDIAC OUTPUT LV FILLING PRESSURELV FILLING PRESSURE

FatigueFatigueFatigueFatigue

Pulmonary edemaPulmonary edemaPulmonary edemaPulmonary edema

HypersomnolenceHypersomnolenceHypersomnolenceHypersomnolence

PulmonaryPulmonaryafferentafferent

stimulationstimulation

PulmonaryPulmonaryafferentafferent

stimulationstimulation

HyperventilationHyperventilationHyperventilationHyperventilation

CENTRAL APNEACENTRAL APNEACENTRAL APNEACENTRAL APNEA

PaCO2PaCO2 PaCO2PaCO2

Sleep disruptionSleep disruptionSleep disruptionSleep disruption

Cardiac OCardiac O22

supplysupply Cardiac OCardiac O22

demanddemand

Cardiac OCardiac O22

supplysupply Cardiac OCardiac O22

demanddemandArousalArousalArousalArousal

ChemosensitivityChemosensitivity ChemosensitivityChemosensitivity

PaOPaO22

PaCOPaCO22

PaOPaO22

PaCOPaCO22

SNASNA CatecholaminesCatecholamines HRHR BPBP

SNASNA CatecholaminesCatecholamines HRHR BPBP

Pathophysiology of Pathophysiology of Non-hypercapnic CSANon-hypercapnic CSA

Respiratory control system instability:Respiratory control system instability: Hyperventilation and hypocapnia with PCOHyperventilation and hypocapnia with PCO22 close close

to apnea threshold to apnea threshold Central apnea occurs when PCOCentral apnea occurs when PCO22 falls below the falls below the

apnea threshold (post-hyperventilation)apnea threshold (post-hyperventilation) Increased chemosensitivityIncreased chemosensitivity CNS state instability and arousalsCNS state instability and arousals Pulmonary congestion and vagal irritant Pulmonary congestion and vagal irritant

stimulation in CHFstimulation in CHF

Bradley and Phillipson. Clin Chest Med 1992

Effects of sleep on Effects of sleep on COCO2 2 responsivenessresponsiveness

and set pointand set point

Xie et al. Am J Respir Crit Care Med 1994

Idiopathic CSA Idiopathic CSA

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

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

AIRAIR COCO22

Peripheral COPeripheral CO22 Sensitivity Sensitivity

Solin P et al. Am J Respir Crit Care Med 2001

Central COCentral CO22 Sensitivity Sensitivity

Solin P et al. Am J Respir Crit Care Med 2001

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

RT

Obstructive Sleep Apnea

Arousals Occurring After Onset of Ventilation in Patients with HF and CSA

AS baseline

AK baseline

Baseline

Subject AK

3-Month Follow-up on CPAP (CSA suppressed)

Subject AK

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

Non-apneaNon-apnea OSAOSA CSACSA P

PAP sys,PAP sys,mm Hgmm Hg

3131±2±2 32±232±2 48±248±2 <0.001<0.001

PAP dias,PAP dias,mm Hgmm Hg

13±213±2 13±113±1 21±121±1 <0.001<0.001

PAP mean,PAP mean,mm Hgmm Hg

20±220±2 20±120±1 33±233±2 <0.001<0.001

PCWP,PCWP,mm Hgmm Hg

12±112±1 12±112±1 23±123±1 <0.001<0.001

CI,CI, L/min/mL/min/m22 2.2±0.12.2±0.1 2.3±0.12.3±0.1 2.0±0.12.0±0.1 NSNS

Right Heart Catheter DataRight Heart Catheter Data

Solin et al. Circulation 1999

Lorenzi -Filho G et al. Eur Respir J 2002

PCWP (mm Hg)PCWP (mm Hg)

Cheyne-Stokes Respiration with Cheyne-Stokes Respiration with Central Sleep ApneaCentral Sleep Apnea

Definition:Definition: Central apneas alternating with hyperpneas Central apneas alternating with hyperpneas

in which there is a waxing and waning of Vin which there is a waxing and waning of VTT

Waxing-waning VWaxing-waning VTT and long periodic and long periodic breathing cycle length originally described breathing cycle length originally described byby CheyneCheyne implies low cardiac output and implies low cardiac output and distinguishes it from other forms of periodic distinguishes it from other forms of periodic breathing breathing

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

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

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

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

Bradley and Floras. Circulation 2003

MSNA Oscillating in Time with Cheyne-Stokes Respiration

*

*

MSNA in Heart Failure with No Sleep Apnea, Obstructive MSNA in Heart Failure with No Sleep Apnea, Obstructive

or Central Sleep Apneaor Central Sleep Apnea

Spaak et al. Hypertension 2005

Leung RST et al. SLEEP 2004

Leung RST et al. SLEEP 2004

Leung RST et al. SLEEP 2004

CONCLUSIONS

VPBs occur more frequently during periods of VPBs occur more frequently during periods of CSR than during regular breathing in the same CSR than during regular breathing in the same patientspatients

VPBs occur preferentially during the VPBs occur preferentially during the hyperpneic phase of the CSR cyclehyperpneic phase of the CSR cycle

The frequency of VPBs is reduced by abolition The frequency of VPBs is reduced by abolition of CSR but not by elimination of hypoxiaof 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

Brooks D et al.J Clin Invest 1997

Brooks D et al.J Clin Invest 1997

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

150 - 0 = 150150 - 0 = 150 200 - 0 = 200200 - 0 = 200 150 - (-50) = 200150 - (-50) = 200

RVRV

IVSIVS

LVLV

PWPW

Leftward shift of the interventricular septum (IVS) Leftward shift of the interventricular septum (IVS) during obstructed inspiration (during obstructed inspiration (Shiomi T, et al Chest 1991)Shiomi T, et al Chest 1991)

M-mode recording with esophageal pressureduring obstructive apnea

PES

Prevalence of LVHPrevalence of LVH(IVS or PW thickness (IVS or PW thickness >> 12 mm) 12 mm)

Non-OSANon-OSA OSAOSA00

2020

4040

6060

8080

100100

P<0.016P<0.016

15.4%15.4%

47.6%47.6%

(%)(%)

Usui et al. Am J Respir Crit Care Med 2006

00

22

44

66

88

1010

1212

1414

00

22

44

66

88

1010

1212

1414

IVSTIVST PWTPWTP<0.001P<0.001

Non-OSA OSANon-OSA OSA Non-OSA OSANon-OSA OSA

Echocardiographic findingsEchocardiographic findings

(mm)(mm) (mm)(mm)

Usui et al. Am J Respir Crit Care Med 2006

Blood Pressure and Heart RateBlood Pressure and Heart Rate

Control Control (n=12)(n=12) CPAP CPAP (n=12)(n=12)

BL 1 mo p BL 1 mo p BL 1 mo p BL 1 mo p

HR, HR, bpmbpm 67±4 67±4 ns 67±4 67±4 ns 68±3 64±3 .007*68±3 64±3 .007*

BPsys, BPsys, mmHgmmHg 128±7 134±8 ns128±7 134±8 ns 126±6 116±5 .020 126±6 116±5 .020††

BPdi, BPdi, mmHgmmHg 60±4 58±3 ns 60±4 58±3 ns 62±4 59±2 ns62±4 59±2 ns

* p=.089 and * p=.089 and † † p=.008 for between group comparisonsp=.008 for between group comparisons

Kaneko et al. NEJM Kaneko et al. NEJM 2003;348:1233-412003;348:1233-41

0

5

10

15

20

25

30

35

40

Control ControlCPAP CPAP

LVEF, % FS, %

Baseline

1 mo

nsp=0.002

ns

p<0.001

p=0.009

p=0.044

LVEF and Fractional ShorteningLVEF and Fractional Shortening

Kaneko et al.Kaneko et al.NEJM NEJM 2003;348:2003;348:1233-411233-41

MSNA bursts/minMSNA bursts/min

0

30

50

70

90

Baseline 1 month Baseline 1 month

Control GroupControl Group CPAP GroupCPAP Group

MS

NA

, bu

rsts

/min

MS

NA

, bu

rsts

/min

ns p < 0.001

p = 0.009

Usui et al. JACC 2005 Usui et al. JACC 2005

CONCLUSIONS CONCLUSIONS

In medically treated CHF patients with OSA, CPAP:In medically treated CHF patients with OSA, CPAP: Reduces BPsys partly as a result of a decrease in Reduces BPsys partly as a result of a decrease in

sympathetic vasoconstrictor tone (MSNA) sympathetic vasoconstrictor tone (MSNA) Improves LV systolic function (LVEF)Improves LV systolic function (LVEF) Increase cardiac vagal activity (i.e. HF-HRV)Increase cardiac vagal activity (i.e. HF-HRV) Improve baroreflex sensitivity (BRS) Improve baroreflex sensitivity (BRS) Decreases the frequency of VPBsDecreases the frequency of VPBs OSA should be considered a therapeutic target in OSA should be considered a therapeutic target in

CHFCHF

0 20 40 60 80 100

Time (months)

0

20

40

60

80

100

Su

rviv

al (

%)

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

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 However, because of the observational nature of the study, they fall short of nature of the study, they fall short of proving mortality benefit in CHF patients proving mortality benefit in CHF patients with OSAwith OSA

Tkacova R et al. Circulation 2001Tkacova R et al. Circulation 2001

PCO2 = 41.2 mm Hg PCO2 = 38.8 mm Hg 30 sec

Overnight Shift from Obstructive to Central ApneaOvernight Shift from Obstructive to Central Apnea

Tkacova et al. Circulation 2000Tkacova et al. Circulation 2000

Overnight Shift from Obstructive to Central ApneaOvernight Shift from Obstructive to Central Apnea

Overnight Changes in Transcutaneous PCOOvernight Changes in Transcutaneous PCO22

Tkacova et al. Circulation 2000Tkacova et al. Circulation 2000

Tkacova et al. Circulation 2000Tkacova et al. Circulation 2000

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

CONCLUSIONSCONCLUSIONS

In CHF patients:In CHF patients:• Overnight shift from OSA to CSA is related to a Overnight shift from OSA to CSA is related to a

fall in PCOfall in PCO22

• Overnight increase in periodic breathing cycle Overnight increase in periodic breathing cycle length and circulation time suggest a decrease in length and circulation time suggest a decrease in cardiac outputcardiac output

• Therefore a fall in PCOTherefore a fall in PCO22 is likely due to increasing is likely due to increasing pulmonary congestion 2pulmonary congestion 200 to increased venous to increased venous return while recumbent and to decreased cardiac return while recumbent and to decreased cardiac output due to cardiovascular stresses of OSAoutput due to cardiovascular stresses of OSA

Differences of BMI between HF patients

and the GP according to the AHI

(† p<0.05, †† p<0.01)

Bo

dy-

mas

s in

dex

20

25

30

35

40

AHI < 5 AHI 5-15 AHI 15

HF

GP ††

†† ††

Arzt M et al. Arch Int Med 2006

00

1010

2020

3030

4040

5050

6060

7070

32032028028024024020020016016012012080804040004040

Change in LFV (ml)Change in LFV (ml)

AH

IA

HI

r = -0.802r = -0.802p < 0.001p < 0.001n = 23n = 23

Redolfi S et al. Am J Respir Crit Care Med 2008Redolfi S et al. Am J Respir Crit Care Med 2008

AH

I (n

o./h

r)

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 = 48N = 48

Yumino D et al. AHA Abstract 2008

OSAOSAOSAOSA

Proposed Interactions between OSA and CHF:Proposed Interactions between OSA and CHF:A Two-Way StreetA Two-Way Street

OSAOSAOSAOSA

Hypoxia Hypoxia BP, BP, SNASNAHypoxia Hypoxia BP, BP, SNASNA

Proposed Interactions between OSA and CHF:Proposed Interactions between OSA and CHF:A Two-Way StreetA Two-Way Street

OSAOSAOSAOSA CHFCHFCHFCHF

Hypoxia Hypoxia BP, BP, SNASNAHypoxia Hypoxia BP, BP, SNASNA

Proposed Interactions between OSA and CHF:Proposed Interactions between OSA and CHF:A Two-Way StreetA Two-Way Street

OSAOSAOSAOSA CHFCHFCHFCHF

Hypoxia Hypoxia BP, BP, SNASNAHypoxia Hypoxia BP, BP, SNASNA

Recumbent Recumbent UA EdemaUA EdemaRecumbent Recumbent UA EdemaUA Edema

Proposed Interactions between OSA and CHF:Proposed Interactions between OSA and CHF:A Two-Way StreetA Two-Way Street

OSAOSAOSAOSA CHFCHFCHFCHF

Hypoxia Hypoxia BP, BP, SNASNAHypoxia Hypoxia BP, BP, SNASNA

Recumbent Recumbent UA EdemaUA EdemaRecumbent Recumbent UA EdemaUA Edema

Proposed Interactions between OSA and CHF:Proposed Interactions between OSA and CHF:A Two-Way StreetA Two-Way Street

OSAOSAOSAOSA Worsening Worsening CHFCHFWorsening Worsening CHFCHF

Hypoxia Hypoxia BP, BP, SNASNAHypoxia Hypoxia BP, BP, SNASNA

Proposed Interactions between OSA, CSA and CHF:Proposed Interactions between OSA, CSA and CHF:A Shifting Spectrum A Shifting Spectrum

OSAOSAOSAOSA Worsening Worsening CHFCHFWorsening Worsening CHFCHF

Hypoxia Hypoxia BP, BP, SNASNAHypoxia Hypoxia BP, BP, SNASNA

Pulmonary Pulmonary EdemaEdemaPulmonary Pulmonary EdemaEdema

Proposed Interactions between OSA, CSA and CHF:Proposed Interactions between OSA, CSA and CHF:A Shifting Spectrum A Shifting Spectrum

OSAOSAOSAOSA Worsening Worsening CHFCHFWorsening Worsening CHFCHF

Hypoxia Hypoxia BP, BP, SNASNAHypoxia Hypoxia BP, BP, SNASNA

Pulmonary Pulmonary EdemaEdemaPulmonary Pulmonary EdemaEdema

Proposed Interactions between OSA, CSA and CHF:Proposed Interactions between OSA, CSA and CHF:A Shifting Spectrum A Shifting Spectrum

Vagal Vagal StimulationStimulationVagal Vagal StimulationStimulation

OSAOSAOSAOSA Worsening Worsening CHFCHFWorsening Worsening CHFCHF

Hypoxia Hypoxia BP, BP, SNASNAHypoxia Hypoxia BP, BP, SNASNA

Pulmonary Pulmonary EdemaEdemaPulmonary Pulmonary EdemaEdema

Proposed Interactions between OSA, CSA and CHF:Proposed Interactions between OSA, CSA and CHF:A Shifting Spectrum A Shifting Spectrum

Vagal Vagal StimulationStimulationVagal Vagal StimulationStimulation

HyperventilationHyperventilation PCOPCO22

HyperventilationHyperventilation PCOPCO22

CSACSACSACSA Worsening Worsening CHFCHFWorsening Worsening CHFCHF

Hypoxia Hypoxia BP, BP, SNASNAHypoxia Hypoxia BP, BP, SNASNA

Pulmonary Pulmonary EdemaEdemaPulmonary Pulmonary EdemaEdema

Proposed Interactions between OSA, CSA and CHF:Proposed Interactions between OSA, CSA and CHF:A Shifting Spectrum A Shifting Spectrum

Vagal Vagal StimulationStimulationVagal Vagal StimulationStimulation

HyperventilationHyperventilation PCOPCO22

HyperventilationHyperventilation PCOPCO22

AknowledgmentsAknowledgments

ColleaguesColleagues John FlorasJohn Floras Sandy LoganSandy Logan John ParkerJohn Parker Gary NewtonGary Newton Susanna MakSusanna Mak Clodagh RyanClodagh Ryan

FellowsFellows Michael ArztMichael Arzt Matthew GilmanMatthew Gilman Yasuyuki KanekoYasuyuki Kaneko Stefania RedolfiStefania Redolfi Pimon RuttanaumpawanPimon Ruttanaumpawan Kengo UsuiKengo Usui Hanqiao WangHanqiao Wang Dai YuminoDai Yumino