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Transcript of Pathophysiological Interactions between Sleep Apnea and Heart Failure T. Douglas Bradley, MD...
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