APNÉIA OBSTRUTIVA DO SONOAPNÉIA OBSTRUTIVA DO SONOe DOENÇA CARDIOVASCULARe DOENÇA CARDIOVASCULARLaboratório do Sono da Disciplina de Pneumologia Laboratório do Sono da Disciplina de Pneumologia

InCor HC- FMUSPInCor HC- FMUSP

Brailia2008

Geraldo Lorenzi-Filho

Trudo FJ, Am J Respir Crit Care Med, 1998Trudo FJ, Am J Respir Crit Care Med, 1998

Prevalência de Distúrbios Respiratórios do Sono entre as Doenças Cardiovasculares

HipertensãoHipertensão

35%35%

Hipertensão Hipertensão RefratáriaRefratária

70%70%

Doença Doença CoronarianaCoronariana

Fibrilação Fibrilação AtrialAtrial

Insuficiência Insuficiência cardíacacardíaca

50%50%

50%50%

30%30%

Leung. AJRCCM 2003

Factors associated with OSA

• Male• Age• Hypertension• Dislipidemia• Diabetes

OSAOSA

OSAOSA AtherosclerosisAtherosclerosis

• Male• Age• Hypertension• Dislipidemia• Diabetes• Smoking

Risk factors for Atherosclerosis

Phenotypic characteristics associated with hypertension in patients with

obstructive sleep apneaNormotensive

N = 76Hypertensive

N = 76p

Age, yrs 4713 6011 <0.001

BMI, kg.m2 315 363 <0.001

Diabetes 9% 34% 0.004

Glucose, mg.dl 9811 11337 0.01

History of Hyp 54% 79% 0.01

Drager LF et al J Hum Hypertens 2006 Jul;20(7):523-8

OSA »»atherosclerosis ?

OSAOSA AtherosclerosisAtherosclerosis

Causal Link ?

• Male• Age• Hypertension• Dislipidemia• Diabetes• Smoking

How can OSA affect the CV system

SaO2SaO2

94%94%78%78%

S2S2 ArousalArousal

roncoronco

Obstructive Obstructive eventevent

SaOSaO22SaOSaO22

--------

--

--

Snore Carotid Arteries

SaO2SaO2 94%94%78%78%

OBSTRUTIVEOBSTRUTIVE

APNEAAPNEA

Vibration

Carotid Arteries

SNORE

CPAP--------------------------

CPAP OSA

Esra Tasali et all PNAS 105 (3):1044-1049, 2008

Slow-wave sleep and the risk of type 2 diabetes

Esra Tasali et all PNAS 105 (3):1044-1049, 2008

Wisconsin coortWisconsin coort

Peppard PE et al. NEJM 2000;342:1378-84.

TRATAMENTO DA APNÉIA OBSTRUTIVA TRATAMENTO DA APNÉIA OBSTRUTIVA DO SONODO SONO

CPAP CPAP ““continuous positive airway pressure”continuous positive airway pressure”

Sullivan, 1981Sullivan, 1981

CPAP and BPCPAP and BP

Before Before AfterAfter

Pepperell JC et al. Lancet. 2002;359:204-10.Pepperell JC et al. Lancet. 2002;359:204-10.

OSA OSA

Cause of Cause of HypertensionHypertension

17

OSA »» Atherosclerosis

AtherosclerosisOSA

HYP

++ +++

OSA »» Atherosclerosis

AtherosclerosisOSA

HYP

++

Ambulatory BP monitoring x clinicAmbulatory BP monitoring x clinic

24 hs 24 hs

BP BP

monitoringmonitoring

Time (hs)

• OSA is associated with absence of nocturnal BP dipping

Suzuki M et all Sleep 1996, 19 (5): 32-7

24 hs 24 hs

BP BP

monitoringmonitoring

Time (hs)

• OSA is associated with absence of nocturnal BP dipping

Suzuki M et all Sleep 1996, 19 (5): 32-7

• Masked Hypertension in OSA 35% Normotensives130 OSA patients 30% Masked HYP 35% HYP

Baguet JP et all J Hypertens 2008, 26 (5): 885-92

Ambulatory BP monitoring x clinic

24 hs BP monitoring24 hs BP monitoring

Somers VK et al. J Clin Invest 1995;96:1897-904

30 min

1 min

Acute modulation of arterial vasomotor tone

• Impaired endothelial relaxation?

Jelic et all Sleep 25(8): 15-20, 2002

Mean arterial pressure

11 ± 6%

8 ± 2 %

Balfors & Franklin AJRCCM150: 1587-1591, 1994

Shear stress

OSA and LV hypertrophyOSA and LV hypertrophy

Drager LF et al. Chest 2007;131:1379-1386Drager LF et al. Chest 2007;131:1379-1386

60

70

80

90

100

110

120

130

Control OSA HTN OSA +HTN

**

LV m

ass

inde

xLV

mas

s in

dex **

****

*P<0,05*P<0,05

Left ventricular hypertrophyLeft ventricular hypertrophy

0

20

40

60

Control OSA HYP OSA +HYP

**

% L

V hy

petr

ophy

% L

V hy

petr

ophy

**

*** ** *

*P<0,05 * * P<0,0001*P<0,05 * * P<0,0001Drager LF et al. Chest 2007;131:1379-1386Drager LF et al. Chest 2007;131:1379-1386

Arterial StiffnessArterial Stiffness

88,5

99,510

10,511

11,512

12,513

Control OSA HTN OSA + HTN

PWV

(m/s

)PW

V (m

/s)

8,78,7

10,710,710,110,1

12,112,1

<0.001<0.001

<0.001<0.001

<0.007<0.007

NSNS<0.001<0.001

<0.007<0.007

Drager LF et al. Chest 2007;131:1379-1386Drager LF et al. Chest 2007;131:1379-1386

LV mass index vs PWVLV mass index vs PWV

PWV (m/s)PWV (m/s)77 99 1111 1313 1515 1717

180180

150150

120120

9090

6060

3030

R=0.72; P<0.0001R=0.72; P<0.0001

LV m

ass

inde

xLV

mas

s in

dex

Drager LF et al. Chest 2007;131:1379-1386Drager LF et al. Chest 2007;131:1379-1386

Heart RemodelingHeart Remodeling

After LoadAfter Load

LV remodelingLV remodeling

Drager LF et al. Chest 2007;131:1379-1386Drager LF et al. Chest 2007;131:1379-1386

Arterial Arterial stiffnessstiffness

HYP

&

OSA

OSA »» Atherosclerosis

AtherosclerosisOSA

HYP

++ +++

LIP+ +++

Savranski et al. Am J Resp Crit Care Med. 2007;175:1290-7

Intermittent Hypoxia and AtherosclerosisIntermittent Hypoxia and AtherosclerosisAnimal ModelAnimal Model

40 male mice

12 weeks

Regular chow diet

Intermittent air

High cholesterol dietIntermittent air

Regular chow diet

Intermittent hypoxia

High cholesterol dietIntermittent hypoxia

IH or Colesterol Diet » NO Aterosclerosis

Control IH

Cholesterol Diet

Savranski et al. Am J Resp Crit Care Med. 2007;175:1290-7

IH + Colesterol Diet » » Aterosclerosis

Control

Cholesterol + IH

IH

Cholesterol Diet

Savranski et al. Am J Resp Crit Care Med. 2007;175:1290-7

OSA »» Atherosclerosis

AtherosclerosisOSA

HYP

++ +++

LIP

Inflammation

+++

+++

+

+

SAOS e eventos cardiovascularesSeguimento de 10 anos: Eventos fatais

Marin JM et al. Lancet. 2005Marin JM et al. Lancet. 2005

Controles

RoncadoresRoncadores

SAOS leveSAOS leve

SAOS graveSAOS grave

SAOS - CPAPSAOS - CPAP

Inci

dênc

ia a

cum

ulad

a de

eve

ntos

fata

is (%

)In

cidê

ncia

acu

mul

ada

de e

vent

os fa

tais

(%)

SAOS e arritimia: Fibrilação Atrial

Kanagala R et al. Circulation 2003Kanagala R et al. Circulation 2003

Rec

orrê

ncia

de

FA

Rec

orrê

ncia

de

FA

após

12

mes

esap

ós 1

2 m

eses

0102030405060708090

100

Controles SAOS tratado SAOS nãotratado

P=0.46P=0.46

P=0.009P=0.009

P=0.013P=0.013

SAOS e Morte SúbitaSAOS e Morte Súbita

NEJM, 2005NEJM, 2005

Early Signs of Atherosclerosis in Patients with Obstructive Sleep Apnea

Luciano F Drager, Luiz A Bortolotto, Maria Cecília Lorenzi, Adelaide C Figueiredo, Eduardo M Krieger and Geraldo

Lorenzi-Filho

Sleep Laboratory, Pulmonary Division, Heart Institute (InCor), University of São Paulo Medical School, Brazil

Methods

• 15 severe OSA patients• 15 mild-to-moderate OSA patients • 12 age and sex-matched healthy volunteers • All participants were free of hypertension, diabetes,

smoking and were not on any medications. OSA patients were naive to treatment.

Baseline Characteristics CCoonnttrrooll ((nn==1122)) MMiilldd--mmooddeerraattee OOSSAA ((nn==1155)) SSeevveerree OOSSAA ((nn==1155)) PP

AAggee ((yyeeaarrss)) 442222 443311 444411 00..6677

MMaalleess ((%%)) 9933 9933 8844 00..6644

BBooddyy mmaassss iinnddeexx ((KKgg//mm22)) 2288..9900..77 2288..4400..66 2299..3300..88 00..6666

CCaauuccaassiiaannss ((%%)) 8833 6677 8800 00..3355

SSBBPP ((mmmm HHgg)) 111155..4433..55 111144..2222..55 111177..4433..00 00..7744

HHeeaarrtt rraattee ((bbppmm)) 775522 775522 776622 00..8877

FFaassttiinngg gglluuccoossee ((mmgg//ddLL)) 996622 995533 998811 00..7744

CChhoolleesstteerrooll ((mmgg//ddLL)) 2222661144 22226666 22336688 00..6677

AAHHII ((eevveennttss//hhoouurr)) 33..1100..33 1166..2211..77 5555..7755..99 <<00..00000011

MMiinniimmaall ooxxyyggeenn ssaattuurraattiioonn

((SSaattOO22mmiinn))990011 881111 773311 <<00..00000011

Pulse wave velocity

CCA

CR CF

RA

FA

A D B

A

B

T

Eco-trackingANTANT POSTPOST

PWV

* p<0.0001

IMT

† p<0.0001

Carotid Diameter

BasalBasal 4 months4 months

NSNS

77

88

99

1010

1111

1212

1313

PWV

(m/s

)PW

V (m

/s)

BasalBasal 4 months4 months

P<0,001P<0,001

PWV

(m/s

)PW

V (m

/s)

77

88

99

1010

1111

1212

1313

P<0,001P<0,001PWV

Grupo ControleGrupo Controle CPAPCPAPDrager LF et al. Drager LF et al. Am J Respir Crit Care Med.Am J Respir Crit Care Med. 2007 2007

Espessura íntima-média da carótida

BasalBasal 4 meses4 meses

Grupo ControleGrupo Controle CPAPCPAP

NSNS

BasalBasal 4 meses4 meses

P=0,04P=0,04P=0,02P=0,02

(( µm

)µm

)

400400

500500

600600

700700

800800

900900

10001000

11001100

12001200

400400

500500(( µ

m)

µm)

600600

700700

800800

900900

10001000

11001100

12001200

Drager LF et al. Drager LF et al. Am J Respir Crit Care Med.Am J Respir Crit Care Med. 2007 2007

““Eu dormia, mas meu coração estava Eu dormia, mas meu coração estava acordado”acordado”

LABORATÓRIO DO SONOLABORATÓRIO DO SONOINSTITUTO DO CORAÇÃOINSTITUTO DO CORAÇÃO

Cântico de Salomão, Cap 5, V 2.Cântico de Salomão, Cap 5, V 2.