Aspectos fisiopatólogicos del SAHS

Ferran BarbéNovembre, 2007

Definitions • APNEA: Airflow cessation longer than 10

seconds• Obstructive: with respiratory effort• Central: without respiratory effort

• HYPOPNEA: Airflow reduction that induce a oxigen desaturation and/or arousal

• AHI: Nº of apneas + nº of hypopneas by hour slept.

Obstructive apnea

No airflow

Increased effort

Desaturation30 s

TRDS

GENES relacionados

con la etiología

GENESque

determinan la susceptibilidad

CraneofacialObesidadS.N.CentralControl VAS

HTACardiovascularSomnolenciaTrans. cognitivosOtros

Factores Etiológicos

(20%) (4%)

SAHS

ConsecuenciasClínicas

TRDS

GENES relacionados

con la etiología

Craneofacial

Obesidad

S.N.Central

Control VAS

Factores Etiológicos

(20%)

Genetics in SAHSGenetics in SAHS

• SAHS: 1p, 2p, 12p, 19pSAHS: 1p, 2p, 12p, 19p

• Obesity: 2p, 7p, 12pObesity: 2p, 7p, 12p

Candidate chromosomes:

Palmer et al, Am J Hum Genet 2003

Genetics in SAHSGenetics in SAHS

• SAHS: 8qSAHS: 8q

• Obesity: 4q, 8qObesity: 4q, 8q

Candidate chromosomes in African-American:

Palmer et al, AJRCCM 2004

TRDS

GENESque

determinan la susceptibilidad

HTA

Cardiovascular

Somnolencia

Trans. Cognitivos

Otros(20%) (4%)

SAHS

ConsecuenciasClínicas

Genetics in OSASGenetics in OSAS

Positive association Apo E є 4. JAMA 2001

TNFalfa ERJ 2004

No association PAI-I (Barceló Res Med 2002)

ACE (Barceló Eur Resp J 2001)

NPS (Hussain 2007)

OSAHS and CV diseaseOSAHS and CV diseasePotential MechanismsPotential Mechanisms

• Metabolic abnormalities (obesity)Metabolic abnormalities (obesity)

• Increased sympathetic toneIncreased sympathetic tone

• Oxidative stressOxidative stress

• Systemic inflammationSystemic inflammation

• Coagulation abnormalitiesCoagulation abnormalities

• Endothelial dysfunctionEndothelial dysfunction

• Genetic backgroundGenetic background

Metabolic abnormalities in OSAHSMetabolic abnormalities in OSAHS

• ObesityObesity is a known cardiovascular risk factor often is a known cardiovascular risk factor often present in patients with OSAHSpresent in patients with OSAHS

• Patients with OSAHS show metabolic abnormalities:Patients with OSAHS show metabolic abnormalities:

– Insulin resistanceInsulin resistance Ip et Ip et al, Am J Respir Crit Care Medal, Am J Respir Crit Care Med 02; 165:670-6 02; 165:670-6 Punjabi Punjabi et al, Am J Respir Crit Care Medet al, Am J Respir Crit Care Med 02; 165: 677-82 02; 165: 677-82 Barceló Barceló et al, Am J Medet al, Am J Med 04 04

– Increased plasma leptin levelsIncreased plasma leptin levels Chin Chin et al, Circulationet al, Circulation 99; 100: 706-12 99; 100: 706-12 Ip Ip et al, Chestet al, Chest 00; 118: 580-6 00; 118: 580-6

Increased sympathetic activity in Increased sympathetic activity in OSAHSOSAHS

• Fletcher et al, Fletcher et al, SleepSleep 1987; 10:35-44 1987; 10:35-44

• Carlson et al, Carlson et al, ChestChest 1993; 103: 1763-8 1993; 103: 1763-8

• Narkiewicz et al, Narkiewicz et al, CirculationCirculation 1999; 100: 2332-5 1999; 100: 2332-5

• Heitmann et al, Heitmann et al, Eur Respir JEur Respir J 2004; 23: 255-62 2004; 23: 255-62

Increased sympathetic activity in Increased sympathetic activity in obesityobesity

• Spraul et al, Spraul et al, J Clin InvestJ Clin Invest 1993; 92: 1730-5 1993; 92: 1730-5

• Scherrer et al, Scherrer et al, CirculationCirculation 1994; 89: 2634-40 1994; 89: 2634-40

• Grassi et al, Grassi et al, HypertensionHypertension 1995; 25: 560-3 1995; 25: 560-3

• Alvarez et al, Alvarez et al, CirculationCirculation 2002; 106: 2533-6 2002; 106: 2533-6

SYMPATHETIC ACTIVITY MARKERSSYMPATHETIC ACTIVITY MARKERS

• NOREPINEPHRINENOREPINEPHRINE

• NEUROPEPTIDE YNEUROPEPTIDE Y

Gullestad et al, Circulation 2000

NEUROPEPTIDE YNEUROPEPTIDE Y

Schwartz and Seeley, N Engl J Med, 97; 336(25)Schwartz and Seeley, N Engl J Med, 97; 336(25)

Non obese Obese Non obese Obese0

20

40

60

80

100

+

Neu

rop

epti

de

Y (

pm

ol/L

)

Non obese Obese Non obese Obese0

10

20

30

*

*

p<0.001p<0.001

OSAS Controls OSASControls

Lep

tin

(n

g/m

l)

Neuropeptide Y and Leptin in Patients with OSAHS: Role of ObesityNeuropeptide Y and Leptin in Patients with OSAHS: Role of Obesity Barcelo A Barcelo A et al. AJRCCM et al. AJRCCM 2005; 171: 183-72005; 171: 183-7

0 3 6 9 120

10

20

30

40

50

60

70

80

90

100

0 3 6 9 120

5

10

15

20

25

30

35

++

+

*

*

*

Neu

rop

epti

de

Y (

pm

ol/L

)

Months

Non obese Obese

Lep

tin

(n

g/m

l)

Months

Neuropeptide Y and Leptin in Patients with OSAHS: Role of ObesityNeuropeptide Y and Leptin in Patients with OSAHS: Role of Obesity Barcelo A Barcelo A et al. AJRCCM et al. AJRCCM 2005; 171: 183-72005; 171: 183-7

ROS

Adhesion molecule expression

VSMC growth

Apoptosis

Lipid oxidation

Alteredvasomotion

MMP activation

Oxidative stress and cardiovascular risk

Harrison et al; Am J Cardiol 03, 91: 7A-11A

OSA hypoxemia hypoxia-reoxigenation

• Direct markers:Direct markers:

• Indirect markers:Indirect markers:

Oxidative stress and OSA

-Increased ROS production-Increased plasma lipid peroxidation

- Activation of redox sensitive gene expression: VEGF, endothelin- Reduced NO availability- Hyperhomocysteinaemia- Reduced levels of antioxidants

• Increased ROS productionIncreased ROS production Schultz Schultz et al.et al. AJRCCM AJRCCM 00; 162: 566-70 00; 162: 566-70

Dyugovskaya Dyugovskaya et al. AJRCCM et al. AJRCCM 02; 165: 934-902; 165: 934-9

• Lipoprotein oxidationLipoprotein oxidation Saarelainen Saarelainen et al. Clin Chem Lab Med et al. Clin Chem Lab Med 99; 37:517-2099; 37:517-20

Barceló Barceló et al. Eur Respir Jet al. Eur Respir J 00; 16: 644-47 00; 16: 644-47

• Plasma homocistein levelsPlasma homocistein levels Lavie Lavie et al. Chestet al. Chest 01; 120: 900-908 01; 120: 900-908

Oxidative stress in OSAHSOxidative stress in OSAHS

Antioxidant status in patients with sleep apnoea and impact of continuous positive airway

pressure treatment.

A. Barceló, F. Barbé, M. de la Peña, M. Vila, G. Pérez, J. Piérola, J. Duran and A.G.N. Agustí´

Eur Respir J 2006; 27: 756–760

1.401.400.020.02**1.501.500.020.02TAS TAS (mmol/L)(mmol/L)

OSAOSA

(n=47)(n=47)

ControlsControls

(n=37)(n=37)

10.810.80.60.611.811.811Hcy Hcy (nmol/L)(nmol/L)

50150181814744745151Vit B12 Vit B12 (pg/mL)(pg/mL)

10.110.10.50.59.59.50.60.6Folic ac (Folic ac (ng/mL)ng/mL)

152515257373**177417748585Vit E Vit E (ug/dL)(ug/dL)

646433**747433Vit A Vit A (ug/dL)(ug/dL)

42423.33.3**32322.92.9GGT GGT (U/L)(U/L)

84484419197987981919GPX GPX (U/L)(U/L)

OXIDATIVE STRESSOXIDATIVE STRESS

  EDSn = 24

No EDSn = 21

p value

TST (min) 401 ± 41 379 ± 61 ns

Sleep latency (min)

11 ± 16 18 ± 16 0.03

Sleep efficiency (%)

90 ± 7 83 ± 12 0.03

Awake (min) 37 ± 29 63 ± 51 0.04

Arousal index 64±21 60±23 ns

Respiratory arousals

58 ± 20 53 ±23 ns

Phase 1 + 2 (%) 80±13 75±12 ns

Phase 3 + 4 (%) 7±9 9±6 ns

REM (%) 13 ± 6 15 ± 7 ns

Min Sat (%) 69 ± 12 78 ± 10 0.007

Mean Sat (%) 86 ± 6 90 ± 5 0.03

Somnolencia diurna y polisomnografia

O Mediano ERJ 2007

Controls

Patients

Endothelial function in OSAHS and response to treatmentEndothelial function in OSAHS and response to treatmentIp MS Ip MS et al. AJRCCM et al. AJRCCM 2004; 169: 348-532004; 169: 348-53

• Positive association Positive association Shamsuzzaman et al. Shamsuzzaman et al. CirculationCirculation 2002; 105: 2462-4 2002; 105: 2462-4

Yokoe et al. Yokoe et al. CirculationCirculation 2003; 107: 1129-34 2003; 107: 1129-34

• No associationNo association Chin K et al. Chin K et al. Am J MedAm J Med 2000; 109: 562-7 2000; 109: 562-7

C-reactive protein and C-reactive protein and OSAHSOSAHS

• Visser et al. Visser et al. JAMAJAMA 1999; 282: 2131-5 1999; 282: 2131-5

• Frölich et al. Frölich et al. Diabetes Care Diabetes Care 2000; 3: 1835-92000; 3: 1835-9

• Escobar et al. Escobar et al. Diabetologia Diabetologia 2003; 46: 625-332003; 46: 625-33

• Aronson et al. Aronson et al. Int J Obes Relat MetabInt J Obes Relat Metab 2004; 28: 674 2004; 28: 674

C-reactive protein and C-reactive protein and obesityobesity

Effects of obesity on C-reactive protein level and metabolic Effects of obesity on C-reactive protein level and metabolic disturbances in male patients with OSAHSdisturbances in male patients with OSAHS

Barcelo A Barcelo A et al. Am.J Medet al. Am.J Med 2004; 117: 118-21 2004; 117: 118-21

*

OSAHS

Controls Non Obese Obese0.0

0.2

0.4

0.6

0.8

1.0

1.2

1.4

1.6

PC

R (

mg

/dL

)

Endothelial dysfunction in OSAHSEndothelial dysfunction in OSAHS

• Nitric OxideNitric Oxide Ip et al. Am J Respir Crit Care Med 2000; 162: 2166-71Ip et al. Am J Respir Crit Care Med 2000; 162: 2166-71

Schulz et al. Thorax 2000; 55: 1046-51Schulz et al. Thorax 2000; 55: 1046-51

Lavie et al. J Mol Neurosci 2003; 21: 57-64Lavie et al. J Mol Neurosci 2003; 21: 57-64

• Endothelin-1Endothelin-1 Saarelainen et al. Endothelium 1997; 5: 115-8Saarelainen et al. Endothelium 1997; 5: 115-8

Phillips et al. J Hypertens 1999; 17: 61-6Phillips et al. J Hypertens 1999; 17: 61-6

• Imagawa et al. Blood 2001; 98: 1255-7• Schulz et al. AJRCCM 2002; 165: 67-70• Gozal et al. Sleep 2002; 25: 59-65• Lavie et al. AJRCCM 2002; 165: 1624-8• Teramoto et al. Intern Med 2003; 42: 681-5

Increased circulating levels of VEGF in OSAHSIncreased circulating levels of VEGF in OSAHS

Szmitko et al. Circulation 03; 108: 1917-23

Areas denudadas del endotelio vascular

Peinado et al. ERJ 2004;24:435s

Células progenitoras endoteliales (CD133+) (técnica de inmunogold)

Peinado et al. ERJ 2004;24:435s

SAHSn = 13

Controln = 13

Age (yr) 45±9 44±9

BMI (kg.m-2) 28±2 27±3

AHIh-1) 49±18 2±2

CD34 + (% linph) 0.11±0.01 0.13±0.01

EPCs (% CD34) 0.62±0.1 1.1±0.3

EPCs (% linphx10(-3)) 0.59±0.07 1.2±0.26*

Endothelial progenitor cells in OSAHSEndothelial progenitor cells in OSAHS

AgradecimientosAgradecimientos

• H Univ Son DuretaH Univ Son Dureta– Antonia BarcelóAntonia Barceló– Monica de la PeñaMonica de la Peña– Antoni LadariaAntoni Ladaria– Margalida BoschMargalida Bosch– Monica CastresanaMonica Castresana– Alvar AgustíAlvar Agustí

• H Univ Arnau de VilanovaH Univ Arnau de Vilanova– Olga MedianoOlga Mediano– Marina LumbierresMarina Lumbierres– Silvia GomezSilvia Gomez– Montse PujolMontse Pujol– Zahid HussainZahid Hussain