aspectos fisiopatólogicos del sahs ferran barbé novembre, 2007
TRANSCRIPT
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Aspectos fisiopatólogicos del SAHS
Ferran BarbéNovembre, 2007
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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.
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Obstructive apnea
No airflow
Increased effort
Desaturation30 s
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TRDS
GENES relacionados
con la etiología
GENESque
determinan la susceptibilidad
CraneofacialObesidadS.N.CentralControl VAS
HTACardiovascularSomnolenciaTrans. cognitivosOtros
Factores Etiológicos
(20%) (4%)
SAHS
ConsecuenciasClínicas
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TRDS
GENES relacionados
con la etiología
Craneofacial
Obesidad
S.N.Central
Control VAS
Factores Etiológicos
(20%)
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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
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Genetics in SAHSGenetics in SAHS
• SAHS: 8qSAHS: 8q
• Obesity: 4q, 8qObesity: 4q, 8q
Candidate chromosomes in African-American:
Palmer et al, AJRCCM 2004
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TRDS
GENESque
determinan la susceptibilidad
HTA
Cardiovascular
Somnolencia
Trans. Cognitivos
Otros(20%) (4%)
SAHS
ConsecuenciasClínicas
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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)
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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
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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
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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
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SYMPATHETIC ACTIVITY MARKERSSYMPATHETIC ACTIVITY MARKERS
• NOREPINEPHRINENOREPINEPHRINE
• NEUROPEPTIDE YNEUROPEPTIDE Y
Gullestad et al, Circulation 2000
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NEUROPEPTIDE YNEUROPEPTIDE Y
Schwartz and Seeley, N Engl J Med, 97; 336(25)Schwartz and Seeley, N Engl J Med, 97; 336(25)
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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
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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
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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
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• 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
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• 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
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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
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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
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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
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Controls
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Patients
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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
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• 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
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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
)
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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
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• 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
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Szmitko et al. Circulation 03; 108: 1917-23
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Areas denudadas del endotelio vascular
Peinado et al. ERJ 2004;24:435s
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Células progenitoras endoteliales (CD133+) (técnica de inmunogold)
Peinado et al. ERJ 2004;24:435s
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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
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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