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Sindrome delle apnee notturneSindrome delle apnee notturneee
ipertensione arteriosaipertensione arteriosa
M. ScoppioM. ScoppioResponsabile reparto di NefrologiaResponsabile reparto di NefrologiaAmbulatorio ipertensione arteriosaAmbulatorio ipertensione arteriosaOspedale San Camillo-ForlaniniOspedale San Camillo-Forlanini26 maggio 200726 maggio 2007
Sleep apnea and hypertensionSleep apnea and hypertension
Il 96% degli uomini e il 65% delle donne con Il 96% degli uomini e il 65% delle donne con “ “ipertensione resistente” hanno OSAipertensione resistente” hanno OSA
Gli ipertesi resitenti con OSA hanno livelli più alti Gli ipertesi resitenti con OSA hanno livelli più alti di aldosterone plasmatico e incidenza più elevata di aldosterone plasmatico e incidenza più elevata di aldosteronismo primario, rispetto agli ipertesi di aldosteronismo primario, rispetto agli ipertesi resistenti senza OSAresistenti senza OSA
OSA E IPERTENSIONE RESISTENTEOSA E IPERTENSIONE RESISTENTEOSA E IPERTENSIONE RESISTENTEOSA E IPERTENSIONE RESISTENTE
Sleep Apnea and Potential Health RisksSleep Apnea and Potential Health Risks
Sleep ApneaSleep Apnea
Excessive sleepinessExcessive sleepiness
Neurocognitive deficitsNeurocognitive deficits
Crashes (motorcar accidentsCrashes (motorcar accidents)
HypertensionHypertension
Cardiovasculare diseaseCardiovasculare disease(IMA,stroke,SCA,CHF)(IMA,stroke,SCA,CHF)
Insulin-resistanceInsulin-resistance
OSAOSA
50%50%------------------------
HypertensionHypertension
25%25%----------------------
CongestiveCongestiveCardiacCardiacFailureFailure
30%30%------------------Acute Acute
CoronaryCoronarySyndromeSyndrome
60%60%----------------StrokeStroke
Prevalence of OSAPrevalence of OSAIn Patients with Cardiovascular and Cerebrovascular DiseaseIn Patients with Cardiovascular and Cerebrovascular Disease
Lattimore Jl JACC 2003;41Lattimore Jl JACC 2003;41
two recent reports have found increased OSA in subjects with APOE ε4, two recent reports have found increased OSA in subjects with APOE ε4, a genetic factor associated with Alzheimer’s disease. a genetic factor associated with Alzheimer’s disease.
The association of APOE ε4 with OSA has been suggested to be The association of APOE ε4 with OSA has been suggested to be mediated by damage to the CNS mediated by damage to the CNS
and resulting abnormal regulation breathing during sleepand resulting abnormal regulation breathing during sleep
Am J Respir Crit Care Med Vol 170. pp 1349–1353, 2007
OSAOSAMorboMorbo
didiAlzheimerAlzheimer
APOE ε4APOE ε4
Link geneticoLink genetico
Peppard PE. N Engl J Med. 2000; 342:1378-84
Obstructive sleep apnea and risk for hypertensionObstructive sleep apnea and risk for hypertension
EVIDENCE ON THE ASSOCIATION BETWEEN EVIDENCE ON THE ASSOCIATION BETWEEN OSA AND HYPERTENSION:OSA AND HYPERTENSION:
Recent Human StudiesRecent Human Studies
• General population epidemiology studiesGeneral population epidemiology studies• Clinic based epidemiology studiesClinic based epidemiology studies• Case control studiesCase control studies• Intervention studiesIntervention studies
EVIDENCE ON THE ASSOCIATION BETWEEN EVIDENCE ON THE ASSOCIATION BETWEEN OSA AND HYPERTENSION:OSA AND HYPERTENSION:
Recent Human StudiesRecent Human Studies
Studio trasversaleStudio trasversale Studio longitudinaleStudio longitudinale
2/3 paz. con OSA2/3 paz. con OSA
OBESIOBESI
½ paz. ipertesi½ paz. ipertesi
OSAOSA
2/3 paz. obesi2/3 paz. obesi
IPERTENSIONEIPERTENSIONE
LINKLINK
OSA and Impaired Glucose OSA and Impaired Glucose MetabolismMetabolism
• Meslier et al 2003Meslier et al 2003• 595 male patients referred for 595 male patients referred for
polysomnography underwent a 2 polysomnography underwent a 2 hour oral glucose tolerance test.hour oral glucose tolerance test.
• 494 pts had OSAS (AHI > 10)494 pts had OSAS (AHI > 10)• Fasting and postload blood glucose Fasting and postload blood glucose
increased with severity of sleep increased with severity of sleep apneaapnea
• Insulin sensitivity decreased with Insulin sensitivity decreased with increasing severity of sleep apneaincreasing severity of sleep apnea
• BMI, age and AHI are all have an BMI, age and AHI are all have an independent effect on blood independent effect on blood glucose and insulin sensitivityglucose and insulin sensitivity
• Ip et al 2002Ip et al 2002• 185 pts with OSAS (AHI>5)185 pts with OSAS (AHI>5)• Insulin resistance increased with Insulin resistance increased with
age obesity (main determinant)age obesity (main determinant)• Independent determinants of OSA Independent determinants of OSA
were AHI and min 02 satwere AHI and min 02 sat
• Punjabi et al 2003 [Review]Punjabi et al 2003 [Review]– Habitual snoring is associated Habitual snoring is associated
with abnormal fasting glucose with abnormal fasting glucose and insulin values independent and insulin values independent of age and BMIof age and BMI
– Prospective data from two Prospective data from two separate studies indicate that separate studies indicate that habitual snoring is associated habitual snoring is associated with more than a 2-fold risk of with more than a 2-fold risk of developing DM type II over a ten developing DM type II over a ten year period independent of BMI year period independent of BMI and other confoundersand other confounders
– Several studies have suggested Several studies have suggested that the minimum oxygen that the minimum oxygen saturation and AHI are saturation and AHI are predictive of glucose predictive of glucose intolerance and insulin intolerance and insulin resistance independent of BMI, resistance independent of BMI, age and waist to hip ratioage and waist to hip ratio
Cluster di fattori di rischio emodinamici e metabolici Cluster di fattori di rischio emodinamici e metabolici tradizionali e non tradizionali (emergenti), tradizionali e non tradizionali (emergenti),
che associati aumentanoche associati aumentano il rischio diil rischio di diabete tipo 2diabete tipo 2 e die di eventi cardiovascolarieventi cardiovascolari
1,54
1,96
2,97
3,35
5,27
0
1
2
3
4
5
6
eventi CV/100 p
az./
anno
1 2 3 4 5
n°fattori di rischio
RR
DannoDannologaritmicologaritmico
Central obesityCentral obesityMen >102 cm Women >88 cm
TGTG ≥150 mg/dL
HDL cholesterolHDL cholesterolMen <40 mg/dLWomen <50 mg/dL
Blood pressureBlood pressure ≥130/≥85mmHg
Fasting glucoseFasting glucose ≥110 mg/dL
Definition of metabolic syndrome
Three or more of the following five risk factors:Three or more of the following five risk factors:
Waist circumferenceWaist circumference
Despite therapeutic advances, Despite therapeutic advances, cardiovascular disease remains the cardiovascular disease remains the
leading cause of deathleading cause of death
0
100
200
300
400
500
Heartdisease and
stroke
Cancer Accidents Chroniclower resp.
disease
Diabetes0
510
15
20
25
30
35
Nu
mb
er o
f d
eath
s (t
ho
usa
nd
s)
Male Female
% of all deaths(right axis)
No. of deaths(left axis)
% A
ll death
s (male +
female)
National Center for Health Statistics 2004Data for 2002
Unmet clinical needs to address in the next Unmet clinical needs to address in the next decadedecade
CARDIOVASCULAR DISEASE
Classical Risk Factors Novel Risk Factors
Major Unmet Clinical Need
Metabolic syndromeMetabolic syndrome
AbdominalObesity
HDL-C
TG
TNF IL-6
PAI-1
Glu
Insulin
T2DM Smoking LDL-C BP
““TWIN EPIDEMICS”TWIN EPIDEMICS”
OBESITA’OBESITA’ DIABETE DIABETE TIPO 2TIPO 2GLOBESITYGLOBESITY
IPERTENSIONEIPERTENSIONEARTERIOSAARTERIOSA
MALATTIEMALATTIECARDIO-CARDIO-
VASCOLARIVASCOLARI
DIABESITYDIABESITY
Childhood Obesity, Inflammation, and ApneaChildhood Obesity, Inflammation, and ApneaWhat Is the Future for Our Children?What Is the Future for Our Children?
numerous recent studies have demonstrated the presence of numerous recent studies have demonstrated the presence of hypertension and increased inflammation in children with OSAShypertension and increased inflammation in children with OSAS
AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE VOL 171 2005AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE VOL 171 2005
Insulino-resistenzaInsulino-resistenza
IpertensioneIpertensione ObesitàObesità
Dislipidemia aterogenaDislipidemia aterogena
OSA e SINDROME METABOLICAOSA e SINDROME METABOLICA
PCOSPCOS
NASHNASH
NEFROPATIANEFROPATIAURATICAURATICA
OSAOSA
L’OSA ha probabilità L’OSA ha probabilità 9 volte9 volte superiore di sviluppare sindrome metabolica superiore di sviluppare sindrome metabolicarispetto alla popolazione di controllorispetto alla popolazione di controllo
Obesità (sindrome metabolica)Obesità (sindrome metabolica)
OSA ?OSA ?
Valutazione del sovrappeso e dell’obesitàValutazione del sovrappeso e dell’obesità
The Practical Guide Identification, Evaluation, and Treatment of Overweight and Obesity in Adults. NIH Publication, October 2000 NIH Pub No 00-4084
The Practical Guide Identification, Evaluation, and Treatment of Overweight and Obesity in Adults. NIH Publication, October 2000 NIH Pub No 00-4084
Indice di massa corporea: Peso (kg)/altezza(m2)
Circonferenza addominale
Rischio elevato:
Uomini > 102 cm
Donne > 88 cm
GRASSO VISCERALEGRASSO VISCERALE
Effetti cardiometabolici sfavorevoli dei prodotti degli adipociti
Adiposetissue
↑ IL-6
↓ Adiponectina
↑ Leptina
↑ TNFα
↑ Adipsina(Complemento D)
↑ Inibitoredell’attivatore delplasminogeno-1
(PAI-1)
↑ Resistina
↑ FFA
↑ Insulina
↑ Angiotensinogeno
↑ Lipoprotein lipasi
↑ Lactato
Infiammazione
Diabetetipo 2
Ipertensione
Dislipidemiaaterogenica
Trombosi
Aterosclerosi
Lyon 2003; Trayhurn et al 2004; Eckel et al 2005
OSAOSA
ipossiemia - ipercapniaipossiemia - ipercapnia
ROSROS(radicali liberi)(radicali liberi) Ipertono simpaticoIpertono simpatico
Eventi cardiovascolariEventi cardiovascolari
InsulinoInsulinoresistenzaresistenza
IpertensionIpertensionee
arteriosaarteriosa
Ag IIAg II
Sindrome MetabolicaSindrome Metabolicaee
OSAOSA
IPERTONO SIMPATICO renaleIPERTONO SIMPATICO renale
Profilo pressorio caratteristico Profilo pressorio caratteristico dell’OSAdell’OSA
Ipertensione arteriosa Ipertensione arteriosa diastolicadiastolica Ipertensione clinicaIpertensione clinicaRitmo circadiano di tipo non-dipperRitmo circadiano di tipo non-dipper
Ipertensione secondaria e resistenteIpertensione secondaria e resistente
Eccessivo rialzo pressorio al risveglioEccessivo rialzo pressorio al risveglio
Alta variabilità pressoria (DS)Alta variabilità pressoria (DS)
UTILITA’ dell’ABPMUTILITA’ dell’ABPM
Rilevanza clinica dei fenomeni pressori nelle 24 oreRilevanza clinica dei fenomeni pressori nelle 24 ore
Pressione notturna più alta
Minore giorno/notte
Eccessivo aumento pressoriomattutino
Aumento della variabilitàpressoria
Picchi pressori eccessivi/numerosi
Pressione notturna più alta
Minore giorno/notte
Eccessivo aumento pressoriomattutino
Aumento della variabilitàpressoria
Picchi pressori eccessivi/numerosi
Danno d’organoDanno d’organo
Rischio cardiovascolareRischio cardiovascolare
Progressione a nefropatia diabetica
Progressione a nefropatia diabetica
Associazione con un picco mattutino
degli eventi cardiovascolari
Associazione con un picco mattutino
degli eventi cardiovascolari
Sander D. et al, Circulation 2000; 102: 1536-1541Sander D. et al, Circulation 2000; 102: 1536-1541Sander D. et al, Circulation 2000; 102: 1536-1541Sander D. et al, Circulation 2000; 102: 1536-1541
Analisi di Kaplan-Meier per gli eventi cardiovascolari fatali e non fatali in pazienti con variabilità pressoria aumentata (> 15 mmHg) o normale (< 15 mmHg)
Analisi di Kaplan-Meier per gli eventi cardiovascolari fatali e non fatali in pazienti con variabilità pressoria aumentata (> 15 mmHg) o normale (< 15 mmHg)
0,80
0,85
0,90
0,95
1,00
0 20 40 60 80 100 120 140 160
Settimane
Lib
eri
da
even
ti c
ard
iova
sco
lari
Variabilità ≤ 15Variabilità ≤ 15Variabilità > 15Variabilità > 15
Variabilità ≤ 15Variabilità ≤ 15Variabilità > 15Variabilità > 15
Variabilità della pressione sistolica come fattore di rischio per ictus e mortalità cardiovascolare negli ipertesi anzianiVariabilità della pressione sistolica come fattore di rischio per ictus e mortalità cardiovascolare negli ipertesi anziani
Journal of Hypertension 2003; 21: 1-7Journal of Hypertension 2003; 21: 1-7Journal of Hypertension 2003; 21: 1-7Journal of Hypertension 2003; 21: 1-7
190 157 123 90 310
1724
31
0
0,05
0,1
0,15
PAS notturna (mmHg) Variabilità notturna della PAS
Ris
ch
io d
i ic
tus
a 2
an
ni
Monitoraggio ambulatorio della PA 24 oreMonitoraggio ambulatorio della PA 24 oreee
rialzo pressorio al risvegliorialzo pressorio al risveglio(morning surge pressure)(morning surge pressure)
OSA e IPERTENSIONE ARTERIOSAOSA e IPERTENSIONE ARTERIOSA
Mortalità nelle prime tre ore dopo il risveglioMortalità nelle prime tre ore dopo il risveglio
Willich. Am J Cardiol 1992; 70: 65-68Willich. Am J Cardiol 1992; 70: 65-68Willich. Am J Cardiol 1992; 70: 65-68Willich. Am J Cardiol 1992; 70: 65-68
Nu
me
ro d
i m
ort
i
0
25
10
20
sonno 0-3 3-6 6-9 9-12 12-15
Ore dopo il risveglio
0
5
10
15
20
25
2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24
Nu
me
ro d
i mo
rti
Variazioni circadiane nell’incidenza di morte cardiaca improvvisa - Framingham Heart Study
Variazioni circadiane nell’incidenza di morte cardiaca improvvisa - Framingham Heart Study
Willich. Am J Cardiol 1987; 60: 801-806Willich. Am J Cardiol 1987; 60: 801-806Willich. Am J Cardiol 1987; 60: 801-806Willich. Am J Cardiol 1987; 60: 801-806
Ore del giorno
Gami, A. S. et al. N Engl J Med 2005;352:1206-1214
Sudden cardiac death Sudden cardiac death and OSAand OSA
CortisoloCortisoloRASRASAgIIAgIIAldosteroneAldosteroneCatecolamineCatecolamineAdesività piastrinicaAdesività piastrinicaViscosità ematicaViscosità ematica
h 24
h 12
h 18
Picchi temporalitemporali dei ritmi circadiani umani
h 6h 6PAPA
FCFC
NONOFibrinolisiFibrinolisi
OSA e EPOOSA e EPO
Circulation. 2003;107
Elevated Levels of C-Reactive Protein and Interleukin-6 in Patients Elevated Levels of C-Reactive Protein and Interleukin-6 in Patients With Obstructive Sleep Apnea Syndrome Are Decreased by Nasal With Obstructive Sleep Apnea Syndrome Are Decreased by Nasal Continuous Positive Airway PressureContinuous Positive Airway Pressure
early clinical signs of atherosclerosis !early clinical signs of atherosclerosis !
Incidence of sleep-related disorders in 440 consecutive patients with HF
Sleep-related disorderSleep-related disorder Incidence (%) Incidence (%)
Central sleep apneaCentral sleep apnea 2525
Obstructive sleep apneaObstructive sleep apnea 2828
Milder sleep-related Milder sleep-related disordersdisorders
1818
No sleep-related disorderNo sleep-related disorder 2929
Lamp B. Heart Failure Society of America 2004 Annual Scientific Meeting; September 12-15, 2004; Toronto
Hypertension 2007;49:34-39
SOSO22 e Massa Ventricolare sinistra e Massa Ventricolare sinistra
Data supporting a possible Data supporting a possible cause and effect relationship cause and effect relationship between OSA and LVH. between OSA and LVH. 6 months of nocturnal CPAP 6 months of nocturnal CPAP to patients with severe OSA to patients with severe OSA was associated with a was associated with a significant reduction significant reduction in LV wall thickness.in LV wall thickness.
Chest 2003;124Chest 2003;124
JACC Vol. 47, No. 7, 2006JACC Vol. 47, No. 7, 2006
Correlazione tra AHI e SS e GCCorrelazione tra AHI e SS e GC
JACC Vol. 47, No. 7, 2006JACC Vol. 47, No. 7, 2006
Effetto della CPAP su SS e GCEffetto della CPAP su SS e GC
Nocturnal Ischemic Events in Patients With Obstructive Sleep Apnea Syndrome.Nocturnal Ischemic Events in Patients With Obstructive Sleep Apnea Syndrome.
Effects of Continuous Positive Air Pressure Treatment.Effects of Continuous Positive Air Pressure Treatment.
10/51 paz. con OSA10/51 paz. con OSA
J Am Coll Cardiol 1999;34J Am Coll Cardiol 1999;34
CPAPCPAP
OSA treatment in CADOSA treatment in CAD
Milleron et al Eur Heart J 2004
Treatment of heart failureTreatment of heart failure
• Once confirmed LV dysfunction on echo (not Once confirmed LV dysfunction on echo (not symptoms alone), treatment is a formula:symptoms alone), treatment is a formula:– DiureticsDiuretics– SpironolactoneSpironolactone– ACE inhibitor/ARBsACE inhibitor/ARBs– Beta blockerBeta blocker
• And now CPAPAnd now CPAP– Drug therapy alone does not decrease severity of Drug therapy alone does not decrease severity of
sleep apnea in heart failuresleep apnea in heart failure
Arrhythmias associated with SDB
• The following have been associated with SDB:– Classically severe bradycardia (sinus arrest, AV
block)– Atrial and ventricular ectopics– SVT, Atrial flutter, AF– Sustained and nonsustained VT
• Causality is not proven but tend to occur most with severe OSA and hypoxia
Gami AS Circulation 2004;110:364-7Gami AS Circulation 2004;110:364-7
OSA e FAOSA e FA
Recurrence of AF 12 months after Recurrence of AF 12 months after cardioversioncardioversion
Kanagala R Circulation 2003;107:2589-94Kanagala R Circulation 2003;107:2589-94
Prevalence of OSA after strokePrevalence of OSA after stroke
HarbisonGood
ParraDyken
Bassetti
Harbison
Wessendorf
Parra
Davies
>40%>40%
Wolk et al. Hypertension, 2003; 42
TERAPIA ANTIPERTENSIVATERAPIA ANTIPERTENSIVA
CONTROLLOCONTROLLOPRESSORIOPRESSORIO
PROTEZIONE PROTEZIONE D’ORGANOD’ORGANO
PROTEZIONEPROTEZIONEMETABOLICAMETABOLICA
SINDROMESINDROMEMETABOLICAMETABOLICA
Terapia antipertensivaTerapia antipertensivanellanella
Sindrome MetabolicaSindrome Metabolica
ACE-inibitoriACE-inibitori SartaniSartani
Farmaci che riducono la pressione arteriosa Farmaci che riducono la pressione arteriosa e che migliorano il quadro metabolicoe che migliorano il quadro metabolico
BLOCCANTI IL SRABLOCCANTI IL SRA
Potenziale influenza di telmisartansui recettori PPAR e sull’Angiotensina IIPotenziale influenza di telmisartansui recettori PPAR e sull’Angiotensina II
Kurtz TW et al. J Hyperten 2004; 22: 2253-2261Kurtz TW et al. J Hyperten 2004; 22: 2253-2261Kurtz TW et al. J Hyperten 2004; 22: 2253-2261Kurtz TW et al. J Hyperten 2004; 22: 2253-2261
SARTANISARTANI
Aterosclerosi Aterosclerosi
Angiotensina IIAngiotensina IIPPARPPAR
–+
Insulino resistenza Insulino
resistenza Dislipidemia Dislipidemia FlogosicellulareFlogosicellulare
Proliferazionecellulare
Proliferazionecellulare Ipertensione Ipertensione Stress
ossidativoStress
ossidativo
treatment of aldosterone excess induces not only the treatment of aldosterone excess induces not only the improvement of the cardiac alterations, but also of the improvement of the cardiac alterations, but also of the metabolic complications related to hyperaldosteronismmetabolic complications related to hyperaldosteronism
Journal of Hypertension 2007, 25:177–186Journal of Hypertension 2007, 25:177–186
ANTIALDOSTERONICIANTIALDOSTERONICI
DiureticsDiuretics
ACE inhibitorsACE inhibitorsACE inhibitorsACE inhibitors
Calcium Calcium antagonistsantagonists
ATAT11-receptor -receptor
blockersblockersß-blockersß-blockers
11-blockers-blockers
2003 European Society of Hypertension - European Society of Cardiology 2003 European Society of Hypertension - European Society of Cardiology guidelines for the management of arterial hypertensionguidelines for the management of arterial hypertension
• ““Among specific sleep disorders, the most serious in Among specific sleep disorders, the most serious in terms of morbidity and mortality is obstructive sleep terms of morbidity and mortality is obstructive sleep apnea.”apnea.”
• ““... it is time for the nation to wake up to the ... it is time for the nation to wake up to the staggering impact of sleep disturbances on the health staggering impact of sleep disturbances on the health and welfare of our society, an impact that rivals that of and welfare of our society, an impact that rivals that of smoking.”smoking.”
Ten Years Ago - April 1993!
SLEEP APNEA – A MAJOR PUBLIC HEALTH PROBLEM
EDITORIAL
M. ScoppioM. Scoppio