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Sindrome delle apnee notturnee
ipertensione arteriosa
Sleep apnea and hypertension
Il 96% degli uomini e il 65% delle donne con “ipertensione resistente” hanno OSA
Gli ipertesi resitenti con OSA hanno livelli più alti di aldosterone plasmatico e incidenza più elevata di aldosteronismo primario, rispetto agli ipertesi resistenti senza OSA
OSA E IPERTENSIONE RESISTENTE
Sleep Apnea and Potential Health Risks
Sleep Apnea
Excessive sleepiness
Neurocognitive deficits
Crashes (motorcar accidents)
Hypertension
Cardiovasculare disease(IMA,stroke,SCA,CHF)
Insulin-resistance
OSA
50%------------
Hypertension
25%-----------
CongestiveCardiacFailure
30%---------Acute
CoronarySyndrome
60%--------Stroke
Prevalence of OSAIn Patients with Cardiovascular and Cerebrovascular Disease
Lattimore Jl JACC 2003;41
two recent reports have found increased OSA in subjects with APOE ε4, a genetic factor associated with Alzheimer’s disease.
The association of APOE ε4 with OSA has been suggested to be mediated by damage to the CNS
and resulting abnormal regulation breathing during sleep
Am J Respir Crit Care Med Vol 170. pp 1349–1353, 2007
OSAMorbo
diAlzheimer
APOE ε4
Link genetico
Peppard PE. N Engl J Med. 2000; 342:1378-84
Obstructive sleep apnea and risk for hypertension
EVIDENCE ON THE ASSOCIATION BETWEEN OSA AND HYPERTENSION:
Recent Human Studies
• General population epidemiology studies• Clinic based epidemiology studies• Case control studies• Intervention studies
EVIDENCE ON THE ASSOCIATION BETWEEN OSA AND HYPERTENSION:
Recent Human Studies
Studio trasversale Studio longitudinale
2/3 paz. con OSA
OBESI
½ paz. ipertesi
OSA
2/3 paz. obesi
IPERTENSIONE
LINK
OSA and Impaired Glucose Metabolism
• Meslier et al 2003• 595 male patients referred for
polysomnography underwent a 2 hour oral glucose tolerance test.
• 494 pts had OSAS (AHI > 10)• Fasting and postload blood glucose
increased with severity of sleep apnea
• Insulin sensitivity decreased with increasing severity of sleep apnea
• BMI, age and AHI are all have an independent effect on blood glucose and insulin sensitivity
• Ip et al 2002• 185 pts with OSAS (AHI>5)• Insulin resistance increased with
age obesity (main determinant)• Independent determinants of OSA
were AHI and min 02 sat
• Punjabi et al 2003 [Review]– Habitual snoring is associated
with abnormal fasting glucose and insulin values independent of age and BMI
– Prospective data from two separate studies indicate that habitual snoring is associated with more than a 2-fold risk of developing DM type II over a ten year period independent of BMI and other confounders
– Several studies have suggested that the minimum oxygen saturation and AHI are predictive of glucose intolerance and insulin resistance independent of BMI, age and waist to hip ratio
Cluster di fattori di rischio emodinamici e metabolici tradizionali e non tradizionali (emergenti),
che associati aumentanoil rischio di diabete tipo 2 e di eventi cardiovascolari
1,54
1,96
2,973,35
5,27
0
1
2
3
4
5
6
eventi CV/
100 paz./anno
1 2 3 4 5
n°fattori di rischio
RR
Dannologaritmico
Central obesityMen >102 cmWomen >88 cm
TG ≥150 mg/dL
HDL cholesterolMen <40 mg/dLWomen <50 mg/dL
Blood pressure ≥130/≥85mmHg
Fasting glucose ≥110 mg/dL
Definition of metabolic syndrome
Three or more of the following five risk factors:
Waist circumference
Despite therapeutic advances, cardiovascular disease remains the leading cause of death
0
100
200
300
400
500
Heartdisease and
stroke
Cancer Accidents Chroniclower resp.
disease
Diabetes05101520253035
Num
ber o
f dea
ths
(thou
sand
s)
Male Female
% of all deaths(right axis)
No. of deaths(left axis)
% A
ll deaths (male + fem
ale)
National Center for Health Statistics 2004Data for 2002
Unmet clinical needs to address in the next decade
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
T2DMSmoking LDL-C BP
“TWIN EPIDEMICS”
OBESITA’ DIABETE TIPO 2
GLOBESITY
IPERTENSIONEARTERIOSA
MALATTIECARDIO-VASCOLARI
DIABESITY
Childhood Obesity, Inflammation, and ApneaWhat Is the Future for Our Children?
numerous recent studies have demonstrated the presence of hypertension and increased inflammation in children with OSAS
AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE VOL 171 2005
Insulino-resistenza
Ipertensione Obesità
Dislipidemia aterogena
OSA e SINDROME METABOLICA
PCOS
NASH
NEFROPATIAURATICA
OSA
L’OSA ha probabilità 9 volte superiore di sviluppare sindrome metabolicarispetto alla popolazione di controllo
Obesità (sindrome metabolica)
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 addominaleRischio elevato:
Uomini > 102 cm
Donne > 88 cm
GRASSO 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
TrombosiAterosclerosi
Lyon 2003; Trayhurn et al 2004; Eckel et al 2005
OSA
ipossiemia - ipercapnia
ROS(radicali liberi) Ipertono simpatico
Eventi cardiovascolari
Insulinoresistenza
Ipertensionearteriosa
Ag II
Sindrome Metabolicae
OSA
IPERTONO SIMPATICO renale
Profilo pressorio caratteristico dell’OSA
Ipertensione arteriosa diastolicaIpertensione clinica
Ritmo circadiano di tipo non-dipper
Ipertensione secondaria e resistente
Eccessivo rialzo pressorio al risveglio
Alta variabilità pressoria (DS)
UTILITA’ 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’organo
Rischio cardiovascolare
Progressione a nefropatia diabetica
Associazione con un picco mattutino
degli eventi cardiovascolari
Sander 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
Libe
ri da
eve
nti c
ardi
ovas
cola
ri
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: 1-7
190 157 123 90 310
1724
310
0,05
0,1
0,15
Ris
chio
di i
ctus
a 2
ann
i
Monitoraggio ambulatorio della PA 24 oree
rialzo pressorio al risveglio(morning surge pressure)
OSA 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: 65-68
Num
ero
di m
orti
0
25
10
20
sonno 0-3 3-6 6-9 9-12 12-15Ore 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
Num
ero
di m
orti
Variazioni circadiane nell’incidenza di morte cardiaca improvvisa - Framingham Heart StudyVariazioni circadiane nell’incidenza di morte cardiaca improvvisa - Framingham Heart Study
Willich. 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 and OSA
CortisoloRASAgIIAldosteroneCatecolamineAdesività piastrinicaViscosità ematica
h 24
h 12
h 18
Picchi temporali dei ritmi circadiani umani
h 6PAFC
NOFibrinolisi
OSA e EPO
Circulation. 2003;107
Elevated Levels of C-Reactive Protein and Interleukin-6 in Patients With Obstructive Sleep Apnea Syndrome Are Decreased by Nasal Continuous Positive Airway Pressure
early clinical signs of atherosclerosis !
Incidence of sleep-related disorders in 440 consecutive patients with HF
Sleep-related disorder Incidence (%)
Central sleep apnea 25Obstructive sleep apnea 28
Milder sleep-related disorders
18
No sleep-related disorder 29
Lamp B. Heart Failure Society of America 2004 Annual Scientific Meeting; September 12-15, 2004; Toronto
Hypertension 2007;49:34-39
SO2 e Massa Ventricolare sinistra
Data supporting a possible cause and effect relationship between OSA and LVH. 6 months of nocturnal CPAP to patients with severe OSA was associated with a significant reduction in LV wall thickness.Chest 2003;124
JACC Vol. 47, No. 7, 2006
Correlazione tra AHI e SS e GC
JACC Vol. 47, No. 7, 2006
Effetto della CPAP su SS e GC
Nocturnal Ischemic Events in Patients With Obstructive Sleep Apnea Syndrome.Effects of Continuous Positive Air Pressure Treatment.
10/51 paz. con OSAJ Am Coll Cardiol 1999;34
CPAP
OSA treatment in CAD
Milleron et al Eur Heart J 2004
Treatment of heart failure• Once confirmed LV dysfunction on echo (not
symptoms alone), treatment is a formula:– Diuretics– Spironolactone– ACE inhibitor/ARBs– Beta blocker
• And now CPAP– Drug therapy alone does not decrease severity of
sleep 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;110:364-7
OSA e FA
Recurrence of AF 12 months after cardioversion
Kanagala R Circulation 2003;107:2589-94
Prevalence of OSA after stroke
HarbisonGood
Parra Dyken
Bassetti
Harbison
WessendorfParra
Davies
>40%
Wolk et al. Hypertension, 2003; 42
TERAPIA ANTIPERTENSIVA
CONTROLLOPRESSORIO PROTEZIONE
D’ORGANOPROTEZIONEMETABOLICA
SINDROMEMETABOLICA
Terapia antipertensivanella
Sindrome Metabolica
ACE-inibitori Sartani
Farmaci che riducono la pressione arteriosa e che migliorano il quadro metabolico
BLOCCANTI 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: 2253-2261
SARTANI
Aterosclerosi
Angiotensina IIPPAR
–+
Insulinoresistenza Dislipidemia Flogosi
cellulareProliferazionecellulare Ipertensione Stress
ossidativo
treatment of aldosterone excess induces not only the improvement of the cardiac alterations, but also of the metabolic complications related to hyperaldosteronism
Journal of Hypertension 2007, 25:177–186
ANTIALDOSTERONICI
Diuretics
ACE inhibitorsACE inhibitors
Calcium antagonists
AT1-receptor blockersß-blockers
1-blockers
2003 European Society of Hypertension - European Society of Cardiology guidelines for the management of arterial hypertension
• “Among specific sleep disorders, the most serious in terms of morbidity and mortality is obstructive sleep apnea.”
• “... it is time for the nation to wake up to the staggering impact of sleep disturbances on the health and welfare of our society, an impact that rivals that of smoking.”
Ten Years Ago - April 1993!
SLEEP APNEA – A MAJOR PUBLIC HEALTH PROBLEM
EDITORIAL
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