Sindrome delle apnee notturne
e
ipertensione arteriosa
26 maggio 2007
M. Scoppio
Responsabile reparto di Nefrologia
Ambulatorio ipertensione arteriosa
Ospedale San Camillo-Forlanini
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
Excessive sleepiness
Neurocognitive deficits
Crashes (motorcar accidents)
Hypertension
Sleep Apnea
Cardiovasculare disease
(IMA,stroke,SCA,CHF)
Insulin-resistance
Prevalence of OSA
In Patients with Cardiovascular and Cerebrovascular Disease
25%
----------Congestive
Cardiac
Failure
50%
-----------Hypertension
OSA
30%
--------Acute
Coronary
Syndrome
60%
-------Stroke
Lattimore Jl JACC 2003;41
Morbo
di
Alzheimer
OSA
Link genetico
APOE ε4
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
Obstructive sleep apnea and risk for hypertension
Peppard PE. N Engl J Med. 2000; 342:1378-84
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
½ paz. ipertesi
OBESI
OSA
LINK
2/3 paz. obesi
IPERTENSIONE
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 aumentano
il rischio di diabete tipo 2 e di eventi cardiovascolari
6
eventi CV/100 paz./anno
5,27
5
RR
4
3,35
2,97
Danno
logaritmico
3
1,96
2
1,54
1
0
1
2
3
4
n°fattori di rischio
5
Definition of metabolic syndrome
Three or more of the following five risk factors:
Central obesity
Men
Women
Waist circumference
>102 cm
>88 cm
TG
≥150 mg/dL
HDL cholesterol
Men
Women
<40 mg/dL
<50 mg/dL
Blood pressure
≥130/≥85mmHg
Fasting glucose
≥110 mg/dL
500
No. of deaths
(left axis)
400
300
Male
Female
% of all deaths
(right axis)
200
100
0
35
30
25
20
15
10
5
0
Heart
disease and
stroke
Cancer
Accidents
Data for 2002
National Center for Health Statistics 2004
Chronic
lower resp.
disease
Diabetes
% All deaths (male + female)
Number of deaths (thousands)
Despite therapeutic advances, cardiovascular disease
remains the leading cause of death
Unmet clinical needs to address in the next decade
Major Unmet Clinical Need
Classical Risk Factors
Novel Risk Factors
Metabolic syndrome
HDL-C
 LDL-C
 BP
TNF IL-6
Insulin
Abdominal
Smoking
Obesity
Glu
TG
PAI-1
CARDIOVASCULAR DISEASE
T2DM
“TWIN EPIDEMICS”
OBESITA’
DIABETE TIPO 2
GLOBESITY
DIABESITY
IPERTENSIONE
ARTERIOSA
MALATTIE
CARDIO-VASCOLARI
Childhood Obesity, Inflammation, and Apnea
What 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
OSA e SINDROME METABOLICA
Ipertensione
Insulino-resistenza
Obesità
Dislipidemia aterogena
OSA
NEFROPATIA
URATICA
PCOS
NASH
L’OSA ha probabilità 9 volte superiore di sviluppare sindrome metabolica
rispetto alla popolazione di controllo
Obesità (sindrome metabolica)
OSA ?
Valutazione del sovrappeso e dell’obesità
Indice di massa corporea: Peso (kg)/altezza(m2)
Circonferenza addominale
Rischio elevato:
Uomini > 102 cm
Donne > 88 cm
GRASSO VISCERALE
The Practical Guide Identification, Evaluation, and Treatment of Overweight
and Obesity in Adults. NIH Publication, October 2000 NIH Pub No 00-4084
Effetti cardiometabolici sfavorevoli dei
prodotti degli adipociti
↑ Lipoprotein lipasi
Infiammazione
↑ Angiotensinogeno
↑ IL-6
↑ TNFα
↑ Insulina
Adipose
tissue
↑ Adipsina
(Complemento D)
↓ Adiponectina
Aterosclerosi
Ipertensione
↑ FFA
Dislipidemia
aterogenica
↑ Resistina
↑ Leptina
↑ Lactato
↑ Inibitore
dell’attivatore del
plasminogeno-1
(PAI-1)
Diabete
tipo 2
Trombosi
Lyon 2003; Trayhurn et al 2004; Eckel et al 2005
Sindrome Metabolica
e
OSA
Insulino
resistenza
OSA
ipossiemia - ipercapnia
ROS
(radicali liberi)
Ag II
Ipertono simpatico
Eventi cardiovascolari
Ipertensione
arteriosa
IPERTONO SIMPATICO renale
Profilo pressorio caratteristico
dell’OSA
Ipertensione arteriosa diastolica
Ipertensione clinica
Ritmo circadiano di tipo non-dipper
Eccessivo rialzo pressorio al risveglio
Alta variabilità pressoria (DS)
Ipertensione secondaria e resistente
UTILITA’ dell’ABPM
Rilevanza clinica dei fenomeni pressori
nelle 24 ore
Pressione notturna
più alta
Minore  giorno/notte
Eccessivo aumento pressorio
mattutino
Aumento della variabilità
pressoria
Picchi pressori eccessivi/
numerosi
Danno d’organo
Rischio cardiovascolare
Progressione a nefropatia
diabetica
Associazione
con un picco mattutino
degli eventi cardiovascolari
Analisi di Kaplan-Meier per gli eventi cardiovascolari fatali
e non fatali in pazienti con variabilità pressoria aumentata
(> 15 mmHg) o normale (< 15 mmHg)
Liberi da eventi cardiovascolari
1,00
0,95
0,90
Variabilità ≤ 15
Variabilità > 15
0,85
0,80
0
20
40
60
80
100
120
140
160
Settimane
Sander D. et al, Circulation 2000; 102: 1536-1541
Variabilità della pressione sistolica come fattore di rischio
per ictus e mortalità cardiovascolare negli ipertesi anziani
Rischio di ictus a 2 anni
0,15
0,1
0,05
31
24
0
17
190
157
10
123
90
3
Journal of Hypertension 2003; 21: 1-7
OSA e IPERTENSIONE ARTERIOSA
Monitoraggio ambulatorio della PA 24 ore
e
rialzo pressorio al risveglio
(morning surge pressure)
Mortalità nelle prime tre ore dopo il risveglio
25
Numero di morti
20
10
0
sonno
0-3
3-6
6-9
9-12
12-15
Ore dopo il risveglio
Willich. Am J Cardiol 1992; 70: 65-68
Variazioni circadiane nell’incidenza
di morte cardiaca improvvisa - Framingham Heart Study
25
Numero di morti
20
15
10
5
0
2
3
4
5
6
7
8
9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24
Ore del giorno
Willich. Am J Cardiol 1987; 60: 801-806
Sudden cardiac death
and OSA
Gami, A. S. et al. N Engl J Med 2005;352:1206-1214
Picchi temporali dei ritmi circadiani umani
h 24
PA
h 18
FC
h 12
h6
Cortisolo
RAS
AgII
Aldosterone
Catecolamine
Adesività piastrinica
Viscosità ematica
NO
Fibrinolisi
OSA e EPO
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 !
Circulation. 2003;107
Incidence of sleep-related disorders in 440 consecutive patients with HF
Sleep-related disorder
Incidence (%)
Central sleep apnea
Obstructive sleep apnea
25
28
Milder sleep-related
disorders
No sleep-related disorder
18
29
Lamp B. Heart Failure Society of America 2004 Annual Scientific Meeting;
September 12-15, 2004; Toronto
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
Hypertension 2007;49:34-39
Correlazione tra AHI e SS e GC
JACC Vol. 47, No. 7, 2006
Effetto della CPAP su SS e GC
JACC Vol. 47, No. 7, 2006
Nocturnal Ischemic Events in Patients With Obstructive Sleep Apnea Syndrome.
Effects of Continuous Positive Air Pressure Treatment.
CPAP
10/51 paz. con OSA
J Am Coll Cardiol 1999;34
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
OSA e FA
Gami AS Circulation 2004;110:364-7
Recurrence of AF 12 months after
cardioversion
Kanagala R Circulation 2003;107:2589-94
Prevalence of OSA after stroke
Good
Harbison
Parra
Dyken
Harbison
Bassetti
Wessendorf
>40%
Parr
a
Davies
Wolk et al. Hypertension, 2003; 42
TERAPIA ANTIPERTENSIVA
SINDROME
METABOLICA
PROTEZIONE
METABOLICA
CONTROLLO
PRESSORIO
PROTEZIONE
D’ORGANO
Terapia antipertensiva
nella
Sindrome Metabolica
Farmaci che riducono la pressione arteriosa
e che migliorano il quadro metabolico
BLOCCANTI IL SRA
ACE-inibitori
Sartani
Potenziale influenza di telmisartan
sui recettori PPAR e sull’Angiotensina II
+
SARTANI
PPAR
Insulino
resistenza
Dislipidemia
–
Angiotensina II
Flogosi
cellulare
Proliferazione
cellulare
Ipertensione
Stress
ossidativo
Aterosclerosi
Kurtz TW et al. J Hyperten 2004; 22: 2253-2261
ANTIALDOSTERONICI
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
2003 European Society of Hypertension - European Society of Cardiology
guidelines for the management of arterial hypertension
Diuretics
ß-blockers
AT1-receptor
blockers
1-blockers
Calcium
antagonists
ACE inhibitors
Ten Years Ago - April 1993!
SLEEP APNEA – A MAJOR
PUBLIC HEALTH PROBLEM
EDITORIAL
• “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.”
M. Scoppio