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