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