Lezione 2 studio ecografico aterosclerosi preclinica [Sola...

CORSO DI CERTIFICAZIONE DI COMPETENZAin ECOGRAFIA VASCOLARE GENERALE

Lezione 2Studio ecografico dell’aterosclerosi pre-clinica:spessore mio -intimale e

Lezione 2Studio ecografico dell’aterosclerosi pre-clinica:spessore mio -intimale e

Settore formazione 2007-2009: Direttore: Paolo G. PinoMarco Campana, Antonella Moreo, Fausto Rigo, Ketty Savino

pre-clinica:spessore mio -intimale e funzione endoteliale

pre-clinica:spessore mio -intimale e funzione endoteliale

ATEROSCLEROSIATEROSCLEROSIRecenti scoperteRecenti scoperte

•• DISFUNZIONE ENDOTELIALEDISFUNZIONE ENDOTELIALE

•• INFIAMMAZIONE INFIAMMAZIONE Carattezzazione PlaccaCarattezzazione Placca

Condizioni morfofunzionali che precedono il Condizioni morfofunzionali che precedono il restringimento del vaso e l’inizio dei sintomi:restringimento del vaso e l’inizio dei sintomi:

•• CALCIFICAZIONECALCIFICAZIONECarattezzazione PlaccaCarattezzazione Placca

Precoci modificazioni molecolari e cellulari del processo aterogenetico

• Ossidazione lipoproteine

• Adesione monociti

• Formazione Foam cells• Ispessimento parietale

Ecografia vascolare Ecografia vascolare

• A causa del remodeling della tunica media lo sviluppo inizialedella placca aterosclerotica non è accompagnatoda una riduzione del lume vascolare.

• In questa fase nonnon sono osservabili modificazioni angiografiche, mentre l’ Ecografia è in grado di visualizzare le alterazioni morfo-funzionali della parete arteriosa

Dipartimento CardioDipartimento Cardio--Toracico Toracico

Università di PisaUniversità di Pisa

-- ECOGRAFIA ECOGRAFIA TRANSCUTANEATRANSCUTANEA(arterie carotidi)(arterie carotidi)

-- ULTRASONOGRAFIA INTRAVSCOLAREULTRASONOGRAFIA INTRAVSCOLARE(arterie periferiche)(arterie periferiche)

VALUTAZIONE SMIVALUTAZIONE SMI

METODI DI VALUTAZIONE METODI DI VALUTAZIONE ANATOMICAANATOMICA

Danno edisfunzioneendoteliale

Espressione molecoledi adesione, adesionemigrazione monociti

I macrofagi fagocitanoox-LDL attraversoscavenger receptor

Migrazione eproliferazionemiociti

Placcaateromasica

cell.schiumosa

monocita

(arterie periferiche)(arterie periferiche)SPESSORE INTIMALESPESSORE INTIMALE

SPESSORE MEDIOSPESSORE MEDIO--INTIMALE CAROTIDEOINTIMALE CAROTIDEODEFINIZIONEDEFINIZIONE

•• Spessore del complesso intimaSpessore del complesso intima--media della parete media della parete carotideacarotidea

•• Misurabile come distanza tra l’interfaccia sangueMisurabile come distanza tra l’interfaccia sangue--intima e l’interfaccia mediaintima e l’interfaccia media--avventiziaavventizia

Dip. CardioDip. Cardio--Toracico Toracico -- Università di PisaUniversità di Pisa

IMPORTANZA CLINICA DELLOSPESSORE MEDIO-INTIMALE CAROTIDEO

• Marker di aterosclerosi periferica

• Marker di aterosclerosi coronarica

• Marker di aterosclerosi periferica

• Marker di aterosclerosi coronarica• Marker di aterosclerosi coronarica

• Studio dell’efficacia degli interventi terapeutici

• Marker di aterosclerosi coronarica

• Studio dell’efficacia degli interventi terapeutici

Dipartimento CardioDipartimento Cardio--Toracico Toracico -- Università di PisaUniversità di Pisa

VALUTAZIONE DELL’IMT

IntimaIntimaMediaMedia

AvventiziaAvventizia

ANATOMIAANATOMIA ECOGRAFIAECOGRAFIAANATOMIAANATOMIA ECOGRAFIAECOGRAFIA

“IMT”“IMT”misura misura “IMT”“IMT”misura misura

PAPA

IntimaIntimaMediaMedia

AvventiziaAvventizia

Lume vascolareLume vascolareLume vascolareLume vascolare

“IMT”“IMT”misura misura validavalida

“IMT”“IMT”misura misura validavalida

misura misura non validanon valida

misura misura non validanon valida

PPPP

Dipartimento CardioDipartimento Cardio--Toracico Toracico –– Università di PisaUniversità di Pisa

INTIMA -MEDIA THICKNESS METHODS OF MEASUREMENT: MANUAL CURSOR PLACEMENT

INTIMA -MEDIA THICKNESS METHODS OF MEASUREMENT:

AUTOMATED COMPUTERIZED EDGE-DETECTION

The three most frequently used measurements in clinical trials are as follows:

• Mean of the maximum IMT of the 4far walls of the carotid bifurcationsand distal common carotid arteries(CBM max)

INTIMA -MEDIA THICKNESSMETHODS OF MEASUREMENT

Dipartimento CardioDipartimento Cardio--Toracico Toracico -- Università Università di Pisadi Pisa

(CBM max)

• Mean maximum thickness (M max) ofup to 12 different sites (right and left,near and far walls, distal common,bifurcation and proximal internalcarotid)

• Overall single maximumIMT (T max)

• Misurare IMT sulla parete posteriore della carotide comune ad1 cm dalla biforcazione in un segmento di carotide di circa 1 cm,prendendo almeno 2- 3 proiezioni (valore medio o massimo)

• immagini “zoomate”

Doppler TSA- IMT

• immagini “zoomate”

• misurazioni ripetute o operatori indipendenti

• segnare le misure IMTdelle 2 CCseparatamente

• segnalare se valore medio o massimo

SPESSORE MEDIO-INTIMALE CAROTIDEOMETODI DI CALCOLO

RIPRODUCIBILITA’ DATI RIPRODUCIBILITA’ DATI

Dipartimento CardioDipartimento Cardio--Toracico Toracico -- Università di PisaUniversità di Pisa

RIPRODUCIBILITA’ DATI

variabilita’ intra

ed interosservatore ?

RIPRODUCIBILITA’ DATI

variabilita’ intra

ed interosservatore ?

Complesso intima-mediaCorrelazione con fattori di rischio CV

••••••

Età, familiarità per malattie CVFumoDiabete, sindrome metabolica & insulino-resistenzaIpertensione arteriosa, ipertrofia ventricolare sinDislipidemie (� LDLc, � trigliceridi, � LP(a), � HDLc)•

• Fattori emocoagulativi (� PAI1, � tPA e � D-Dimero,� Viscosità plasmatica, � WWF, � fibrinog., � VIIIc)

• � Omocisteina• Nuovi FDR (CMV, Clamidia, parodontopatie, � livellidi antiossidanti, D allele dell’ACE, � sideremia eferritina)...

SM

AR

Tsco

re

Complesso intima-mediaCorrelazione con score riassuntivo dei fattori di rischio CV

12

9

R = 0,719p < 0,0001

SM

AR

Tsco

re

0,2 0,4 0,6 0,8 10 1,2

6

3

0 Common carotid IMT (mm)Lupi, ESC 2002

La diagnosi precoce di aterosclerosi coronarica - Torino 20/11/2004

Complesso intima-mediaCorrelazione con AS coronarica

La diagnosi precoce di aterosclerosi coronarica - Torino 20/11/2004

Anderson, JACC 1995

Complesso intima-mediaCorrelazione con malattia AS vascolare (ARIC study)

P<0.01

Burke, Stroke 1995

Complesso intima-mediaCorrelazione con prognosi (CH Study)

’Leary,O’Leary, NEJM 1999

p<0.01 vs 1t Quintile

Complesso intima-mediaCorrelazione con prognosi (CH Study)

Crouse, Circulation 2003

p<0.05 vs Pravastatina

Complesso intima-mediaEnd-point surrogati e studi di intervento farmacologico

Taylor, Circulation 2002 (ARBITER study)

Lo Studio dellaFunzione Endoteliale

L’ENDOTELIO NELLA PATOLOGIA CARDIOVASCOLAREL’ENDOTELIO NELLA PATOLOGIA CARDIOVASCOLARE

“ ENDOTHELIAL CELLS…(ARE)…MORE THAN“ ENDOTHELIAL CELLS…(ARE)…MORE THANA SHEAT OF NUCLEATED CELLOPHANE”A SHEAT OF NUCLEATED CELLOPHANE”

LORD FLOREY, 1966LORD FLOREY, 1966

RUOLO CENTRALE NELLA REGOLAZIONERUOLO CENTRALE NELLA REGOLAZIONERUOLO CENTRALE NELLA REGOLAZIONERUOLO CENTRALE NELLA REGOLAZIONEDELL’OMEOSTASI CARDIOCIRCOLATORIADELL’OMEOSTASI CARDIOCIRCOLATORIA

19981998

•• TONO VASCOLARETONO VASCOLARE

•• ADESIONE E AGGREGAZIONEADESIONE E AGGREGAZIONE

PIASTRINICAPIASTRINICA

•• COAGULAZIONE LOCALECOAGULAZIONE LOCALE

•• CRESCITA VASCOLARECRESCITA VASCOLARE

•• INFIAMMAZIONEINFIAMMAZIONE

Malattie Cardiovascolari e Disfunzione EndotelialeMalattie Cardiovascolari e Disfunzione Endoteliale

Scompenso Scompenso cardiacocardiaco TrombosiTrombosi

IperlipidemiaIperlipidemia

Angiopatia Angiopatia diabeticadiabetica

VasospasmoVasospasmo

AterosclerosiAterosclerosi

Danno Danno da riperfusioneda riperfusione DISFUNZIONE DISFUNZIONE diabeticadiabetica

Reazioni immuniReazioni immuniRiocclusioneRiocclusione

IpertensioneIpertensione

da riperfusioneda riperfusione

Arteriopatie Arteriopatie obliteranti perifericheobliteranti periferiche

InfiammazioneInfiammazione

Dipartimento Cardio Toracico – Università di Pisa

DISFUNZIONE DISFUNZIONE ENDOTELIALEENDOTELIALE

How is endothelial How is endothelial function assessed ?function assessed ?function assessed ?function assessed ?

FISIOLOGIA DELL’ENDOTELIOFISIOLOGIA DELL’ENDOTELIO

SANGUESANGUE

CELLULECELLULE FORZE ELASTICHEFORZE ELASTICHE SOSTANZE VASOATTIVESOSTANZE VASOATTIVE

• PMN• Monociti• Piastrine

•• Shear stress• Pressione

•• Acetilcolina • Peptidi ( trombina, sostanza P,

vasopressina)• Chinine (bradichinina)• Amine (serotonina)• Nucleotidi (ATP; ADP)• Metaboliti (leucotriene C4)• Metaboliti (leucotriene C4)

ENDOTELIOENDOTELIO ““ FATTORI DI DERIVAZIONE ENDOTELIALIFATTORI DI DERIVAZIONE ENDOTELIALI ””

MUSCOLATURAMUSCOLATURALISCIA LISCIA

VASCOLAREVASCOLAREproliferazioneproliferazionecontrazionecontrazionerilasciamentorilasciamento

Dipartimento Cardio Toracico – Università di Pisa

PRINCIPALI MECCANISMI INTRACELLULARI PRINCIPALI MECCANISMI INTRACELLULARI MEDIANTI L’AZIONE DELL’NOMEDIANTI L’AZIONE DELL’NO

BRADICHININABRADICHININAAchAch

SHEAR STRESSSHEAR STRESS

CELLULA CELLULA ENDOTELIALEENDOTELIALE LL--Arg Arg →→→→→→→→ RR--NONO

NONO

M

CaCa++++/Mg/Mg++++

ATPasiATPasi

CELLULA MUSCOLARE

LISCIA

NONO

GTP GTP →→→→→→→→ cGMPcGMP

KK ++

CaCa++++

GG--KinasiKinasi

VASODILATAZIONEVASODILATAZIONE

CaCa++++

GCGC?

?

•• Vasodilatazione (attraverso rilasciamento della Vasodilatazione (attraverso rilasciamento della cellule della muscolatura liscia)cellule della muscolatura liscia)

•• Inibizione della crescita (attraverso azioni sulla Inibizione della crescita (attraverso azioni sulla cellula della muscolatura liscia)cellula della muscolatura liscia)

•• Inibizione dell’adesione/aggregazione Inibizione dell’adesione/aggregazione

EFFETTI VASOPROTETTORI DELL’ NO

Dip. Cardio-Toracico - Università di Pisa

•• Inibizione dell’adesione/aggregazione Inibizione dell’adesione/aggregazione piastrinicapiastrinica

•• Inibizione delle interazioni endotelio/leucocitiInibizione delle interazioni endotelio/leucociti

•• Controbilancia l’effetti dell’anione Controbilancia l’effetti dell’anione superossido?superossido?

ASSESSMENT OF ENDOTHELIAL FUNCTION IN HUMANS

STUDY OF VASCULAR REACTIVITY

STUDY OF VASCULAR REACTVITY

• MACROCIRCULATION: • MACROCIRCULATION: - EPICARDIAL ARTERIES - BRACHIAL, RADIAL, FEMORAL ARTERIES

• MICROCIRCULATION:• CORONARY • CUTANEOUS • MUSCLE

ART.PERIFERICHEART.PERIFERICHE(art.radiale,art.femorale(art.radiale,art.femoraleCORONARIECORONARIE

MACROCIRCOLOMACROCIRCOLO

VALUTAZIONE CLINICA DELL’ENDOTELIOVALUTAZIONE CLINICA DELL’ENDOTELIO

ANGIOGRAFIA ANGIOGRAFIA QUANTITATIVAQUANTITATIVA

Dipartimento Cardio Toracico Dipartimento Cardio Toracico –– Università di PisaUniversità di Pisa

QUANTITATIVAQUANTITATIVA++

IVUSIVUS

ULTRASONOGRAFIA NON INVASIVAULTRASONOGRAFIA NON INVASIVA(ECO(ECO--DOPPLER TRANSCUTANEO)DOPPLER TRANSCUTANEO)

FLOW (Q)

Endothelium

FLOW (Q)

SHEAR STRESS (ττττ) = 4µQππππR2

ENDOTHELIUM-INDEPENDENT STIMULI

• NITRATES:SODIUM NITROPRUSSIDE, NITROGLYCERIN

• DIRECT VASODILATORS:PAPAVERINE, ADENOSINE (?)

NON INVASIVE EVALUATION OF ENDOTHELIAL FUNCTION IN THE BRACHIAL ARTERY

Technique

• Subject preparation• Equipment: high resolution ultrasound with broad-band ( 7 to 12

Mhz) linear array transducers • Image acquisition: 2D gray-scale imaging, Stereotactic probe-

holding device

NON INVASIVE EVALUATION OF ENDOTHELIAL FUNCTION IN THE BRACHIAL ARTERY

FMD endothelium-dependent

TIMING OF FMD

Sinoway et al. Circ Res 1989

STIMULUS: REACTIVE HYPEREMIA

BASELINE AFTER ISCHEMIA

Flow velocity

Reactive hyperemia is calculated as maximal per cen t flow increment above baseline after ischemia.

Arterial flow: flow velocity x heart rate x vessel area (ππππr2).

Flow velocity (Doppler)

NO IS RESPONSIBLE FOR FMD OF HUMAN PERIPHERAL CONDUIT ARTERIES IN VIVO

• JOANNIDES R • JOANNIDES R CIRCULATION 1995

• LIEBERMAN Am J Cardiol 1996

FMD following wrist and upper arm occlusion in humans: the contribution of NO

Doshi S Clinical Science 2001

• Dilatation following upper armocclusion is greater than thatobservedafterwrist occlusion.observedafterwrist occlusion.

• L-NMMA infusion revealedthat FMD following upper armocclusion is substantialcomponent not mediated byNO, most probablyrelated totissue ischaemiaaround thebrachial artery.

NON INVASIVE EVALUATION OF ENDOTHELIAL FUNCTION IN THE BRACHIAL ARTERY

FMD endothelium-independent: NTG

NON INVASIVE EVALUATION OF ENDOTHELIAL FUNCTION IN THE BRACHIAL ARTERY

Analysis: Anatomic landmarks

1. Caliper measurement1. Caliper measurement

2. Computerized measurement

CALIPER MEASUREMENT (manual) OF FMD

0.340

0.360

0.380

-360 -300 -240 -180 -120 -60 0 60 120 180

TIME (seconds)

diam

eter

(cm

)

baseline: 0.349 cm

cuff inflation cuff deflation

60 s: 0.373 cm FMD = 6.9%

AFTER REACTIVE

HYPEREMIABASELINE

• 40 HEALTHY SUBJECTS (21-51 YEARS)• 4 MEASUREMENTS (BASELINE, 1-2 DAYS, 1-2 WEEKS, 2-4 MONTHS)• FMD 7±1% (RANGE 0-17%)• REPRODUCIBILITY (INTEROBSERVER VARIABILITY): 1.2±0. 4 (17%)• VARIATION COEFFICIENT AMONG DIFFERENT MEASUREMENTS: 1.8 (25%)

SORENSEN KE ET AL. BR HEART J 1995

COMPUTERIZED MEASUREMENT

edge-detection software system

ENDOTHELIUM-DEPENDENT RESPONSE

6

810

% o

f dia

met

er FMD max

* flow velocity by doppler

FMD 60 s

FMD AUC

-4-2

024

-360 -300 -240 -180 -120 -60 0 60 120 180

seconds%

of d

iam

eter

ISCHEMIA

* *

* doppler

COMPUTERIZED MEASUREMENT

40 healthy subjects (26-56 years)

2 measurements in the same day

40 healthy subjects (21-51 years)4 measurements

(baseline, 1 -2 days, 1 -2 weeks, 2 -4 months)

CALIPER MEASUREMENT (manual) OF FMD

NON INVASIVE EVALUATION OF ENDOTHELIAL FUNCTION IN THE BRACHIAL ARTERY

Validation and Relevance of The Method

• fmd 7±1% (range 0-17%)• reproducibility (interobserver

variability): 1.2±0.4 (17%)• var. coeff. : 1.8 (25%)Sorensen ke et al. br heart j 1995

• max FMD (56 sec) 6.5±2.9%Var. Coeff: 10%• FMD (60 sec) 4.2±2.5%Var. Coeff: 18 %• FMD AUC (56 sec) 525±260%Var. Coeff: 21 %• max FMD, FMD 60 sec e FMD AUC are

significantly related (r=0.75-0.82) Beux F Ultrasound Med Biol 2001

(baseline, 1 -2 days, 1 -2 weeks, 2 -4 months)

7

8

9

10Brachial artery

diameter(% change)

NormalCAD**

* p < 0.05* p < 0.05

CLINICAL EVALUATION OF ENDOTHELIUMCLINICAL EVALUATION OF ENDOTHELIUMFlow- mediated vasodilation in patients with CAD

0

1

2

3

4

5

6

Reactive hyperemia Nitroglycerin

E. H. Lieberman Am. J. of Cardiol.1996

* p < 0.05* p < 0.05

**

8

10

12

14

16

18

(n= 26)(n=11)(n=7)

CLOSE RELATION OF ENDOTHELIAL FUNCTION IN THE HUMANCLOSE RELATION OF ENDOTHELIAL FUNCTION IN THE HUMANCORONARY AND PERIPHERAL CIRCULATIONSCORONARY AND PERIPHERAL CIRCULATIONS

*

BRACHIAL ARTERY

DIAMETER( % change)

NON INVASIVE EVALUATION OF ENDOTHELIAL FUNCTION IN THE BRACHIAL ARTERY

Validation and Relevance of The Method

0

2

4

6

8

(n= 26) (n=11) (n=7)

T. Anderson et al. JACC 1995

* *

**P < 0.001

*P = 0.08

*

CAD (angio) and

Coronary Endothelial Dysfunction

No CAD(angio) and

Coronary Endothelial Dysfunction

No CAD (angio)and

Normal Coronary Endothelial function

REACTIVEHYPEREMIA

Ultrasound Study

Early Disease• Asymptomatic Children and young

adults with RF for ATS- Lancet 1992• Hypercolesterolemia in Children -J

Studies of Reversibility

• Antioxidant Vit.C in CAD-Circul.1996• Hypercolesterolemia in Children -J

Clin Invest 1994• Active Smoking- Circul. 1993• Passive Smoking- EHJ• Diabete Mellitus JACC 1996• Hyperhomocisteinemia- Circul 1997

Circul.1996• L-arginina in Hypercholest.- J

Clin Invest• Estrogen Therapy- Clin

Endocr.

EVALUATION OF ENDOTHELIAL FUNCTION IN THE BRACHIAL ARTERY

ADVANTAGES• non invasive procedure• large repeatibility over the time• correlation with coronary circulation• correlation with clinical end -points• correlation with clinical end -points

DISADVANTAGES• reproducibility• low degree of response →→→→ large number of

subjects to study• limited possibility to assess mechanisms

European Heart Journal (2005) 26, 363–368

GUIDELINESGUIDELINESFOR THE FOR THE

ULTRASOUNDULTRASOUNDASSESEMENTASSESEMENT

OFOFENDOTHELIALENDOTHELIALENDOTHELIALENDOTHELIALDEPENDENTDEPENDENT

FMDFMDOFOF

BRACHIAL BRACHIAL ARTERYARTERY

JACCJACC20022002

Ruolo della disfunzione endoteliale nella stratificazione del rischio cardiovascolare

LongLongLongLong----Term FollowTerm FollowTerm FollowTerm Follow----Up of Patients With Mild Coronary Up of Patients With Mild Coronary Up of Patients With Mild Coronary Up of Patients With Mild Coronary Artery Disease and Endothelial DysfunctionArtery Disease and Endothelial DysfunctionArtery Disease and Endothelial DysfunctionArtery Disease and Endothelial Dysfunction

Suwaidi J, Circulation. 2000;101:948• FollowFollowFollowFollow----upupupup (average(average(average(average 28282828 monthmonthmonthmonth;;;; 11111111 totototo 52525252 months)months)months)months) waswaswaswas obtainedobtainedobtainedobtained inininin 157157157157 patientspatientspatientspatients withwithwithwith mildlymildlymildlymildly

diseaseddiseaseddiseaseddiseased coronarycoronarycoronarycoronary arteriesarteriesarteriesarteries (angiographically(angiographically(angiographically(angiographically coronarycoronarycoronarycoronary arteryarteryarteryartery lesionslesionslesionslesions <<<<40404040%%%% lumenlumenlumenlumen diameterdiameterdiameterdiameterstenosisstenosisstenosisstenosis withoutwithoutwithoutwithout evidenceevidenceevidenceevidence ofofofof coronarycoronarycoronarycoronary spasm)spasm)spasm)spasm)

• CoronaryCoronaryCoronaryCoronary vascularvascularvascularvascular reactivityreactivityreactivityreactivity evaluationevaluationevaluationevaluation:::: gradedgradedgradedgraded administrationadministrationadministrationadministration ofofofof intracoronaryintracoronaryintracoronaryintracoronary acetylcholine,acetylcholine,acetylcholine,acetylcholine,adenosine,adenosine,adenosine,adenosine, andandandand nitroglycerinnitroglycerinnitroglycerinnitroglycerin andandandand intracoronaryintracoronaryintracoronaryintracoronary ultrasoundultrasoundultrasoundultrasound atatatat thethethethe timetimetimetime ofofofof diagnosticdiagnosticdiagnosticdiagnostic studystudystudystudy

• PatientsPatientsPatientsPatients werewerewerewere divideddivideddivideddivided onononon thethethethe basisbasisbasisbasis ofofofof theirtheirtheirtheir responseresponseresponseresponse totototo acetylcholineacetylcholineacetylcholineacetylcholine intointointointo 3333 groupsgroupsgroupsgroups:::: groupgroupgroupgroup 1111(n=(n=(n=(n=83838383),),),), patientspatientspatientspatients withwithwithwith normalnormalnormalnormal endothelialendothelialendothelialendothelial functionfunctionfunctionfunction;;;; groupgroupgroupgroup 2222 (n=(n=(n=(n=32323232),),),), patientspatientspatientspatients withwithwithwith mildmildmildmild endothelialendothelialendothelialendothelialdysfunctiondysfunctiondysfunctiondysfunction;;;; andandandand groupgroupgroupgroup 3333 (n=(n=(n=(n=42424242),),),), patientspatientspatientspatients withwithwithwith severesevereseveresevere endothelialendothelialendothelialendothelial dysfunctiondysfunctiondysfunctiondysfunction....

174200 1415†

% C

hang

e C

BF

(Ach

)

174

24

-38-500

50

100150

200

Group 1 Group 2 Group 3

*

0 0

14

0

5

10

15

Group 1 Group 2 Group 3

*

% C

hang

e C

BF

(Ach

)

% C

ardi

ac e

vent

s

CBF: Volumetric coronary blood flow;CBF: Volumetric coronary blood flow;CBF: Volumetric coronary blood flow;CBF: Volumetric coronary blood flow;Normal coronary endothelium: CBF of >50%; Normal coronary endothelium: CBF of >50%; Normal coronary endothelium: CBF of >50%; Normal coronary endothelium: CBF of >50%;

mild: CBF between 0% to 50%; mild: CBF between 0% to 50%; mild: CBF between 0% to 50%; mild: CBF between 0% to 50%; severe: percent change in CBF <0%. severe: percent change in CBF <0%. severe: percent change in CBF <0%. severe: percent change in CBF <0%.

P<0.001

P<0.05

LongLongLongLong----Term FollowTerm FollowTerm FollowTerm Follow----Up of Patients With Mild Coronary Up of Patients With Mild Coronary Up of Patients With Mild Coronary Up of Patients With Mild Coronary Artery Disease and Endothelial DysfunctionArtery Disease and Endothelial DysfunctionArtery Disease and Endothelial DysfunctionArtery Disease and Endothelial Dysfunction

Suwaidi J, Circulation. 2000;101:948

September

1995

ECG of 58ECG of 58ECG of 58ECG of 58----yearyearyearyear----old patient at time of endothelial function evaluation old patient at time of endothelial function evaluation old patient at time of endothelial function evaluation old patient at time of endothelial function evaluation (September 7, 1995).(September 7, 1995).(September 7, 1995).(September 7, 1995). Mean Mean Mean Mean

B, ECG when patient presented with 3 hours of typical anginal pain and elevated creatine B, ECG when patient presented with 3 hours of typical anginal pain and elevated creatine B, ECG when patient presented with 3 hours of typical anginal pain and elevated creatine B, ECG when patient presented with 3 hours of typical anginal pain and elevated creatine kinase to 800 U kinase to 800 U kinase to 800 U kinase to 800 U (July 6,1997),(July 6,1997),(July 6,1997),(July 6,1997), revealing new Trevealing new Trevealing new Trevealing new T----wave inversion in anterolateral leads. wave inversion in anterolateral leads. wave inversion in anterolateral leads. wave inversion in anterolateral leads.

July, 1997

ECG of 58ECG of 58ECG of 58ECG of 58----yearyearyearyear----old patient at time of endothelial function evaluation old patient at time of endothelial function evaluation old patient at time of endothelial function evaluation old patient at time of endothelial function evaluation (September 7, 1995).(September 7, 1995).(September 7, 1995).(September 7, 1995). Mean Mean Mean Mean percent change in CBF in response to acetylcholine was percent change in CBF in response to acetylcholine was percent change in CBF in response to acetylcholine was percent change in CBF in response to acetylcholine was ----35%.35%.35%.35%.

LongLongLongLong----Term FollowTerm FollowTerm FollowTerm Follow----Up of Patients With Mild Coronary Up of Patients With Mild Coronary Up of Patients With Mild Coronary Up of Patients With Mild Coronary Artery Disease and Endothelial DysfunctionArtery Disease and Endothelial DysfunctionArtery Disease and Endothelial DysfunctionArtery Disease and Endothelial Dysfunction

Suwaidi J, Circulation. 2000;101:948

A,A,A,A, CoronaryCoronaryCoronaryCoronary angiogramangiogramangiogramangiogram (left(left(left(left coronarycoronarycoronarycoronaryarteryarteryarteryartery inininin leftleftleftleft cranialcranialcranialcranial view)view)view)view) ofofofof 51515151----yearyearyearyear----oldoldoldold patientpatientpatientpatient atatatat timetimetimetime ofofofof endothelialendothelialendothelialendothelialfunctionfunctionfunctionfunction evaluationevaluationevaluationevaluation (January(January(January(January 11111111,,,,1996199619961996),),),), demonstratingdemonstratingdemonstratingdemonstrating 20202020%%%% diameterdiameterdiameterdiameterstenosisstenosisstenosisstenosis inininin midmidmidmid----LADLADLADLAD (arrow)(arrow)(arrow)(arrow).... MeanMeanMeanMeanpercentpercentpercentpercent changechangechangechange inininin CBFCBFCBFCBF inininin responseresponseresponseresponse totototoacetylcholineacetylcholineacetylcholineacetylcholine waswaswaswas ----50505050%%%%.... January acetylcholineacetylcholineacetylcholineacetylcholine waswaswaswas ----50505050%%%%....

B,B,B,B, PatientPatientPatientPatient whowhowhowho presentedpresentedpresentedpresented onononon AugustAugustAugustAugust 1111,,,,1997199719971997,,,, withwithwithwith progressiveprogressiveprogressiveprogressive exertionalexertionalexertionalexertionalanginaanginaanginaangina andandandand dyspneadyspneadyspneadyspnea.... ExerciseExerciseExerciseExercisesestamibisestamibisestamibisestamibi revealedrevealedrevealedrevealed large,large,large,large, reversiblereversiblereversiblereversibleanterolateralanterolateralanterolateralanterolateral perfusionperfusionperfusionperfusion defectdefectdefectdefect,,,, andandandandrepeatedrepeatedrepeatedrepeated coronarycoronarycoronarycoronary angiographyangiographyangiographyangiographyrevealedrevealedrevealedrevealed 95959595%%%% diameterdiameterdiameterdiameter stenosisstenosisstenosisstenosis ininininmidmidmidmid----LADLADLADLAD (arrow)(arrow)(arrow)(arrow).... PatientPatientPatientPatient successfullysuccessfullysuccessfullysuccessfullyunderwentunderwentunderwentunderwent percutaneouspercutaneouspercutaneouspercutaneous coronarycoronarycoronarycoronaryangioplastyangioplastyangioplastyangioplasty andandandand stentstentstentstent placementplacementplacementplacement withwithwithwithresolutionresolutionresolutionresolution ofofofof symptomssymptomssymptomssymptoms....

January

1996

Aug.

1997

Peripheral vascular endothelial function testing as Peripheral vascular endothelial function testing as Peripheral vascular endothelial function testing as Peripheral vascular endothelial function testing as a noninvasive indicator of coronary artery disease a noninvasive indicator of coronary artery disease a noninvasive indicator of coronary artery disease a noninvasive indicator of coronary artery disease

• SubjectsSubjectsSubjectsSubjects withwithwithwith CADCADCADCAD bybybyby ExMPIExMPIExMPIExMPI (n(n(n(n ==== 23232323)))) hadhadhadhad aaaalowerlowerlowerlower FMDFMDFMDFMD ((((6666....3333 ±±±± 0000....7777%%%%)))) thanthanthanthan thosethosethosethose withoutwithoutwithoutwithoutCADCADCADCAD bybybyby ExMPIExMPIExMPIExMPI (n(n(n(n ==== 71717171)))) ((((10101010....5555 ±±±± 0000....6666%%%%;;;; PPPP ====0000....0004000400040004))))....

• FlowFlowFlowFlow----mediatedmediatedmediatedmediated dilationdilationdilationdilation waswaswaswas highlyhighlyhighlyhighlypredictivepredictivepredictivepredictive forforforfor CADCADCADCAD withwithwithwith anananan oddsoddsoddsodds ratioratioratioratio ofofofof1111....32323232 forforforfor eacheacheacheach percentpercentpercentpercent decreasedecreasedecreasedecrease inininin FMDFMDFMDFMD (p(p(p(p ====predictivepredictivepredictivepredictive forforforfor CADCADCADCAD withwithwithwith anananan oddsoddsoddsodds ratioratioratioratio ofofofof1111....32323232 forforforfor eacheacheacheach percentpercentpercentpercent decreasedecreasedecreasedecrease inininin FMDFMDFMDFMD (p(p(p(p ====0000....001001001001))))....

• TwentyTwentyTwentyTwenty----oneoneoneone ofofofof 23232323 subjectssubjectssubjectssubjects whowhowhowho werewerewerewerepositivepositivepositivepositive forforforfor ExMPIExMPIExMPIExMPI hadhadhadhad anananan FMDFMDFMDFMD <<<<10101010%%%%(sensitivity(sensitivity(sensitivity(sensitivity 91919191%%%%),),),), whereaswhereaswhereaswhereas onlyonlyonlyonly twotwotwotwo ofofofof 40404040subjectssubjectssubjectssubjects withwithwithwith anananan FMDFMDFMDFMD 10101010%%%% werewerewerewere ExMPIExMPIExMPIExMPI----positivepositivepositivepositive (negative(negative(negative(negative predictivepredictivepredictivepredictive valuevaluevaluevalue:::: 95959595%%%%))))....

• IndividualsIndividualsIndividualsIndividuals withwithwithwith anananan FMDFMDFMDFMD <<<<10101010%%%% exercisedexercisedexercisedexercisedforforforfor aaaa shortershortershortershorter durationdurationdurationduration thanthanthanthan thosethosethosethose withwithwithwith ananananFMDFMDFMDFMD 10101010%%%% ((((456456456456 ±±±± 24242424 vsvsvsvs.... 544544544544 ±±±± 31313131 s,s,s,s,respectivelyrespectivelyrespectivelyrespectively;;;; PPPP ==== 0000....02020202))))....

(ExMPI)(ExMPI)(ExMPI)(ExMPI)

Kuvin JT, JACC Vol.38,7 2001:1843Kuvin JT, JACC Vol.38,7 2001:1843Kuvin JT, JACC Vol.38,7 2001:1843Kuvin JT, JACC Vol.38,7 2001:1843

Impaired Flow-Mediated Dilation and Risk of Restenosis inPatients Undergoing Coronary Stent Implantation

• Was studied 136 patients with single-vesselCAD undergoing percutaneous coronaryintervention (PCI) with stenting and at least6 months of follow-up.

• All patients underwent ultrasound detectionof brachial artery reactivity 30 days afterPCIPCI

Risk Stratification for Postoperative Cardiovascular Events via Noninvasive Assessment of Endothelial Function

Gokce N, Circulation. 2002;105:1567-1572• WasWasWasWas preoperativelypreoperativelypreoperativelypreoperatively examinedexaminedexaminedexamined brachialbrachialbrachialbrachial

arteryarteryarteryartery vasodilationvasodilationvasodilationvasodilation usingusingusingusing ultrasoundultrasoundultrasoundultrasound inininin187187187187 patientspatientspatientspatients undergoingundergoingundergoingundergoing vascularvascularvascularvascularsurgerysurgerysurgerysurgery.... PatientsPatientsPatientsPatients werewerewerewere prospectivelyprospectivelyprospectivelyprospectivelyfollowedfollowedfollowedfollowed forforforfor 30303030 daysdaysdaysdays andandandand 1111....2222 yearsyearsyearsyears afterafterafteraftersurgerysurgerysurgerysurgery

• FortyFortyFortyForty----fivefivefivefive patientspatientspatientspatients hadhadhadhad aaaa postoperativepostoperativepostoperativepostoperativeevent,event,event,event, includingincludingincludingincluding cardiaccardiaccardiaccardiac deathdeathdeathdeath ((((3333),),),),myocardialmyocardialmyocardialmyocardial infarctioninfarctioninfarctioninfarction ((((12121212),),),), unstableunstableunstableunstableangina/ischemicangina/ischemicangina/ischemicangina/ischemic ventricularventricularventricularventricular fibrillationfibrillationfibrillationfibrillation((((2222),),),), strokestrokestrokestroke ((((3333),),),), orororor elevatedelevatedelevatedelevated troponintroponintroponintroponin I,I,I,I,

High (>8.1%) High (>8.1%) High (>8.1%) High (>8.1%)

Low tertile (<4.2%) Low tertile (<4.2%) Low tertile (<4.2%) Low tertile (<4.2%)

Middle (4.2Middle (4.2Middle (4.2Middle (4.2––––8.1%)8.1%)8.1%)8.1%)

High (>8.1%) High (>8.1%) High (>8.1%) High (>8.1%)

((((2222),),),), strokestrokestrokestroke ((((3333),),),), orororor elevatedelevatedelevatedelevated troponintroponintroponintroponin I,I,I,I,reflectingreflectingreflectingreflecting myocardialmyocardialmyocardialmyocardial necrosisnecrosisnecrosisnecrosis ((((25252525))))....

• PreoperativePreoperativePreoperativePreoperative endotheliumendotheliumendotheliumendothelium----dependentdependentdependentdependentFMDFMDFMDFMD waswaswaswas significantlysignificantlysignificantlysignificantly lowerlowerlowerlower inininin patientspatientspatientspatientswithwithwithwith anananan eventeventeventevent ((((4444....9999±±±±3333....1111%%%%)))) thanthanthanthan inininin thosethosethosethosewithoutwithoutwithoutwithout anananan eventeventeventevent ((((7777....3333±±±±5555%%%%;;;; PPPP<<<<0000....001001001001),),),),whereaswhereaswhereaswhereas endotheliumendotheliumendotheliumendothelium----independentindependentindependentindependentvasodilationvasodilationvasodilationvasodilation totototo nitroglycerinnitroglycerinnitroglycerinnitroglycerin waswaswaswas similarsimilarsimilarsimilarinininin bothbothbothboth groupsgroupsgroupsgroups....

• WhenWhenWhenWhen aaaa flowflowflowflow----mediatedmediatedmediatedmediated dilationdilationdilationdilation cutpointcutpointcutpointcutpointofofofof 8888....1111%%%% waswaswaswas used,used,used,used, endothelialendothelialendothelialendothelial functionfunctionfunctionfunctionhadhadhadhad aaaa sensitivitysensitivitysensitivitysensitivity ofofofof 95959595%%%%,,,, specificityspecificityspecificityspecificity ofofofof37373737%%%%,,,, andandandand negativenegativenegativenegative predictivepredictivepredictivepredictive valuevaluevaluevalue ofofofof98989898%%%% forforforfor eventseventseventsevents....

Low tertile (<4.2%) Low tertile (<4.2%) Low tertile (<4.2%) Low tertile (<4.2%)

Middle (4.2Middle (4.2Middle (4.2Middle (4.2––––8.1%)8.1%)8.1%)8.1%)

Endothelial Dysfunction and Cardiovascular Risk Prediction in Peripheral Arterial Disease Additive Value of FMD to Ankle-BrachialPressure Index

• 131131131131 patientspatientspatientspatients monitoredmonitoredmonitoredmonitored forforforfor aaaa meanmeanmeanmean ofofofof 23232323±±±±10101010 monthsmonthsmonthsmonths....

• 18181818 hadhadhadhad aaaa coronarycoronarycoronarycoronary event,event,event,event, 12121212 aaaacerebrovascularcerebrovascularcerebrovascularcerebrovascular event,event,event,event, andandandand 9999 aaaaperipheralperipheralperipheralperipheral eventeventeventevent....

• TheTheTheThe medianmedianmedianmedian FMDFMDFMDFMD waswaswaswas lowerlowerlowerlower inininin patientspatientspatientspatients

FMD > median FMD < median FMD > median FMD < median FMD > median FMD < median FMD > median FMD < median

• TheTheTheThe medianmedianmedianmedian FMDFMDFMDFMD waswaswaswas lowerlowerlowerlower inininin patientspatientspatientspatientswithwithwithwith anananan eventeventeventevent thanthanthanthan inininin thosethosethosethose withoutwithoutwithoutwithout ((((5555....8888%%%%versusversusversusversus 7777....6666%%%%,,,, PPPP0000....05050505))))

• TheTheTheThe cardiovascularcardiovascularcardiovascularcardiovascular eventeventeventevent raterateraterate waswaswaswas higherhigherhigherhigherinininin patientspatientspatientspatients withwithwithwith FMDFMDFMDFMD belowbelowbelowbelow thethethethe medianmedianmedianmedianversusversusversusversus thosethosethosethose withwithwithwith FMDFMDFMDFMD aboveaboveaboveabove thethethethe medianmedianmedianmedian((((PPPP0000....001001001001))))....

• BelowBelowBelowBelow----medianmedianmedianmedian ABPIABPIABPIABPI andandandand FMDFMDFMDFMD combinedcombinedcombinedcombinedwaswaswaswas moremoremoremore accurateaccurateaccurateaccurate inininin predictingpredictingpredictingpredicting riskriskriskrisk

Brevetti G, Circulation. 2003; 108:2093

Prognostic Role of Reversible EndothelialPrognostic Role of Reversible EndothelialPrognostic Role of Reversible EndothelialPrognostic Role of Reversible EndothelialDysfunction in Hypertensive Postmenopausal WomenDysfunction in Hypertensive Postmenopausal WomenDysfunction in Hypertensive Postmenopausal WomenDysfunction in Hypertensive Postmenopausal Women

• AAAA totaltotaltotaltotal ofofofof 400400400400 consecutiveconsecutiveconsecutiveconsecutivepostmenopausalpostmenopausalpostmenopausalpostmenopausal womenwomenwomenwomen withwithwithwithmildmildmildmild----totototo----moderatemoderatemoderatemoderate hypertensionhypertensionhypertensionhypertensionandandandand impairedimpairedimpairedimpaired FMDFMDFMDFMD underwentunderwentunderwentunderwentultrasonographyultrasonographyultrasonographyultrasonography ofofofof thethethethe brachialbrachialbrachialbrachialarteryarteryarteryartery atatatat baselinebaselinebaselinebaseline andandandand afterafterafterafter sixsixsixsixmonths,months,months,months, whilewhilewhilewhile optimaloptimaloptimaloptimal controlcontrolcontrolcontrol ofofofofbloodbloodbloodblood pressurepressurepressurepressure waswaswaswas achievedachievedachievedachievedusingusingusingusing antihypertensiveantihypertensiveantihypertensiveantihypertensive therapytherapytherapytherapy....usingusingusingusing antihypertensiveantihypertensiveantihypertensiveantihypertensive therapytherapytherapytherapy....

• TheyTheyTheyThey werewerewerewere thenthenthenthen followedfollowedfollowedfollowed upupupup forforforfor aaaameanmeanmeanmean periodperiodperiodperiod ofofofof 67676767 monthsmonthsmonthsmonths (range(range(range(range57575757 totototo 78787878))))....

Modena M.G. J Am Coll Cardiol 2002;40:505Modena M.G. J Am Coll Cardiol 2002;40:505Modena M.G. J Am Coll Cardiol 2002;40:505Modena M.G. J Am Coll Cardiol 2002;40:505

CONCLUSIONICONCLUSIONI

Lo Lo Lo Lo funzione endotelialefunzione endotelialefunzione endotelialefunzione endoteliale rappresenta un rappresenta un rappresenta un rappresenta un marker della “marker della “marker della “marker della “salutesalutesalutesalute” ” ” ” vascolarevascolarevascolarevascolare e gioca un ruolo importante nella patogenesi e e gioca un ruolo importante nella patogenesi e e gioca un ruolo importante nella patogenesi e e gioca un ruolo importante nella patogenesi e

nella prognosi delle malattie cardiovascolari.nella prognosi delle malattie cardiovascolari.nella prognosi delle malattie cardiovascolari.nella prognosi delle malattie cardiovascolari.LoLoLoLo studio della funzione endotelialestudio della funzione endotelialestudio della funzione endotelialestudio della funzione endoteliale rappresenta unrappresenta unrappresenta unrappresenta un valido valido valido valido

Lo Lo Lo Lo funzione endotelialefunzione endotelialefunzione endotelialefunzione endoteliale rappresenta un rappresenta un rappresenta un rappresenta un marker della “marker della “marker della “marker della “salutesalutesalutesalute” ” ” ” vascolarevascolarevascolarevascolare e gioca un ruolo importante nella patogenesi e e gioca un ruolo importante nella patogenesi e e gioca un ruolo importante nella patogenesi e e gioca un ruolo importante nella patogenesi e

nella prognosi delle malattie cardiovascolari.nella prognosi delle malattie cardiovascolari.nella prognosi delle malattie cardiovascolari.nella prognosi delle malattie cardiovascolari.LoLoLoLo studio della funzione endotelialestudio della funzione endotelialestudio della funzione endotelialestudio della funzione endoteliale rappresenta unrappresenta unrappresenta unrappresenta un valido valido valido valido

Dipartimento Cardio Toracico – Università di Pisa

LoLoLoLo studio della funzione endotelialestudio della funzione endotelialestudio della funzione endotelialestudio della funzione endoteliale rappresenta unrappresenta unrappresenta unrappresenta un valido valido valido valido strumento clinico.strumento clinico.strumento clinico.strumento clinico.

La mancanza di una La mancanza di una La mancanza di una La mancanza di una procedura standardizzataprocedura standardizzataprocedura standardizzataprocedura standardizzata dello studio dello studio dello studio dello studio della funzione endoteliale ne limitano a tutt’oggi l’impiego della funzione endoteliale ne limitano a tutt’oggi l’impiego della funzione endoteliale ne limitano a tutt’oggi l’impiego della funzione endoteliale ne limitano a tutt’oggi l’impiego

nella pratica clinica quotidiana.nella pratica clinica quotidiana.nella pratica clinica quotidiana.nella pratica clinica quotidiana.

LoLoLoLo studio della funzione endotelialestudio della funzione endotelialestudio della funzione endotelialestudio della funzione endoteliale rappresenta unrappresenta unrappresenta unrappresenta un valido valido valido valido strumento clinico.strumento clinico.strumento clinico.strumento clinico.

La mancanza di una La mancanza di una La mancanza di una La mancanza di una procedura standardizzataprocedura standardizzataprocedura standardizzataprocedura standardizzata dello studio dello studio dello studio dello studio della funzione endoteliale ne limitano a tutt’oggi l’impiego della funzione endoteliale ne limitano a tutt’oggi l’impiego della funzione endoteliale ne limitano a tutt’oggi l’impiego della funzione endoteliale ne limitano a tutt’oggi l’impiego

nella pratica clinica quotidiana.nella pratica clinica quotidiana.nella pratica clinica quotidiana.nella pratica clinica quotidiana.