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.
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