CORSO DI CERTIFICAZIONE DI COMPETENZA
in ECOGRAFIA VASCOLARE GENERALE
Lezione 2
Studio ecografico dell’aterosclerosi
pre-clinica:spessore mio-intimale e
funzione endoteliale
Settore formazione 2007-2009: Direttore: Paolo G. Pino
Marco Campana, Antonella Moreo, Fausto Rigo, Ketty Savino
ATEROSCLEROSI
Recenti scoperte
Condizioni morfofunzionali che precedono il
restringimento del vaso e l’inizio dei sintomi:
• DISFUNZIONE ENDOTELIALE
• INFIAMMAZIONE
Carattezzazione Placca
• CALCIFICAZIONE
• Ossidazione lipoproteine
Precoci modificazioni molecolari e
cellulari del processo aterogenetico
• Adesione monociti
• Formazione Foam cells
• Ispessimento parietale
Ecografia vascolare
• A causa del remodeling della tunica media
lo sviluppo iniziale della placca
aterosclerotica non è accompagnato da
una riduzione del lume vascolare.
• In questa fase non sono osservabili
modificazioni angiografiche, mentre
l’Ecografia è in grado di visualizzare le
alterazioni morfo-funzionali della parete
arteriosa
Dipartimento CardioCardio-Toracico
Università di Pisa
METODI DI VALUTAZIONE
ANATOMICA
- ECOGRAFIA TRANSCUTANEA
(arterie carotidi)
VALUTAZIONE SMI
- ULTRASONOGRAFIA INTRAVSCOLARE
(arterie periferiche)
SPESSORE INTIMALE
monocita
Danno e
disfunzione
endoteliale
cell.
schiumosa
Espressione molecole I macrofagi fagocitano Migrazione e
di adesione, adesione ox-LDL attraverso
proliferazione
miociti
migrazione monociti scavenger receptor
Placca
ateromasica
SPESSORE MEDIOMEDIO-INTIMALE CAROTIDEO
DEFINIZIONE
• Spessore del complesso intima
intima--media della parete
carotidea
• Misurabile come distanza tra l’interfaccia sangue
sangue-intima e l’interfaccia mediamedia-avventizia
Dip. CardioCardio-Toracico - Università di Pisa
IMPORTANZA CLINICA DELLO
SPESSORE MEDIO-INTIMALE CAROTIDEO
• Marker di aterosclerosi periferica
• Marker di aterosclerosi coronarica
• Studio dell’efficacia degli interventi terapeutici
Dipartimento CardioCardio-Toracico - Università di Pisa
VALUTAZIONE DELL’IMT
ANATOMIA
PA
ECOGRAFIA
Avventizia
Media
Intima
Lume vascolare
PP
Intima
Media
Avventizia
Dipartimento CardioCardio-Toracico – Università di Pisa
“IMT”
misura
non valida
“IMT”
misura
valida
INTIMA-MEDIA THICKNESS
METHODS OF MEASUREMENT: MANUAL CURSOR PLACEMENT
INTIMA-MEDIA THICKNESS
METHODS OF MEASUREMENT:
AUTOMATED COMPUTERIZED EDGE-DETECTION
INTIMA-MEDIA THICKNESS
METHODS OF MEASUREMENT
The three most frequently used
measurements in clinical trials are as
follows:
• Mean of the maximum IMT of the 4
far walls of the carotid bifurcations
and distal common carotid arteries
(CBM max)
• Mean maximum thickness (M max) of
up to 12 different sites (right and left,
near and far walls, distal common,
bifurcation and proximal internal
carotid)
• Overall single maximum IMT (T max)
Dipartimento CardioCardio-Toracico - Università
di Pisa
Doppler TSA- IMT
• Misurare IMT sulla parete posteriore della carotide comune ad
1 cm dalla biforcazione in un segmento di carotide di circa 1 cm,
prendendo almeno 2- 3 proiezioni (valore medio o massimo)
• immagini “zoomate”
• misurazioni ripetute o operatori indipendenti
• segnare le misure IMT delle 2 CC separatamente
• segnalare se valore medio o massimo
SPESSORE MEDIO-INTIMALE CAROTIDEO
METODI DI CALCOLO
RIPRODUCIBILITA’ DATI
variabilita’ intra
ed interosservatore ?
Dipartimento CardioCardio-Toracico - Università di Pisa
Complesso intima-media
Correlazione con fattori di rischio CV
Età, familiarità per malattie CV
Fumo
Diabete, sindrome metabolica & insulino-resistenza
Ipertensione arteriosa, ipertrofia ventricolare sin
Dislipidemie ( LDLc, trigliceridi, LP(a), HDLc)
Fattori emocoagulativi ( PAI1, tPA e D-Dimero,
Viscosità plasmatica, WWF, fibrinog., VIIIc)
• Omocisteina
• Nuovi FDR (CMV, Clamidia, parodontopatie, livelli
di antiossidanti, D allele dell’ACE, sideremia e
ferritina)...
•
•
•
•
•
•
Complesso intima-media
Correlazione con score riassuntivo dei fattori di rischio CV
12
6
SMARTscore
9
R = 0,719
p < 0,0001
3
0,2
0
0,4
0,6
0,8
10
Common carotid IMT (mm)
Lupi, ESC 2002
La diagnosi precoce di aterosclerosi coronarica - Torino 20/11/2004
1,2
Complesso intima-media
Correlazione con AS coronarica
Anderson, JACC 1995
La diagnosi precoce di aterosclerosi coronarica - Torino 20/11/2004
Complesso intima-media
Correlazione con malattia AS vascolare (ARIC study)
P<0.01
Burke, Stroke 1995
Complesso intima-media
Correlazione con prognosi (CH Study)
p<0.01 vs 1t Quintile
O’Leary,
’Leary, NEJM 1999
Complesso intima-media
Correlazione con prognosi (CH Study)
Crouse, Circulation 2003
Complesso intima-media
End-point surrogati e studi di intervento farmacologico
p<0.05 vs Pravastatina
Taylor, Circulation 2002 (ARBITER study)
Lo Studio della
Funzione Endoteliale
L’ENDOTELIO NELLA PATOLOGIA CARDIOVASCOLARE
“ ENDOTHELIAL CELLS…(ARE)…MORE THAN
A SHEAT OF NUCLEATED CELLOPHANE”
LORD FLOREY, 1966
RUOLO CENTRALE NELLA REGOLAZIONE
DELL’OMEOSTASI CARDIOCIRCOLATORIA
1998
• TONO VASCOLARE
• ADESIONE E AGGREGAZIONE
PIASTRINICA
• COAGULAZIONE LOCALE
• CRESCITA VASCOLARE
• INFIAMMAZIONE
Malattie Cardiovascolari e Disfunzione Endoteliale
Aterosclerosi
Scompenso
cardiaco
Vasospasmo
Danno
da riperfusione
Trombosi
Iperlipidemia
DISFUNZIONE
ENDOTELIALE
Angiopatia
diabetica
Reazioni immuni
Riocclusione
Infiammazione
Ipertensione
Arteriopatie
obliteranti periferiche
Dipartimento Cardio Toracico – Università di Pisa
How is endothelial
function assessed ?
FISIOLOGIA DELL’ENDOTELIO
SANGUE
CELLULE
• PMN
• Monociti
• Piastrine
ENDOTELIO
MUSCOLATURA
LISCIA
VASCOLARE
FORZE ELASTICHE
• Shear stress
• Pressione
SOSTANZE VASOATTIVE
• Acetilcolina
• Peptidi ( trombina, sostanza P,
vasopressina)
• Chinine (bradichinina)
• Amine (serotonina)
• Nucleotidi (ATP; ADP)
• Metaboliti (leucotriene C4)
“FATTORI DI DERIVAZIONE ENDOTELIALI”
rilasciamento contrazione proliferazione
Dipartimento Cardio Toracico – Università di Pisa
PRINCIPALI MECCANISMI INTRACELLULARI
MEDIANTI L’AZIONE DELL’NO
SHEAR STRESS
BRADICHININA
Ach
M
CELLULA
ENDOTELIALE
L-Arg → R-NO
NO
CELLULA
MUSCOLARE
LISCIA ?
GC
GTP → cGMP
K+
Ca++
?
G-Kinasi
Ca++/Mg++
ATPasi
Ca++
VASODILATAZIONE
EFFETTI VASOPROTETTORI DELL’ NO
• Vasodilatazione (attraverso rilasciamento della
cellule della muscolatura liscia)
• Inibizione della crescita (attraverso azioni sulla
cellula della muscolatura liscia)
• Inibizione dell’adesione/aggregazione
piastrinica
• Inibizione delle interazioni endotelio/leucociti
• Controbilancia l’effetti dell’anione
superossido?
Dip. Cardio-Toracico - Università di Pisa
ASSESSMENT OF ENDOTHELIAL
FUNCTION IN HUMANS
STUDY OF VASCULAR REACTIVITY
STUDY OF VASCULAR
REACTVITY
•
•
•
•
MICROCIRCULATION:
CORONARY
CUTANEOUS
MUSCLE
• MACROCIRCULATION:
- EPICARDIAL ARTERIES
- BRACHIAL, RADIAL,
FEMORAL ARTERIES
VALUTAZIONE CLINICA DELL’ENDOTELIO
MACROCIRCOLO
CORONARIE
ART.PERIFERICHE
(art.radiale,art.femorale
ANGIOGRAFIA
QUANTITATIVA
+
IVUS
ULTRASONOGRAFIA NON INVASIVA
(ECO--DOPPLER TRANSCUTANEO)
(ECO
Dipartimento Cardio Toracico – Università di Pisa
FLOW (Q)
Endothelium
SHEAR STRESS (ττ) = 4µQ
πR2
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 probeholding 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
(Doppler)
Reactive hyperemia is calculated as maximal per cent flow
increment above baseline after ischemia.
Arterial flow: flow velocity x heart rate x vessel area (π
πr2).
NO IS RESPONSIBLE FOR FMD OF HUMAN PERIPHERAL
CONDUIT ARTERIES IN VIVO
• 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 arm
occlusion is greater than that
observed after wrist occlusion.
• L-NMMA infusion revealed
that FMD following upper arm
occlusion
is
substantial
component not mediated by
NO, most probably related to
tissue ischaemia around the
brachial 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 measurement
2. Computerized measurement
CALIPER MEASUREMENT (manual) OF FMD
baseline: 0.349 cm
diam eter (cm )
BASELINE
-360 -300 -240 -180 -120
cuff inflation
•
•
•
•
•
60 s: 0.373 cm
FMD = 6.9%
0.380
AFTER REACTIVE
HYPEREMIA
0.360
0.340
-60
0
TIME (seconds)
60
120
180
cuff deflation
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
% of diameter
10
8
6
flow velocity by
*
doppler
4
2
0
-360 -300 -240 -180 -120 -60 -2 0
-4
ISCHEMIA
*
*
FMD max
FMD 60 s
FMD AUC
60
120 180
seconds
NON INVASIVE EVALUATION OF ENDOTHELIAL FUNCTION IN THE
BRACHIAL ARTERY
Validation and Relevance of The Method
CALIPER MEASUREMENT
(manual)
OF FMD
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%)
• var. coeff. : 1.8 (25%)
Sorensen ke et al. br heart j 1995
COMPUTERIZED
MEASUREMENT
40 healthy subjects (26-56 years)
2 measurements in the same day
• 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
CLINICAL EVALUATION OF ENDOTHELIUM
Flow- mediated vasodilation in patients with CAD
10
Brachial artery 9
diameter
8
(% change)
7
Normal
CAD
*
* p < 0.05
6
5
*
4
3
2
1
0
Reactive hyperemia
Nitroglycerin
E. H. Lieberman Am. J. of Cardiol.1996
NON INVASIVE EVALUATION OF ENDOTHELIAL FUNCTION IN THE BRACHIAL
ARTERY
Validation and Relevance of The Method
CLOSE RELATION OF ENDOTHELIAL FUNCTION IN THE HUMAN
CORONARY
AND PERIPHERAL CIRCULATIONS
18
16
BRACHIAL
ARTERY
DIAMETER
( % change)
REACTIVE
HYPEREMIA
14
12
10
8
6
(n= 26)
(n=11)
(n=7)
*
* *
4
2
0
(n= 26)
*
P = 0.08
**
P < 0.001
CAD (angio)
and
Coronary Endothelial
Dysfunction
(n=11)
No CAD(angio)
and
Coronary Endothelial
Dysfunction
(n=7)
No CAD (angio)
and
Normal Coronary Endothelial
function
T. Anderson et al. JACC 1995
Ultrasound Study
Early Disease
• Asymptomatic Children and young
adults with RF for ATS- Lancet 1992
• Hypercolesterolemia in Children-J
Clin Invest 1994
• Active Smoking- Circul. 1993
• Passive Smoking-EHJ
• Diabete Mellitus JACC 1996
• Hyperhomocisteinemia- Circul 1997
Studies of
Reversibility
• Antioxidant Vit.C in CADCircul.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
DISADVANTAGES
• reproducibility
• low degree of response→
→ large number of
subjects to study
• limited possibility to assess mechanisms
European Heart Journal (2005) 26, 363–368
GUIDELINES
FOR THE
ULTRASOUND
ASSESEMENT
OF
ENDOTHELIAL
DEPENDENT
FMD
OF
BRACHIAL
ARTERY
JACC
2002
Ruolo della disfunzione endoteliale nella
stratificazione del rischio cardiovascolare
LongLong-Term FollowFollow-Up of Patients With Mild Coronary
Artery Disease and Endothelial Dysfunction
Suwaidi J, Circulation. 2000;101:948
FollowFollow-up (average 28 month;
month; 11 to 52 months) was obtained in 157 patients with mildly
diseased coronary arteries (angiographically coronary artery lesions <40%
40% lumen diameter
stenosis without evidence of coronary spasm)
Coronary vascular reactivity evaluation:
evaluation: graded administration of intracoronary acetylcholine,
adenosine, and nitroglycerin and intracoronary ultrasound at the time of diagnostic study
Patients were divided on the basis of their response to acetylcholine into 3 groups:
groups: group 1
(n=83
(n=83),
83), patients with normal endothelial function;
function; group 2 (n=32
(n=32),
32), patients with mild endothelial
dysfunction;
dysfunction; and group 3 (n=42
(n=42),
42), patients with severe endothelial dysfunction.
dysfunction.
•
% Change CBF (Ach)
•
200
150
100
50
0
-50
174
P<0.001
*
24
*
-38
Group 1
Group 2
CBF: Volumetric coronary blood flow;
Normal coronary endothelium: CBF of >50%;
mild: CBF between 0% to 50%;
severe: percent change in CBF <0%.
†
15
Group 3
% Cardiac events
•
14
10
5
0
P<0.05
0
Group 1
0
Group 2
Group 3
LongLong-Term FollowFollow-Up of Patients With Mild Coronary
Artery Disease and Endothelial Dysfunction
Suwaidi J, Circulation. 2000;101:948
September
1995
ECG of 5858-yearyear-old patient at time of endothelial function evaluation (September 7, 1995). Mean
percent change in CBF in response to acetylcholine was -35%.
July, 1997
B, ECG when patient presented with 3 hours of typical anginal pain and elevated creatine
kinase to 800 U (July 6,1997), revealing new TT-wave inversion in anterolateral leads.
LongLong-Term FollowFollow-Up of Patients With Mild Coronary
Artery Disease and Endothelial Dysfunction
Suwaidi J, Circulation. 2000;101:948
A, Coronary angiogram (left coronary
artery in left cranial view) of 5151-yearyearold patient at time of endothelial
function evaluation (January 11,
11,
1996),
20% diameter
1996), demonstrating 20%
stenosis in midmid-LAD (arrow).
(arrow). Mean
percent change in CBF in response to
acetylcholine was -50%
50%.
B, Patient who presented on August 1,
1997,
1997, with progressive exertional
angina and dyspnea.
dyspnea. Exercise
sestamibi revealed large, reversible
anterolateral perfusion defect,
defect, and
repeated
coronary
angiography
revealed 95%
95% diameter stenosis in
midmid-LAD (arrow).
(arrow). Patient successfully
underwent percutaneous coronary
angioplasty and stent placement with
resolution of symptoms.
symptoms.
January
1996
Aug.
1997
Peripheral vascular endothelial function testing as
a noninvasive indicator of coronary artery disease
•
Subjects with CAD by ExMPI (n = 23)
23) had a
lower FMD (6.3 ± 0.7%) than those without
CAD by ExMPI (n = 71)
71) (10.
10.5 ± 0.6%; P =
0.0004)
0004).
•
Flowdilation
was
highly
Flow-mediated
predictive for CAD with an odds ratio of
1.32 for each percent decrease in FMD (p =
0.001)
001).
•
TwentyTwenty-one of 23 subjects who were
positive for ExMPI had an FMD <10%
10%
(sensitivity 91%
91%), whereas only two of 40
subjects with an FMD 10%
10% were ExMPIExMPIpositive (negative predictive value:
value: 95%
95%).
•
Individuals with an FMD <10%
10% exercised
for a shorter duration than those with an
FMD 10%
10% (456 ± 24 vs.
vs. 544 ± 31 s,
respectively;
respectively; P = 0.02)
02).
(ExMPI)
Kuvin JT, JACC Vol.38,7 2001:1843
Impaired Flow-Mediated Dilation and Risk of Restenosis in
Patients Undergoing Coronary Stent Implantation
•
Was studied 136 patients with single-vessel
CAD undergoing percutaneous coronary
intervention (PCI) with stenting and at least
6 months of follow-up.
•
All patients underwent ultrasound detection
of brachial artery reactivity 30 days after
PCI
Risk Stratification for Postoperative Cardiovascular Events via
Noninvasive Assessment of Endothelial Function
Gokce N, Circulation. 2002;105:1567-1572
•
•
Was preoperatively examined brachial
artery vasodilation using ultrasound in
187 patients undergoing vascular
surgery.
surgery. Patients were prospectively
followed for 30 days and 1.2 years after
surgery
FortyForty-five patients had a postoperative
event, including cardiac death (3),
myocardial infarction (12),
12), unstable
angina/ischemic ventricular fibrillation
(2), stroke (3), or elevated troponin I,
reflecting myocardial necrosis (25)
25).
•
Preoperative
endotheliumendothelium-dependent
FMD was significantly lower in patients
with an event (4.9±3.1%) than in those
without an event (7.3±5%; P<0.001),
001),
whereas
endotheliumendothelium-independent
vasodilation to nitroglycerin was similar
in both groups.
groups.
•
When a flowflow-mediated dilation cutpoint
of 8.1% was used, endothelial function
had a sensitivity of 95%
95%, specificity of
37%
37%, and negative predictive value of
98%
98% for events.
events.
High (>8.1%)
High (>8.1%)
Middle (4.2–
(4.2–8.1%)
Low tertile (<4.2%)
Middle (4.2–
(4.2–8.1%)
Low tertile (<4.2%)
Endothelial Dysfunction and Cardiovascular Risk Prediction in Peripheral
Arterial Disease Additive Value of FMD to Ankle-BrachialPressure Index
FMD > median
•
131 patients monitored for a mean of 23
±10 months.
months.
•
18 had a coronary event,
cerebrovascular event, and
peripheral event.
event.
•
The median FMD was lower in patients
with an event than in those without (5.8%
versus 7.6%, P0.05)
05)
•
The cardiovascular event rate was higher
in patients with FMD below the median
versus those with FMD above the median
(P0.001)
001).
•
BelowBelow-median ABPI and FMD combined
was more accurate in predicting risk
Brevetti G, Circulation. 2003; 108:2093
12
9
a
a
FMD < median
Prognostic Role of Reversible Endothelial
Dysfunction in Hypertensive Postmenopausal Women
• A total of 400 consecutive
postmenopausal women with
mildhypertension
mild-toto-moderate
and impaired FMD underwent
ultrasonography of the brachial
artery at baseline and after six
months, while optimal control of
blood pressure was achieved
using antihypertensive therapy.
therapy.
• They were then followed up for a
mean period of 67 months (range
57 to 78)
78).
Modena M.G. J Am Coll Cardiol 2002;40:505
CONCLUSIONI
Lo funzione endoteliale rappresenta un marker della “salute”
vascolare e gioca un ruolo importante nella patogenesi e
nella prognosi delle malattie cardiovascolari.
Lo studio della funzione endoteliale rappresenta un valido
strumento clinico.
La mancanza di una procedura standardizzata dello studio
della funzione endoteliale ne limitano a tutt’oggi l’impiego
nella pratica clinica quotidiana.
Dipartimento Cardio Toracico – Università di Pisa