EUROECHO 2007 Lisbon, Portugal, December 5 – 8, 2007
Carotid scanning:an extension of the routine echocardiography study?
Damiano Baldassarre
Enrica Grossi Paoletti Centre Department of Pharmacological Sciences,
University of Milanand
Cardiologico Monzino Centre IRCCS
INTIMA-MEDIA THICKNESS AND ATHEROSCLEROSIS
INTIMA MEDIA THICKNESS (IMT)
Near wall
Far wall
COMMON CAROTID BULB
ICA
ECA
Non-invasive marker of early arterial wall alteration.Easily assessed by B-mode ultrasound.
IMT
Ultrasound
Histology
Echogenic lines{{
Lumen
Adventitia
Intima Media Thickness (IMT)Media Adventitia interface
Blood intima interface
Intimal plus media thickness of the arterial wall: a direct measurement with ultrasound imaging.
Pignoli P, Tremoli E, Poli A, Oreste P, Paoletti R. Circulation 1986;74:1399-1406
Methodology for IMT measurement (widely used in clinical research)
PUBMED KEYWORDS: “Carotid IMT” OR "intima media thickness" OR "intimal medial thickness" OR "intima-media thickness" OR "intimal plus medial complex“. Pubmed limits: Humans and English
1986
-1990 19
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Year of publication 20
05
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100
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N° o
f stu
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r yea
r(a
s an
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rest
of t
he s
cien
tific
co
mm
unity
for t
his
met
hodo
logy
)
starting from 1986, when the study of Pignoli was published
the interest increases exponentially with the time(about a 1000 papers published in the last 3 years )
What have we learned from this big amount of information?
CAROTID IMT is associated:• with the same vascular risk factors known to affect
atherosclerosis at coronary level
• with the extent of coronary disease as assessed by angiography
• with the presence of clinical signs of coronary disease (i.e. AMI, angina etc.)
• with the incidence of previous vascular events
IMT is now widely used in clinical trials as amarker of atherosclerosis
to evaluate the effects of pharmacological agents
Despite this big amount of information, little is known about the usefulness of IMT as an
additive marker of cardiovascular risk to be used in clinical practice on an individual basis.
Carotid IMT, measured with an electronic caliper(a method feasible in routine clinical practice)
provides suitable information to associate carotid IMT– with atherosclerosis in other vascular districts– with the risk profile of the patient.
In a first series of cross-sectional studies, mainly performed in patients attending our
Lipid Clinic, we have shown that carotid IMT,as measured in clinical practice,
correlates well with coronary VRFsCAROTID ARTERY INTIMA-MEDIA THICKNESS MEASURED BY ULTRASONOGRAPHY IN NORMAL
CLINICAL PRACTICE CORRELATES WELL WITH ATHEROSCLEROSIS RISK FACTORS.Baldassarre D, Amato M, Bondioli A, Sirtori CR, Tremoli E.
Stroke 2000;31: 2426-2430.
INCREASED CAROTID ARTERY INTIMA-MEDIA THICKNESS IN SUBJECTS WITH PRIMARY HYPOALPHALIPOPROTEINEMIA.
Baldassarre D, Amato M, Pustina L, Tremoli E, Sirtori CR, Calabresi L, Franceschini G.Arterioscler, Thromb Vasc Biol 2002;22:317-322.
CORRELATION OF PARENTS’ LONGEVITY WITH CAROTID INTIMA-MEDIA THICKNESS IN PATIENTS ATTENDING A LIPID CLINIC.
Baldassarre D, Amato M, Veglia F, Pustina L, Castelnuovo S, Sirtori CR, and Tremoli E. Atherosclerosis 2005;179:111-117.
Characteristics of subjects with and without Coronary Heart Disease (CHD)
With CHD(n=133)
Without CHD (n=266)
p
Men (%) 76 76 matchAge (years) 57.5 57.5 matchSmokers (%) 22.6 29.7 nsBMI (Kg/m2 ) 24.6 24.4 nsSBP (mmHg) 138.9 138.8 nsDBP (mmHg) 82.8 84.1 nsTC (mg/dl) 258.8 258.9 matchLDL-C (mg/dl) 176.5 179.6 nsHDL-C (mg/dl) 47.4 49.4 nsTG (mg/dl) 2.16 2.17 nsLp(a) (mg/dl) 1.25 1.1 nsBlood glucose (mg/dl) 97.1 95.2 nsUric acid (mg/dl) 5.11 5.09 nsMax-IMT (mm) 2.36 1.94 0.0001MM-IMT (mm) 1.08 0.94 0.005
Baldassarre et al., Stroke 2000;31: 2426-2430.
even when measured in the routine clinical practice, carotid IMT is a suitable marker:
These results support very well the concept that:
• to investigate the effect of vascular risk factors
• to identify groups of patients with and without a history of vascular events
they do not provide any information concerning the potential role of IMT as a
test for predictive purposeson individual basis
Before a new test can be used for predictive purposes
Essential
to establish its performance in the recognition of those individuals who
PREVENTIVE MEDICINE
effectively had
experienced the target end point.
had not
Thus, we have performed a study aimed at investigating
on an individual basis whether IMT measurements can be added
to, or used instead of, vascular risk factors in the recognition of patients with and without a
history of vascular events
RECOGNITION OF PATIENTS WITH AND WITHOUT VASCULAR EVENTS BY
ARTIFICIAL NEURAL NETWORK ANALYSES
Combining some ultrasonic variables with a set of clinical variables, it was possible to reach an accuracy of prediction of about 92%, with
• 95% of correct classification of patients with a history of vascular events
• 91% of correct classification of those without
Patientswithoutevents(specificity)
91%
Patientswith
events(sensitivity)
95%
WeightedMean
(Prediction accuracy)
92%
Thus, also the results of this study supported a potential role of carotid IMT
to be used for predictive purposes
Baldassarre et al., Ann Med. 2004;36(8):630-40.
1. Is there a direct correlation between carotid and coronary atherosclerosis?
Before trying to use carotid IMT for predictive purposes three further questions
had to be answered:
2. In what kind of patients IMT measurement may actually have the highest clinical usefulness?
3. what threshold value has to be adopted to obtain the maximal IMT predictive capacity?
1. Is there a direct correlation between carotid and coronary disease?
2. In what kind of patients IMT measurement may actually have the highest clinical usefulness?
3. what threshold value has to be adopted to obtain the maximal IMT predictive capacity?
Before trying to use carotid IMT for predictive purposes three questions had to
be answered:
AUTOPSY STUDIES Significant correlation between
carotid and coronary atherosclerosis (correlation coefficient = 0.5-0.6)
CAROTID AND CORONARY ATHEROSCLEROSIS
Young et al., Am J Cardiol 1960;6:300-308.Holme et al. Arteriosclerosis 1981Mitchell et al. BMJ 1962;5288:1293-301
CCBif
ICA
ECA
weaker correlations
(r ≈ 0.3)
VS
(B-mode Ultrasound) (Quantitative angiography)
CarotidAtherosclerosis
CoronaryAtherosclerosis
IN VIVO STUDIES
Adams Circulation 1995 - Balbarini Angiology 2000 - Holaj Can J Cardiovasc 2003
This lower correlation was just due to methodological problems
HYPOTHESIS
External carotid ultrasound(ECU)
is focused on arterial wall
Quantitative coronary angiography (QCA)
provides information on arterial lumen diameter
INTRAVASCULAR ULTRASOUND (IVUS)
The miniaturisation of high-frequency intravascular ultrasound transducers has allowed the direct
examination, in living humans, of the thickening of vessel walls of coronary arteries
AIM OF THE STUDY
To evaluate whether a correlation closer to the one obtained in autopsy studies can be
obtained by measuring carotid and coronary atherosclerosis by using more homogeneous
arterial wall parameters,i.e. IMT, in both vascular districts
APPROACHCarotid wall
B-Mode ultrasound
Coronary lumen
Classical approach
VS
Angiography
Coronary wall
More homogeneous parameters from both vascular
districts
VS
Intravascular ultrasound
Correlation coefficients between Carotid and Coronary atherosclerosis
0.30
0.35
0.40
0.45
0.50
0.55
0.60
0.51
AutopsyStudies
(mean of3 studies)
Cor
rela
tion
coef
ficie
nt (r
)
PRESENT STUDY
DATA REPORTED IN LITERATURE
0.36 0.35
Carotid IMTVs
Angiography (mean of 6 studies)
%DS
0.550.52
Carotid IMTVs
IVUS (Present study)
C-IMTMean
C-IMTMaxThus, carotid IMTcorrelates very well withcoronary atherosclerosis
Correlation coefficients between carotid IMT and
coronary lumen were much lower than those
observed in autopsy studies
those obtained evaluating IMT in both arterial districts were much higher and reach values very similar to the ones observed in studies post-mortem
1. Is there a direct correlation between carotid and coronary disease?
2. In what kind of patients IMT measurement may actually have the highest clinical usefulness?
3. what threshold value has to be adopted to obtain the maximal IMT predictive capacity?
Before trying to use carotid IMT for predictive purposes three questions had to
be answered:
Patients at high risk(e.g. those with a Framingham Risk Score >20%)
are already qualified for aggressive treatment
Is the population with FRS≥20% (high risk) a good target for IMT measurements?
Thus, in this kind of patients, no further risk stratification tools are
needed.
Patients at intermediate-risk (FRS: 10-20%)
represent for many clinicians a gray decision area
In fact, although these patients do not currently qualify for aggressive treatment, epidemiological and clinical evidences show that cardiac events occur in many of
these individuals
The number of patients at intermediate-risk is high(for instance, they constitute 40% of the US population)
Thus, tools to further stratify the risk in patients at intermediate-
risk are actually needed
1. Is there a direct correlation between carotid and coronary disease?
2. In what kind of patients IMT measurement may actually have the highest clinical usefulness?
3. what threshold value has to be adopted to obtain the maximal IMT predictive capacity?
Before trying to use carotid IMT for predictive purposes three questions had to
be answered:
2,381,881,380,880,38
Freq
uenc
y400
300
200
100
0
MEAN MAX IMT
IMT ≥ 1 mm
Low High
Epidemiologic data currently available indicate that a value of IMT equal or greater than 1 mm at any age is associated with a significantly
increased risk of myocardial infarction or cerebrovascular disease.
Folsom et al. Diabetes Care 2003;26:2777-84. Chambless et al. Clin Epidemiol 2003;56:880.Salonen et al. Arterioscler Thromb 1991;11:1245-9.Chambless et al. Am J Epidemiol 1997;146:483.
Risk of CAD and CVD
GENERAL POPULATION
A longitudinal observational study aimed at investigating whether the measurement,
in clinical practice,of carotid Max-IMT could be combined with the
FRS to improve the predictability of cardiovascular events in patients who are at low
or intermediate risk
AIM OF THE STUDY
Baldassarre et al., Atherosclerosis 2006 May 6 [Epub ahed of print]
The addition to the FRS of the“plaque status”,
expressed in terms of presence or absence of a Max-IMT value ≥1 mm (or even ≥ 1.3 mm), did not significantly improve the predictive
power of the FRS.
Thus, can we say that IMT has not predictive capacity?
NO !
Age and sex known to have a major impact on IMT measurements have not been taken into account.
Baldassarre et al., STROKE 2000;31: 2426-2430
0.5
1.0
1.5
2.0
Women Men
Age
adj
uste
d M
ax-IM
T (m
m)
P<0.0001
Effect of gender on carotid IMT
0
2
4
6
8
0 20 40 60 80
r =0.43p<0.0001
Age (years)
Max
-IMT
(mm
)Effect of age on
carotid IMT
MEN
0.0
1.0
2.0
3.0
4.0
20-29 30-39 40-49 50-59 60-69 70-79DECADES OF AGE (years)
Max
-IMT
(mm
)
90th
80th
70th
60th
50th
40th
30th
20th
10th
WOMEN
0.0
1.0
2.0
3.0
4.0
20-29 30-39 40-49 50-59 60-69 70-79DECADES OF AGE (years)
Max
-IMT
(mm
)
90th
80th
70th
60th
50th
40th
30th
20th
10th
Deciles of M
ax-IMT distribution
Deciles of M
ax-IMT distribution
Deciles of Max-IMT distribution in men and women calculated in a group of about 2000 Italian dyslipidemic patients, plotted for 10-
years age intervals.
Baldassarre et al., Atherosclerosis. 2007;191(2):403-408.
0.0
1.0
2.0
3.0
4.0
20-29 30-39 40-49 50-59 60-69 70-79DECADES OF AGE (years)
Max
-IMT
(mm
)
90th
80th
70th
60th
50th
40th
30th
20th
10th
0.0
1.0
2.0
3.0
4.0
20-29 30-39 40-49 50-59 60-69 70-79DECADES OF AGE (years)
Max
-IMT
(mm
)
90th
80th
70th
60th
50th
40th
30th
20th
10th
Deciles of M
ax-IMT distribution
Deciles of M
ax-IMT distribution
In selected populations affected by major risk factors like patients with dyslipidemia, hypertension, or diabetes, an IMT greater than
1 mm is present in almost every patient above 50 years of age
MEN WOMEN
Baldassarre et al., Atherosclerosis. 2007;191(2):403-408.
0.0
1.0
2.0
3.0
4.0
20-29 30-39 40-49 50-59 60-69 70-79DECADES OF AGE (years)
Max
-IMT
(mm
)
90th
80th
70th
60th
50th
40th
30th
20th
10th
0.0
1.0
2.0
3.0
4.0
20-29 30-39 40-49 50-59 60-69 70-79DECADES OF AGE (years)
Max
-IMT
(mm
)
90th
80th
70th
60th
50th
40th
30th
20th
10th
Deciles of M
ax-IMT distribution
Deciles of M
ax-IMT distribution
In addition, if age and sex are not taken into account, each patient with an IMT ≥1 mm is classified as having the same risk either if man or women, and either if young or old;
MEN WOMEN
Baldassarre et al., Atherosclerosis. 2007;191(2):403-408.
0.0
1.0
2.0
3.0
4.0
20-29 30-39 40-49 50-59 60-69 70-79DECADES OF AGE (years)
Max
-IMT
(mm
)
90th
80th
70th
60th
50th
40th
30th
20th
10th
0.0
1.0
2.0
3.0
4.0
20-29 30-39 40-49 50-59 60-69 70-79DECADES OF AGE (years)
Max
-IMT
(mm
)
90th
80th
70th
60th
50th
40th
30th
20th
10th
Deciles of M
ax-IMT distribution
Deciles of M
ax-IMT distribution
In addition, if age and sex are not taken into account, each patient with an IMT ≥1 mm is classified as having the same risk either if man or women and either if young or old;
MEN WOMEN
but , if we consider for example an IMT value of 1.3 mm, this may be the highest value within the IMT distribution of young patients but even the lowest one when the IMT
distribution of patients older 50 are considered
Baldassarre et al., Atherosclerosis. 2007;191(2):403-408.
0.0
1.0
2.0
3.0
4.0
20-29 30-39 40-49 50-59 60-69 70-79DECADES OF AGE (years)
Max
-IMT
(mm
)
90th
80th
70th
60th
50th
40th
30th
20th
10th
0.0
1.0
2.0
3.0
4.0
20-29 30-39 40-49 50-59 60-69 70-79DECADES OF AGE (years)
Max
-IMT
(mm
)
90th
80th
70th
60th
50th
40th
30th
20th
10th
Deciles of M
ax-IMT distribution
Deciles of M
ax-IMT distribution
In addition, by using this approach, each patient with an IMT value greater than 1 mm is classified as having the same risk
either if he has an IMT of 1.1 mm or if he has an IMT of 2.5 mm or greater: this is out of any biological plausibility.
MEN WOMEN
Baldassarre et al., Atherosclerosis. 2007;191(2):403-408.
MEN
0.0
1.0
2.0
3.0
4.0
20-29 30-39 40-49 50-59 60-69 70-79DECADES OF AGE (years)
Max
-IMT
(mm
)
90th
80th
70th
60th
50th
40th
30th
20th
10th
WOMEN
0.0
1.0
2.0
3.0
4.0
20-29 30-39 40-49 50-59 60-69 70-79DECADES OF AGE (years)
Max
-IMT
(mm
)
90th
80th
70th
60th
50th
40th
30th
20th
10th
Deciles of M
ax-IMT distribution
Deciles of M
ax-IMT distribution
To overcome this problem in our study the “best threshold values” (BTVs), above which to consider Max-IMT as abnormally high, were calculated for each 10-years age interval
in men and women.
Baldassarre et al., Atherosclerosis. 2007;191(2):403-408.
MEN
0.8 0.9
1.4
2.0
2.5
3.0
0.0
1.0
2.0
3.0
4.0
20-29 30-39 40-49 50-59 60-69 70-79DECADES OF AGE (years)
Max
-IMT
(mm
)
90th
80th
70th
60th
50th
40th
30th
20th
10th
WOMEN
0.7
1.31.7
2.12.5
3.0
0.0
1.0
2.0
3.0
4.0
20-29 30-39 40-49 50-59 60-69 70-79DECADES OF AGE (years)
Max
-IMT
(mm
)
90th
80th
70th
60th
50th
40th
30th
20th
10th
Deciles of M
ax-IMT distribution
Deciles of M
ax-IMT distribution
To overcome this problem in our study the “best threshold values” (BTVs), above which to consider Max-IMT as abnormally high, were calculated for each 10-years age interval
in men and women. These were found to be the 60th and 80th percentiles of Max-IMT distribution for men and
women, respectively, for each decade of age.
Baldassarre et al., Atherosclerosis. 2007;191(2):403-408.
By using these new IMT threshold values the results of the analyses
completely changed
a FRS above 10%was associated with an
HR of 2.60; p = 0.03(95% CI 1.07 - 6.3)
Baldassarre et al., Atherosclerosis. 2007;191(2):403-408.
Repeating the Cox analysis, using these BTVs
as stratification tools:
FRS
Max-IMT
a Max-IMT above BTV gave a
HR of 2.42; p = 0.04(95% CI 1.04 - 5.66)
independent predictors of new cardiovascular events.
Max-IMT < BTV
Max-IMT ≥ BTV
FRS < 10%10<FRS<20%
Max-IMT best threshold value (BTV):men = 60th percentilewomen = 80th percentile
Stratifying the study population according to the presence ofa FRS above or below 10%
and Max-IMT above or below BTV
Values are adjusted for pharmacological treatments
012345
67
Haz
ard
ratio
Baldassarre et al., Atherosclerosis. 2007;191(2):403-408.
Max-IMT < BTV
Max-IMT ≥ BTV
FRS < 10%10<FRS<20%
Max-IMT best threshold value (BTV):men = 60th percentilewomen = 80th percentile
Values are adjusted for pharmacological treatments
012345
6
7
4.1P<0.05
4.2P<0.05
6.7 (p=0.01)
Haz
ard
ratio
Baldassarre et al., Atherosclerosis. 2007;191(2):403-408.
the strength of the associations
between Max-IMT and outcome was at
least as strong as the associations seen
with FRS
the concomitant presence of FRS ≥10% and Max-IMT above the BTV yielded a
marked increase in the HR.
Stratifying the study population according to the presence ofa FRS above or below 10%
and Max-IMT above or below BTV
Log
Haz
ard
Rat
io
Values are adjusted for pharmacological treatments
Max-IMT best threshold value (BTV):men = 60th percentilewomen = 80th percentile p=0.67
0
1
2
3
Baldassarre et al., Atherosclerosis. 2007;191(2):403-408.
Max-MT<BTV Max-MT≥BTV
Intermediate risk10≤FRS<20%
Low riskFRS<10%
High risk20<FRS<30%
HR FOR HAVING A NEW CARDIOVASCULAR EVENT IN LOW, INTERMEDIATE AND HIGH RISK GROUPS
In addition, compared to low-risk
patients
Max-MT< BTV Max-MT ≥ BTV Max-MT< BTV Max-MT ≥ BTV
Inci
denc
e of
car
diov
ascu
lar e
vent
s (%
)
Low risk patients(FRS<10%)
Intermediate risk patients(10%<FRS<20%)
Threshold for drug therapy
0
10
20
30
40
50 Predicted incidence by the Framingham Risk ScoreObserved incidence
incidence of new cardiovascular events predicted on the basis of FRS
vs.
incidence actually observed (estimated by the Kaplan-Meyer method)
Baldassarre et al., Atherosclerosis. 2007;191(2):403-408.
Predicted incidence by the Framingham Risk Score
Inci
denc
e of
car
diov
ascu
lar e
vent
s (%
)
Threshold for drug therapy
0
10
20
30
40
50
Observed incidence
Max-MT< BTV Max-MT ≥ BTV
Low risk patients(FRS<10%)
incidence of new cardiovascular events predicted on the basis of FRS
vs.
actually observed incidence (estimated by the Kaplan-Meyer method)
Max-MT< BTV Max-MT ≥ BTV
Intermediate risk patients(10%<FRS<20%)
Baldassarre et al., Atherosclerosis. 2007;191(2):403-408.
Predicted incidence by the Framingham Risk Score
Inci
denc
e of
car
diov
ascu
lar e
vent
s (%
)
Low risk patients(FRS<10%)
Threshold for drug therapy
0
10
20
30
40
50
Observed incidence
incidence of new cardiovascular events predicted on the basis of FRS
vs.
actually observed incidence (estimated by the Kaplan-Meyer method)
Max-MT ≥ BTV
Intermediate risk patients(10%<FRS<20%)
Ratio = 3.11
Baldassarre et al., Atherosclerosis. 2007;191(2):403-408.
On the basis of the two last histograms it can be calculated that the “actually observed incidence of new cardiovascular events” can be better predicted by FRS if this is multiplied for 3.11 .
IMT as predictor of vascular events
O’Leary et al. New Eng J Med 1999
One American study provides convincing evidences that carotid artery IMT is a
good predictor of new vascular events.
about the 95% of the subjects with an IMT classifiable in the first quintile were free of vascular events.
In contrast, the percentage of subjects free of vascular events in the group with the highest quintile of IMT was less than 75%
4500 patients65 years or older
Follow up: about 7 years
Thus suggesting that carotid IMT may be effectively considered as
a good marker of evolutive atherosclerotic disease.
THE IMPROVE STUDYCarotid Intima Media Thickness (IMT) and IMT-Progression as
Predictors of Vascular Events in a High Risk European Population
The IMPROVE Study is a multicenter, longitudinal, observational study carried out in
an Pan-European population of 3732 patients at high risk of cardiovascular disease for the
presence of at least three vascular risk factors.
DESIGN
Vascular risk factors:
Male or Female at least 5 years after menopause
Hypercholesterolemia
Hypertriglyceridemia
Hypo-alpha-lipoproteinemia
Hypertension
Diabetes
Smoking habits
Family history of cardiovascular diseases
SWEDEN n=533
FINLAND n=1050 (2 clinical centers)
FRANCE n=501
THE NETHERLANDs n=553
ITALY n=1095 (2 clinical centers)
OBJECTIVE
Cross-sectionalcarotid IMT
To evaluate the association between
the rate of subsequent vascular events
Carotid IMT-progressionwithin 15 months
Baseline carotid IMTMean-Max as predictor of new cardiovascular events
1st quintile
2nd quintile
3rd quintile
4th quintile
5th quintile
0.98
0 1 2 3
% e
vent
free
0.89
0.92
0.95
follow-up (years)
1.00
IMTMean-Max < 1.04
>1.701.42 - 1.701.22 - 1.41 1.04 - 1.20
Thus, also in an European population carotid IMT is a very good predictor of
new vascular events
Since carotid IMT:
• correlates well with atherosclerosis risk factors
• correlates well with coronary atherosclerosis
• can be used in clinical practice to enhance the predictability of cardiovascular events in patients who fall into the intermediate-risk category
• is a very good predictor of new vascular events
Summary
Carotid IMT is an excellent marker of carotid and even coronary
atherosclerosis
CONCLUSION