EUROECHO 2007 Lisbon, Portugal, December 5 – 8, 2007 Carotid scanning: an extension of the routine...

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 Milan

and

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

-199

019

9119

9219

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9719

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0020

0120

0220

0320

04

Year of publication 20

05

0

100

200

300

400

2006

N°

of

stu

die

s p

ub

lish

ed p

er y

ear

(as

an i

nd

ex o

f in

tere

st o

f th

e sc

ien

tifi

c co

mm

un

ity

for

this

met

ho

do

log

y)

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 a

marker 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 match

Age (years) 57.5 57.5 match

Smokers (%) 22.6 29.7 ns

BMI (Kg/m2 ) 24.6 24.4 ns

SBP (mmHg) 138.9 138.8 ns

DBP (mmHg) 82.8 84.1 ns

TC (mg/dl) 258.8 258.9 match

LDL-C (mg/dl) 176.5 179.6 ns

HDL-C (mg/dl) 47.4 49.4 ns

TG (mg/dl) 2.16 2.17 ns

Lp(a) (mg/dl) 1.25 1.1 ns

Blood glucose (mg/dl) 97.1 95.2 ns

Uric acid (mg/dl) 5.11 5.09 ns

Max-IMT (mm) 2.36 1.94 0.0001

MM-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?



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)

Co

rre

lati

on

co

eff

icie

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 IMT

correlates very well with

coronary 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





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





be answered:

2,381,881,380,880,38

Fre

quen

cy400

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

Ag

e ad

just

ed M

ax-I

MT

(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)

Ma

x-I

MT

(m

m)

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 70-79

DECADES OF AGE (years)

Max

-IM

T (

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 70-79


Max

-IM

T (

mm

)

90th

80th

70th

60th

50th

40th

30th

20th

10th

Deciles o

f Max-IM

T d

istribu

tion

Deciles o

f Max-IM

T d

istribu

tion

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 70-79


Max

-IM

T (

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 70-79


Max

-IM

T (

mm

)

90th

80th

70th

60th

50th

40th

30th

20th

10th

Deciles o

f Max-IM

T d

istribu

tion

Deciles o

f Max-IM

T d

istribu

tion

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


0.0

1.0

2.0

3.0

4.0

20-29 30-39 40-49 50-59 60-69 70-79


Max

-IM

T (

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 70-79


Max

-IM

T (

mm

)

90th

80th

70th

60th

50th

40th

30th

20th

10th

Deciles o

f Max-IM

T d

istribu

tion

Deciles o

f Max-IM

T d

istribu

tion

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


0.0

1.0

2.0

3.0

4.0

20-29 30-39 40-49 50-59 60-69 70-79


Max

-IM

T (

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 70-79


Max

-IM

T (

mm

)

90th

80th

70th

60th

50th

40th

30th

20th

10th

Deciles o

f Max-IM

T d

istribu

tion

Deciles o

f Max-IM

T d

istribu

tion

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


0.0

1.0

2.0

3.0

4.0

20-29 30-39 40-49 50-59 60-69 70-79


Max

-IM

T (

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 70-79


Max

-IM

T (

mm

)

90th

80th

70th

60th

50th

40th

30th

20th

10th

Deciles o

f Max-IM

T d

istribu

tion

Deciles o

f Max-IM

T d

istribu

tion

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


MEN

0.0

1.0

2.0

3.0

4.0

20-29 30-39 40-49 50-59 60-69 70-79


Max

-IM

T (

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 70-79


Max

-IM

T (

mm

)

90th

80th

70th

60th

50th

40th

30th

20th

10th

Deciles o

f Max-IM

T d

istribu

tion

Deciles o

f Max-IM

T d

istribu

tion

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.


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 70-79


Max

-IM

T (

mm

)

90th

80th

70th

60th

50th

40th

30th

20th

10th

WOMEN

0.7

1.31.7

2.1

2.5

3.0

0.0

1.0

2.0

3.0

4.0

20-29 30-39 40-49 50-59 60-69 70-79


Max

-IM

T (

mm

)

90th

80th

70th

60th

50th

40th

30th

20th

10th

Deciles o

f Max-IM

T d

istribu

tion

Deciles o

f Max-IM

T d

istribu

tion

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.


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)


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

0

1

2

3

4

5

6

7

Haz

ard

rat

io


Max-IMT < BTV

Max-IMT ≥ BTV

FRS < 10%10<FRS<20%

Max-IMT best threshold value (BTV):men = 60th percentilewomen = 80th percentile


0

1

2

3

4

5

6

7

4.1P<0.05

4.2P<0.05

6.7 (p=0.01)

Haz

ard

rat

io


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


Max-IMT best threshold value (BTV):men = 60th percentilewomen = 80th percentile p=0.67

0

1

2

3


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

den

ce o

f ca

rdio

vasc

ula

r ev

ents

(%

)

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 Score

Observed incidence

incidence of new cardiovascular events predicted on the basis of FRS

vs.

incidence actually observed (estimated by the Kaplan-Meyer method)


Predicted incidence by the Framingham Risk Score

Inci

den

ce o

f ca

rdio

vasc

ula

r ev

ents

(%

)


0

10

20

30

40

50

Observed incidence

Max-MT< BTV Max-MT ≥ BTV



vs.

actually observed incidence (estimated by the Kaplan-Meyer method)

Max-MT< BTV Max-MT ≥ BTV



Predicted incidence by the Framingham Risk Score

Inci

den

ce o

f ca

rdio

vasc

ula

r ev

ents

(%

)



0

10

20

30

40

50

Observed incidence


vs.

actually observed incidence (estimated by the Kaplan-Meyer method)

Max-MT ≥ BTV


Ratio = 3.11


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

ven

t fr

ee

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

EUROECHO 2007 Lisbon, Portugal, December 5 – 8, 2007 Carotid scanning: an extension of the routine...

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