Is carotid intima media thickness a clinical marker of evolutive atherosclerotic disease?

E. Grossi Paoletti Center and Cardiologico Monzino Center,

Department of Pharmacological Sciences, University of Milan

Damiano Baldassarre

ESC CONGRESS 2003 VIENNA, 30 August - 3 September

• The asymptomatic coronary disease is prevalent in the general population  

• Individuals with asymptomatic coronary disease have a higher risk than healthy subjects to progress to an overt coronary disease and to a myocardial infarction  

Early identification and preventative treatment of this kind of patients could potentially lower the risk of the consequent overt coronary disease development

ANGIOGRAPHIC TECHNIQUES ALLOW TO MONITOR PROGRESSION AND REGRESSION OF ATHEROSLEROTIC LESIONS

Angiography

• Inappropriate to investigate early vascular lesions in asymptomatic subjects

• Invasive

• Not applicable in primary prevention trials

No information about arterial wall characteristics

LimitationsAdvantages

• ideal method to visualise severe atherosclerotic lesions in deep vessels (coronary arteries)

Angiography vs intravascular ultrasound (IVUS)

B-mode ultrasound image of a carotid bifurcation

CC

ECA ICA

BULB

B-mode ultrasound image of a carotid bifurcation

CC

ECA ICA

BULB

ComplicatedAtherosclerotic

plaque

Size andcharacteristics

of thearterial wall

Intima Media thickness (IMT)

Blood intima interface

media-adventitia interface

IMTCOMMON CAROTID

BULB

ICA

ECA

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

Ultrasound

Histology

Echogenic lines{{

Lumen

Adventitia

Intima Media thickness (IMT)

Media Adventitia interface

Blood intima interface

Intimal medial thickness of superficial arteries: marker of atherosclerosis in clinical and epidemiological studies to evaluate:

the natural evolution of atherosclerotic disease in the superficial arteries

the influence of atherosclerosis risk factors on the arterial walls

the arterial wall changes induced by diet or pharmacological treatments

High resolution Ultrasonography

epidemiological and clinical evidences that allow to answer the

question:

Is carotid intima media thickness a

clinical marker of evolutive

atherosclerotic disease ?

IMT is related with the same vascular risk factors known to affect atherosclerosis in other vascular districts

Age and Gender Baldassarre et al., Stroke 2000

Smoking habits Haapanen et al., Circulation 1989

Diabetes Kawamori et al., Diabetes Care 1992; Niskanen et al., Stroke 1996

Hyperomocysteinemia Malinow et al. Circulation 1993; Demuth et al. ATVB 1998

Hypertension Suurkula et al., Arterioscler Thromb 1994; Lemne et al., Stroke 1995

Hypercholesterolemia Poli et al., Atherosclerosis 1988; Wendelhag et al., Arterioscler Thromb 1992

Hypoalphalipoproteinemia Baldassarre et al ATVB 2002

High levels of Lp(a) Baldassarre et al., Stroke 96; Tatò et al., Atherosclerosis. 1993

High levels of triglycerides and post prandial lipemiaGronholdt et al., Stroke 1996; Karpe et al., Atherosclerosis 1998

Many others..

An increased IMT is associated with the coronary disease assessed from a clinical

point of view

Crouse et al. Stroke 1986Craven et al. Circulation 1990Chambless et al. Am J Epidemiol 1997Vrtovec et al. Coronary Artery Dis 1999Nowak et al. Stroke 1998

Chambless et al. Am J Epidemiol 1997

Association of Coronary Heart Disease incidence with CC-IMTThe Atherosclerosis Risk In Communities (ARIC Study)

The risk of myocardial infarction comparing patients with an IMT

< 1 vs > 1 was 5.07 for women and 1.85 for men

Bas

ale

IMT

(m

m)

0.78

0.97

0.66

0.8

0.6

0.71

0.5

0.6

0.7

0.8

0.9

1

1.1Women

0.89

1.01

0.74

0.82

0.660.69

Men

No CHDeventn=7193

CHDeventn=96

No CHDeventn=5358

CHDeventn=194

BifurcationInternal

Common

An increased IMT is associated with the occurrence and severity of coronary

disease assessed by angiography

Wofford et al. Arterioscl Thromb 1991Geroulakos et al. Eur Heart J 1994Kallikazaros et al. Stroke 1999

Relation of extent of extracranial carotid artery atherosclerosis as measured by B-mode ultrasound to the

extent of coronary atherosclerosis

0

2

4

6

8

10

12

0 1 2 3 4Number of coronary vessels

with an obstruction of 50% or greater

B-m

ode

scor

e (m

m)

WomenMen

Wofford et al. Arterioscl Thromb 1991

Carotid artery IMT progression, recorded in 2 years of follow up by B-mode ultrasound, is related to the atherosclerotic change occurring at coronary levels as measured by quantitative angiography in the same period of time.

Mack et al., Atherosclerosis 2000

POST HOC ANALYSIS OF THE CLAS STUDY

An increased IMT value is associated with abnormal ECG

Bruckert et al. Atherosclerosis 1992Okin et al. Hypertension 1997 Nagai et al. Circulation 1998

s

Bruckert et al. Atherosclerosis 1992

Exercise ECGTotal

n=778

Negative

(%)

Borderline

(%)

Positive

(%)

NormalArtery (IMT < 1 mm) 418 89.7 6.5 3.8

IMT (> 1 mm) 129 81.4 10.9 7.8

Plaque (< 30% of stenosis) 196 86.7 7.7 5.6

Stenosis (> 30% of stenosis) 35 65.7 8.6 25.7

Carotid stenosis is a powerful predictor of a positive exerciseelectrocardiogram in a large hyperlipidemic population

An increased IMT is a good predictor of future vascular events

Salonen et al. Arterioscler Thromb 1991Bots et al. J Int Med 1995Hodis et al. Ann Int Med 1998Bots et al. Circulation 1999O’Leary et al. New Eng J Med 1999

1

2,17

4,15

6,71

0

1

2

3

4

5

6

7

8

Normal Thickening Plaque Stenosis

Rel

ativ

e h

azar

d o

f a

coro

nar

y ev

ent

Salonen et al. Arterioscler Thromb 1991

Ultrasonographically assessed carotid morphology and the risk of Coronary Heart Disease

05

101520253035404550

1 2 3 4 5Intima-Media Thickness

(quintiles)

Ab

solu

te r

isk

(%

)

Death

CHDStroke

Absolute 10-year risk of stroke, 10-year of Coronary Heart Disease and 11.5-year risk of death by common

carotid Intima-Media Thickness

Bots et al., J Int Med, 1995

0.795

0.858

0.909

0.5

0.6

0.7

0.8

0.9

1

Controlsubjects

MyocardialInfarction

Stroke

n=1373 n=98 n=96

Bots et al. Circulation 1999

CC

-IM

T (

mm

)

CC-IMT and Risk of Stroke and Myocardial Infarction:the Rotterdam Study

Per SD increase in CC-IMT:the risk of myocardial infarction increased 43%

the risk of stroke increased 41%

Baseline characteristics

9.2

16.4 16

23.8

36.5

8.6

13.7

21.4 22.3

36.1

7.8

13.6

18.4

40.9

22.2

0

10

20

30

40

1 2 3 4 5Quintiles of IMT

Rat

e o

f m

yoca

rdia

l in

farc

tio

no

r st

roke

per

100

0 p

erso

n-y

ears

Maximal CCA IMT

Maximal ICA IMT

Maximal CCA and ICA IMT

Carotid artery intima and media thickness as a risk factor for Myocardial infarction and stroke in older adults

O’Leary et al. New Eng J Med 1999

Cumulative Event-free Rates for the Combined End Point of Myocardial Infarction or Stroke, According to Quintile of

Combined Intima-Media Thickness

O’Leary et al. New Eng J Med 1999

Before routine measurement of IMT can be proposed in clinical practice as a diagnostic tool for stratifying cardiovascular risk in primary prevention and for aggressive treatment decision

• the methods of measurement, including the site and the analysis of it, have to be standardized

• a threshold of IMT above which the risk of cardiovascular event can be considered to be substantially increased in one person have to be clearly and precisely defined

• inter-reader variability is fairly high and have to be improved

LIMITATIONS OF INTIMA MEDIA THICKNESS I

The atherosclerotic nature of ultrasound-detected IMT have to be unequivocally proved.

The fact that IMT may be considered as a marker of atherosclerosis, also depends on whether the

plaques are incorporated into the IMT measurements or not

1 cm

1 cm

CC

B-MODE ULTRASOUND PROTOCOL

1 cm CC

BULB

ICA

Multiple carotid site Common carotid

} Arterial wallIntimaMediaAdventitia

}

INTIMA THICKENING MEDIA THICKENING

ATHEROSCLEROSIS ? MEDIAL HYPERTROPHY ?

CC-IMT {

Ultrasonography cannot distinguish

?

The ability of IMT to predict an event may be limited by:

the presence of coronary artery remodelling process (arterial dilatation which occurs in the presence of atherosclerotic plaque which tends to maintain the arterial lumens until late in the atherosclerotic process)

conditions associated with medial thickening (Glycation of extracellular matrix in diabetic patients), in which changes in IMT may be less representative of changes in cardiovascular risk.

In addition:The occurrence of an acute event, such as myocardial infarction, depends not only on the condition of the arterial walls but also on the existence of precipitating factors for which the IMT may not be a good indicator.

LIMITATIONS OF INTIMA MEDIA THICKNESS II

IMT gives a comprehensive picture of the alterations caused by multiple risk factors over time on arterial walls.

Prospective primary and secondary prevention studies demonstrated that an increased IMT is associated to coronary artery disease and that it is a powerful predictor of coronary and cerebrovascular complications.

Thus, on the basis of the studies I have presented we can conclude that, at least from a research point of view, carotid intima media thickness may be effectively considered as a good clinical marker of evolutive atherosclerotic disease.

Several evidences also suggest that, once that the methodological limitation will be overcome, IMT measurement might participate in the stratification risk of asymptomatic patients in primary prevention and for the decision to treat or not the patient with an aggressive therapeutic intervention.

CONCLUSIONS