Cardiovascular diseases represent the leading cause of morbidity and mortality in industrialized countries. Most cardiovascular epidemiologic studies have emphasized clinical end-points, such as cardiovascular events or death.
Cardiovascular diseases represent the leading cause of morbidity
and mortality in industrialized countries. Most cardiovascular
epidemiologic studies have emphasized clinical end-points, such as
cardiovascular events or death. However, these clinical end-points
represent an interaction between the location, extent, and severity
of atherosclerosis, and factors precipitating the acute arterial
occlusion, such as plaque rupture, thrombosis, and inflammatory
mechanisms. The relation between a risk factor and atherosclerosis
would be strengthened substantially if the measurement of arterial
involvement could be isolated from the total process leading to
clinical events. Furthermore, in many epidemiologic studies, only a
minority of individuals exposed to risk factors developed a
clinical disease during a given follow-up period. The natural
history of atherosclerosis is a long process including a period
during which "preclinical" involvement is detectable, although
there are no clinical signs or symptoms of the disease. Therefore,
the measurement of atherosclerosis itself from the beginning of its
development represents an ultimate surrogate end-point of
epidemiologic and therapeutic studies focused on
In the past, the evaluation of atherosclerosis was limited
either to angiography or postmortem evaluation. These studies
clearly demonstrated the relationship between the extent of
atherosclerosis and clinical events, such as sudden death.
Such approaches have major limitations, however, and their findings
can not be extrapolated easily to large population samples.
During the past 15 years, modern high-resolution imaging
ultrasound techniques have allowed researchers to quantify the
presence and progression of early atherosclerosis in large
peripheral arteries noninvasively in large population samples.
Since the early study by Pignoli et al,
demonstrating that the double-line arterial sonographic interface
corresponds to intima-media thickness (IMT), the IMT of carotid
arteries became the most studied preclinical parameter of vascular
involvement. We will review the IMT pathophysiology, the role of US
in IMT measurement, and its implications.
Structural changes of great arteries
The sonographic appearance of arterial structural changes is
double: Focal lesions correspond mostly to atherosclerotic plaques,
which are found predominantly at the level of arterial
bifurcations. Diffuse thickening of the vessel wall, measurable as
IMT, may be of atherosclerotic or non atherosclerotic origin. Early
atherosclerotic involvement of the vessel wall is usually circular
and smooth. Atherosclerosis-related vascular changes are influenced
to a large extent not only by disease progression, but also by
physical forces, in particular shear stress. Adaptive mechanisms
tend to maintain the effective luminal cross-sectional area
unchanged and lead to compensatory vessel enlargement.
Despite these changes, there is a point beyond which the artery
seems no longer able to adapt, and the lesion begins to constrict
Non-atherosclerotic diffuse wall thickening is due primarily to
hypertrophy of the media in response to physical forces
or to long lasting blood pressure elevation.
Shear stress changes in hypertension lead also to intimal
fibrocellular hyperplasia, which may contribute to wall thickening
and vessel remodeling.
Parietal thickening in hypertension with increased IMT can be seen
in the radial artery, where atherosclerosis is not found.
Therefore, the wall thickening demonstrated by ultrasound
studies cannot be considered a priori only as a marker of early
atherosclerosis. In intermediate and more advanced stages of the
disease, however, there is a clear relationship between focal and
diffuse arterial involvement, suggesting atherosclerosis as the
common underlying mechanism.
There is a long latency period before the atherosclerotic lesions,
such as plaque instability and hemodynamically significant
stenosis, become clinically apparent. Therefore, wall thickness
measurement is useful to monitor the early stages of arterial
Ultrasound imaging allows precise measurement of the total
intima and media thickness of large- and medium-size peripheral
arteries like the carotid, femoral, or radial arteries. Due to
physical principles of diagnostic ultrasound, the measurement is
reliable only at the distant (far) arterial wall (figure 1) and
does not indicate whether the thickening is due to intima or media
infiltration and/or hypertrophy.
Using distensibility or compliance assessment for the
characterization of underlying processes remains difficult; these
parameters exhibit significant variability in patients with
advanced IMT thickening
and are present in patients with hypertension as well as
Until now, the largest epidemiologic studies have used only IMT and
diameter measurement to quantify the early atherosclerotic
Physical principles of intima-media thickness
IMT is defined as the distance between the lumen-intima
interface and the media-adventitia interface. These interfaces are
well defined only in the far arterial wall where there is a clear
interface between the anechoic vessel lumen and the echogenic
intima, and between the hypoechoic media and the echogenic
adventitia (figure 2). Even when the proximal wall IMT is well
visualized, its measurement remains gain-dependent and unreliable.
Intima and media thicknesses can not be measured separately.
Although some reports contested the anatomic correlate of the
many in-vitro studies confirmed that the sonographically measured
IMT correlates well with histologic findings.
Intima-media measurement techniques
Several methods can be used to measure IMT. Only a few authors
have used M-mode sonography, as used in echocardiography.
The use of M-mode-derived radio frequency signal is more frequent.
The main disadvantage of this approach is a single-point
measurement of a diffuse and sometimes uneven parietal involvement.
The most common method to measure IMT is based on high-resolution
(figure 1). Repeated and averaged manual measurement is easy to
but is operator-dependent and of poor reproducibility. Modern
computer-assisted methods allow easy, semi-automatic
measurement with excellent reproducibility.
In our studies, we used a computer-assisted technique
developed by IO Data Processing (IODP, Paris, France).
Its algorithm analyzes the gray scale of digitized images (figure
3). The system requires a horizontal visualization of the artery in
a longitudinal view with a well-defined double-line pattern
corresponding to the IMT. The operator defines a region of
interest, and the IMT detection and measurement is then fully
automated. Grayscale analysis is
performed in each column of pixels perpendicular to the vessel
wall. By interpolation, a continuous curve is derived from the
histogram of gray density values. Then the curve is analyzed by a
dedicated mathematical algorithm, which defines the exact position
of lumen-intima and media-adventitia interfaces. The software also
includes an auto-correlation algorithm excluding aberrant or
invalid points. As there are substantial systolic-diastolic
differences in IMT, images are frozen in end-diastole, when IMT
changes are minimal.
Similar computer-based systems are now widely available.
Carotid intima-media thickness measurements and
IMT is often measured as an average continuous variable in
arterial segments not involved by localized atherosclerotic
plaques, usually only in the common carotid artery (sometimes
Some authors express IMT as the maximal measured value (or an
average of maximal values in different segments) on the common
or the common and the internal carotid artery (including or
excluding the carotid bulb).
This approach describes early structural arterial changes including
possibly non-atherosclerotic adaptational processes in response to
physical forces or early atherosclerosis.
The second possibility is to express IMT as the maximal measured
value including the thickness of plaques if present.
This second approach addresses mainly atherosclerotic changes as
thick plaques obscure the minimal changes in wall thickness due to
diffuse infiltration or hypertrophy. Another approach, focused on
atherosclerosis assessment, expresses IMT as a dichotomous variable
using different scoring systems, (e.g., 0=no lesion, 1=wall
thickening, 2=plaque, 3=stenosis),
or assuming wall thickening if IMT exceeds a predefined percentile
or threshold value.
Although there is now a great deal of agreement about IMT
measurement of the common carotid (or femoral) artery far wall,
there are still many differences concerning the method.
Nevertheless, the major differences between studies are not related
to the technique itself but to whether or not plaque thickness
should be included in IMT measurements.
Prognostic implications of carotid intima-media
Intima-media thickness and coronary artery disease
Cross-sectional studies have demonstrated that patients with
symptomatic coronary artery disease (CAD) have increased IMT
compared to asymptomatic control subjects.
Carotid wall thickening was also found in subjects with silent
and vasospastic angina.
The relationship between IMT and CAD severity is constant but
Nevertheless, large prospective epidemiologic studies have
demonstrated that IMT may serve as a useful marker of CAD
progression. Main findings from these studies are summarized in
table 1. The Kuopio Ischemic Heart Disease (KIHD) risk factor study
included 2181 patients. During the 4-year follow-up period, the
incidence of myocardial infarction (MI) increased progressively in
relation with carotid atherosclerotic involvement. Each 0.1 mm IMT
increase was associated with a 4.4% increase in incidence of MI.
The Atherosclerosis Risk in Communities (ARIC) study included 7289
women and 5552 men without signs of CAD at inclusion. A common
carotid artery IMT above 1 mm was associated with a 5.07 (95% CI
3.08-8.36) increase in the relative risk of CAD in women and 1.85
(95% CI 1.28-2.69) in men.
Similar results were found in 4476 asymptomatic participants of the
Cardiovascular Health Study (CHS)
and in almost 6000 patients included in the Rotterdam Study (ERGO).
Absolute IMT values and the progression rate of IMT were predictive
for recurrent MI in the Cholesterol Lowering Atherosclerosis Study
(CLAS) participants, including subjects with previous surgical
In all of these studies, the predictive role of IMT remained
significant even after adjustment for classic cardiovascular risk
Intima-media thickness and cerebrovascular disease
The number of studies assessing the relationship of IMT with
cerebrovascular events is much smaller than with CAD. Japanese
authors demonstrated an increased IMT in elderly patients with CT
findings of cerebral infarctions
and similar findings were reported in the Rotterdam Study using
IMT was also shown to be related to the impairment of cognitive
functions in the elderly.
Screening data from 12,205 participants in the ARIC study have
shown a strong relationship between carotid IMT and a history of
transient ischemic attacks and/or stroke.
However, the most frequent findings in patients with a history of a
cerebrovascular event are heterogeneous plaques and/or significant
carotid artery stenosis.
The predictive value of IMT for cerebrovascular disease was
confirmed by CHS and the Rotterdam Study (Table 1). CHS
demonstrated a progressive increase in relative risk of MI and
stroke with increasing IMT
and a similar linear relationship was found in the Rotterdam Study.
Intima-media thickness and peripheral obstructive
The association between thickened carotid arterial wall and
symptomatic peripheral obstructive arterial disease was found in
Carotid IMT correlates well with Doppler-derived ankle-arm pressure
However, this relationship is stronger with femoral than with
Internal carotid artery IMT was also found to be associated with
abdominal aortic aneurysms.
Factors influencing intima-media thickness
Age--Aging is the main determinant of IMT, except in subjects
under 18 years of age without cardiovascular risk factors.
In patients with familial hypercholesterolemia, however, the effect
of age is already present in children.
The influence of age was found consistently in large studies such
as well as in smaller studies investigating patients with various
cardiovascular risk factors, including arterial hypertension,
isolated systolic hypertension,
and renal failure.
Longitudinal studies demonstrated a continuous increase in IMT over
Increasing IMT seems to reflect a natural aging process of the
arterial wall, which could be accentuated in the presence of risk
Body habitus and gender-- Although the influence of body habitus
has been demonstrated repeatedly, it is usually neglected and
arterial IMT and diameters are rarely corrected for body mass index
(BMI) or body surface area. The body habitus plays a major role in
determining IMT in children and adolescents,
and overweight subjects tend to have higher IMT than non-obese
individuals. IMT correlated with body weight and BMI in many
Moreover, the highest IMT values have been found in subjects with
android (central, abdominal) adiposity
and IMT is increased in subjects with abdominal adiposity even with
Adult men have constantly higher IMT and diameter values
and faster progression of atherosclerosis
than women. There are only limited data on the influence of ethnic
factors on IMT.
Differences between ethnic groups may reflect different lifestyle
habits, risk profiles, and sensitivity to risk factors.
Blood pressure--Blood pressure (BP) is a major determinant of
IMT. Patients with established arterial hypertension have increased
IMT is thickened in particular in individuals with isolated
In contrast, subjects with white-coat hypertension tend to have
virtually normal IMT values.
IMT seems to be affected by blood pressure variability.
Beside the absolute BP level, another determinant of IMT is the
Blood lipidsThe increase in IMT in patients with dyslipidemia
is considered to reflect atherosclerotic infiltration. Accordingly,
almost all atherogenic lipoproteins were found to be associated
with arterial wall thickening.
Since the first report on IMT increase in hypercholesterolemia,
abundant data confirming this relationship have been accumulated.
Increased IMT values in subjects with hypercholesterolemia were
found in children,
in particular in patients with familial forms of
There is a linear correlation between plasma cholesterol levels and
and apparently there is no threshold value beyond which IMT would
escape the influence of cholesterol level. Some authors have
emphasized the significance of LDL cholesterol
rather than that of total cholesterol. Undoubtedly, oxidized LDL
particles also play an important role.
A negative relationship between HDL cholesterol levels and IMT
has also been reported.
In men with low HDL cholesterol, IMT is increased even without an
increase in LDL cholesterol.
Low HDL cholesterol is a strong risk factor for intima-media
thickening particularly in patients with diabetes.
Furthermore, IMT is also correlated with LDL to HDL cholesterol
The relationship between IMT and apolipoproteins reflects their
involvement in different lipoprotein particles; there is a negative
correlation between IMT and apoA-I level and a positive correlation
between IMT and apoB level.
Apolipoprotein gene polymorphism has been extensively studied.
Until now, only limited data are available concerning apo A-I,
C-III, and A-IV.
In contrast, many authors studied apoE polymorphism. Some did not
found any association,
whereas most studies confirmed an increase in IMT in subjects with
and less frequently in subjects with apoE3 allele.
The atherogenic role of triglycerides is now widely recognized.
Many studies have shown a positive relationship between VLDL
lipoproteins or triglycerides and IMT.
Entry data from the Cholesterol Lowering Atherosclerosis Study
(CLAS) and the Monitored Atherosclerosis Regression Study (MARS)
demonstrated that the relationship between IMT and
triglyceride-rich particles is independent of HDL cholesterol
The association of IMT with IDL particles seems to be particularly
Finally, many studies, including ARIC, have demonstrated a
positive association between the level of lipoprotein (a) [Lp(a)]
and carotid IMT.
SmokingThe role of smoking has been demonstrated most
decisively in large observational studies such as the KIHD and the
or by analyzing entry data of interventional studies such as the
European Lacidipine Study on Atherosclerosis (ELSA)
or the Multicenter Isradipine Diuretic Atherosclerosis Study)
The association between smoking and IMT is well established.
IMT depends on lifelong smoking dose and active smokers tend to
have thicker arterial wall than former smokers.
Passive smoking is also associated with increased IMT values.
The results of a 12- to 14-year follow-up study of 2073 ARIC
participants showed a gradient in IMT from lowest values in
non-smokers, intermediate in passive smokers, higher in former
smokers, and highest values in active smokers.
Smoking also influences the progression rate of wall thickening
The MARS study demonstrated that this progression could be slowed
by decreasing tobacco consumption and by changes in lifestyle.
Insulin resistance and diabetes Impaired glucose tolerance and
diabetes are accompanied by a high frequency of vascular
complications. Noninvasive markers of vascular involvement such as
IMT are particularly useful and may serve as indicators of the need
for intensified therapeutic intervention.
The relationship between IMT and fasting blood glucose, insulin,
or proinsulin levels is weak.
The large Insulin Resistance Atherosclerosis Study (IRAS) did not
find a significant increase in IMT even in subjects with impaired
oral glucose tolerance test.
Results of more sensitive tests of insulin resistance have shown a
correlation with arterial wall thickness.
It was demonstrated that insulin resistance promotes wall
thickening through the associated dyslipidemia.
Non-insulin dependent diabetic patients have significantly
increased IMT compared to non-diabetic subjects.
Highest IMT values are found in patients with microvascular
Diabetes-related IMT in-crease is linked to disease duration
and quality of disease control.
Insulin-dependent diabetes is also associated with increased IMT
even when compared with noninsulin-dependent patients.
Similarly, in this type of diabetes, IMT correlates with the
presence of other end-organ involvement such as retinopathy
Diabetes management is crucial, as better disease control is
associated with lower IMT
particularly in subjects under intensified insulin treatment.
Intima-media thickness and multifactorial risk estimates
Large epidemiologic trials like the Framingham Heart Study
or PROCAM study (the Munster Heart Study)
assessed the influence of multiple cardiovascular risk factors on
prognosis. In a large French study, IMT values correlated well with
the global cardiovascular risk based on Framingham equations.
A similar relationship between IMT and a risk score was found in
the British Regional Heart Study.
Even a simple count of risk factors correlates well with wall
Clearly, IMT reflects the influence of the association of different
risk factors over time and could be used as a valid marker of
Intima-media thickness and hormonal status in women
In women, IMT values are lower
and disease progresses slower than in men.
The effect of hormonal replacement therapy (HRT) was evaluated in
many studies. In the large ARIC trial, HRT improved the lipid
profile but did not affect IMT values.
In contrast, in a group of almost 3,000 women participating in the
Cardiovascular Health Study, HRT improved both lipid concentrations
and carotid IMT.
Decrease in IMT occurred in women receiving HRT in the Asymptomatic
Carotid Artery Plaque Study (ACAPS), which evaluated the effect of
Decreased IMT values in women receiving HRT were confirmed by other
The impact on IMT of estrogen alone versus combined
estro-progestative treatment is similar, although only estrogen
treatment was shown to improve the wall elasticity of large
Intima-media thickness and hemostatic factors
The role of hemostasis in the progression of atherosclerosis is now
widely recognized. In the ARIC study, however, only fibrinogen
level was associated with IMT whereas other factors including
factor VII, factor VIII, C protein, antithrombin III, and von
Willebrandt factor were not.
Fibrinogen has been studied extensively and its association with
markers of atherosclerosis seems to be a constant finding,
although a negative association has been reported.
In the Edinburgh Artery Study, IMT also correlated with fibrinogen
and whole blood viscosity,
and in the KIHD study, an association between IMT and erythrocyte
aggregability was found.
The role of hemostatic factors in the progression of
atherosclerosis is definite. The association between these factors
and IMT is weaker that that of classic risk factors, however.
Other cardiovascular risk factors
Patients with familial homocystinuria have a higher incidence of
atherosclerosis-related complications. Increased IMT was found in
subjects with homozygous homocystinuria,
and the influence of homocystein was confirmed in the large
As stated above, a relationship exists between oxidized LDL
concentration and arterial wall thickening. The French EVA (Etude
de Vieillessemment Artériel)
studies suggested a possible role of low circulating antioxidant
substances in the progression of atherosclerosis. The influence of
oxidative stress was confirmed also in the KIHD study.
Furthermore, the ARIC investigators studied the role of vitamins C
and E and demonstrated a protective role of vitamin C in men and
vitamin E in women.
Inflammatory diseases and infection: IMT is increased in many
autoimmune vasculitis, including Takayashu disease
or systemic lupus.
The role of bacterial (chlamydia pneumoniae, helicobacter pylori)
or viral (cytomegalovirus, Epstein-Barr virus) infection in
progression of atherosclerosis is currently being studied.
Finally, IMT may be increased as a direct consequence of
Physical activity and high-level physical training
The protective role of regular physical activity is well documented
and was confirmed by studies showing a negative relationship
between cardiopulmonary fitness and IMT.
In contrast, our study investigating IMT in the participants of the
famous "Tour de France" cycling race demonstrated an increase in
IMT in athletes as compared to sedentary healthy individuals.
Renal failure and hemodialysis: Patients in renal failure,
particularly those on hemodialysis, have an increased risk of
cardiovascular complications often related to dyslipidemia. In
those patients, IMT is increased
and the increase correlates with the duration of dialysis and LDL
If the hyperlipidemia is not successfully corrected after renal
transplantation, the increase in IMT persists.
Intima-media thickness and therapeutic interventions
Studies of multifactorial intervention are extremely difficult,
since the compliance of patients to lifestyle modifications is
rarely perfect. Therefore, the outcome is not always obvious.
In contrast, the benefit of such a multifactorial approach was
shown in the placebo arm of the MARS study. A reduction of BMI by 5
kg/m2, of cigarette consumption by 10/day, and of cholesterol
intake by 100 mg/day was associated with significant reduction in
the progression rate of IMT.
The first valid data about the effect of lipid-lowering treatment
on carotid IMT were published in 1993. IMT was measured in a
subgroup of the participants of the randomized, placebo-controlled
CLAS with colestipol and niacin. This study included patients after
previous surgical myocardial revascularization followed for up to 4
years. After 1 year of treatment, there was a significant
regression in IMT,
which persisted during subsequent follow-up.
In contrast, in the placebo group, a significant IMT progression
A significant decrease in the progression rate was also
demonstrated with probucol in patients with hypercholesterolemia
and with gemfibrozil in diabetic patients with hyperlip-idemia.
Studies of statin treatment using IMT as a surrogate end-point are
summarized in table 2.
Antihypertensive treatment--Various BP-lowering drugs have been
or being tested to stop the progression of atherosclerosis using
carotid IMT as a surrogate end-point with variable results.
Ultrasound IMT assessment is a noninvasive, reproducible method
for the detection of early arterial structural changes associated
with various risk factors for atherosclerosis. Arterial wall
thickening reflects the influence of multiple risk factors over
time and has a strong prognostic value for cardiovascular events,
such as myocardial infarction or stroke. IMT allows convenient
stratification of patients at risk for cardiovascular disease and
has proved to be a good marker of the efficacy of antiatherogenic
drugs. The ease and accuracy of computer-assisted IMT measurement
makes it a useful and practical marker of cardiovascular
involvement in atherosclerosis.
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