Applied Radiology

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 atherosclerosis.

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. ¹ 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, ² 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. ^3,4 Despite these changes, there is a point beyond which the artery seems no longer able to adapt, and the lesion begins to constrict the lumen.

Non-atherosclerotic diffuse wall thickening is due primarily to hypertrophy of the media in response to physical forces ⁵ or to long lasting blood pressure elevation. ^6,7 Shear stress changes in hypertension lead also to intimal fibrocellular hyperplasia, which may contribute to wall thickening ^8,9 and vessel remodeling. ^10,11 Parietal thickening in hypertension with increased IMT can be seen in the radial artery, where atherosclerosis is not found. ¹²

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. ^13-15 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 involvement.

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. ^16,17 Using distensibility or compliance assessment for the characterization of underlying processes remains difficult; these parameters exhibit significant variability in patients with advanced IMT thickening ¹⁸ and are present in patients with hypertension as well as atherosclerosis. ¹⁹ Until now, the largest epidemiologic studies have used only IMT and diameter measurement to quantify the early atherosclerotic involvement.

Physical principles of intima-media thickness measurement

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. ^16,17 Although some reports contested the anatomic correlate of the double-line pattern, ²⁰ many in-vitro studies confirmed that the sonographically measured IMT correlates well with histologic findings. ^2,21-23

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. ²⁴ The use of M-mode-derived radio frequency signal is more frequent. ^25,26 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 B-mode imaging
(figure 1). Repeated and averaged manual measurement is easy to perform, ^27-29 but is operator-dependent and of poor reproducibility. Modern computer-assisted methods allow easy, semi-automatic ^30,31 or automatic ^21,32,33 measurement with excellent reproducibility. ^21,32,34,35

In our studies, we used a computer-assisted technique ^21,32,36-39 developed by IO Data Processing (IODP, Paris, France). ⁴⁰ 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. ²¹ Similar computer-based systems are now widely available.

Carotid intima-media thickness measurements and interpretation

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 unilaterally). ^{17,21,28,32,36-39,41-43} Some authors express IMT as the maximal measured value (or an average of maximal values in different segments) on the common carotid artery, ^27,44-47 or the common and the internal carotid artery (including or excluding the carotid bulb). ^48-52 This approach describes early structural arterial changes including possibly non-atherosclerotic adaptational processes in response to physical forces or early atherosclerosis. ^5-12 The second possibility is to express IMT as the maximal measured value including the thickness of plaques if present. ^53-57 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), ^58,59 or assuming wall thickening if IMT exceeds a predefined percentile ⁶⁰ or threshold value. ⁶¹

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 thickness

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. ^62,63 Carotid wall thickening was also found in subjects with silent ischemia ^64,65 and vasospastic angina. ⁶⁶ The relationship between IMT and CAD severity is constant but rather weak. ^67-71 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. ⁷² 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. ⁷³ Similar results were found in 4476 asymptomatic participants of the Cardiovascular Health Study (CHS) ⁷⁴ and in almost 6000 patients included in the Rotterdam Study (ERGO). ^75,76 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 myocardial revascularization. ⁷⁷ In all of these studies, the predictive role of IMT remained significant even after adjustment for classic cardiovascular risk factors.

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 ^78,79 and similar findings were reported in the Rotterdam Study using MRI. ⁸⁰ IMT was also shown to be related to the impairment of cognitive functions in the elderly. ^81,82 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. ⁸³ However, the most frequent findings in patients with a history of a cerebrovascular event are heterogeneous plaques and/or significant carotid artery stenosis. ⁸⁴ 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 ⁷⁴ and a similar linear relationship was found in the Rotterdam Study. ^75,76,85

Intima-media thickness and peripheral obstructive arterial disease

The association between thickened carotid arterial wall and symptomatic peripheral obstructive arterial disease was found in many studies. ^85-87 Carotid IMT correlates well with Doppler-derived ankle-arm pressure index. ^88,89 However, this relationship is stronger with femoral than with carotid IMT. ⁹⁰ Internal carotid artery IMT was also found to be associated with abdominal aortic aneurysms. ⁹¹

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. ⁹² In patients with familial hypercholesterolemia, however, the effect of age is already present in children. ^93,94 The influence of age was found consistently in large studies such as KIHD ^27,95 or ARIC, ⁵⁰ as well as in smaller studies investigating patients with various cardiovascular risk factors, including arterial hypertension, ^21,28,96 isolated systolic hypertension, ^28,41 cigarette smoking, ⁹⁵ hypercholesterolemia, ^32,93 diabetes, ⁹⁷ and renal failure. ⁹⁸ Longitudinal studies demonstrated a continuous increase in IMT over time. ⁹⁹ Increasing IMT seems to reflect a natural aging process of the arterial wall, which could be accentuated in the presence of risk factors.

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, ⁹² and overweight subjects tend to have higher IMT than non-obese individuals. IMT correlated with body weight and BMI in many studies. ^100-103 Moreover, the highest IMT values have been found in subjects with android (central, abdominal) adiposity ¹⁰¹ and IMT is increased in subjects with abdominal adiposity even with normal BMI. ¹⁰⁴

Adult men have constantly higher IMT and diameter values ^{11,96,105,106} and faster progression of atherosclerosis ^50,86 than women. There are only limited data on the influence of ethnic factors on IMT. ¹⁰⁷ Differences between ethnic groups may reflect different lifestyle habits, risk profiles, and sensitivity to risk factors. ¹⁰⁸

Blood pressure--Blood pressure (BP) is a major determinant of IMT. Patients with established arterial hypertension have increased IMT. ^{21,96,109-111} IMT is thickened in particular in individuals with isolated systolic hypertension. ^28,41 In contrast, subjects with white-coat hypertension tend to have virtually normal IMT values. ^112-114 IMT seems to be affected by blood pressure variability. ¹¹⁵ Beside the absolute BP level, another determinant of IMT is the pulse pressure. ^{46, 116,117}

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, ⁴² abundant data confirming this relationship have been accumulated. Increased IMT values in subjects with hypercholesterolemia were found in children, ^93,94 in particular in patients with familial forms of hypercholesterolemia. ^118-120 There is a linear correlation between plasma cholesterol levels and IMT ^{32,27,103,116,121-123} 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 ^116,124 rather than that of total cholesterol. Undoubtedly, oxidized LDL particles also play an important role. ^125-127

A negative relationship between HDL cholesterol levels and IMT has also been reported. ^{116,121,124,128} In men with low HDL cholesterol, IMT is increased even without an increase in LDL cholesterol. ¹²⁹ Low HDL cholesterol is a strong risk factor for intima-media thickening particularly in patients with diabetes. ^121,130 Furthermore, IMT is also correlated with LDL to HDL cholesterol ratio. ^93,116,131

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. ¹²⁴ Apolipoprotein gene polymorphism has been extensively studied. Until now, only limited data are available concerning apo A-I, C-III, and A-IV. ¹³² In contrast, many authors studied apoE polymorphism. Some did not found any association, ^133,134 whereas most studies confirmed an increase in IMT in subjects with apoE4 allele ^135-137 and less frequently in subjects with apoE3 allele. ¹³⁸

The atherogenic role of triglycerides is now widely recognized. Many studies have shown a positive relationship between VLDL lipoproteins or triglycerides and IMT. ^28,118,139 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 levels. ¹⁴⁰ The association of IMT with IDL particles seems to be particularly strong. ¹⁴¹

Finally, many studies, including ARIC, have demonstrated a positive association between the level of lipoprotein (a) [Lp(a)] and carotid IMT. ^139,142-147

Smoking­­The role of smoking has been demonstrated most decisively in large observational studies such as the KIHD and the ARIC studies, ¹⁴⁸ or by analyzing entry data of interventional studies such as the European Lacidipine Study on Atherosclerosis (ELSA) ¹¹⁶ or the Multicenter Isradipine Diuretic Atherosclerosis Study) (MIDAS). ⁴⁸ The association between smoking and IMT is well established. ^{21,98,149,150} IMT depends on lifelong smoking dose and active smokers tend to have thicker arterial wall than former smokers. ¹⁵¹ Passive smoking is also associated with increased IMT values. ¹⁴⁸ 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. ¹⁵² Smoking also influences the progression rate of wall thickening with aging. ⁹⁵ The MARS study demonstrated that this progression could be slowed by decreasing tobacco consumption and by changes in lifestyle. ¹⁵³

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. ¹⁵⁴

The relationship between IMT and fasting blood glucose, insulin, or proinsulin levels is weak. ^155,101 The large Insulin Resistance Atherosclerosis Study (IRAS) did not find a significant increase in IMT even in subjects with impaired oral glucose tolerance test. ¹⁵⁶ Results of more sensitive tests of insulin resistance have shown a correlation with arterial wall thickness. ^157-159 It was demonstrated that insulin resistance promotes wall thickening through the associated dyslipidemia. ¹⁶⁰

Non-insulin dependent diabetic patients have significantly increased IMT compared to non-diabetic subjects. ^156,161,162 Highest IMT values are found in patients with microvascular complications ¹⁶³ and microalbuminuria. ^164,165 Diabetes-related IMT in-crease is linked to disease duration ^130,166 and quality of disease control. ¹⁶¹

Insulin-dependent diabetes is also associated with increased IMT values, ¹⁶⁷ even when compared with noninsulin-dependent patients. ⁹⁷ Similarly, in this type of diabetes, IMT correlates with the presence of other end-organ involvement such as retinopathy ¹⁶⁸ and/or nephropathy. ¹⁶⁹ Diabetes management is crucial, as better disease control is associated with lower IMT ⁹⁷ particularly in subjects under intensified insulin treatment. ¹⁷⁰

Intima-media thickness and multifactorial risk estimates -- Large epidemiologic trials like the Framingham Heart Study ¹⁷¹ or PROCAM study (the Munster Heart Study) ¹⁷² 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. ¹⁷³ A similar relationship between IMT and a risk score was found in the British Regional Heart Study. ¹⁷⁴ Even a simple count of risk factors correlates well with wall thickness measurements. ¹⁷⁵ Clearly, IMT reflects the influence of the association of different risk factors over time and could be used as a valid marker of cardiovascular prognosis.

Intima-media thickness and hormonal status in women -- In women, IMT values are lower ^96,105,106 and disease progresses slower than in men. ^50,86 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. ¹⁷⁶ In contrast, in a group of almost 3,000 women participating in the Cardiovascular Health Study, HRT improved both lipid concentrations and carotid IMT. ⁷⁴ Decrease in IMT occurred in women receiving HRT in the Asymptomatic Carotid Artery Plaque Study (ACAPS), which evaluated the effect of lovastatin treatment. ¹⁷⁷ Decreased IMT values in women receiving HRT were confirmed by other authors. ^178,179 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 arteries. ^178,179

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. ¹⁸⁰ Fibrinogen has been studied extensively and its association with markers of atherosclerosis seems to be a constant finding, ^47,181 although a negative association has been reported. ¹⁸² In the Edinburgh Artery Study, IMT also correlated with fibrinogen and whole blood viscosity, ¹⁸³ and in the KIHD study, an association between IMT and erythrocyte aggregability was found. ⁹⁵ 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 --Homocystein: Patients with familial homocystinuria have a higher incidence of atherosclerosis-related complications. Increased IMT was found in subjects with homozygous homocystinuria, ¹⁸⁴ and the influence of homocystein was confirmed in the large population-based Rotterdam ¹⁸⁵ and ARIC ¹⁸⁶ studies.

Oxidative stress: As stated above, a relationship exists between oxidized LDL concentration and arterial wall thickening. The French EVA (Etude de Vieillessemment Artériel) ¹⁸⁷ and ARIC ¹⁸⁸ 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. ¹⁸⁹ 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. ¹⁹⁰

Inflammatory diseases and infection: IMT is increased in many autoimmune vasculitis, including Takayashu disease ^191,192 or systemic lupus. ¹⁹³ The role of bacterial (chlamydia pneumoniae, helicobacter pylori) or viral (cytomegalovirus, Epstein-Barr virus) infection in progression of atherosclerosis is currently being studied. ¹⁹⁴ Finally, IMT may be increased as a direct consequence of therapeutic irradiation. ¹⁹⁵

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. ¹⁹⁶ 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. ³⁹

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 ¹⁹⁷ and the increase correlates with the duration of dialysis and LDL cholesterol levels. ¹⁹⁸ If the hyperlipidemia is not successfully corrected after renal transplantation, the increase in IMT persists. ¹⁹⁹

Intima-media thickness and therapeutic interventions

Multifactorial intervention ­­ 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. ^46,200 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. ¹⁵³

Lipid-lowering treatment ­­ 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, ²⁰¹ which persisted during subsequent follow-up. ²⁰² In contrast, in the placebo group, a significant IMT progression occurred. ²⁰² A significant decrease in the progression rate was also demonstrated with probucol in patients with hypercholesterolemia ²⁰³ and with gemfibrozil in diabetic patients with hyperlip-idemia. ²⁰⁴ Studies of statin treatment using IMT as a surrogate end-point are summarized in table 2. ^52,205-21

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. ^49,215-227

Conclusion

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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