Introduction  
Although research over the past 50 years has resulted in an immense amount of information concerning risk factors that lead to the initiation and progression of atherosclerosis, the ability of these same risk factors to predict cardiovascular events has been less impressive [1]. This is due to the fact that atherosclerosis is a multifactorial disease with a genetic basis in which each individual varies in their susceptibility to environmental factors and in the development and progression of atherosclerosis. As such, traditional risk factors may or may not reflect the atherosclerotic process at the arterial wall level. In response to the limited predictive power of traditional risk factor assessment, development of techniques to directly measure atherosclerosis (the summed result of an individuals own response to his or her own risk factor burden) has become one of the most active fields of atherosclerosis research [2].
Since the lumen-intima and media-adventitia echoes in carotid ultrasound images were first identified by Pignoli and coworkers in 1986 [3], B-mode ultrasonography has become one of the most popular techniques for directly measuring atherosclerosis. Pignoli and coworkers [3] found that the distance between the two lines (the double-line pattern) seen with carotid artery B-mode ultrasonography highly correlated (r=0.90) with the intima-media thickness (IMT) measured on histologic specimens.
Epidemiologic Studies  
Several large-scale epidemiologic studies have demonstrated an association between carotid artery IMT and cardiovascular risk factors in both men [4] and women [5]. Studies have also demonstrated a relationship between carotid IMT and the angiographic presence of coronary artery disease (CAD) [6,7], and carotid IMT and the extent of coronary atherosclerosis determined by the number of vessels with lesions [8]. In addition, studies have demonstrated a relationship between carotid IMT and a confirmed history of CAD [9]. In these studies, carotid IMT demonstrated as a good or better correlation with CAD than did traditional lipid- and nonlipid-cardiovascular risk factors. Overall, the results of these studies suggest that the association between carotid artery IMT and CAD depends, in part, on exposure of both arterial beds to the same atherosclerosis risk factors.

Kuopio Ischaemic Heart Disease Risk Factor Study
A growing number of reports indicate that carotid artery IMT is related to the risk of clinical coronary events [10,11,12,13,14]. The Kuopio Ischaemic Heart Disease Risk Factor Study (KIHD) [10] was a population-based study designed to investigate cardiovascular risk factors and carotid artery atherosclerosis in eastern Finnish men, aged 42 to 60 years, who were free of cardiovascular disease. Eastern Finnish men have one of the highest rates of coronary heart disease mortality. B-mode carotid ultrasonography was conducted in a subsample of 1257 subjects. After a follow-up period of 1 month to 3 years, 36 fatal and nonfatal myocardial infarctions had occurred. The maximal common carotid artery IMT was significantly associated with the risk of myocardial infarction (MI). For each 0.1 mm of common carotid IMT, the risk of MI increased by 1.11 (95% CI, 1.06 to 1.16; P<0.001).

Atherosclerosis Risk in Communities Study
The Atherosclerosis Risk in Communities Study (ARIC) [11] assessed the relationship between carotid IMT and coronary heart disease incidence over a period of 4 to 7 years in 7289 women and 5552 men, aged 45 to 64 years, who were initially free of clinical symptoms of coronary heart disease. In this study, an average carotid IMT was determined from the mean of IMT measurements from six sites of the carotid arteries using B-mode ultrasonography. After a median follow-up of 5.2 years, 290 MIs and coronary heart disease deaths occurred in 96 women and 194 men. The hazard rate ratio for MI and coronary heart disease death for each 0.19-mm (one SD) increment of carotid IMT was significantly elevated for the overall mean carotid IMT and for each specific site in both women and men (Table 1).
Table 1   Hazard rate ratios for myocardial infarction and coronary heart disease death in the Atherosclerosis Risk in Communities study (ARIC)* 
  Women  Men 
Carotid IMT site  Hazard rate ratio  95% CI  Hazard rate ratio  95% CI 
Mean  1.69  1.501.90  1.36  1.231.51 
Bifurcation  1.40  1.291.53  1.23  1.151.31 
Internal  1.28  1.181.39  1.15  1.081.23 
Common  1.92  1.662.22  1.32  1.131.54 
*per one SD (0.19 mm) of carotid intima-media thickness.
IMTintima-media thickness.
Data from Chambless et al. [11].

The Rotterdam Study
The Rotterdam study [12] was a prospective follow-up study designed to determine disease and disability in 7983 men and women 55 years of age and older living in a suburb of Rotterdam, Netherlands. B-mode ultrasound images of the common carotid artery were obtained in 5965 patients at baseline who were then followed for a mean duration of 2.7 years. A nested case-control approach was used to study the relationship between carotid IMT and incident MI and stroke based on hospital discharge records. Analysis was based on 99 MIs (31% women) and 95 strokes (60% women). Average common carotid IMT was measured for all of the patients who had an MI or stroke, and a sample of 1373 patients (64% women) who remained free from MI and stroke during the follow-up period.
The odds ratio for stroke for each 0.163-mm (one SD) increment of common carotid IMT was 1.41 (95% CI, 1.25 to 1.82). When subjects with a previous history of MI and stroke were excluded from the analysis (28% of the cohort), the odds ratio for stroke for each 0.163-mm (one SD) increment of common carotid IMT was 1.57 (95% CI, 1.25 to 1.94). The odds ratio for MI for each 0.163-mm (one SD) increment of common carotid IMT was 1.43 (95% CI, 1.16 to 1.78). When subjects with a previous history of MI and stroke were excluded from the analysis, the odds ratio for MI for each 0.163-mm (one SD) increment of common carotid IMT was 1.51 (95% CI, 1.18 to 1.78). The odds ratios for men and women were similar.

Cardiovascular Health Study
The Cardiovascular Health Study (CHS) [13] was a prospective study designed to determine the incidence of cardiovascular disease in 5888 men (38.8%) and women, aged 65 years or older, in four geographical areas of the United States. B-mode ultrasound images of the common and internal carotid artery were obtained in 4476 subjects without clinical cardiovascular disease at baseline. Maximal IMT of the common and internal carotid artery as well as a composite measure that combined the maximal common- and internal-carotid artery IMT were determined. After a median follow-up of 6.2 years (maximum follow-up was 7 years), there were 267 new MIs and 284 new strokes. The relative risk for MI, stroke, and MI and stroke combined was significantly elevated for each 0.20-mm (one SD) increment of maximal common-carotid artery IMT, and for each 0.55-mm (one SD) increment of maximal internal-carotid artery IMT (P<0.001 for both) (Table 2). Combined maximal common- and internal-carotid artery IMT showed similar relative risks of cardiovascular events per SD as did the maximal common-carotid and internal-carotid artery IMT measurements separately.
Table 2   Relative risk for cardiovascular events in the Cardiovascular Health Study (CHS)* 
Cardiovascular event  Relative Risk  95% CI 
  Maximal CCA IMT/0.20-mm increase 
Myocardial infarction  1.46  1.331.60 
Stroke  1.49  1.371.62 
Myocardial infarction or stroke  1.47  1.371.57 
  Maximal CCA IMT/0.55-mm increase 
Myocardial infarction  1.57  1.421.74 
Stroke  1.47  1.331.63 
Myocardial infarction or stroke  1.51  1.401.64 
*Per one SD of carotid intima-media thickness.
CCAcommon carotid artery; ICAinternal carotid artery; IMTintima-media thickness.
Data from OLeary et al. [13].
Cholesterol Lowering Atherosclerosis Study  
Design
The four studies discussed previously have all examined the relation between a single measure of carotid IMT and cardiovascular events. To date, only one study, the Cholesterol Lowering Atherosclerosis Study (CLAS) [14], has examined the relation of the progression of carotid IMT with clinical coronary events. CLAS was a randomized, placebo-controlled, 2-year, serial angiographic/ultrasonographic trial conducted in 188 nonsmoking men, aged 40 to 59 years, who had previous coronary-artery bypass graft surgery. Patients were randomly assigned to receive either colestipol-niacin plus dietary therapy or dietary therapy alone to determine the effects of lipid-lowering on the progression of atherosclerosis. Atherosclerosis was assessed with angiography of the coronary, carotid, and femoral arteries and with B-mode ultrasonography of the carotid arteries [15]. Lipid-lowering therapy significantly reduced the progression of coronary artery and femoral atherosclerosis [16,17,18]. In addition, the progression of carotid atherosclerosis, as determined with serial mean common-carotid artery IMT measurements, was also reduced [19,20].

Results
After completion of the 2-year treatment period, the occurrence of major medical events was determined in the CLAS cohort [14,21]. The coronary events analyzed were nonfatal acute MI, coronary death, and coronary artery revascularization, including percutaneous transluminal coronary angioplasty and coronary-artery bypass graft surgery. Carotid IMT change rate was determined in 146 patients. During an average of 8.8 years of follow-up (range, 0.7 to 12 years), 68 (47%) of the 146 patients had at least one clinical coronary event (27 patients in the drug group, 41 patients in the placebo group). The average of approximately 80 IMT measurements over 1 cm of the distal common-carotid artery was measured with an automated computerized edge-detection algorithm [22]. The rate of change of mean common-carotid artery IMT progression was significantly related to the risk for subsequent clinical coronary events [14]. The relative risk for MI or coronary death was 2.2 (95% CI, 1.4 to 3.6; P<0.001) for each 0.03-mm/y (one SD) increase in the mean common-carotid artery IMT. The relative risk for any coronary event (nonfatal MI, coronary death, or coronary artery revascularization) was 3.1 (95% CI, 2.1 to 4.5; P<0.001) for each 0.03-mm/y (one SD) increase in the mean common-carotid artery IMT.
As in the four, larger epidemiologic studies discussed previously, a single measure of carotid IMT was also significantly related to clinical coronary events in CLAS [14]. The relative risk for MI or coronary death and for any coronary event was 1.4 (95% CI, 1.1 to 1.8; P<0.02) and 1.4 (95% CI, 1.2 to 1.7; <0.002), respectively, for each 0.13-mm (one SD) increment of mean common-carotid artery IMT.

Analysis
The data from CLAS are uniquely important in that the progression of atherosclerosis was monitored across several vascular beds, which provided researchers the opportunity to confirm the important relationship between the progression of common carotid IMT and CAD by sequential coronary angiography in the same cohort. CLAS data have indicated that similar cardiovascular risk factors are associated with progression of common carotid artery IMT and CAD [16,19,23]. As such, the reduction in the progression of common carotid IMT with lipid-lowering therapy in CLAS was paralleled by the reduction in the progression of CAD [16,17,19]. In addition, progression of both common carotid artery IMT and CAD measured by sequential coronary angiography is significantly related to the risk of subsequent clinical coronary events [14,21]. These data are consistent with the observation that the progression of common carotid artery IMT is significantly correlated with the progression of CAD determined by serial quantitative coronary angiography [24].
Conclusion  
The data from these studies indicate that carotid IMT is a significant predictor of cardiovascular events [10,11,12,13,14]. Although the data that demonstrate this relationship were derived from five independent and diverse cohorts with a broad range of cardiovascular risk factors, they are remarkably consistent (Table 3). These data also indicate that carotid IMT is predictive of cardiovascular events in men and women with and without clinical evidence of cardiovascular disease. The cumulative data indicate that the measurement of carotid IMT is an excellent determinant of atherosclerosis and that carotid IMT can be used as an alternative endpoint for cardiovascular disease and death, which traditionally have been used in observational studies and clinical trials.
Table 3   Summary of common carotid artery intima-media thickness and risk for clinical cardiovascular events* 
Study  Gender of participants  No. of participants  Age range, y  Percent of participants with previous CVD symptoms  Duration of follow-up, y  Relative risk, (95% CI)  Event 
KIHD [10]  male  1257  4260  0  0.083  1.11 (1.061.16)  MI 
ARIC [11]  male  5552  4564  0  47 (median 5.2)  1.16 (1.071.26)  MI, CD 
  female  7289        1.41 (1.311.52)   
Rotterdam [12]  male and female  1567  55  28  2.7, mean  1.25 (1.101.42)  MI 
        0    1.29 (1.111.42)   
        28    1.23 (1.151.44)  Stroke 
        0    1.32 (1.151.50)   
CHS [13]  male and female  4476  65  0  6.2, median  1.21 (1.151.26)  MI 
            1.22 (1.171.27)  Stroke 
            1.21 (1.171.25)  MI, stroke 
CLAS [14]  male  146  4059  100  0.712 (mean 8.8)  1.30 (1.081.57)  MI, CD 
            1.30 (1.151.50)  MI, CD, PTCA, CABG 
* Relative risk is per 0.1-mm increment of intima-media thickness.
ARICAtherosclerosis Risk in Communities study; CABGcoronary artery bypass graft; CDcoronary death; CHSCardiovascular Health Study; CLASCholesterol Lowering Atherosclerosis Study; CVDcardiovascular disease; KIHDKuopio Ischaemic Heart Disease risk factor study; MImyocardial infarction; PTCApercutaneous transluminal coronary angioplasty.
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