We have found that (1) CCA and ICA IMT have similar associations with cardiovascular risk factors; (2) Framingham risk factors are associated with both measures of atherosclerosis and explain a large proportion of their variability; and (3) the maximum ICA IMT is more strongly associated with the presence of symptomatic CVD than the mean CCA IMT.
We studied the mean CCA IMT and maximum ICA IMT as measures of subclinical CVD because these measures have been proposed by two consensus groups16,21
as means of assessing global cardiovascular risk. We did not measure the mean CCA IMT from multiple projections of the CCA as is done in epidemiologic studies, yet we obtained strong associations with cardiovascular risk factors. We show that up to 29% of the variability of the mean CCA IMT is explained by cardiovascular risk factors, with a very strong association between CCA IMT and age. As in other studies, age and gender are the two strongest predictors of IMT. We also show strong associations between the maximum ICA IMT and risk factors. In difference to the mean CCA IMT, the maximum ICA IMT is an estimate of carotid artery plaque. Although it can be argued that a subjective assessment of plaque as being either present or absent might suffice for global risk assessment, the two consensus panels recommend some form of quantitative measurement.16,21
The definition of plaque varies. From absolute IMT values that vary from of 1.222
mm to a relative increase of 50% compared with the baseline IMT.11
However, these definitions have not been validated in large cross-sectional studies looking at associations with risk factors or in large outcomes studies. As such, our study offers a new insight into using plaque as a quantitative measurement of the maximum IMT. Consideration should also be given to the fact that we used an experienced and certified registered diagnostic medical sonographer to perform our measurements. As such, the subjective judgment of the presence or absence of plaque should have been superior to that in studies done with sonographers without years of proven experience in carotid ultrasound.
A potential limitation of our measurements is the fact that they required measurements offline on a workstation from manual tracings processed by a validated algorithm.14
They were not performed on the ultrasound device by a sonographer using calipers.24
However, because the reader was blinded to the participant demographics, our estimates of IMT are less likely to be biased than those of a sonographer because a sonographer might be influenced by the physical appearance of the individual being imaged and the clinical history.
Although cardiovascular risk factors are associated with the mean CCA IMT and maximum ICA IMT, the maximum ICA IMT is more strongly associated with prevalent CVD. This difference reflects on the fact that ICA IMT is a measure of atherosclerotic plaque and has different pathologic characteristics that the mean CCA IMT. The mean CCA IMT is a response to shear-stress25
and lesions in the CCA tend to be diffuse and composed of foam cells.28
The mean CCA IMT is a measure of wall hypertrophy,11
which responds to cholesterol-lowering interventions.10
The maximum IMT is a measure of plaque taken at the carotid bifurcation and proximal ICA, where complex oscillatory low shear stress promotes the primary deposition of low-density lipoprotein cholesterol in the wall.29,30
There is, however, a slight difference between pathologically defined plaque and ultrasound-defined plaque. The maximum ICA IMT is the distance from the lumen to the media,11,15,31
whereas plaque is a pathologic substance affecting the intima.32
In addition, plaque is not pathologically defined beyond an absolute size measurement but by a relative increase in the thickness of the intima.32
We opted to report a single maximum ICA IMT rather than average the maximum IMT measurements15,33
because this is consistent with the recommendation made by the consensus panels.11,16
Although the normally obtained mean of the maximum ICA IMT and mean of the mean ICA IMT are well suited for epidemiologic studies looking at outcomes or longitudinal changes in IMT,34–36
these measurements underestimate the presence of early plaque. An IMT measurement of 1.5 mm made at one site combined with a measurement of 0.7 mm at another site gives a mean of the maximum IMT of 1.1 mm. In this hypothetical case, 1.1 mm is below accepted thresholds for plaque, either 1.222,31,37
mm. Nevertheless, our data show that image selection should be made at the discretion of the sonographer because the maximum IMT was obtained from the additional projection selected by the sonographer in 53.7% of cases.
We find that the associations between risk factors and the maximum ICA IMT are similar to those for the mean CCA IMT. Although these differences can be argued to be of statistical significance and qualitatively different, as shown in , they are, from a practical point of view, very similar. In fact, after accounting for age and gender, the remaining Framingham risk factors explain a small amount of the variability in IMT, approximately 5.1% for both the mean CCA IMT and maximum ICA IMT. This does not detract from the value of IMT when it comes to being a potential predictor of incident events because the variability in IMT that is not explained by risk factors likely holds some predictive value for outcomes.
We compared the overall sensitivity and specificity of both the maximum ICA IMT and mean CCA IMT based on ROC curves. These data give a coarse appreciation of the differences between both variables. In essence, they describe the relative accuracy for confirming the presence of prevalent CVD. This task, in itself, is a verification of the validity of the measurement but not a criterion for overall predictive value. The latter needs to be verified in outcomes studies. The overall correlations between each of the two variables and risk factors reflect the possible causal relationship between a given risk factor and the IMT variable of interest. As such, they may represent key differences in the way that risk factors interact with changes in the artery wall.
Our data show relatively weak associations between IMT and cholesterol levels. Much of the data studying IMT have focused on populations with hypercholesterolemia in which the association between IMT and cholesterol levels is easily determined. We, however, note an effect of modern therapy in individuals who have prevalent CVD. Lipid-lowering therapies are seen in 38.7% of individuals with prevalent CVD compared to 9.7% without. This likely explains the blunting of the association between cholesterol and IMT as well as between cholesterol and prevalent CVD.
Results looking at the associations of risk factors and IMT measured at different locations at and below the carotid bifurcation have been contradictory. Espeland et al39
showed mild segmental differences in the associations of IMT with age and hypertension in women but did not report on the overall strength of the associations between IMT at different carotid artery locations and risk factors. Tell et al40
found age, hypertension, and cigarette smoking to affect all segments in a similar fashion, but quantitative ICA IMT measurements were not made. Schott et al41
used a complex statistical approach to show that systolic BP showed similar associations with the CCA and mean ICA IMT but did not see any strong association of ICA or bulb IMT with age. The Vascular Aging Study, which was limited to women, showed results different from ours, but that study did not use quantitative ICA IMT measurements.42
In the San Antonio study, Wei et al43
showed that total cholesterol and systolic BP were more strongly associated with CCA IMT than with ICA IMT but found a much lower correlation between risk factors and IMT than ours (22% variability for CCA IMT and only 12% for ICA IMT).43
O’Leary et al44
compared CCA IMT with ICA IMT but used average values over multiple segments and found that risk factors explained 18% of the variability in CCA IMT and 17% in ICA IMT, both values lower than what we report. None of these studies reported on results for the maximum ICA IMT.
We note that although the maximum ICA IMT is more strongly associated with prevalent CVD than CCA IMT, the relative effect of a 1-mm change in CCA IMT is more significant than an equivalent 1-mm increase in ICA IMT (). This is in part explained by the larger values and wider range for ICA IMT compared with CCA IMT ().
A possible limitation to our study was the use of an older-generation ultrasound device to obtain carotid IMT measurements. However, the associations of carotid IMT with cardiovascular risk factors and prevalent CVD1,6,45
were also observed for IMT values derived from images taken with older-generation ultrasound imaging devices such the Biosound 200IISA (Atherosclerosis Risk in Communities45
), ATL Ultramark 4 (Rotterdam Elderly Study1
) and Toshiba SSA-270A (Cardiovascular Health Study6
). Our results are consistent with these studies with the exception that we were better able to obtain estimates of ICA IMT and show slight differences between CCA and ICA IMT. Another limitation of our study was the cross-sectional nature of our data. Analyses with incident cardiovascular events are pending.
In summary, this study suggests that the maximum ICA IMT might add value to the mean CCA IMT for cardiovascular risk assessments.