Pii: s0002-9149(01)02329-3

An Update on Carotid Ultrasound
Measurement of Intima-Media Thickness
Jacques D. Barth, MD, PhD Coronary atherosclerosis is a chronic, multifactorial dis-
tomatic period. Several techniques for assessing arterial
ease process. Some individuals with atherosclerosis re-
health are available, including quantitative intima-
ceive treatment in the form of mechanical or pharmaco-
media thickness (QIMT) measurement by carotid ultra-
logic interventions after an acute event has occurred.
sound. QIMT is a safe, validated, and portable method
Others receive treatment in the form of risk factor– based
that may prove highly useful in screening for atheroscle-
systemic intervention, the effectiveness of which is as-
rosis and in providing a surrogate measure for response
sessed by its ability to prevent an acute event. Surrogate
to disease interventions. 䊚2002 by Excerpta Medica,
endpoints in the study of atherosclerosis interventions
are needed to better define disease course and disease
Am J Cardiol 2002;89(suppl):32B–39B
response to interventions during the prolonged asymp-
Complications of atherosclerosis occur suddenly, unlikely, particularly in the case of systemic therapy
but they are a very long time and asymptomatic in that must be administered for prolonged durations. For the making. Most health professionals in the field example, ␤-blocker therapy may reduce blood pres- agree on how atherosclerosis develops. A normal sure but may also adversely affect lipid metabolism.
healthy endothelium is exposed to a variety of dam- Such potential effects go unrecognized if the effect of aging factors. Eventually, the healthy tissue is injured treatment is assessed as effect on the risk factor rather and endothelial dysfunction results. If the damage than on the disease process itself—that is, if measures persists, raised lesions in the vessel wall and athero- of the effects of treatment on the disease process itself sclerotic plaques develop, carrying the risk of plaque are not available or are not used. Similarly, assessing vulnerability and rupture.1,2 Familiarity with the response to treatment (and putative effect on disease course of disease is vital in determining how to de- course), by assessing response of the risk factor tar- velop and use surrogate markers in clinical trials, geted by treatment, fails to take into account the because different markers may be more appropriate at different degrees to which different risk factors may different stages of cardiovascular disease (Figure 1).3 contribute to disease course at different stages of the The notion that we do not need such markers and can disease. Most recognized risk factors do not exhibit a rely instead on observation of symptomatic disease to linear relation with disease progression. As shown in trigger treatment or to evaluate effectiveness of treat- Figure 2, the relation of major reversible risk factors ment is based on a number of incorrect assumptions to risk of progression varies, indicating that the time about the disease process. One assumption is that point at which the risk factor is assessed is important acute treatment of a disease event constitutes treat- in determining the impact of the risk factor. Figure 2A ment of the disease; this assumption appears to be shows the linear relation between smoking and pro- coupled with the assumption that reversal of disease is gression of disease. Figure 2B shows the relation still an option after an acute event has occurred. Acute between serum cholesterol and risk of progression. A events are almost always treatable, and treatment may threshold value needs to be exceeded before excess prevent damage to the heart or vessels. However, it is levels contribute exponentially to progression, reflect- well known that in ⱖ25% of patients with coronary ing the physiologic requirement for cholesterol and artery disease, their first symptom of disease is sudden reminding us that there is some limit to the dictum of cardiac death. The likelihood of reversibility is also "the lower the better." Figure 2C displays the famous thrown into question because about 40% of cardiac "J curve" association of hypertension and risk, and patients have normal blood pressure and/or normal Figure 2D shows the "inverse S curve" association of blood cholesterol levels.
lack of exercise with disease progression.
It also seems to be tacitly assumed that intervention Some individuals with normal cholesterol levels based on a single risk factor has a neutral effect on the have major coronary events. Others with very high many other potential factors involved in disease pro- cholesterol levels do not have coronary events. With gression or in protection from disease—some 250 regard to the latter, consider a recent report of potential factors by recent count.4 This seems highly Sijbrands et al,5 who assessed 200 years of a Dutchfamilial hypercholesterolemia pedigree and found From the Southern California Prevention and Research Center, Encino, that, although the family members were hypercholes- California, USA.
terolemic, 40% of them had a normal life span. Instead Address for reprints: Jacques D. Barth, MD, PhD, Southern Cali- of using different risk-factor measurements, a triage fornia Prevention and Research Center (SPARC), 16550 Ventura Bou-levard, Suite #212, Encino, California 91436. E-mail: jbarth@ using quantitative intima-media thickness (QIMT) as surrogate endpoint would help disease management.
2002 by Excerpta Medica, Inc.
0002-9149/02/$ – see front matter All rights reserved.
FIGURE 1. Sequence of events leading to adverse outcomes in coronary artery disease if cardiovascular risk factors persist, and pro-
posed technique for assessing disease or response at disease stage. FMD ⴝ flow-mediated dilation (via IMTHeartScan; Ultrascan
Health Technologies, Salt Lake City, UT); IMT ⴝ intima-media thickness; IVUS ⴝ intravascular ultrasonography; MI ⴝ myocardial in-
farction. (Reprinted with permission from Am J Cardiol.3)
After all, the disease itself should be treated and not a method that uses ultrasound images and permits quan- risk factor for the disease. It would appear that the titative measurements. As with intravascular ultra- precise mechanism of disease course in such individ- sonography, QIMT provides a direct assessment of uals is better determined by a surrogate marker of the disease. It is suitable for use in all stages of athero- disease itself than by evaluation of a risk factor, and sclerotic disease, permitting both diagnosis and fol- that management of disease, as assessed by such a low-up evaluation of disease. Specific advantages of marker, may be preferable to management of the risk QIMT are: (1) portability, (2) the existence of a large factor for disease.
reference database, and (3) relatively low cost. The A surrogate endpoint is a biomarker intended to large database (⬎26,000 individuals) of Prevention substitute for a clinical endpoint in a clinical trial.
Concepts, Inc. (PCI, West Los Angeles, CA), with a Surrogate markers have some inherent limitations. For long-term follow-up period (ⱕ10 years) of different example, response, as determined using the surrogate populations and ethnic groups, makes a reliable out- marker, may not translate into clinical benefit or sur- come prediction for cardiovascular and cerebrovascu- vival benefit and may not be intervention dependent.
lar complications a reality. QIMT findings correlate Nevertheless, the wait for clinical endpoints, such as with (1) cardiac and cerebrovascular outcome; (2) revascularizations, angina, and acute myocardial in- absolute and relative risk, as assessed by cardiovas- farction in the prolonged asymptomatic phase of dis- cular risk factors; and (3) change in risk during disease ease, can be as long as a decade.6 Development of management.7–11 The technique has now been used as surrogate markers allows us to establish prevention the sole surrogate endpoint in the additional approval measures during this time frame, and it is hoped that process of a number of lipid-modifying compounds.
these measurements will provide us a safe, noninva- Data from the 10-year follow-up study of the Ath- sive, and reproducible method for assessing the pro- erosclerosis Risk in Communities (ARIC) study indi- gression and change of the disease.
cate that the findings, made by imaging the far wall of Several noninvasive vascular imaging procedures the common carotid artery, correlate well with all have been developed as potential surrogate measures major risk factors.12 This confirms our earlier finding of disease. It is important to determine whether such during the Cholesterol Lowering Atherosclerosis techniques can provide a useful surrogate endpoint to Study (CLAS) that carotid IMT 1 cm below the bulb identify high-risk subjects. The focus of this report is was reproducible and showed a remarkable correlation on carotid ultrasound measurement of intima-media with cardiovascular events during 10 years of fol- thickness (IMT).
low-up study.8,9 A striking finding of that early re- QIMT is a safe, standardized, and validated search was that there was no discrepancy over time A SYMPOSIUM: DOCUMENTING REGRESSION OF ATHEROSCLEROSIS FIGURE 2. Relation between level of risk factor and risk of progression of disease events for smoking (A), serum cholesterol (B), sys-
tolic blood pressure (C), and lack of exercise (D).
between direction of disease in coronary arteries on the finding that only the assessment of the far wall of angiography and on imaging of the carotid IMT; with the common carotid artery shows significant correla- hindsight, we appreciate that we had already identified tion with coronary artery changes. An explanation can those patients who would benefit from lipid lowering be found by considering the rheology in the carotid with a combination of colestipol and niacin after an tree (Figure 4)16; laminar flow indicative of general- intervention of only 6 months (Figure 3).13 Data from ized atherosclerosis is present only proximal to the the Monitored Atherosclerosis Regression Study bulb. The coronary arteries also adhere to the laws of (MARS) confirmed these findings in patients receiv- physics and therefore have a similar impact on ing statin therapy.14 Subsequently, in the Pravastatin, changes in blood flow. These findings are of particular Lipids, and Atherosclerosis in the Carotid Arteries interest, because image acquisition of 12 points is a (PLAC II) study, Byington et al15 confirmed that the much more time-consuming process than image ac- part of the carotid tree that most reliably indicated the quisition of 1 reliable area, and the analyses of these efficacy of lipid lowering in the coronary tree was the points cannot always be done by other groups with a far wall of the common carotid artery. In this study, no computerized system. In addition, we should realize other imaging point, not even the aggregate of 12 that plaque formation in the bulb is more dependent on different points, was significantly correlated with pro- different risk factors than those for coronary artery gression or regression of disease. Other studies that disease. Risk factors for the development of cardio- we have conducted with different lipid-lowering vascular plaque formation seems to be different than agents (eg, rosuvastatin) provide further support for thickness of the IMT.17 34B THE AMERICAN JOURNAL OF CARDIOLOGY姞
FEBRUARY 21, 2002 FIGURE 3. Change in carotid intima-media thickness during 48 months of treatment with colestipol/niacin (solid circles) or placebo
(open circles) in the Cholesterol Lowering Atherosclerosis Study (CLAS). (Adapted with permission from Arterioscler Thromb.13)
Figure 5 shows 2 examples of digitized images of the left does not have these major reversible risk the common carotid artery in 2 patients matched for factors. It is notable that the near wall of the common age, sex, and ethnicity. The patient on the right has carotid artery is difficult to assess, because the focus hypercholesterolemia and hypertension; the patient on can be on only 1 part of the picture.
The availability of our large QIMT database has enabled us to establish that the measurement of the farwall of the common carotid artery alone is the mostreliable and reproducible measurement for predictingcoronary disease. In addition, our comparisons ofmanual and quantitative assessments have made itclear that a computerized contour detection techniqueis far more reproducible and accurate than caliper ormanual assessment (Figure 6). We found that accord-ing to standardized measures, the computer programwas 4 times more accurate than the caliper IMT, andrepeated caliper measurements were within the normalvariation of the technique.
The predictive value of QIMT has been established in a number of populations. Smoking, blood pressure,and low socioeconomic status are each correlated withcarotid IMT.18–20 Lakka et al18 found that blood pres-sure was significantly correlated with carotid IMT.
Postprandial blood sugar correlates with IMT in indi-viduals without diabetes, as does duration of diseasein patients with diabetes.21,22 In addition, Hanefeld etal21 established that plasma blood sugar level is anindependent risk factor for increased carotid IMT inindividuals without diabetes. The impact of troglita-zone on IMT was found to be dramatic in diabetespatients.23 Both Diez-Roux et al24 and Salonen et al25found that smoking and secondary smoking had apotent effect on progression of carotid atherosclerosis.
FIGURE 4. Depiction of the carotid artery showing the region of
Nevertheless, the predictive accuracy of QIMT varies flow separation with formation of secondary vortices. Although
among different cultures,26 with Woo et al27 warning flow remains laminar and mainly unidirectional in the high-shear
that it is sometimes difficult to extrapolate findings flow-divider area, a very low-shear area is present on the lateral
among individuals with different ethnic backgrounds.
wall of the internal carotid artery. This area is where plaques
are most likely to form and where blood flow accelerates with
Baldassarre et al28 investigated the use of IMT to each cardiac cycle. (Adapted with permission from Stroke.16)
manage risk factors in the clinical setting, supporting A SYMPOSIUM: DOCUMENTING REGRESSION OF ATHEROSCLEROSIS

FIGURE 5. Digitized images of the common carotid artery (on the right side of each picture) and the bulb (on the left side of each pic-
ture). The far wall of the common carotid is visible in both pictures, as is the jugular vein, which is located above and parallel to the
common carotid artery. The 1-cm ruler in the middle of the artery indicates where analyses were done. The picture on the right
shows the thickened value in a patient with some hypertension and hypercholesterolemia, whereas the picture on the left shows the
value for a patient matched by age, sex, and ethnicity but without hypercholesterolemia and hypertension. Note the fussy boundaries
in the near wall above the ruler. (Pictures using the Arterial Imaging Software [ARTIS] postprocessing software system, courtesy of
Prevention Concepts, Inc., West Los Angeles, CA).
FIGURE 6. Quantitative intima-media thickening (QIMT; IMTHeartScan, Ultrascan Health Technologies, Salt Lake City, UT) versus cali-
per intima-media thickening. Comparison of absolute laser-measured carotid intima-media thickness (IMT) by user-pointed caliper
method with 2 operators (right) and the same measurement by the same 2 experienced operators using QIMT with a computerized
edge contour measurement technique (left). (Reprinted with permission from Am J Cardiol.3)
our experience of using IMT as a triage point for olemic, and 14% had a carotid atherosclerotic lesion.30 further risk-factor management. IMT also predicts This rate of atherosclerosis is consistent with the rate plaque formation in men and women, independently of 17% found by Tuzcu et al31 in intravascular ultra- of baseline plaque.29 Indeed, a study we performed in sound transplant studies in a young population. More- 13- to 17-year-old high school students showed that over, providing these young individuals with a cus- 10% were hypertensive, 15% were hypercholester- tomized image of their carotid artery led many to 36B THE AMERICAN JOURNAL OF CARDIOLOGY姞
FEBRUARY 21, 2002 make lifestyle changes, including weight loss, diet characterization. Use of magnetic resonance imaging improvement, and cessation of smoking,30 consistent may be feasible in the near future in a clinical setting, with other findings we have obtained in a large, pa- but the costs of this procedure prohibit its routine tient group.32 In this latter group, IMT decreased over clinical use at this time. In addition, magnetic reso- time in the patients given a customized picture of their nance imaging is still too experimental for use as an Risk factors for the development of cardiovascular Atherosclerosis is prevalent in all countries, and plaque formation seem to be different than risk factors clinical trials can be conducted globally in this type of for IMT thickness.17 In our experience, about 40% of disease. Therefore, availability of various tests must plaques are asymptomatic. In these plaques, which are be considered, because many countries do not have mostly located in the bulb, tissue type rather than facilities similar to those in Western countries, which plaque size is the most important factor for determin- limits the ability to translate findings consistently from ing vulnerability to rupture. It has been shown that country to country.26,27 calcified plaques are not correlated with stroke,whereas soft plaques have a greater likelihood of rupturing and causing stroke; therefore, an analysis of In conclusion, atherosclerosis is a multifactorial the constituents of the plaques is critical.33,34 The disease, resulting from interaction of multiple risk Plaque Tissue Typing option provided by Arterial factors with varying effect over a prolonged course.
Imaging Software (ARTIS; PCI) can help us to deter- Thus, it is preferable to study the disease and not just mine whether a plaque has a thin vulnerable cap, the risk factors for the disease. Furthermore, with which would make it more likely to rupture than a many patients not having an abnormal cardiovascular stable plaque with a relatively small cholesterol core.
risk factor profile, a noninvasive low-cost technique This computerized system enables us to discriminate for assessing is disease imperative. QIMT is an ap- between "hot" and "cold" plaques, the former imply- propriate technique for use as a surrogate marker both ing a plaque with increased likelihood of vulnerability to screen for disease and to manage disease when risk and rupture and the latter implying a stable plaque.
factors are being modified. QIMT/FMD might be These findings have been validated, and they indicate added to several ongoing studies to evaluate the best that plaque tissue typing would be of great benefit.
marker for different stages of cardiovascular disease.
Other noninvasive imaging techniques include (1) FMD might be especially suitable if no obstructive measurement of flow-mediated dilation (FMD), (2) disease is present, because FMD can detect whether a electron-beam computed tomography (EBCT) mea- pathophysiologic state is present. When cardiovascu- surement of calcium, and (3) magnetic resonance im- lar risk is present, QIMT is the best method, if there is aging. FMD assessment of endothelial function is a endothelial dysfunction and suspected thickening of good surrogate measure of initial risk for atheroscle- the far wall of the common carotid artery. Given its rosis. It indicates very early disease, shows rapid standardization, QIMT is especially suited to multi- response to change, is an ambulatory method, and may center studies. If there is plaque formation, tissue better reflect pathophysiologic response. However, characterization should be performed.
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Alan Guerci, MD (Roslyn, New York, USA): With
suggest that there is more soft plaque than calcified respect to the drawbacks of electron-beam computed plaque at the site of plaque rupture. However, the tomography (EBCT), you noted that soft plaques, not interesting thing is that often both are present, and 1 of calcified plaques, are most vulnerable to rupturing, the hypotheses generated is that juxtaposition of soft and that calcified plaques are not correlated with and calcified plaque is a predisposing factor for rup- stroke. However, there are abundant data showing that ture. This may be why people are making different calcified plaque in the coronary arteries is a marker for findings; it may be that having a soft plaque next to a vulnerable plaque. In a study by von Birgelen et al,1 noncompliant structure is associated with rupture— pretty much the "bible" on coronary pathology in however, we don't know that yet.
patients with stable and unstable coronary syndromes, Dr. Guerci: A couple of years ago, 2 studies had
about 1,300 patients undergoing coronary interven- autopsy data on ⬎1,200 subjects and showed that tion were examined by intravascular ultrasound people dying suddenly or dying of acute myocardial (IVUS). The investigators, who had no particular rea- infarction had 3 to 9 times as much coronary calcium son to be biased for or against EBCT, made a very as age-matched controls who died accidentally or of strong statement that calcified plaque on IVUS is a other natural causes. Another point is that in a slide Dr. Barth showed, there was a "⫾" next to EBCT for Steven E. Nissen, MD (Cleveland, Ohio, USA): I
association with clinical outcome. I'm sorry, but that probably know the IVUS literature as well as any- is just factually incorrect. Every study looking at the one—and there is more to this issue. Several studies issue that I'm aware of has shown a significant asso- 38B THE AMERICAN JOURNAL OF CARDIOLOGY姞
FEBRUARY 21, 2002 ciation between high calcium score and risk of myo- carotid artery IMT to the coronary arteries. Trials that cardial infarction or death, consistent with the autopsy have looked at both show a poor correlation between data. The question is not whether EBCT predicts hard coronary angiographic progression and carotid IMT events, but whether it predicts them as well or better progression—a correlation value of about 0.2. There- than standard risk factors. Finally, because I believe fore, I think the IMT is a great test for the carotids, but what we're supposed to be talking about is coronary that's not the heart. Carotid thickening is driven far disease—not stroke or transient ischemic attack—I more by hypertension.
don't think the correlation of intima-media thickness Dr. Nissen: I think we have to be careful in talking
(IMT)– defined carotid pathology and coronary ath- about correlations, because the data we have to date erosclerosis is that strong; the number I carry in my correlate progression of angiographic stenosis in the head is about 0.4, but Dr. Crouse may know the coronary lumen versus carotid plaque. We don't know literature better than I do.
the correlation between progression of the carotid John Robert Crouse III, MD (Winston-Salem,
plaque and, for example, progression of coronary North Carolina, USA): The extent of disease in the
plaque on IVUS. Maybe they correlate more closely. I carotids correlates with the extent of disease in the think it would be of interest to study whether the coronary arteries with an r-value of about 0.5. How- people whose plaques progress by IVUS are the samepeople whose plaques progress by carotid IMT and ever, the extent of disease in the left coronary artery whose calcium scores progress on EBCT, and, more correlates with the extent of disease in the right cor- importantly, whether drug treatment shows benefits onary artery with an r-value of about 0.5, too. There- using each of these endpoints separately.
fore, the carotid artery correlates as well with thecoronary artery as the coronary arteries correlate witheach other.
1. von Birgelen C, Klinkhart W, Mintz GS, Papatheodorou A, Herrmann J,
Christie Ballantyne, MD (Houston, Texas, USA):
Baumgart D, Haude M, Wieneke H, Ge J, Erbel R. Plaque distribution and I think that there are great data on IMT from clinical vascular remodeling of ruptured and nonruptured coronary plaques in the samevessel: an intravascular ultrasound study in vivo. J Am Coll Cardiol 2000;37: trials. However, the big problem is the jump from 1864 –1870.
A SYMPOSIUM: DOCUMENTING REGRESSION OF ATHEROSCLEROSIS

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