Carotid wall thickness test withstands scrutiny

Mr. Meijer is manager of scientific services for Bio-Imaging Technologies in Leiden, the Netherlands. Prof. Bots is an associated professor of epidemiology at the Julius Center for Health Sciences and Primary Care of the University Medical Center Utrecht, also in the Netherlands.

Several population studies have shown that a relatively simple measurement of carotid vessel wall thickness (carotid intima media thickness, or CIMT) made by carotid B-mode ultrasound (Figure 1) could detect atherosclerosis at an early stage. The test can also identify individuals at increased risk for atherosclerotic events, such as acute myocardial infarction or ischemic stroke.^1-10 Clinics worldwide have begun to offer this noninvasive, low-cost risk-assessment service.

Data from long-running population studies can also be used to estimate an individual's "vascular age," that is, age based on the state of a person's blood vessels rather than that person's chronological age.^11-13 Evidence suggests that when carotid artery vessel walls show signs of aging (thickening, plaques) before an individual's chronological age would warrant, that person has a higher risk of experiencing cardiovascular events sooner than an age-matched control.

The market for cardiovascular risk screening is evolving rapidly. Major players in the ultrasound industry have identified this opportunity and implemented CIMT measurement and reporting software into the vascular calculation packages of their ultrasound systems (Figure 2).

The growing interest in this area should be no surprise. Programs designed to prevent illness and to identify the presence of modifiable disease are becoming popular. More responsibility for well-being is being shifted from the state to individuals and employers with the intention of keeping the aging population fit and well, thereby reducing healthcare costs.

Cardiovascular disease is the number one killer in the Western world. CIMT screening of underlying atherosclerosis has the potential to create a new market for ultrasound manufacturers and prevention clinics. Screening followed by adequate, appropriate risk management could help prevent future vascular events. Several studies have shown that development of atherosclerosis can be slowed or even reversed by medication, change of lifestyle, change of diet, or a combination of all these approaches.^9,14-18

The real challenge is to not only identify individuals at risk, but also engender changes in lifestyle and diet that will lower those individuals' risk of a cardiovascular event. CIMT may be a way to do this. Individuals who undergo screening can be shown signs of vascular damage directly, which should encourage them to comply with appropriate advice. The psychological impact of telling an apparently healthy person that significant plaque is present in his or her carotid artery-and probably elsewhere-endangering future health, should not be ignored. Professional guidance will be necessary to handle this type of communication.

Among the common imaging techniques that can be used to assess and monitor atherosclerosis in clinical trials and population studies, B-mode ultrasound stands out owing to its availability, low cost, noninvasiveness, and capacity to image peripheral vessel wall anatomy in great detail, including vessel wall dynamics.

Examinations typically focus on the carotid artery. The carotid artery's superficial position in the neck means it can be imaged easily with B-mode ultrasound. Vessel wall thickness can be monitored and atherosclerotic plaques observed. The disadvantages are that B-mode ultrasound is highly operator-dependent, access to the target area is restricted, and thick or short necks hamper imaging of the carotids with ultrasound.

CIMT measurements have evolved as a valuable and powerful biomarker for cardiovascular disease in clinical trials over the past two decades. More than 800 publications involving CIMT have appeared since the 1980s, and this number is growing rapidly. Standardization among CIMT imaging approaches and measurements, however, is lacking. Interstudy comparisons of data are, consequently, not always possible.

This lack of standardization makes it difficult to correlate CIMT values with any biological consequence. In one study, patients at high risk for a cardiovascular event who had undergone a coronary artery bypass graft showed common CIMT values of around 0.6 mm. In another study, CIMT values among the general population were around 0.7 mm. Comparisons of target patients with reference populations will not be meaningful if the imaging and measurement protocols are not identical.^1,9 Differences in CIMT values between separate groups may also be due to technical, not true biological differences.

Researchers are still struggling to determine the "best" way to detect and monitor atherosclerosis. A carotid imaging protocol to assess CIMT in a clinical trial may range from a single image of a posterior vessel wall segment somewhere in the common carotid artery (CCA), with measurement acquired from the screen using calipers, to a highly standardized multi-angle protocol involving the anterior and posterior vessel wall, using a specially developed carotid arc (Meijer Carotid Arc) to verify scan angles on multiple predetermined segments (Figure 3).^15,19 These extensive protocols often use sophisticated offline analysis software with QA programs in an attempt to reduce operator and reader variability.

Data on baseline CIMT values, annual progression, and treatment effects may vary according to the imaging and measurement methods used. CIMT values will depend on:

• characteristics of the population studied;

• ultrasound equipment and protocol;

• operator's expertise;

• carotid segments measured; and

• process for analyzing intima media thickness.

Many background factors must also be considered. Populations with risk factors for atherosclerotic disease likely will have higher baseline values than healthy populations from similar age groups. Annual progression rates in subjects who have atherosclerotic disease are higher than those in subjects who have no signs of atherosclerosis. Progression of atherosclerosis is segment-specific, being more pronounced in the bifurcation and internal carotid then in the common carotid artery.²⁰ To determine the best way to conduct a study is clearly difficult and will depend on the goal of the CIMT measurement.

RISK RATIONALE

Numerous studies have indicated that observed abnormalities in the carotid artery mirror the presence of atherosclerosis in other areas of the cardiovascular system. The "vascular age" principle mentioned earlier relies on the fact that aging increases vessel wall thickness and stiffness, which are early signs of atherosclerosis. Focal plaques will then eventually appear. This vascular aging process is accelerated in some individuals who have an unhealthy lifestyle, higher levels of established vascular risk factors, and/or chronic disease. "Vascular age" then supersedes "calendar age" (Figure 4). These individuals will be at higher risk for stroke or heart infarct compared with people whose vessels are normal for their age.

Traditional screening tools, such as the Framingham heart score, can also identify these high-risk groups. They are less accurate, however, when it comes to identifying and further stratifying high-risk subjects, especially in the younger groups.^9,11,21-23 Improvements to traditional screening methods will be most welcome. CIMT might indeed help in refining individuals' risk profiles and possibly shifting them to different risk classes. That is, when someone at intermediate risk based on Framingham score has an IMT that is compatible with a more advanced age, it may make sense to use that age in the table and therefore shift this person to a higher risk class. However, this claim has not yet been firmly established.

The number of cardiovascular health screening programs that use CIMT to assess risk is growing rapidly; so is awareness among public, government, and health insurance companies that CIMT can help to identify subjects at risk. These entities are also coming to understand that the information from CIMT can increase patients' awareness of risk and encourage them to actively change their lifestyle. Screening may be part of a prevention program, sponsored by the state or a health insurance provider, or it may be performed individually on a commercial basis.

Application of the CIMT tool in cardiovascular screening makes sense. Increased CIMT or presence of plaque means increased risk of cardiovascular events. As yet, however, no hard evidence shows that CIMT can reliably add much to traditional risk factors and improve risk profiling. Questions about the type of CIMT measurement that should be used and the most appropriate reference population also remain unanswered.

Some screening programs perform only a limited evaluation of the posterior CCA vessel wall and base their risk assessment on this single image. Individuals whose CIMT in the distal CCA segment is normal for their calendar age may, however, have significant atheromatous plaques in other carotid segments. Evaluations based on CCA alone will produce a certain proportion of false-negative results. Some clinics may use data from population studies but not follow the exact protocol used in the reference study, leading to a questionable outcome.

The definition of "increased CIMT" is arbitrary. The risk of vascular disease increases gradually with increasing CIMT. Every cutoff point, whether 0.9 mm, 1 mm, or 1.2 mm, has been chosen arbitrarily.

Controlling the quality and accuracy of cardiovascular screening based on CIMT is consequently of the utmost importance. National certification or centrally controlled analysis may be necessary to protect individuals from mistakes and from inappropriate treatment and/or advice.

BEST PRACTICE

CIMT measurements in many clinical trials are performed in three segments (distal CCA, bifurcation, and proximal internal carotid artery [ICA]) over a width of 10 mm per segment (Figure 5). CIMT thickening and any emerging or preexisting plaques outside that predefined 10-mm segment are generally not taken in account.

This imaging protocol is fine for studies comparing the effects of treatment in different groups, or in observational studies, but it raises an interesting question for risk assessment. Should we ignore plaques that are outside of our target region when assessing risk? Scientifically, we should not deviate from the image protocol of the particular study on whose data the risk assessment is based. Our clinical thinking will probably be in trouble if we assume that thickening and plaques elsewhere also increase cardiovascular risk.

The locations from which CIMT measurements are taken are often based on internal landmarks; for example, the tip of the carotid flow divider (Figure 5). Most online and offline CIMT software packages use a default 10-mm measurement width so that they are compatible with published study data. This will increase the reproducibility of follow-up measurements. ECG is generally used to control timing, select the best end-diastolic frame for maximum CIMT measurement, and eliminate thickness during the cardiac cycle.

The latest software program allows real-time CIMT measurements using a semiautomated boundary trace. Data on lumen changes are used to detect the end-diastolic phase, from which the maximal CIMT can be measured. This eliminates the need to use ECG. Other software programs calculate the average CIMT during one or more cardiac cycles. It is not yet clear which approach is best.

The ideal imaging and analysis protocol should be accurate, reasonably simple to perform, and time-efficient. It should also be complete, reproducible, and compliant with the imaging protocol used as a baseline reference to assess age and cardiovascular risk. These requirements can be difficult to fulfill. Image acquisition and analysis protocols used in reference studies may be too demanding for routine use. Quality-control programs used to monitor the integrity of data generated during research may also be absent from a clinical screening situation.

B-mode ultrasound CIMT imaging is extremely dependent on the operator's expertise and the subject being examined. Monitoring small changes to vessel wall thickness or plaques (<0.02 mm annually) is a considerable challenge.14 A highly standardized imaging approach appears to be a prerequisite for measuring the effects of any intervention in large population studies.^9,14 The variability of CIMT measurements on ultrasound suggests that it would be wiser to evaluate the process affected by the intervention: blood pressure, lipids, or glucose levels.

CLINICAL SCREENING

Several ultrasound companies have introduced automated boundary trace software to measure and report CIMT. More will certainly follow, bringing CIMT measurement into the general clinical arena. Cardiologists and vascular specialists may want to start using such a tool to optimize risk profiling and patient care.

Cardiovascular health screening centers may integrate CIMT measurement into their standard screening programs. Health insurance companies have shown some interest in offering this option to clients, to enhance awareness of cardiovascular disease and prompt at-risk individuals to implement lifestyle changes. Large companies may want to include a CIMT risk assessment in their existing corporate healthcare programs for the same reasons.

Regulatory bodies and professional societies will probably ask that the technique be certified and standardized, or they will recommend centralized analysis, to safeguard quality and accuracy of results.⁹

B-mode CIMT measurement may provide us with an opportunity to translate arterial wall thickness into a cardiovascular risk marker, allowing noninvasive identification of individuals at high risk for heart attack and stroke. The incremental value of CIMT measurement on top of information on predicted risk from other sources has not been established, however, and it is necessary to appreciate the technique's limitations and the need for standardization and quality control.

Another important issue is the impact of a CIMT assessment on individuals being screened. Ideally, they will opt to follow an intervention program, preferably a lifestyle change, to try to slow down the atherosclerotic process and reduce cardiovascular risk. If so, CIMT measurement may have an important role in reducing premature mortality and morbidity in our aging population.

References

1. Lorenz MW, Markus HS, Bots ML, et al. Prediction of clinical cardiovascular events with carotid intima-media thickness: a systematic review and meta-analysis. Circulation 2007;115(4):459-467.
2. Crouse JR, Imaging atherosclerosis; state of the art. J Lipid Res 2006;47(8):1677-1699.
3. Howard G, Sharrett AR, Heiss G, et al. Carotid artery intimal-medial thickness distribution in general populations as evaluated by B-mode ultrasound. ARIC investigators Stroke 1993;24(9):1297-1304.
4. Chambless LE, Folsom AR, Clegg LX, et al. Carotid wall thickness is indicative for incident clinical stroke: the atherosclerosis risk in communities (ARIC) study. Am J Epidemiol 2000;151(5):478-487.
5. Ebrahim S, Papacosta O, Whincup P, at al. Carotid plaque intima-media thickness cardiovascular risk factors and prevalent cardiovascular disease in men and women: the British Regional Heart Study. Stroke 1999;30(4);841-850.
6. Bots ML, Hoes AW, Koudstaal PJ, et al, Common carotid intima-media thickness and risk of stroke and myocardial infarction: the Rotterdam Study. Circulation 1997;96(5):1432-1437.
7. Lorenz MW, von Kegler S, Steinmetz H, et al. Carotid intima-media thickening indicates a higher vascular risk across a wide age range: prospective data from the Carotid Atherosclerosis Progression Study (CAPS). Stroke 2006;37(1):87-92.
8. O'Leary DH, Polak JF, Kronmal RA, et al. Thickening of the carotid wall. A marker of atherosclerosis in the elderly? Cardiovascular Health Study Collaborative Research Group. Stroke 1996;27(2):224-231.
9. Stoerk S, Feelders RA, van den Beld AW, et al. Prediction of mortality risk in the elderly. Am J Med 2006;119(6):519-525.
10. Riley WA. Cardiovascular risk assessment in individual patients from carotid intimal medial thickness measurement. Curr Atheroscler Rep 2004;6(3):225-231.
11. Labropoulos N, Leon LR Jnr, Brewster LP, et al. Are your arteries older than your age? Europ J Vasc Endovasc Surg 2005;30(6):588-596.
12. Stein JH, Fraizer MC, Aeschlimann SE, et al. Vascular age: integrating carotid intima-media thickness measurements with global coronary risk assessment. Clin Cardiol 2004;27(7):388-392.
13. Gepner AD, Keevil JG, Wyman RA, et al. Use of carotid intima-media thickness and vascular age to modify cardiovascular risk prevention. J Am Soc Echocardiogr 2006;19(9):1170-1174.
14. Bots ML, Evans GW, Riley WA, Grobbee DE. Carotid intima-media thickness measurements in intervention studies: design options, progression rates, and sample size considerations: a point of view. Stroke 2003;34(12):2985-2994.
15. Crouse JR 3rd, Raichlin JS, Riley WA, et al. Effect of rosuvastatin on progression of carotid intima-media thickness in low risk individuals with subclinical atherosclerosis: the METEOR trial. JAMA 2007;297(12):1344-1353.
16. Mazzone T, Meyer PM, Feinstein S, et al. Effect of pioglitazone compared with glimepiride on carotid intima media thickness in type 2 diabetes: a randomized trial. JAMA 2006;296(21):2572-2581.
17. Wildman RP, Schott LL, Brockwell S, et al. A dietary and exercise intervention slows down menopausal associated progression of subclinical atherosclerosis as measured by intima-media thickness of the carotid artery. J Am Coll 2004;44(3):579-585.
18. Hjerkinn EM, Abdelnoor M, Breivik L, et al. Effect of diet or very long chain of -3 fatty acids on the progression of atherosclerosis, evaluated by carotid plaques, intima-media thickness and pulse wave propagation in elderly men with hypercholesterolaemia. Europ J Cardiovasc Prev Rehabil 2006;13(3):325-333.
19. Simons PC, Algra A, Bots ML. Common carotid intima-media thickness in patients with peripheral arterial disease or abdominal aortic aneurysm: the SMART study. Second Manifestations of ARTerial disease. Atherosclerosis 1999;146(2):243-248.
20. Mackinnon AD, Jerrard-Dunne P, Sitzer M, et al. Rates and determinants of site-specific progression of carotid artery intima-media thickness: the carotid artery progression study. Stroke 2004;35(9):2150-2154.
21. Touboul PJ, Labruece J, Vicaut E, et al. Carotid intima-media thickness, plaques and Framingham risk score as independent determinants of stroke risk. Stroke 2005;36(8):1741-1745.
22. Vogel RA, Benitez RM. Noninvasive assessment of cardiovascular risk: from Framingham to the future. Rev Cardiovasc Med 2000;1(1):34-42.
23. Wynman RA, Fraizer MC, Keevil JG, et al. Ultrasound detected carotid plaque as a screening tool for advanced subclinical atherosclerosis. Am Heart J 2005;150(5):1081-1085.