|Year : 2017 | Volume
| Issue : 1 | Page : 39-46
Carotid ultrasound for cardiovascular risk prediction: From intima-media thickness to carotid plaques
Ravi R Kasliwal, Mansi Kaushik, Hardeep Kaur Grewal, Manish Bansal
Department of Cardiology, Medanta - The Medicity, Gurgaon, Haryana, India
|Date of Web Publication||7-Apr-2017|
Ravi R Kasliwal
Medanta - The Medicity, Sector 38, Gurgaon - 122 001, Haryana
Source of Support: None, Conflict of Interest: None
Carotid intima-media thickness (CIMT) and nonstenotic carotid plaques are established measures of subclinical atherosclerosis and are useful for prediction of future cardiovascular disease (CVD) risk. Compared with CIMT, the incremental predictive value of carotid plaques is more robust. Although the guidelines differ, carotid ultrasound-based assessment of CIMT and carotid plaques has a role in risk stratification and management of asymptomatic individuals who present with one or more CVD risk factors. The presence of significantly elevated CIMT or carotid plaque burden should lead to reclassification of the individuals into high-risk category with the appropriate intensification of the risk reduction measures. In addition, demonstration of increased CIMT and/or presence of the plaques may also help in improving patients' health behavior and their compliance toward antiatherosclerotic measures. In future, plaque progression/regression assessment by three-dimensional ultrasound and the use of contrast agents may further enhance the utility of carotid ultrasound for monitoring the clinical course of atherosclerotic vascular disease.
Keywords: Atherosclerosis, cardiovascular disease, carotid intima-media thickness, carotid plaques, primary prevention
|How to cite this article:|
Kasliwal RR, Kaushik M, Grewal HK, Bansal M. Carotid ultrasound for cardiovascular risk prediction: From intima-media thickness to carotid plaques. J Indian Acad Echocardiogr Cardiovasc Imaging 2017;1:39-46
|How to cite this URL:|
Kasliwal RR, Kaushik M, Grewal HK, Bansal M. Carotid ultrasound for cardiovascular risk prediction: From intima-media thickness to carotid plaques. J Indian Acad Echocardiogr Cardiovasc Imaging [serial online] 2017 [cited 2018 Aug 14];1:39-46. Available from: http://www.jiaecho.org/text.asp?2017/1/1/39/204070
| Introduction|| |
The world's major disease burden is contributed by noncommunicable diseases (NCDs), of which almost half is accounted for by atherosclerotic cardiovascular disease (CVD) alone. CVD is the leading cause of death globally. In 2012, NCDs led to 38 million (68%) deaths out of a total of 56 million deaths worldwide. Of these, 16 million (40%) deaths were premature deaths occurring before the age of 70 years. Low- and middle-income countries (LMICs) are the worst affected as almost 75% of all NCD deaths and 82% of premature deaths occur in LMICs. Although the disability-adjusted life years lost due to CVD is greater in high-income countries (18% vs. 10%), the economic loss is likely to be substantial in LMICs because in these countries, CVD predominantly affects the working class adult population.
India is currently in the midst of this global CVD epidemic. As per the Registrar General of India report 2001–2003, annual deaths in India were more than 10.5 million, of which CVD accounted for 20.3% deaths in men and 16.9% deaths in women. Another report from the Registrar General of India (2010–2013) stated that out of 32% adult deaths, 23% were CVD related. These disturbing statistics clearly underscore the need to urgently devise and implement strategies for CVD prevention.
Atherosclerosis starts in early childhood and advances over several decades. The atherosclerotic disease becomes symptomatic only when there is hemodynamically significant narrowing of the vessels or when sudden thrombus formation occurs over a ruptured plaque. The slow, insidious progression of atherosclerosis allows an opportunity to detect the disease during its subclinical stage and to halt its progression through appropriate remedial measures. Although not all patients with subclinical atherosclerosis necessarily develop clinical CVD, the risk of future cardiovascular events is substantially higher in those with early evidence of atherosclerosis.,,,, Carotid ultrasound for the measurement of carotid intima-media thickness (CIMT) and plaque assessment is one of the commonly used modalities for subclinical atherosclerosis assessment. This review describes the clinical utility of carotid ultrasound for CVD risk prediction and management.
| Technical Considerations|| |
Carotid intima-media thickness measurement
Duplex ultrasound imaging of the extracranial carotid artery displays the carotid wall as two echodense linear structures representing intima and adventitia, respectively. The intervening media appear as an echolucent zone [Figure 1]. Although most of the atherosclerotic changes occur in the intima, combined thickness of intima and media is measured because of the inability to accurately measure the thickness of intima alone. The ultrasound-based measurement of CIMT has been validated in in vitro histologic studies.,,
|Figure 1: Ultrasound image of carotid bifurcation from the “optimum angle of incidence” showing the “tuning fork view.” “Double lines” of intima and adventitia are also seen at the far wall of the common carotid artery. CCA: Common carotid artery; ECA: External carotid artery; ICA: Internal carotid artery. Modified from: Kasliwal RR, Bansal M, Desai N, et al. Indian Heart J 2016;68:821-7|
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Extracranial carotid arteries consist of four segments - common carotid artery (CCA), carotid bulb, and the proximal segments of internal carotid artery and external carotid artery (ICA and ECA, respectively). Ultrasound imaging of the wall of ICA and carotid bulb is generally difficult as they lie at an oblique angle, whereas CCA is at right angle to the ultrasound beam. This makes measurements of CCA intima-media thickness (IMT) easier and more reproducible.,,, Far wall IMT measurements are preferred over near wall as near wall measurements lack accuracy. This is because increased echogenicity of adventitia interferes with proper delineation of media-adventitia interface in the near wall. In addition, the gain settings also influence the near wall IMT measurement., In contrast, far wall CCA IMT measurements can be obtained quite accurately and have been shown to correlate with histologic studies.
The American Society of Echocardiography has provided detailed recommendations for measurement of CIMT.
The patient should be lying in supine position with head slightly tilted to the opposite side of the measurement. Extracranial carotid arteries are imaged using a 7.5 MHz frequency linear array transducer attached to a standard vascular ultrasound machine. The standard imaging sector depth is 4 cm but can be increased in patients with thick necks and deep-seated vessels. The carotid vessels are scanned to obtain the “optimal angle of incidence,” defined as the plane in which distal CCA, carotid bulb, and its bifurcation into ICA and ECA are all visualized simultaneously (the “tuning fork view”) [Figure 1]. Once this view is obtained, further adjustments can be done in the transducer position and orientation to make CCA horizontal in the image sector and to clearly visualize the “double line” sign of intima and media in the far wall of CCA. If it is not feasible to obtain the “tuning fork view” due to any reason, then at least the distal CCA and carotid bulb should be visualized as described above. Once the desired image is developed, an electrocardiogram (ECG)-gated video clip is stored for subsequent offline analysis. The CCA is then imaged in two more complimentary planes at approximately 45° anterior and posterior to the optimum angle of incidence obtained earlier [Figure 2]. The process is then repeated on the other side to yield a total of six images.
|Figure 2: Optimum position of the head and orientation of the imaging planes for measurement of carotid intima-media thickness|
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Simultaneously, the presence of carotid plaques should also be looked for. A plaque is the localized thickening of the arterial wall that protrudes into the lumen. To be classified as a plaque, it should have a thickness which is at least 50% more than the adjacent vessel wall thickness or there should be a focally increased CIMT (>1.5 mm). If any plaques are visualized, then additional video clips are stored to document their presence. Imaging the carotid arteries for plaques increases the sensitivity for the detection of subclinical atherosclerosis.,,
The measurement of CIMT is performed offline, at the distal 1 cm of the far wall of both the CCAs. Automated quantification software should be used to measure mean thickness of IMT over 1 cm length [Figure 3]. Measurement should coincide with the peak of R-wave on the ECG. If a plaque is present within the distal 1 cm of CCA, it should be included in the measurement of CIMT. Average of all the six CIMT values (three on each side) should be calculated to derive the mean CCA CIMT, which is used for the risk stratification purposes.
|Figure 3: Carotid intima-media thickness measurement using an automated analysis software|
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Normative values of carotid intima-media thickness
CIMT values vary according to age, gender, and ethnicity of the individual. Accordingly, ethnic-specific normative data are required for interpreting CIMT values in a given individual. While several large-scale studies have already described normal CIMT values in different ethnic groups, until recently, no such data were available for Indian participants. However, a recent, reasonably large study has described the age- and gender-specific normal values of CIMT in Indians also [Table 1]. This study included 1229 asymptomatic participants, more than 30 years of age and without any history of coronary artery disease (CAD). The CIMT measurements were performed according to the American Society of Echocardiography guidelines outlined above.
|Table 1: Age- and gender-wise distribution of mean carotid intima-media thickness* in Indian subjects|
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Assessment of carotid plaque
Traditionally, carotid plaque assessment for the purpose of CVD risk prediction has been performed only qualitatively, documenting just the presence and the hemodynamic significance of the plaque. Accordingly, most earlier studies reporting on the predictive accuracy of carotid plaques for CVD risk have only considered the presence of nonstenotic or stenotic plaques as the predicting variable.,,, However, more recent studies have described several quantitative measures of carotid plaque burden to provide a more accurate assessment of CVD risk. These include planimetered plaque area measured from the longitudinal or cross-sectional images [Figure 4],,, or plaque volume derived using three-dimensional imaging of the carotid arteries.
|Figure 4: Measurement of carotid plaque area in a short axis image. Total plaque burden is derived by adding plaque areas measured from successive cross-sectional images|
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| Clinical Implications|| |
A stenotic carotid plaque is considered as an evidence of established CVD and is not truly a marker of subclinical atherosclerosis. Therefore, the following discussion focuses on the role of CIMT and nonstenotic carotid plaques for CVD risk assessment and management.
Carotid ultrasound for cardiovascular disease risk prediction
Carotid intima-media thickness and cardiovascular disease risk prediction
CIMT is a well-documented marker of subclinical atherosclerosis and has been widely used in studies involving atherosclerosis. Increased CIMT has been shown to be associated with a number of different cardiovascular risk factors.,,, Numerous studies have also demonstrated that CIMT correlates well with the presence and severity of existing CAD.,,,,, The likelihood of obstructive CAD increases with increasing value of CIMT with values >1–1.1 mm being commonly associated with multivessel disease or left main CAD., Due to its association with the existing CAD, some investigators have proposed CIMT to be a useful tool for deciding about the need for coronary angiography in patients scheduled for heart valve surgery.
However, from a clinical perspective, the greatest value of CIMT is for predicting future CVD risk in individuals who present with one or more CVD risk factors but do not yet have established atherosclerotic vascular disease. A large number of studies enrolling several thousand patients have shown that CIMT is indeed a reliable predictor of future CVD risk., 12, ,,,,, Kuopio Ischemic Heart Disease Study demonstrated that for every 0.1 mm increase in CIMT, the risk of myocardial infarction increased by 11%. Similarly, in the Cardiovascular Health Study, which included 5858 elderly participants, the relative risk of myocardial infarction or stroke for the highest versus lowest quintile of CIMT was 3.87. The Atherosclerosis Risk in Communities (ARIC) Study is one of the largest studies to assess the predictive accuracy of CIMT. It included 7289 women and 5552 men aged 45–64 years who were free from clinical CAD at baseline. Compared to mean CIMT < 1 mm, the values > 1 mm had hazard ratios of 1.85 and 5.07 for coronary events in men and women, respectively. Several other large prospective studies have reported similar findings. A meta-analysis of several of these studies has shown that for an absolute increase in CIMT by 0.1 mm, the future risk of myocardial infarctions increases by 10%–15% and the stroke risk increases by 13%–18%.
Incremental value of carotid intima-media thickness for cardiovascular disease risk prediction
While it is well established that CIMT is a reliable predictor of future CVD risk to be clinically meaningful as a tool for cardiovascular risk stratification, it needs to have incremental value over conventional risk assessment tools. Unfortunately, the available evidence has been rather conflicting in this regard.
In the Cardiovascular Health Study described above, the association between CIMT and risk of CVD events was independent of traditional CV risk factors. Similarly, in the ARIC  and the Rotterdam studies, CIMT was found to have incremental value over several of the conventional risk factors. However, another study - Carotid Atherosclerosis Progression - which followed up 4904 participants for 10 years concluded that even though CIMT was predictive of CVD endpoints, it did not consistently improve the risk classification of individuals over conventional tools such as Framingham risk score. Similarly, in Multi-ethnic Study of Atherosclerosis, CIMT failed to predict the risk of both CAD and stroke when added to Framingham risk score. A meta-analysis was recently performed to evaluate the incremental value of common CIMT over Framingham risk score for prediction of the risk of myocardial infarction and stroke. Fourteen population-based studies enrolling over 45,000 patients were included in the study. It was found that the addition of CIMT to standard prediction methods did not yield any incremental value. The net reclassification index (which measures the net effect of addition of a biomarker to risk prediction model) for common CIMT was just 0.8% for the overall cohort and 3.6% for the intermediate-risk patients.
Several reasons have been suggested to explain these conflicting results. Simon et al. observed that there has been considerable heterogeneity among various studies regarding the characteristics of the study participants, CIMT methodology and measurement protocols, and the interpretation of the study findings. These differences make it practically difficult to compare and combine the results of various studies. At the same time, the lack of robust incremental predictive value of CIMT may also be related to the fact that inclusion of media in CIMT measurement makes it susceptible to arteriosclerotic changes also, in addition to atherosclerosis. Thus, apart from intimal thickening, CIMT also represents smooth muscle hypertrophy, which can result from pressure overload and/or age-related sclerosis.,, Indeed, the Rating Atherosclerotic Disease by Imaging with a New cholesteryl ester transfer protein Inhibitor 2 study, which indirectly evaluated the effect of blood pressure on CIMT, showed that blood pressure had more detrimental effect on CIMT as compared to atherosclerosis.
Common carotid artery intima-media thickness versus intima-media thickness of other carotid segments
Previous studies have suggested a differential relationship between CVD risk and CIMT measurements obtained from different segments of the extracranial carotid arteries. The British Regional Heart Study showed that although CCA IMT and bulb IMT correlated with each other, CCA IMT was better related to risk factors for stroke, whereas bulb IMT had a stronger relationship with ischemic heart disease. Similarly, several other studies have demonstrated that CCA IMT is superior for stroke prediction, whereas ICA IMT is more associated with atherosclerotic cardiac events. With the improvement in pixel resolution and imaging techniques for ICA, recent studies have also revealed that ICA IMT is associated with higher relative risk than CCA IMT for CVD. However, an analysis from the ARIC study showed that there was no difference in the predictive accuracy of common CIMT or all-segments CIMT (i.e., combined CIMT of CCA, bulb, and ICA) when added to plaques and traditional risk factors. This lack of difference could be because ICA IMT could be measured only in 43% of participants and therefore combined all-segments CIMT was actually the CCA and bulb IMT in majority of the cases. Nonetheless, based on these findings, the authors concluded that common CIMT was preferable for routine use because of its ease of measurement and similar predictive accuracy as for all-segments CIMT.
Carotid intima-media thickness versus carotid plaque for cardiovascular disease risk prediction
Unlike CIMT, the incremental predictive accuracy of carotid plaques is much better established. Several studies have demonstrated that qualitative or quantitative assessment of carotid plaques is a superior predictor of future CVD risk as compared to CIMT., 25, ,, Carotid plaque burden of >300 mm 2 correlates with a coronary calcium score of >100 and seems to be a reasonable threshold for predicting high CVD risk. Interestingly, combined carotid and femoral plaque assessment seems to provide even more accurate risk prediction as compared to carotid plaques alone.,
The superior predictive accuracy of carotid plaques as compared to CIMT may relate to the fact that the plaques represent atherosclerotic process whereas CIMT may be influenced by both atherosclerosis and arteriosclerosis, as discussed above. This argument is further supported by the observations that genetic makeup has influential effect on CIMT, while plaque formation largely depends on conventional risk factors such as hypertension, diabetes, hypercholesterolemia, and nicotine intake.
Carotid ultrasound as a modifier of risk behavior
A few studies have evaluated if identifying increased CIMT or carotid plaque could alter physicians' treatment plans and patients' motivation regarding health-related behaviors., In a multicenter study, Korcarz et al. found that when increased CIMT or carotid plaque was detected, the physicians were more likely to prescribe aspirin and lipid-lowering therapy. In addition the patients were more likely to believe they were at higher risk of developing heart disease and were therefore more likely to report increases in plans to take cholesterol-lowering medication. Similarly, in a small randomized study, smokers were more likely to stop smoking if they were shown images of carotid plaques.
Role in clinical practice
The 2010 American College of Cardiology Foundation/American Heart Association guideline for assessment of cardiovascular risk in asymptomatic adults provided Class IIa recommendation for CIMT measurement in intermediate-risk adults. However, keeping in view the results of the recent meta-analysis that failed to demonstrate incremental value of CIMT, the most recent iteration of the guideline subsequently downgraded the role of CIMT for this purpose. Nonetheless, compared with coronary calcium scoring, which is currently the most predictive measure of subclinical atherosclerosis, carotid ultrasound assessment has several advantages. It is less expensive, widely available, simple to perform, and the most importantly does not involve radiation exposure. Therefore, despite the recent discouraging recommendations, carotid ultrasound seems to have a definite role in CVD risk stratification of intermediate-risk individuals. Given the strong association between increased CIMT and subsequent CVD risk, it seems appropriate that when accurately performed, increased CIMT, particularly if >1 mm, should lead to up-titration of the CVD risk, resulting in more aggressive risk reduction strategy. The predictive accuracy is even greater if plaque burden is also increased or if there is another evidence of subclinical atherosclerosis., However, the current evidence does not justify downgrading CVD risk in patients with normal CIMT and no carotid plaques, except in elderly individuals with minimum risk factors in whom statin therapy may otherwise be indicated due to age alone. in addition, as discussed above, carotid ultrasound can also be used to motivate the patients to adopt healthier lifestyle practices and to comply with the pharmacological therapies as indicated. Finally, carotid ultrasound has also been used to monitor regression or progression of atherosclerosis, but the changes are too slow to be clinically meaningful.
With the emergence of three-dimensional ultrasound, accurate measurement of plaque burden has become much easier. In cross-sectional imaging, plaque areas are traced and added to calculate total plaque burden. In addition, plaque volume can also be measured and used as a follow-up technique for atherosclerosis regression. Newer technologies also help in better characterization of complex plaques. Pixel distribution analysis is a method for quantitative assessment of the plaque composition. This method has been successfully correlated with histological studies of endarterectomy specimen , and also with clinical outcomes. Echolucency and irregular plaque surface are known to be associated with increased stroke risk. Plaque lucency is more reproducible than plaque thickness. Plaque neovascularization can be assessed by the use of contrast agents  and may be a useful marker because plaque vascularity is an indicator of activity of atherosclerosis. However, sufficient data to support the use of contrast agents for prognostic evaluation are currently lacking.
| Conclusion|| |
CIMT and nonstenotic carotid plaques are reliable markers of subclinical atherosclerosis. Accordingly, screening for CIMT and carotid plaques by duplex ultrasound can serve as a useful tool for CVD risk stratification. It is a noninvasive, safe, and easily reproducible technique. The conflicting results of various studies involving CIMT appear to be largely related to variations in methodologies used in these studies. The evaluation of CIMT and carotid plaque, if incorporated in clinical practice can help in the management of asymptomatic individuals who present with one or more CVD risk factors. The presence of significantly elevated CIMT or carotid plaque burden should lead to reclassification of such individuals into high-risk category with appropriate intensification of the risk reduction measures. In addition, demonstration of increased CIMT and/or presence of the plaques may also help in improving patients' health behavior and their compliance toward antiatherosclerotic measures. However, whether this can have a long-term and cost-effective reduction in CVD risk is yet to be evaluated. In future, plaque progression/regression assessment by three-dimensional ultrasound and the use of contrast agents may further enhance the utility of carotid ultrasound for monitoring the course of atherosclerotic vascular disease.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3], [Figure 4]