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Carotid intima–media thickness: ultrasound measurement, prognostic value and role in clinical practice
  1. Satheesh Balakrishnan Nair1,2,
  2. Rayaz Malik1,2,
  3. Rajdeep S Khattar3
  1. 1Manchester Heart Centre, Manchester Royal Infirmary, Manchester, UK
  2. 2The University of Manchester, Manchester, UK
  3. 3Department of Cardiology, Royal Brompton and Harefield NHS Trust, London, UK
  1. Correspondence to Dr Rajdeep Singh Khattar, Consultant Cardiologist and Honorary Clinical Senior Lecturer, Royal Brompton and Harefield NHS Trust, Royal Brompton Hospital, Sydney Street, London, SW3 6NP, UK; rskhattar{at}gmail.com

Abstract

Ultrasound measurement of carotid intima–media thickness (IMT) has become a valuable tool for detecting and monitoring progression of atherosclerosis and recently published recommendations provide guidance for proper standardisation of these measurements. Important determinants of carotid IMT include age, gender, systolic blood pressure, diabetes mellitus and serum cholesterol levels. Many studies have shown carotid IMT to correlate with the severity of coronary atherosclerosis assessed by CT coronary calcification scores, coronary angiography and intravascular ultrasound. Consistent with its correlation with cardiovascular risk factors and coronary artery disease, a meta-analysis of large observational studies has shown carotid IMT to be a strong predictor of future cardiovascular events. Moreover, in patients with established coronary artery disease a reduction in carotid IMT has been shown to translate into a reduction in future cardiovascular events. Consensus statements now also recommend carotid IMT measurements to further refine the prognostic assessment of patients traditionally considered to be at an intermediate risk of cardiovascular disease.

  • Cardiology
  • ischaemic heart disease
  • valvular heart disease
  • cardiac epidemiology
  • echocardiography
  • thoracic medicine
  • statistics and research methods
  • education and training (see medical education and training)
  • medical education and training
  • internal medicine

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Introduction

The atherosclerotic process is a generalised process affecting the arterial tree which begins in childhood, progresses over decades and may remain clinically silent in the majority of people. In the coronary arteries, it remains asymptomatic until it progresses to cause a haemodynamically significant flow limiting lesion leading to symptoms of myocardial ischaemia. However, a substantial proportion of patients progress abruptly from inapparent disease to a myocardial infarction or possible death, due to thrombus formation following acute rupture or erosion of non-stenotic plaques.1 ,2 This highlights the importance of detecting atherosclerosis in the early phase of disease to facilitate effective disease modification strategies in predisposed individuals. In recent years, high-resolution ultrasound techniques have been developed extensively to detect early atherosclerotic changes. A generalised increase in common carotid artery (CCA) intima–media thickness (IMT) is an early manifestation of the atherosclerotic process and is readily measured by ultrasound imaging. This article discusses: (1) methodological aspects of ultrasound measurement of carotid IMT, (2) the determinants of carotid IMT, (3) the relationship of carotid IMT to coronary atherosclerosis, (4) the value of carotid IMT in predicting cardiovascular disease and (5) the potential role of carotid IMT in clinical practice as a means to risk stratify patients. In view of the limited scope of this article, the implications of detecting manifest carotid atherosclerotic plaque will not be specifically addressed.

Carotid ultrasound imaging

Using high resolution ultrasound imaging, carotid IMT assessment has emerged as a valuable tool for detecting and monitoring progression of atherosclerosis. The intima is the innermost layer of the arterial wall and consists of a single layer of endothelial cells in direct contact with blood, while the media consists mainly of smooth muscle cells constituting most of the thickness of the arterial wall with the adventitia making up the outermost layer which is mainly composed of collagen. Although ultrasound imaging cannot discriminate between the intimal and medial layers because of insufficient axial resolution, the intima–media complex can be identified as the double line density of the intimal–luminal and the medial–adventitial interfaces (figure 1). The validity of this ultrasound measurement of carotid IMT has been well established by comparison with histological specimens.3

Figure 1

High resolution ultrasound image of the common carotid artery and carotid bulb. The distance between the two arrows (black and white) is the intima–media thickness in the far wall of the common carotid artery, approximately 1 cm to proximal to the carotid bulb.

Methodology of carotid IMT measurement

Although the general principles of carotid IMT measurement are common to all B-mode ultrasound studies, the methodologies used in these studies vary considerably with regard to image acquisition and analysis as shown in table 1. Measurements of IMT can be taken from the CCA, carotid bifurcation (bulb) and internal carotid artery (ICA). Since the CCA is a tubular structure and is perpendicular to the ultrasound beam, measurement yield and reproducibility of IMT in this region are greater than for IMT measurements in the bulb or ICA. Both near and far walls can be visualised on B-mode scans, but studies comparing ultrasound measurements with histology suggest that far wall carotid IMT measurements are more representative of the true thickness of the arterial wall.3 Near wall IMT measurements, in comparison, are limited by their dependence on the axial resolution and gain settings of the equipment used and hence are less accurate and reproducible. However, visualisation and reproducibility of near wall measurements, in particular, may be improved by the use of contrast ultrasound agents to enhance intimal border detection.4

Table 1

Summary of carotid IMT measurement methodologies in observational studies

The quantification of IMT values may be divided into two methodologies, measurement of the mean IMT and maximum IMT. The mean IMT is estimated as the mean of all the IMT measurements made over single or multiple segments of the carotid arteries from the right and left sides and from the near and far walls of the arteries. The maximum IMT is the highest value of IMT measured over the carotid artery segments. As shown in table 1, large scale observational studies have used varying methodologies in single or multiple carotid artery segments.5–10

Electrocardiographic gating is crucial for measuring IMT and lumen diameter since these parameters vary during the cardiac cycle. During systole, lumen diameter expands with a degree of thinning of IMT because of longitudinal stretching, and the opposite occurs during diastole. Hence, standardised measurement techniques are especially important in clinical trials assessing the magnitude of change in IMT values over time. The American Society of Echocardiography recommends using end-diastolic measurements of carotid IMT.

In earlier studies, IMT measurements were performed by visually detecting the leading edges of the blood–intima and media–adventitia interfaces. However, recent studies have used a computer based automated edge detection method. This involves determining ultrasound interfaces using pixel intensity and employs a multi-step gradient-based algorithm to accurately identify the intima–media complex. This technique distinguishes IMT values to within 0.01 mm and reduces operator dependency, thereby improving the reproducibility rates of measurements.

Several studies have verified the reproducibility of carotid IMT measurements. A review of 23 studies found intraobserver variability in the selected studies to be between a mean±SD difference of 0.02±0.02 mm and 0.66±1.13 mm, and an error percentage of 2.5% and 15.9%. The inter-observer variability was between a mean±SD difference of 0.01±0.04 mm and 0.65±0.69 mm, with an error percentage of 5.9% and 13.7%. Variability was less when measurements were made in the CCA rather than the ICA and bulb, when mean rather than maximum IMT measurements were recorded, and when using an automated edge-tracking method as opposed to manual measurements.11

Normal carotid IMT values

Normal carotid IMT values have been defined based on their distribution within a general healthy population and have been classified according to age and gender.6 ,8 However, many of the earlier studies including the ARIC study,8 Cardiovascular Health Study6 and The Rotterdam study10 used varying methodologies and incorporated common carotid IMT measurement and mean carotid IMT measurement which included the carotid bulb and ICA where plaque is more prevalent. Consequently, data from the ARIC study suggest that a value of ≥1 mm of mean IMT (measured from the right and left CCA, bulb and ICA) is associated with a significantly increased absolute risk of coronary artery disease (CAD).8 Other investigators have suggested the normal range of carotid IMT to be 0.5–1.2 mm and have defined plaques as carotid IMT >1.2 mm.12 However, carotid IMT is a continuous variable, and the transition to focal plaque is arbitrary. Accordingly, the use of a single cut-off point seems inappropriate and the Mannheim Carotid IMT Consensus defines plaque as a focal structure that encroaches into the arterial lumen by at least 0.5 mm or 50% of the surrounding IMT value or demonstrates a plaque thickness of >1.5 mm.13 The consensus recommends measurement of IMT in a region free of plaque whether in the far wall of the CCA, carotid bulb or origin of the ICA. A review of the published data suggests that the normal range of IMT in the CCA in healthy middle-aged adults approximates between 0.6 and 0.7 mm.14 The definition of the upper limit of normal is arbitrary but is frequently set at the 75th percentile of carotid IMT distribution for the determination of increased relative cardiovascular disease risk.

Determinants and anatomical distribution of carotid IMT

Age and sex have been found to be major determinants of carotid IMT in all clinical and epidemiological studies. In the ARIC study, at all ages, men had higher mean IMT values than women and IMT increased with age in both sexes and in all arterial segments. The rate of progression of IMT in the CCA was approximately 0.01 mm/year and this was similar in both men and women. However, the rates of progression were higher at the bulb and the ICA ranging from 0.015 to 0.020 mm/year, reflecting the propensity for atherosclerotic plaque formation at these arterial locations. Case-control studies have found that hypertensive subjects have significantly greater values of IMT compared with normotensive subjects.15 ,16 Also, cross-sectional studies and studies on selected populations have found a significant correlation with systolic blood pressure.16 ,17 However, the correlation with diastolic blood pressure is less consistent. A meta-analysis of 21 studies of patients with type 2 diabetes18 found that they had 13% greater carotid IMT values compared with non-diabetic subjects. Carotid IMT values were also greater in those with impaired glucose tolerance, but to a lesser extent than in overt diabetes. The Insulin Resistance and Atherosclerosis study19 showed that diabetic patients without known CAD had similar IMT values when compared with non-diabetic patients with CAD. The progression of IMT was 25% greater in diabetic patients when compared with non-diabetic patients, even after correcting for known cardiovascular risk factors. Carotid IMT has been found to be associated with smoking17 ,20 ,21 and is also significantly increased in patients with familial hypercholesterolaemia.22 ,23 Moreover, the Kuoppio Ischaemic Heart Disease study showed greater progression of IMT values over a 2-year period in men with high LDL cholesterol levels.24

Association among carotid IMT, myocardial ischaemia and coronary angiographic findings

Limited studies have assessed the association between carotid IMT and imaging techniques for detecting myocardial ischaemia. In a study of symptomatic patients undergoing coronary angiography, 74% of those with a positive exercise or pharmacological stress test and significant coronary artery stenosis had carotid IMT values >75th percentile, compared with 44% of those without significant CAD.25 In asymptomatic diabetic subjects, higher carotid IMT values have been shown to be highly predictive of ischaemia on radionuclide myocardial perfusion imaging.26 With respect to anatomical correlations of carotid IMT with the severity of coronary atherosclerosis, the Muscatine and Rotterdam coronary calcification study27 ,28 found a significant correlation with CT coronary artery calcium score, even after adjusting for cardiovascular risk factors. A coronary angiographic study found a strong correlation between carotid IMT and coronary artery stenosis >50% luminal narrowing; if mean IMT was more than 1.15 mm, patients had a 94% probability of having significant CAD.29 Baldassarre et al found a significant correlation between carotid IMT and coronary IMT values measured by intravascular ultrasound of the coronary arteries, with correlation coefficients ranging from 0.49 to 0.55. A mean carotid IMT value of >1 mm was associated with a sevenfold increased risk of having a significant coronary stenosis (minimal lumen area <4 mm2) by intravascular ultrasound.30 Maximum and mean IMT values have also been found to correlate significantly with the severity, extent and atheroma burden assessed by quantitative coronary angiography.31 However, the predictive value of carotid IMT was weaker for proximal segments when compared with mid-segments and distal segments of the major coronary arteries. Lekakis et al found that high IMT scores, estimated by incorporating data from carotid and femoral arteries, correlated well with the extent of angiographic CAD and were also predictive of multivessel disease.32 Kato et al found carotid IMT values were significantly higher in acute coronary syndrome patients with angiographically complex coronary plaques when compared with those with a solitary plaque.33

Carotid IMT in the prediction of cardiovascular events

Consistent with its correlation with past exposure to cardiovascular risk factors, carotid IMT is also associated with the development of future cardiovascular events (table 2). The relationship between carotid IMT and subsequent coronary events was first demonstrated in the Kuoppio Ischaemic Heart Disease study, in which, for every 0.1 mm increment of IMT, the risk of myocardial infarction increased by 11%.5 For IMT values >1 mm, there was a twofold greater risk of myocardial infarction over a 3-year follow-up period. The ARIC study showed a 5% prevalence of myocardial infarction in subjects in the highest quartile of carotid IMT and for every 0.19 mm increment in IMT, the risk of subsequent myocardial infarction or death increased by 36%.34 The coronary risk was almost twofold greater in men with mean carotid IMT >1 mm.8 In the Cardiovascular Health Study, the OR for symptomatic CAD was 2.8 when the highest quartile of carotid IMT was compared with the lowest quartile.17 A follow-up analysis of this study estimated an adjusted RR for myocardial infarction or stroke of 3.8 for the highest IMT quintile compared with the lowest quintile.6 In the Rotterdam study, a population-based cohort study among subjects more than 55 years old, increased carotid IMT was associated with an increased risk of future cardiovascular events.10 Further follow-up of these subjects found that carotid IMT measurements and the presence of manifest carotid plaque were strongly predictive of incident MI, even after adjusting for cardiovascular risk factors and medication use.35 Incorporating the above data, a meta-analysis of eight observational studies including 37 197 subjects showed carotid IMT to be a strong predictor of future cardiovascular events during a mean follow-up period of 5.5 years.36 The age and sex adjusted RR of myocardial infarction was 1.26 and for stroke was 1.32 per 1-SD difference in CCA IMT. For an absolute carotid IMT difference of 0.1 mm, the future risk of MI increased by 10%–15%, and the stroke risk increased by 13%–18%.

Table 2

Summary of studies showing the predictive value of carotid IMT for cardiovascular events and death

Many studies in patients with hypercholesterolaemia or established CAD have shown that aggressive cholesterol lowering therapies lead to reductions in carotid IMT. Moreover, in patients with established CAD, a reduction in carotid IMT has been shown to translate into a reduction in future cardiovascular events. Accordingly, in a long term follow-up of the Cholesterol Lowering Atherosclerosis study,37 it was shown that for each 0.03 mm increase per year in common carotid IMT, there was an approximate threefold increased RR for a coronary event (figure 2). In the Regression Growth Evaluation Statin study, which assessed the effect of pravastatin on progression of IMT, a 0.05 mm annual reduction in mean carotid and femoral artery IMT reduced the absolute risk of cardiac events over a 2-year period by 10%.38 These studies add weight to the use of carotid IMT as a surrogate marker of atherosclerosis and to estimate the risk of future cardiovascular events.

Figure 2

Graph showing the RR for cardiovascular outcomes in relation to carotid intima—media thickness (IMT) progression rates (mm/year) in a long term follow-up of the Cholesterol Lowering Atherosclerosis Study cohort. CHD, coronary heart disease.

Clinical role of carotid IMT

Under normal circumstances, in the primary prevention population of asymptomatic patients without pre-existing cardiovascular disease, the appropriateness of drug therapy for treating modifiable risk factors such as mild hypertension and hypercholesterolaemia is guided by the use of cardiovascular risk scores. The Framingham risk score (FRS) is a well established and extensively studied scoring system which derives a 10-year estimate of cardiovascular risk and accordingly categorises patients into low, intermediate and high risk groups. However, the score may not adequately predict cardiovascular risk in the low or intermediate risk groups. For example, it has been shown that a significant proportion of younger patients presenting with acute myocardial infarction would have been classified as low or intermediate risk based on the FRS. Potential reasons for this include the fact that risk factors including diabetes, obesity and ethnicity are not included in the risk prediction model. More fundamentally, a general increase in the prevalence of risk factors in the patient population may have the effect of diluting the predictive power of these parameters. Consequently, imaging of subclinical atherosclerosis to further assess cardiovascular risk seems to be the logical next step and in view of the independent predictive value of carotid IMT, many studies have assessed the value of incorporating IMT measurements with the FRS. One such study found both FRS and carotid IMT to be independent predictors of cardiovascular outcome in dyslipidaemic patients categorised as low or intermediate risk.39 The HR was estimated as 6.7 in those with an intermediate 10%–20% 10-year risk of an event and elevated IMT above 60th percentile for men and 80th percentile for women. These patients, who are not aggressively treated based on current guidelines, proved to have a risk similar to those with an FRS of 20%–30%. The ARIC follow-up study found that carotid IMT, when added to traditional risk factors, improved CAD risk prediction in men. This study also examined the net effect of adding a marker to the risk prediction scheme and found that the model including carotid IMT was especially predictive in the FRS assigned intermediate risk group.40 It is also possible that in patients without evidence of myocardial ischaemia on stress imaging techniques such as stress echocardiography, the finding of a raised carotid IMT may provide an incremental prognostic value. The Mannheim Carotid IMT consensus,13 the ASE consensus statement41 and the American College of Cardiology Foundation/American Heart Association guidelines42 recommend IMT measurements for patients at intermediate CVD risk and in subjects in the following clinical circumstances: (1) a family history of premature CVD in first-degree relatives; (2) individuals <60-years-old with severe abnormalities in a single risk factor who otherwise would not be candidates for pharmacotherapy; (3) women <60 years of age with at least two CVD risk factors; and (4) in all epidemiological and interventional trials dealing with vascular diseases to better characterise the population investigated. In the above populations, if the carotid IMT is increased (>75th percentile for the given population), aggressive medical therapies should be advocated aiming for target levels used in secondary prevention.43

Epidemiological studies demonstrate that carotid IMT typically progresses at an average rate of <0.03 mm per year, and the rate of progression is related to the risk of CV events. Progression can be slowed by cholesterol lowering drugs and other risk factor modifications. However, serial scanning of carotid IMT is challenging in individual patients across short time intervals due to variability in measurement in relation to the rate of disease progression and is therefore not recommended in clinical settings.42

Limitations and future directions

As discussed earlier, many of the large population based studies used varying methodologies for carotid IMT measurement and may have included plaque thickness in the derived mean IMT measurements. Therefore, it may be difficult to know whether carotid IMT and carotid plaque are closely representative of the same disease process or whether carotid IMT is more closely linked with markers of hypertrophy than atherosclerosis. However, most of these studies were in asymptomatic, presumed low risk populations with a low prevalence of plaque and hence this may not have been a major confounding factor. Further studies using the agreed standardised protocol for measuring carotid IMT, excluding plaque measurements, will be required to further assess the mechanistic and prognostic significance of diffuse carotid IMT measurements.

The above indications for carotid IMT measurement are based on observational data and are limited to merely assessing future cardiovascular risk in these patients. It is not known whether a strategy of cardiovascular screening incorporating carotid imaging either alters clinical practice, translates into a reduction of future cardiovascular events or is cost effective in any particular group of patients. Ideally, prospective randomised trials are needed to determine whether preventive measures guided by carotid IMT over and above traditional risk factors have any impact on cardiovascular outcome and are cost effective. Until this information becomes available, the aggressive management of traditional cardiovascular risk factors should remain the focus of current clinical practice, but carotid IMT measurements may provide useful supplementary information in individual cases.

Main messages

  • Ultrasound measurement of carotid intima–media thickness (IMT) is a well validated and useful method for detecting and monitoring progression of atherosclerosis.

  • Carotid IMT correlates with traditional cardiovascular risk factors and coronary atherosclerosis severity.

  • Carotid IMT is a strong predictor of future cardiovascular events and a reduction in IMT is associated with a reduction in events.

  • Carotid IMT is commonly used as a surrogate end point in clinical trials as a marker of atherosclerosis.

  • Carotid IMT may be a useful screening tool in asymptomatic individuals with an intermediate risk of future cardiovascular disease.

Current research questions

  • What is the impact on future cardiovascular events and the cost effectiveness of preventive strategies based on carotid intima–media thickness (IMT) measurement?

  • Does carotid IMT have a similar value to carotid plaque for the prediction of future cardiovascular events?

  • Can the inclusion of carotid IMT in a cardiovascular risk scoring system improve the management and prognosis of low or intermediate risk individuals?

Key references

▶ Touboul PJ, Hennerici MG, Meairs S, et al. Mannheim carotid intima-media thickness consensus (2004-2006). An update on behalf of the Advisory Board of the 3rd and 4th Watching the Risk Symposium, 13th and 15th European Stroke Conferences, Mannheim, Germany, 2004, and Brussels, Belgium, 2006. Cerebrovasc Dis 2007;23:75–80.

▶ Amato M, Montorsi P, Ravani A, et al. Carotid intima-media thickness by B-mode ultrasound as surrogate of coronary atherosclerosis: correlation with quantitative coronary angiography and coronary intravascular ultrasound findings. Eur Heart J 2007;28:2094–101.

▶ 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;115:459–67.

▶ Baldassarre D, Amato M, Pustina L, et al. Measurement of carotid artery intima-media thickness in dyslipidemic patients increases the power of traditional risk factors to predict cardiovascular events. Atherosclerosis 2007;191:403–8.

▶ Stein JH, Korcarz CE, Hurst RT, et al. Use of carotid ultrasound to identify subclinical vascular disease and evaluate cardiovascular disease risk: a consensus statement from the American Society of Echocardiography Carotid Intima-Media Thickness Task Force. Endorsed by the Society for Vascular Medicine. J Am Soc Echocardiogr 2008;21:93–111; quiz 89–90.

Self-assessment questions (True/False: Answers after the references)

  1. The intima consists mainly of smooth muscle cells constituting most of the arterial wall thickness.

  2. Ultrasound measurement of carotid IMT has been validated by comparison with histological specimens.

  3. Far wall carotid IMT measurements are more representative of the true thickness of the arterial wall than the near wall measurements.

  4. During systole the carotid artery lumen diameter expands and the IMT becomes relatively thin.

  5. Plaque is defined as a focal structure that encroaches into the arterial lumen by twice the thickness of the surrounding IMT value.

Answers

  1. False

  2. True

  3. True

  4. True

  5. False

References

Footnotes

  • Competing interests None.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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