Farouk Mookadam, MD, FRCPC, MSc, Consultant, Cardiovascular Diseases and Internal Medicine, Associate Professor, Mayo College of Medicine, Mayo Clinic Arizona, 13400 East Shea Boulevard, Scottsdale, AZ 85259 E-mail: email@example.com
Cardiovascular risk factors have utility in risk prediction but have limitations in predicting individual risk. Identifying an individual’s risk remains a challenge. Emerging technologies such as carotid artery ultrasonography and measures of carotid intima-media thickness (CIMT) may be useful in identifying the susceptible patient who may benefit from more aggressive preventive therapy. This screening test is noninvasive, reproducible, inexpensive, and radiation-free. Recent data have improved our understanding of the application of CIMT as a screening tool for cardiovascular disease. CIMT measurement may place an individual into a higher- or lower-risk category, allowing for appropriate institution of preventive strategies.
The global burden of cardiovascular (CV) disease continues to rise as developing nations adopt lifestyle changes that augment CV risk.1 Primary prevention of CV events is effective in populations traditionally considered low-risk.2,3 Identification and treatment of an individual at risk is particularly relevant, considering that sudden death is the sentinel event of CV disease in a fifth of the population.4 Guidelines recommend population-based screening algorithms that include the Framingham Risk Score (FRS),5 Systematic Coronary Risk Evaluation (SCORE),6 QRESEARCH Cardiovascular Risk Algorithm second version (QRISK2) (QRESEARCH, Nottingham, United Kingdom),7 and the Reynolds Score.8 While these models are valuable in assessing population risk, they are less useful in assessing individual risk. Some investigators,9 but not others,10 have questioned their value in identifying the large group of “low-risk” individuals who ultimately experience a cardiac event. In the standardized case-control study of risk factors for first myocardial infarction (MI) in 52 countries and over 27,000 subjects (INTERHEART), the measured modifiable risk factors are associated with >90% of the risk of an acute MI, which was consistent across all geographic regions and ethnic groups of the world. Modification of currently known risk factors has the potential to prevent most premature cases of MI worldwide.11 The presence of these modifiable risk factors, however, may not always translate into manifest atherosclerotic heart disease on the one hand, and on the other hand an absence of these modifiable risk factors does not translate into an absence of atherosclerotic change in the arterial tree.
The quest for enhanced CV screening markers has led to an interest in novel biomarkers such as C-reactive protein, among others, to predict population risk, but they are limited at predicting individual risk. Noninvasive imaging studies are an emerging tool to assist in risk stratification, but they have some drawbacks. Computed tomography coronary artery calcium (CAC) testing is superior to FRS in predicting risk,12 but its use as a general screening test is limited due to lack of sensitivity in younger populations, cost, limited availability, and radiation exposure, which limits serial assessment.13 Echocardiographic assessment of left atrial size has been shown to predict CV risk in older patients and hence has limited external validity.14 Epicardial fat is an emerging marker that warrants further investigation (F.M., unpublished data, 2009). CAC and carotid intima-media thickness (CIMT) have the most data accumulated for assessing individual CV risk.15,16
Revascularization procedures targeting severely stenotic vessels do not improve mortality rates in stable coronary artery disease (CAD). The majority of lesions causing acute coronary syndromes have luminal diameters <70%.17 Traditional risk factors for atherosclerosis lead to the development of unstable plaque within the vasculature. The vulnerable thin-capped plaque is prone to ulceration and thrombosis. The changes within the vascular wall associated with atherosclerosis may provide an improvement in the ability to identify an individual at risk for a CV event.17 The purpose of this review is to present the emerging data on the role of CIMT in assessing individual CV risk.
We performed a systematic search of the English-language literature published in the MEDLINE database using the following search terms for human adults: “carotid intima-media thickness,”“atherosclerosis,”“coronary artery disease,” and “cardiovascular risk.” The computer search was augmented by manual searches of reference lists. An independent search by a qualified librarian supplemented our search. Outcome data were independently extracted by the two reviewers (FM and SM) with disagreement resolved by consensus. Major endpoints were prognosis and outcome after different treatment strategies. We focused on articles from the past 5 years, especially those including prognosis and outcome after different treatment strategies for patients with subclinical atherosclerosis.
Measurement of CIMT
CIMT is an independent predictor of CV risk,18–25 and the presence of carotid plaque is a strong predictor of CV events and mortality.24–27 Normal CIMT values are obtained from general population databases from several large population studies.19,28–30
B-mode ultrasonography is a relatively inexpensive, noninvasive, safe technique to evaluate the carotid arteries for plaque and to measure CIMT. Recent published guidelines are available on CIMT assessment.15 Essentially, a linear-array transducer operating at a fundamental frequency of at least 7 MHz is used to interrogate the carotid arteries. CIMT measurements are acquired with the patient in the supine position with slight hyperextension and rotation of the neck to the opposite side. B-mode ultrasonography is preferred over M-mode and is best acquired at end-diastole. CIMT can be measured from the near carotid wall, closer to the skin surface, or the far wall. The intima-media thickness of the far wall is constantly visualized and reflects the true thickness of the arterial wall in comparison to the near wall. The task force recommends that the distal 1 cm of the far wall of each common carotid artery (CCA) should be obtained and compared with normal values.15 Different segments of the carotid artery, each 1 cm in length, can be assessed to measure CIMT: the CCA, the internal carotid artery (ICA), and the carotid bifurcation. Measurement of CIMT of the CCA has better reproducibility than that of the ICA or the bifurcation because of its ease of access. Measurements can be reported either as the mean CIMT of the right and left CCAs or as the mean CIMT of different sites. Because atherosclerosis is a heterogenous disease that progresses more rapidly in the bifurcation and ICA than the CCA, the mean CIMT of the CCAs may underestimate atherosclerotic burden. The consensus statement from the American Society of Echocardiography recommends imaging the CIMT of the distal 1 cm of the far wall of each CCA, as well as plaques of the extracranial carotid arteries, especially at the bifurcation and the ICA, because irrespective of CIMT, patients with carotid plaques are at high risk (Figures 1–3).15,28,29
Carotid plaque is defined as the presence of focal wall thickening that is at least 50% greater than that of the surrounding vessel wall or as a focal region with CIMT >1.5 mm that protrudes into the lumen. If carotid artery plaque is identified, the individual is deemed to be at high risk for future CV events and no further imaging is necessary. If no plaque is identified, the far wall CIMT of the distal 1 cm of the CCA is measured from an anterior, mid, and posterior view. CIMT is a measure that combines the thickness of the tunica intima and media. A high-risk CIMT result is defined as ≥75th percentile adjusted for the patient’s age, sex, and ethnicity.15
Correlation Between CIMT and CV Event Risk
CIMT and CV event rate risk has been evaluated in large prospective trials with long-term follow-up in patients with known CAD (Table I). Consistently, CIMT is associated with risk of CV events in these populations. In healthy persons (18–99 years) followed over 12 years, the addition of CIMT >1 mm added predictive value to a high FRS in predicting stroke.31 In healthy adults (19–90 years) followed over 4.2 years, CIMT was an independent predictor of stroke, MI, and death.21 In 1289 Japanese men aged 60 to 74 years, followed for 4.5 years, a CIMT >1.07 mm had a relative risk for stroke of 3.0 (1.1–8.3) vs a CIMT of <0.77 mm.23 In a study of 5163 Swedish men and women free of CV disease observed over a 7-year period for fatal or nonfatal MI or death from CAD, CIMT was associated with coronary events but was not associated with short- or long-term mortality after the events.24 Common and internal CIMT are independently associated with decline in kidney function (common CIMT ≥1.14 mm and internal CIMT >1.82 mm are independently associated with a rapid decline in renal function).32
47% of patients with CAC of zero had evidence for carotid atherosclerosis
CIMT vs CAC for Defining CV Event Risk
CIMT may be more sensitive than CAC for defining CV risk in young to middle-aged patients. In a population of men and women (49±6 years; n=89), 47% of patients with no CAC (low-risk) had evidence of carotid plaque or CIMT >75% for age, sex, and race.13 Carotid plaque was found in 30 (34%) and CIMT >75th percentile was found in 12 (13%) patients.13 This finding was corroborated in a separate study (mean age, 57 years) without history of cerebrovascular disease and a CAC of 0. The prevalence of carotid plaque was 55%.33 In the Multiethnic Study of Atherosclerosis (MESA) cohort, CAC was a better predictor of CV events than CIMT, but CIMT was a better predictor of stroke.30 These discrepant findings between reports may be explained by the higher mean age in the MESA cohort (61.8–63.1 years depending on ethnicity).34 CAC may be a better predictor in this age group because it detects more advanced disease in the coronary bed by the presence of calcification than CIMT, which by definition identifies early, noncalcified subclinical atherosclerotic change. Recent guidelines have recommended that CAC scoring may be appropriate in older individuals, with an intermediate risk by FRS.16 The American Society of Echocardiography guidelines recommend CIMT assessment in those with an FRS of 6% to 20% without established CAD, peripheral artery disease, cerebrovascular disease, diabetes mellitus, or abdominal aortic aneurysm.15 Other clinical circumstances in which one would consider CIMT screening include a positive family history of premature CV events, individuals <60 years old with a severe abnormality in any single risk factor, or women <60 years old with at least 2 risk factors for CV disease.15
Therapeutic Strategies for Patients With Abnormal CIMT
Lipid-Lowering Agents: Statins With or Without Ezetimibe
Several medical therapies have been studied to evaluate changes in CIMT (Table II). In the Measuring Effects on Intima-Media Thickness: An Evaluation of Rosuvastatin (METEOR) trial, 984 individuals with modest CIMT thickness (1.2 to <3.5 mm), elevated low-density lipoprotein cholesterol (LDL-C; mean, 154 mg/dL), 1 risk factor for CAD, or FRS <10%, were randomized to rosuvastatin or placebo.35 In the treatment arm, LDL-C after 2 years was 78 mg/dL. Rosuvastatin significantly reduced progression of maximum CIMT in the CCA (0.0004 mm/y) but did not induce disease regression. No outcome data were assessed during this trial.35 Aggressive LDL-C lowering seems to exert its beneficial effect on atherosclerosis progression during the first 12 months of treatment.36 High-dose atorvastatin therapy (80 mg) was shown to reduce mean CIMT over 26 weeks compared to low-dose atorvastatin therapy (10 mg), which did not reduce mean CIMT. LDL-C was similar at baseline in treated and control participants (105±33 vs 116±39 mg/dL, respectively) and decreased to 65±23 and 87±26 in the high- and low-dose groups, respectively.37 In the Stop Atherosclerosis in Native Diabetics Study (SANDS), mean CIMT was compared in diabetics >40 years old receiving a statin or statin plus ezetimibe. Reductions from baseline were similar in both groups with LDL-C levels after 36 months of treatment as follows: 78 (72–84) mg/dL in the ezetimibe group and 68 (65–72) mg/dL in the statin only group. Mean CIMT regressed similarly in both groups.38 In a comparable trial, the Ezetimibe and Simvastatin in Hypercholesterolemia Enhances Atherosclerosis Regression (ENHANCE) trial, the investigators evaluated the change in CIMT with the combination of simvastatin and ezetimibe compared to simvastatin monotherapy. There was no significant difference in outcome between the groups.39 In a recent Mexican study, Vytorin on Carotid Intima-Media Thickness and Overall Arterial Rigidity (VYCTOR), the investigators included 90 high-risk coronary patients allocated to 3 groups: pravastatin 40 mg, simvastatin 40 mg, and the combination of simvastatin 20 mg and ezetimibe 10 mg initially. If the therapeutic goals were not attained, patients in group 1 received pravastatin 40 mg and ezetimibe 10 mg, those in group 2 received simvastatin 80 mg, and those in group 3 received simvastatin 40 mg and ezetimibe 10 mg. The overall baseline CIMTs were 1.33±0.32 mm, 1.30±0.11 mm, and 1.23±0.28 mm for groups 1, 2, and 3, respectively. After 1 year, CIMT values were 0.93±0.13 mm, 0.90±0.11 mm, and 0.92±0.01 mm for groups 1, 2, and 3, respectively (P<.01 in intra-group analysis), providing evidence that dual therapy has a beneficial effect on a surrogate marker of atherosclerosis.40
Table II. Satins With or Without Ezetimibe Effects on CIMT
N=252 Age: >40 y Type II DM with no CV events, LDL-C ≤70 mg/dL, non–HDL-C ≤100 mg/dL, SBP <115 mm Hg
Secondary analysis from RCT
Statin or statin+ezetimibe
Change in CIMT
Aggressive LDL-C reduction resulted in similar regression of CIMT in patients who attained equivalent LDL-C reductions from a statin alone or statin plus ezetimibe. CIMT increased in those achieving standard targets
Pravastatin±ezetimibe, simvastatin±ezetimibe, and simvastatin+ezetimibe
Change in CIMT, LDL-C and hsCRP
Dual therapy has a beneficial effect on a surrogate marker of atherosclerosis
Other Lipid-Lowering Agents
Fenofibrate has been shown to inhibit the progression of CIMT in patients with essential hypertension and mild hyperlipidemia41 but does not seem to slow the rate of CIMT progression in diabetics (Table III).42 Zhu and associates studied 225 patients with hypertension and mild hyperlipidemia.41 Treatment included micronized fenofibrate for 24 months in addition to antihypertensive therapy. A reduction in total cholesterol, LDL-C, triglycerides, and pro-inflammatory markers with increased concentrations of high-density lipoprotein cholesterol (HDL-C) by the end of follow up was seen in the treatment group. Common and internal CIMT remained unchanged during the 24-month intervention. However, the mean CCA CIMT/diameter ratio and ICA CIMT/diameter ratio were significantly decreased in the fenofibrate intervention group. In contrast, the same ratios increased in the control group. The incidence rates of carotid artery plaque formation and stroke in the fenofibrate group were significantly lower than in the control group.41 In contradistinction, the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) substudy showed that CIMT and the augmentation index (a measure of large artery stiffness) increased equally in both treatment and control groups.42
Table III. Novel and Other Lipid-Lowering Agents’ Effects on CIMT
N=225 Age: mean 60.3 y HTN and mild hyperlipidemia
Micronized fenofibrate 160 mg/d vs placebo
Common and internal CIMT and cerebrovascular events
The combination of antihypertensive agents with micronized fenofibrate can effectively prevent the progression of carotid atherosclerosis and reduce the incidence of stroke in patients with essential HTN
N=892 Heterozygous for familial hypercholesterolemia Age: 40–75 y
100 mg/d of pactimibe (n=443) or placebo (n=438) in addition to standard lipid-lowering therapy
Change in maximum and mean CIMT
Pactimibe had no effect on atherosclerosis with increased mean CIMT as well as incidence of major CV events
The use of extended-release niacin may cause a significant regression of CIMT when combined with a statin and is superior to ezetimibe. In a recent study that enrolled patients who had CAD or a CAD risk equivalent and were receiving long-term statin therapy, participants were randomized to treatment with extended-release niacin or ezetimibe. The trial was terminated early, on the basis of efficacy, according to a prespecified analysis conducted after 208 patients had completed the trial. Niacin had greater efficacy compared to ezetimibe in reducing mean CIMT over 14 months (P=.003), leading to a significant reduction of both mean (P=.001) and maximal CIMT (P≤.001 for all comparisons). Paradoxically, ezetimibe was significantly associated with an increase in CIMT. The incidence of major CV events was also lower in the niacin group than in the ezetimibe patients (1% vs 5%, P=.04).43
Novel Lipid-Lowering Agents
The cholesteryl ester transfer protein (CETP) inhibitor torcetrapib leads to augmentation of HDL-C, which could benefit atherogenic-prone patients with low HDL-C concentrations (Table III). Disappointing increases in CIMT were seen with torcetrapib when compared with atorvastatin or placebo. In addition, torcetrapib has been shown to increase CV event rates despite conferring a significant HDL-C augmentation.44,45 Bots and colleagues enrolled 683 patients randomized to either atorvastatin or atorvastatin with torcetrapib.44 The change in maximum CIMT was 0.025±0.005 mm/y in patients receiving torcetrapib with atorvastatin and 0.030±0.005 mm/y in those receiving atorvastatin alone (P=.46). Systolic blood pressure increased by 6.6 mm Hg in the combined-treatment group and 1.5 mm Hg in the atorvastatin-only group (P<.0001).44 In a pooled analysis of 904 patients with familial hypercholesterolemia and 752 with mixed dyslipidemia from the Rating Atherosclerotic Disease Change by Imaging With a New CETP Inhibitor (RADIANCE) 1 and 2 studies, patients were randomized to either atorvastatin or torcetrapib/atorvastatin combination. Mean common CIMT progression increased in patients receiving torcetrapib/atorvastatin compared with those receiving atorvastatin alone (0.0076±0.0011 vs 0.0025±0.0011 mm/y; P=.0014). Again, patients receiving torcetrapib plus atorvastatin displayed higher systolic blood pressure and also increased plasma sodium and bicarbonate levels in conjunction with lower potassium levels. Patients receiving torcetrapib plus atorvastatin with the strongest LDL-C reduction showed the smallest CIMT progression, whereas those with the highest systolic blood pressure increase showed the largest CIMT progression. HDL-C increase was not associated with CIMT change.45
Pactimibe is a potent inhibitor of both acyl coenzyme A:cholesterol acyltransferase (ACAT) 1 and 2, an intracellular enzyme involved in cholesterol accumulation. It showed promising results for the prevention of atherosclerosis in various animal models, but in patients it was associated with increased mean CIMT over 40 weeks of treatment.46 The Carotid Atherosclerosis Progression Trial Investigating Vascular ACAT Inhibition Treatment Effects (CAPTIVATE) was conducted in 892 patients heterozygous for familial hypercholesterolemia. They received either pactimibe or matching placebo in addition to standard lipid-lowering therapy. The study was terminated prematurely after 15 months because mean CIMT measurement revealed an increase of 0.014 mm (P=.04) in patients receiving pactimibe over placebo. Major CV events (death, MI, and stroke) occurred more often in patients receiving pactimibe vs placebo (P=.01).46
Long-term treatment with sulfhydryl angiotensin-converting enzyme inhibitors (ACEIs) may slow the progression of CIMT, while the nonsulfhydryl ACEI may exhibit a neutral effect (Table IV).47,48 Forty-eight patients with newly diagnosed mild hypertension were randomly assigned either to enalapril (nonsulfhydryl-containing ACEI) or zofenopril (sulfhydryl-containing ACEI). There was a significant reduction in CIMT in the zofenopril group but not in the enalapril group (P<.05) by the end of 5 years follow-up. This effect was coupled with a favorable nitric oxide/oxidative stress profile in the zofenopril group.47 In another study by Lonn and associates, 1425 persons with impaired glucose tolerance and/or impaired fasting glucose were randomized to ramipril or its placebo and to rosiglitazone or its placebo.48 Rosiglitazone significantly reduced the annualized change of the mean far wall left and right common CIMT. There were no outcome differences between the ramipril and placebo groups.48
Table IV. Antihypertensive Medications and Vitamin B Supplementation Effects on CIMT
Abbreviations: AAA, Amlodipine vs ARB in Atherosclerosis Study; ACEI, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker; CIMT, carotid intima-media thickness; CVD, cardiovascular disease; DM, diabetes mellitus; ELSA, European Lacidipine Study on Atherosclerosis; HTN, hypertension; IFG, impaired fasting glucose; IGT, impaired glucose tolerance; MITEC, Media Intima Thickness Evaluation of Candesartan; RCT, randomized controlled trial; STARR, Study of Atherosclerosis With Ramipril and Rosiglitazone; tHcy, total homocysteine.
N=506 Age: 40–89 y No DM and CVD; initial tHcy >8.5 μmol/L
High-dose B vitamin supplementation (5 mg folic acid+0.4 mg vitamin B12+50 mg vitamin B6) or matching placebo
Change in CIMT, aortic and coronary artery calcium
High-dose B vitamin supplementation significantly reduces progression of CIMT in well-nourished healthy B vitamin– “replete” individuals at low risk for CVD with a fasting tHcy ≥9.1 μmol/L
Angiotensin receptor blockers (ARBs) have uncertain effects, whereas calcium channel blockers can decrease CIMT in diabetic hypertensive patients.49,50 Two hundred nine patients were randomized to either candesartan or amlodipine daily for a minimum of 1 month, after which, if blood pressure was not normalized, the dosage was doubled, followed by the addition of hydrochlorothiazide if necessary. CIMT regression was observed in 52.2% of patients receiving candesartan and in 51.3% of those receiving amlodipine with no significant differences observed between the 2 groups (P=.9).49 In another study, by Ikeda and associates, which included 104 hypertensive patients with type 2 diabetes mellitus, patients were divided into an amlodipine group (n=58) and an ARB group (n=46), who received either losartan, candesartan, valsartan, or telmisartan. The amlodipine group showed a significant decrease in CIMT compared to the ARB group (−0.046 mm vs 0.080 mm, P<.05). Blood pressure did not show any significant change during the observation period.50
In the large prospective double-blind randomized European Lacidipine Study on Atherosclerosis (ELSA), CIMT and plaque number were measured in 2334 hypertensive patients at baseline and repeated annually for up to 4 years (average, 3.75 years). Patients received either lacidipine-based or atenolol-based antihypertensive treatment. The principal results have shown that lacidipine-based treatment significantly reduced the progression of CIMT compared with atenolol-based treatment.51 Pooled data reanalysis showed progressively lower survival free of any outcome except stroke, with increasing baseline CIMT quartiles or increasing CIMT values, even after adjustment for major baseline risk factors. Incidence of any outcome except stroke was related to the baseline number of carotid plaques. However, when both baseline and on-treatment CIMT values were entered into Cox proportional hazards models, differences in CIMT compared with baseline did not predict CV outcomes, indicating failure to show a predictive role of treatment-dependent CIMT changes. However, the investigators explained that these negative conclusions should be tempered by limitations inherent in these minor changes compared with the large individual differences in baseline CIMT.52
High-Dose B Vitamin Supplementation
High-dose B vitamin supplementation may reduce progression of CIMT in individuals at low risk for CV disease with a fasting total homocysteine (tHcy) ≥9.1 μmol/L (Table IV).53 Five hundred six participants with an initial tHcy >8.5 μmol/L without diabetes mellitus and CV disease were randomized to high-dose B vitamin supplementation or matching placebo for 3.1 years. Although the overall CIMT progression rate was lower with B vitamin supplementation than with placebo, statistically significant between-group differences were not found (P=.31). However, among patients with baseline tHcy ≥9.1 μmol/L, those randomized to B vitamin supplementation had a significantly lower average rate of CIMT progression compared with placebo (P=.02).53
The need for individual risk prediction tools is enormous given the burden of CV disease. CIMT has shown its utility to predict CV events, especially in younger populations. The identification of atherosclerotic burden rather than the probability of clinically overt disease is appealing. Equally appealing is the shift toward “individualized risk” prediction with simple and inexpensive tools such as CIMT.
Statins seem to exert beneficial effects on atherosclerosis progression. Aggressive LDL-C lowering can lead to regression of carotid atherosclerotic disease, while low-dose regimens may only prevent disease progression. Despite an incremental improvement in LDL-C, the addition of ezetimibe has provided no incremental benefit with respect to CIMT. Fibric acid derivatives may inhibit the progression of CIMT in patients with essential hypertension but not in diabetics. When combined with a statin, niacin may cause significant regression of CIMT. The CETP inhibitor torcetrapib and ACAT inhibitor pactimibe showed no clinical benefit or atheroprotection.
Antihypertensive medications may have variable effects on CIMT. Long-term treatment with sulfhydryl ACEIs may slow the progression of CIMT, while the nonsulfhydryl ACEIs may exhibit a neutral effect. The effects of ARBs are inconclusive, whereas calcium channel blockers may decrease CIMT especially in diabetic hypertensive patients. Diabetics might benefit from therapy with rosiglitazone, as it may reduce CIMT progression. High-dose B vitamin supplementation may reduce progression of CIMT in individuals at low risk for CV disease.
Despite the promising results noted above, further studies are needed to determine the appropriate intervention to halt atherosclerosis progression and the optimum method for screening. CIMT as a clinical tool based on current data and guidelines is helpful in individual risk stratification and clinical decision making when uncertainty or reluctance exists in implementing a prevention treatment strategy.