Fig. 12.1
IMT measurement methodology. CCA, ICA, and ECA common, internal, and external carotid artery
Validation Criteria to Validate a New Biomarker
The AHA published the principles to specifically address criteria for evaluation of new risk markers [4]. To be considered as useful for risk prediction , it should:
Have an independent statistical association with risk after accounting for readily available and inexpensive risk markers. This association should be based on studies including large numbers of outcome events.
Include calibration, discrimination, and reclassification index of the predictive model.
Calibration addresses the prediction of the proportion of cases that will experience disease. It should display observed versus expected event rates across quartiles of predicted risk for models that do and do not include the new risk marker.
Discrimination addresses the ability to discriminate between the patients who are at higher compared with lower risk. The calculation of this parameter is performed by the C index, which is comparable to the area under the ROC curve.
Reclassification index evaluates the number of subjects reclassified into other risk categories based on models that include the new risk marker.
These principles allow a better understanding of the ability of a new biomarker to be included as a potential diagnostic test for clinical evaluation.
IMT and Atherosclerosis
Baseline IMT is significantly correlated to plaque occurrence at the bifurcation. The prospective studies conducted in general populations [5], aiming at evaluating the plaque occurrence according to the baseline tertile of IMT, have shown that the rate of occurrence of new plaques was greater when the baseline IMT was in a higher tertile [6]. This is true in both sexes and shows that high IMT may predict evolving atherosclerosis. The correlation between IMT and asymptomatic coronary disease has also been demonstrated in coronary angiographic studies.
Predictive Value on Cardiovascular Events and Cardiovascular Risk Evaluation
All studies evaluating the predictive value of IMT on myocardial infarction and stroke occurrence have shown that IMT was an independent and significant factor for myocardial infarction and stroke prediction. In the meta-analysis gathering 37,197 subjects, Lorenz et al. [7] found an overall estimate of the relative risk of myocardial infarction of 1.26 (95% CI, 1.21–1.30) per 1 standard deviation common carotid artery IMT difference and 1.15 (95% CI, 1.12–1.17) per 0.10-mm common carotid artery IMT difference (CIMT). For stroke, the relative risks were 1.32 (95% CI, 1.27–1.38) per 1 standard deviation common carotid artery IMT difference and 1.18 (95% CI, 1.16–1.21) per 0.10-mm common carotid artery IMT difference. However, age distribution, site, and type of measurement were quite heterogeneous in these studies. The Cardiovascular Health Study has shown comparable results on an asymptomatic population of 65-year-old individuals with a mean follow-up of 6.2 years by comparing the rate of cardiovascular events between the fifth and the first quintile of IMT measured at baseline.
They concluded that carotid IMT was a strong predictor of future vascular events. The relative risk per IMT difference is slightly higher for the endpoint stroke than for myocardial infarction. In future IMT studies, ultrasound protocols should be aligned with published studies. Data for younger individuals are limited and more studies are required.
Recent studies suggest that measuring coronary artery calcification (CAC) may be superior to atherosclerotic biomarkers in predicting cardiovascular risk; however, very few studies using imaging that directly quantifies atherosclerosis in different vascular beds were performed in a single cohort.
The BioImage Study (A Clinical Study of Burden of Atherosclerotic Disease in an At-Risk Population) [8] sought to identify imaging biomarkers that predict near-term (3-year) atherothrombotic events. This study enrolled 5808 asymptomatic US adults (mean age, 69 years; 56.5% female) in a prospective cohort evaluating the role of vascular imaging on cardiovascular risk prediction. All patients were evaluated by CAC and carotid ultrasound. Plaque areas from both carotid arteries were summed as the carotid plaque burden (cPB) . The primary endpoint was the composite of major adverse cardiac events (MACE) (cardiovascular death, myocardial infarction, and ischemic stroke). A broader secondary MACE endpoint also included all-cause death, unstable angina, and coronary revascularization.
MACE occurred in 216 patients (4.2%), of which 82 (1.5%) were primary events. After adjustment for risk factors and compared with individuals without any cPB, hazard ratios for MACE were 0.78 (95% confidence interval [CI], 0.31–1.91), 1.45 (95% CI, 0.67–3.14), and 2.36 (95% CI, 1.13–4.92) with increasing cPB tertile, with similar results for CAC. Net reclassification significantly improved with either cPB (0.23) or CAC (0.25). MACE rates increased simultaneously with higher levels of both cPB and CAC. The authors conclude in this large prospective study that detection of subclinical carotid or coronary atherosclerosis improves risk predictions and reclassification compared with conventional risk factors, with comparable results for either modality.
IMT and Cardiovascular Risk Assessment
Age is the major component of Framingham risk score (FRS) and CIMT, but CIMT may add information on genetics, protective factors, and time exposure to risk factors such as blood pressure, lipids, smoking, and unknown risk factors. It finally provides individual vascular phenotype.
ACC/AHA Recommendations Provided in 2010 Guidelines for Cardiovascular Risk Assessment
Coronary calcium scoring was e valuated as class IIa for intermediate risk (10–20%, 10-year risk) and class IIb for low to intermediate (6–20%, 10-year risk). Measurement of IMT class IIa for intermediate risk (10–20%—10-year risk) (Level B), flow-mediated dilatation on brachial artery and arterial stiffness as class III (no benefit) [9].
Current risk evaluation is based on risk factors in NCEP-ATPIII [10], including hypertension, low HDL, age (men >45 years, women >55 years), and family history of premature coronary health disease (first degree <55 years male, <65 years female). Population having less than two risk factors is considered at low risk and over two risk factors as intermediate to high risk.
Khot et al. [11] published the prevalence of conventional risk factors in a population of 87,869 patients with coronary heart disease. They found a cumulated prevalence of 62.4% for the subjects with 0 or 1 risk factor, confirming that conventional score evaluation needed to be improved by complementary and independent markers of cardiovascular risk in asymptomatic populations. Some studies failed to demonstrate the added value of IMT on top of the Framingham or European score; however, they may have had a too low power explained by the low occurrence of clinical events in the general population and, hence, the noise created by “normal” population and by. long-term design necessary for atherosclerosis studies.
In a recent study reported by Nambi [12], the population of ARIC study, including 13,145 individuals, was followed for approximately 15 years for incident hard coronary events, and revascularization was analyzed. CIMT measurements, which included both IMT and carotid plaque, were incremental to traditional risk factors for prediction of incident cardiovascular events. In particular, among intermediate-risk patients (10–20%, 10-year estimated risk group), the addition of carotid IMT and plaque information led to clinical net reclassification improvement of approximately 9.9%.
Another study investigated the impact of subclinical cardiovascular disease derived from echocardiography and carotid ultrasonography on traditional coronary risk stratification using the FRS in a community-based, multiethnic population [13]. Ultrasonography was performed on 1445 subjects (aged >39 years; 40% men; 53% Hispanic, 20% white, 24% black) from the Northern Manhattan Study. Subclinical cardiovascular disease was defined as the presence of left ventricular hypertrophy and/or carotid plaque greater than the gender-specific 75th percentile of the left ventricular mass index and maximal carotid plaque thickness distribution. The prevalence of subclinical cardiovascular disease was examined in each FRS category (low, intermediate, and high risk). In subjects with low or intermediate FRSs, 35% had subclinical cardiovascular disease (low FRS 29%, intermediate FRS 42%). In the intermediate FRS category, subclinical cardiovascular disease was significantly more prevalent in women than in men (53 versus 32%, p < 0.0001) and in black and white subjects than in Hispanics (59% and 46 versus 33%, p < 0.0001 and p = 0.040, respectively). In that study, the ultrasound assessment of subclinical cardiovascular disease may have helped to reclassify one-third of the subjects with low or intermediate FRS into higher-risk groups. In the intermediate FRS category, FRS appears to underestimate the coronary risk more in women than in men and more in whites, and especially in blacks, than in Hispanics.
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