Over the last 30–40 years in most Western countries, for the first time the number of people developing coronary artery disease (CAD) and mortality rates from cardiovascular disease has gradually decreased. This reduction has been mainly achieved using nationwide atherosclerotic risk-factor control programmes. Nevertheless, cardiovascular diseases remain the major cause of premature death in the US and Europe.1 However, in many Eastern and developing countries a tremendous increase in CAD is documented. Thus, the need for further implementation of CAD prevention strategies in asymptomatic individuals (primary prevention strategies) is a priority worldwide.
According to the Framingham score, seven major independent risk factors for premature CAD have been identified: cigarette smoking, hypercholesterolaemia (total and low-density lipoprotein [LDL] cholesterol), low serum high-density lipoprotein (HDL) cholesterol, diabetes mellitus, hypertension, male gender and advanced age. On the basis of the number of risk factors present, each subject is classified as low-, intermediate- or high-risk for future events. Subjects with two or more risk factors are considered to be high-risk (10-year risk >20%), and are most likely to benefit from preventative measures. Similarly, recent European guidelines1 stated that the following individuals should be prioritised in clinical practice concerning primary preventative measures:
- asymptomatic individuals with ≥5% 10-year risk of CAD death;
- patients with diabetes (type 2 and 1) with microalbuminuria;
- individuals with markedly increased single risk factors; and
- close relatives of subjects with premature atherosclerotic CAD or who are at a particularly high risk.
Evidence exists suggesting that risk factors, although aetiologically important, are not ideal for screening to find those who are at a high risk of coronary events,2 as paradigmatically shown in the British Regional Heart Study (BRHS) risk score, in which only 40% of the total events occurred in the high-risk subgroup, while 60% occurred in the rest of the population.3 In patients with suspected CAD, a variety of techniques such as bicycle or treadmill exercise electrocardiogram (ECG) testing, stress echocardiography or radionuclide scintigraphy are routinely used in diagnostic work-up programmes in the clinic, but due to the time required and the relative complexity of these tools they have rarely been used in the general population for screening purposes.1
In recent years, with the improved understanding of the atherosclerotic process and the availability of multiple new non-invasive tools for arterial wall and plaque imaging, a debate has been initiated as to whether this approach can identify high-risk subjects more effectively than the traditional risk-factor assessment. Moreover, because atherosclerosis begins at a young age and remains clinically silent for decades, the identification of subclinical stages of the disease has become a distinct opportunity for early intervention. Currently, a number of non-invasive approaches are available for plaque imaging: B-mode ultrasonography of carotid (and femoral) arteries, computed tomography (CT) for coronary calcium scoring and CT coronarography and magnetic resonance imaging (MRI). A number of high-quality studies have demonstrated that these tests can predict risk.3,4
In this article I will focus on B-mode ultrasonography of carotid (and femoral) arteries. I believe that this is a more effective tool for CAD primary prevention in clinical practice than simple risk-factor assessment, and that clinical cardiologists should incorporate this approach with the aim of improving treatment plans for patients in an office-based setting.5 The role of coronary calcium score (CCS) in this clinical context will also be briefly discussed. The imaging of atherosclerosis has evolved into a central method in clinical cardiology with a great potential for improving CAD risk prediction.2–11 The intima-media thickness (IMT) of carotid arteries and coronary artery calcium detection by cardiac CT have been convincingly shown to be independent predictors of incident CAD events. Expert recommendations have endorsed the use of these imaging modalities in a primary prevention setting,9 allowing a step-up progression towards individualised CAD prevention through a more effective use of drugs. Population-based studies have shown a correlation between the severity of atherosclerosis in one arterial territory and the involvement of other arteries. As carotid and femoral arteries, as well as abdominal aorta, are more accessible for non-invasive examinations than coronary or intra-cerebral arteries, the early detection of atherosclerosis in these vessels has become a standard reference for atherosclerosis burden evaluation in the individual.
Carotid Artery Intima-media Thickness and Plaque Imaging
During the last 20 years, after the seminal papers by Pignoli and his co-workers in the 1980s12–15 on the feasibility of direct measurement of arterial wall thickness with B-mode imaging of in vitro specimens of human aortic and carotid arteries, the use of this non-invasive approach has become the standard reference method for assessing the presence and amount of atherosclerosis in living humans. Carotid ultrasonography can provide IMT and plaque imaging. Today, we know that increased carotid IMT and the presence of plaques reflect the presence of cardiovascular risk factors, are early markers of atherosclerosis, are associated with CAD, can predict clinical coronary events and can help in monitoring the effects of treatment as well as establishing its aggressiveness.16–20 As suggested in a recent review paper,20 evidence exists from both observational and intervention studies indicating the appropriateness of using carotid IMT as a surrogate marker for CAD and that its application in studies is based on the assumption that carotid plaques and changes in carotid IMT are related to the presence of coronary atherosclerosis and the incidence of CAD events, respectively.
Predicting Coronary Artery Disease Events
It has been shown that in patients with multiple focal thickening, the sum of the area of all focal lesions observed in the carotid tree is a superior correlate of risk factors and a better prognosticator than IMT alone.21,22 In general, a greater IMT value is associated with a greater event risk, and an increased IMT value has been found to correlate with cardiovascular risk factors and CAD and to predict cardiovascular events,23–29 as well as to identify patients who remained event-free in the follow-up period based on their low IMT value.28
In the Kuopio Study,27 the risk of myocardial infarction increased by 11% for each 0.1mm increase in IMT of the common carotid artery. However, due to the influence of non-lipid factors such as age or hypertension, which induce medial hypertrophy, an increase in IMT value may be observed independently of the atherosclerotic process. Accordingly, early studies demonstrated that CAD events are best predicted by plaque rather than IMT imaging.6–9 This correlation is higher, and the prognostic value of IMT measurements for predicting future CAD events is increased, when data from all three segments (common carotid artery, carotid bifurcation and internal carotid segments) are combined.9 Moreover, studies showed that crude measures directly assessing plaques are equally good or better at predicting the risk of future CAD events.30,31 Of note, risk estimates for femoral artery atherosclerosis30 were slightly weaker than those for measures of carotid or aortic atherosclerosis. Evidence from intervention studies reinforces the observational data linking carotid IMT with CAD events.
A significant positive association between the progression of carotid IMT over the two to four years of therapy and combined incidence of nonfatal myocardial infarction and coronary death has in fact been observed in a long-term follow-up of patients in the Cholesterol-lowering Atherosclerosis Study (CLAS) trial who received colestipol–niacin or placebo following coronary artery bypass graft (CABG) surgery.32 A recent meta-analysis of seven statin trials33 showed a significant relationship between the progression of carotid IMT and the incidence of CAD events. In this meta-analysis it has been suggested that carotid IMT met clinical and statistical criteria for use as a surrogate end-point for cardiovascular events in clinical trials of statins.
Atherosclerosis Regression Studies
Randomised trials using carotid ultrasonography have demonstrated that intensive lipid-lowering therapy can induce atherosclerosis regression34–36 or reduce its progression even in low-risk individuals.37 This was true not only in a primary prevention setting but also in patients with known CAD despite normal/below average cholesterol levels,38 ultimately indicating that non-invasive modalities of atherosclerosis imaging by ultrasound are mature enough to be incorporated by cardiologists into their office-based CAD risk assessment (mostly in patients deemed intermediate-risk for future events by traditional risk factors). In my experience, direct patient involvement in the visualisation and discussion of his or her ultrasound findings increases patient co-operation in the risk-assessment process, the decision-making process and follow-up adherence to a treatment plan. A similar impact of anatomically based screening on patient management in a primary prevention setting has been documented in a recent six-year study using CCS.39 It has been suggested that biomarkers of pre-clinical disease progression, such as those obtainable using plaque imaging, could help to enhance the process of new drug development and characterisation several years before the results from clinical end-point trials become available.20
Carotid Plaque Echolucency by Back-scatter Analysis
Demonstration of the extensibility of the carotid plaque findings to other arterial territories, and to coronary arteries in particular, has been obtained in a very interesting study by Honda et al.40 Seventy-one patients with acute CAD syndrome and 215 with stable CAD were submitted to coronary angiography and carotid ultrasonography with integrated back-scatter (IBS) analysis to objectively assess plaque echolucency, an indicator of plaque lipid content. Three major findings emerged from this study: patients with acute CAD had more echolucent carotid plaques; echolucent carotid plaques accurately predicted the presence of complex coronary plaques by coronary angiography (predictive power 83%); and stable CAD patients with echolucent carotid plaques showed a very high risk of future coronary events in the 30-month follow-up period independently of other risk factors. In another study comparing middle-aged and elderly subjects with myocardial infarction patients, it has been shown that despite similar IMT values in the three groups, IBS was significantly higher in elderly subjects and lower in high-risk middle-aged subjects and myocardial infarction patients, with 11% of low-risk middle-age subjects, 29% of high-risk middle-age subjects and 63% of myocardial infarction patients exhibiting lipid-rich regions of carotid arteries.41 These data strongly suggest that, in conjunction with conventional IMT measurements, IBS analysis allows us to identify high-risk subjects requiring aggressive risk-factor reduction.
In order to increase the diffusion and usefulness of carotid scanning to facilitate clinical screening for subclinical atherosclerosis in assisting with cardiovascular risk prediction, an abbreviated protocol has been proposed.42 This protocol has combined plaque screening and isolated IMT measurement of the common carotid artery’s far wall and exhibited a 100% sensitivity for an increased IMT. If either plaque or increased IMT of the common carotid artery is identified, a more aggressive risk factor modification should be considered. A similar statement has been reported in a recent report from the American Society of Echocardiography (ASE) and the Society of Vascular Medicine.19
Atherosclerosis Imaging in Metabolic Syndrome
According to recent European guidelines,1 the metabolic syndrome identifies individuals with an increased risk of developing cardiovascular disease in accordance with the clustering of cardiovascular risk factors in individuals with obesity or insulin resistance, but does not indicate risk of cardiovascular disease over and above the effect of the risk factors involved. An increasing frequency of the components of metabolic syndrome since paediatric age has recently been observed,43 and in a cohort study of 280,678 Danish schoolchildren followed up for decades it has been shown that the risk of CAD events later in life was positively associated with BMI at seven to 13 years of age for boys and 10 to 13 years of age for girls,44 confirming that atherosclerosis is a paediatric problem and needs intervention even during childhood to reduce the risk of future CAD.
During the first three decades of life, arterial lesions increase mainly because lipids accumulate at a relatively slow and predictable rate in susceptible individuals.45 At this age the fatty streaks transform into raised lesions and high-risk subjects become apparent and diverge from the low-risk population. These observations further suggest the need to be prepared to face the increasing burden. It has been also been shown that patients with the metabolic syndrome, regardless of the definition used, have a greater burden of subclinical carotid atherosclerosis by IMT assessment, and that this burden is mediated entirely through the risk factor components of the syndrome itself, ultimately suggesting that the diagnosis of metabolic syndrome per se may not provide additional clinical information, and further supporting the relevance of non-invasive imaging of atherosclerosis in this clinical setting.46
Coronary Calcium Score by Non-contrast Cardiac Computed Tomography Scan
Over the course of time, atherosclerotic plaques mineralise by calcium deposition and the presence of any detectable level of calcium in the coronary tree indicates the presence of atherosclerosis, the amount of which (by calcium score) correlates with the risk factors, extent of atherosclerosis and age. Cardiac CT began with electron-beam CT in the early 1980s and continues with multidetector CT. The quantification of coronary artery calcium as a reliable estimate of atherosclerotic plaque burden is the current major application of non-contrast cardiac CT. High-risk subjects have been identified in earlier studies using electron-beam CT by a score above 80–160.47 Plaque burden is quantified by the Agatstone score,48 according to which a score greater than 400 is associated with an increased risk of CAD.8 CT coronary angiography is the major application of contrast-enhanced CT, allowing a more detailed estimation of total plaque burden as well as ruling out obstructive CAD.49 The 64-slice CT allows the detection of non-calcified coronary atherosclerotic plaques and volume changes over time.8,50 With this technique a 22% annualised volume increase of the plaque by natural course has been found50 to be comparable to a 24% natural progression of coronary artery calcium (CAC) by Agatstone score51 as opposed to a 24% reduction in non-calcified plaques reported after lipid-lowering therapy with 64-slice CT in the New Age II Pilot Study.52 However, radiation is the main limit of this technique as a screening tool.53,54 With the increased clinical applications and development of CT scanners (with more detector arrays), a potential increase in radiation exposure for patients exists, and cardiologists should make thoughtful decisions about radiation doses and the associated cancer risk.
Atherosclerosis is a generalised process that begins very early in life and must be viewed as a preventable disease. The recent technological revolution has clearly influenced the decision-making process in the primary cardiovascular prevention setting, which could – and should – be approached not only in terms of risk-factor control, but also in terms of early disease detection, plaque prevention and plaque stabilisation. In this context, and compared with X-rays or magnetic resonance-based technologies, the IMT and in particular the early plaque detection by ultrasound may be viewed as the most sensitive, easy, reliable, safe and cheap method for identifying individuals at an increased risk. In general, the clinically relevant idea that emerged from a great number of papers is that the carotid and femoral arteries can be considered the ‘sentinel vessels’ of coronary artery status.55,56 Higher-quality imaging and measurement technology improvements would make this approach suitable for more patients. More effective preventative and therapeutic measures as well as appropriate drug selection and dosing could be developed, not only for patients with an established CAD but also in the primary care setting. In particular, plaque imaging by ultrasound allows us to establish the need for aggressive treatment in a primary prevention setting for subjects deemed to be intermediate-risk by traditional risk factors57 (see Figure 1). The assessment of CCS adds specific information about the plaque burden at a coronary level, being a sensitive marker for obstructive CAD but not a specific one. In my view, the risk of the associated radiation exposure makes this approach potentially unsafe, and it should possibly be avoided when subsequent examinations are thought to be required. Due to safety, logistic and cost-effectiveness limitations, coronary angiography and atherosclerosis imaging by MRI cannot currently be considered as real possibilities in the setting of cardiovascular risk assessment and event prevention beyond individual cases.
We do not actually know whether a population screening for atherosclerosis by carotid ultrasound could reduce CV events rate in the way that mammography works for breast cancer and fibre optic colonscopy for colon cancer. My opinion is that, while waiting for this evidence, cardiologists should include in their office-based risk assessment carotid and femoral artery ultrasound examination in all patients with an intermediate 10-year risk for CAD by traditional risk factors and treat them aggressively if plaques are present, possibly reducing their total blood cholesterol level by around 130–150mg/dl using statins. Smokers should be supported by professional antismoking clinics or pharmacotherapy,58 and should be advised that we cannot help them at all if they do now quit smoking.