Cardiovascular disease is the leading cause of death in developed countries, in which coronary artery disease (or coronary heart disease) accounts for almost 50 % of all deaths, followed by stroke with around 17 % and heart failure with around 7 % (Fig. 10.1). In recent epidemiological studies, coronary artery disease had a prevalence of around 7 % in all adults over 20 years of age and an incidence of 785,000 new and 470,000 recurrent coronary events per year in America. It is a disease of the older population, and prevalence and incidence increase with age. With the current demographic changes in the world, shifting the aging society toward a population of the old and very old, the disease will become even more relevant in the future. It is estimated that over the next 20 years, the prevalence of cardiovascular disease will increase by 10 %.

In 2007, one out of every six deaths in the United States was caused by coronary artery disease. With direct and indirect costs of estimated 177 billion dollars per year in the United States, coronary artery disease is the most costly disease in the health-care system (Roger et al. 2011).

The National Institutes of Health (NIH) define coronary artery disease as a narrowing of the blood vessels that supply blood and oxygen to the heart (Chen and Zieve 2011). The most common cause is atherosclerosis of epicardial coronary arteries, leading to reduction of myocardial blood flow. This happens through asymmetric remodeling of the artery wall, leading to stenosis and/or the formation of a thrombus on top of a ruptured atherosclerotic plaque, the latter being regarded as the key mechanism of acute coronary syndrome and sudden cardiac death (Maseri 1997).

The first step in the process of atherosclerosis, which usually takes decades, is the infiltration and retention of lipoproteins in the arterial intima. High plasma levels of low-density lipoproteins (LDL) promote the trapping of these particles in the extracellular matrix of lesion-prone sites. In this environment, the lipoproteins undergo oxidative modification (Hansson 2005). This happens either spontaneously or by enzymatic reactions through resident macrophages. Subsequently, endothelial cells are activated and increase the expression of adhesion molecules (e.g., vascular cell adhesion molecule, E-selectin, macrophage chemotactic protein 1). Leucocytes enter through adherence and diapedesis into the subendothelial space. Monocytes differentiate into tissue macrophages and express scavenger receptors. Those receptors are capable of internalizing a broad range of molecules, like bacterial endotoxins, cell fragments, and oxidized LDL particles. Especially lipids (i.e., esterified cholesterol) accumulate in the cytoplasm of macrophages, which are then referred to as foam cells. This activation of macrophages, which is now a chronic inflammatory process, is enhanced by cytokines like interleukin-1, tumor necrosis factor alpha, macrophage chemotactic protein 1, macrophage colony-stimulating factor, and platelet-derived growth factor. These macrophages interact with T cells, enhancing the cytokine and growth factor production even more (i.e., fibroblast growth factor, transforming growth factor beta, platelet-derived growth factor), which promotes the migration and proliferation of smooth muscle cells (Rosenfeld 2000). The formation of a fibrous cap is the crucial step that turns a fatty streak into an atheroma. In this transition, smooth muscle cells migrate from the media to the intima and produce large amounts of extracellular matrix in order to stabilize the lesion and prevent more lipoprotein particles from entering the vessel wall. The thickness and integrity of the fibrous cap is a predictor of the vulnerability of the lesion. With progression of the disease, a lipid-rich core, with necrotic and apoptotic cellular debris, forms the center of the atheroma. Lipid-laden foam cells perish or experience programmed cell death through mediators like tumor necrosis factor alpha, Fas ligand, and oxidized lipids (Glass and Witztum 2001). The lipid-rich necrotic core contains extracellular lipids, calcifications, and cell fragments, and its enlargement causes destabilization of the fibrous cap. Another factor that compromises the fibrous cap is the degradation of the extracellular matrix by matrix metalloproteinases secreted by macrophages (Glass and Witztum 2001). This ­process occurs predominantly in the shoulder region of the plaque. If the destabilization continues, the fibrous cap is more likely to rupture. A rupture exposes highly thrombogenic subendothelial tissue, which triggers platelets and clotting factors of the blood to form a thrombus. Infarction occurs when this occlusion critically reduces the blood flow in the subsequent tissue.

Many atherosclerotic lesions, especially more advanced ones, contain calcification. The expression of bone-related proteins as well as histologically visible calcification is detectable in atheromas with a lipid-rich necrotic core. Enchondral ossification via formation of cartilage followed by osteoblast induction has been shown to be the mechanism of calcification in atherosclerosis (Johnson et al. 2006). Whether calcification in general is a factor in vulnerable lesions is controversial. It seems that the amount of calcium and its localization are important criteria in that matter. Superficial calcified nodules are associated with an increased risk of plaque rupture (Virmani et al. 1998; Naghavi et al. 2003). Deep, concentric medial calcification on the other hand has been reported to be a feature of more stable plaques (Ge et al. 1999). However, it has been shown that the amount of calcification correlates with the overall burden of disease. Thus, patients who have calcified plaques are also more likely to have noncalcified or “soft” plaques that are prone to rupture and acute coronary thrombosis (Greenland et al. 2007).

The cause of atherosclerotic lesions varies and several factors determine their vulnerability. Common concepts of vulnerability, like degree of stenosis, might not suffice and need to be extended. Furthermore, there are significant differences in the temporal development and progression of lesions in different patients. Some lesions are more stable than others. We have already discussed how some lesions turn into highly fibrosed and/or calcified plaques that are not associated with a significant increase in cardiovascular events (e.g., myocardial infarction). The next chapter describes risk factors of atherosclerosis in general and features of atherosclerotic lesions that are associated with increased risk of cardiovascular events.

Several large epidemiological studies (e.g., the Framingham study Kagan et al. 1962) have revealed risk factors that are associated with cardiovascular disease (CVD) (Kannel et al. 1964; Kannel et al. 1968; Dawber and Kannel 1972). Today many genetic and environmental factors that promote atherosclerosis are known and research in the field is ongoing. Table 10.2 shows some of the most common risk factors for CAD (Lusis 2000; Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults 2001). The identification of these risk factors has helped in the prevention of CVD in the general ­population (i.e., antismoking campaigns, treatment of hypertension or hyperlipidemia) and has led to declining death rates from CAD (Roger et al. 2011). However, the high prevalence of traditional risk factors (e.g., LDL cholesterol) in persons without atherosclerosis makes the risk factors alone only poor predictors for individual CAD risk (Castelli 1996). Furthermore, having multiple risk factors increases the risk for acute myocardial infarction significantly (Fig. 10.2). Studies showed that typical CAD risk factors are capable of explaining more than 90 % of the overall risk for acute myocardial infarction (Yusuf et al. 2004). Therefore, multivariate scores (the Framingham risk score and SCORE, for systematic coronary risk evaluation) have been developed to attribute an individual short-term risk (10 years) for CAD events (i.e., angina pectoris, coronary insufficiency, myocardial infarction, and coronary death). The Framingham risk score defines three risk categories (low-, intermediate-, and high-risk patients), each with different implications for treatment. These scoring systems do improve the individual risk evaluation (e.g., different values for men and women) but are far from a universal tool for CAD risk assessment. Studies showed that they are ­suboptimal for young patients and non-Caucasians and they focus only on short-term events and not on lifetime events (Akosah et al. 2003; Liu et al. 2004). Furthermore, many of the risk factors are CAD markers that have been known for more than 60 years. In other words, current scoring concepts neglect newer CAD markers and tools that can identify asymptomatic atherosclerosis.

The above-mentioned risk assessment is population-based and a good tool to predict the presence of CVD in individuals. However, absence of risk factors does not necessarily translate into absence of disease and predictions about the individual prognosis of the disease can hardly be made. It has been shown that the sensitivity of the scores for patients with asymptomatic CVD is low. “Low risk” does not mean “no risk,” and according to recent National Health and Nutrition Examination Survey data, among healthy adults aged 20–79 years, 85 % had low-risk Framingham scores, while only 2 % had high-risk scores. Low-risk individuals were responsible for approximately two-thirds of the overall population risk (Lauer 2007). This emphasizes the importance of improving the conventional risk scores, so that the risk of each individual could be determined.

Diagnostic imaging techniques have been most promising in the assessment of atherosclerosis and show a high potential for individual risk evaluation. They can be used to look at morphological, functional, and molecular characteristics of atherosclerotic lesions. One generally accepted approach is the concept of the vulnerable plaque (Naghavi et al. 2003). The crucial mechanism for acute myocardial infarction and sudden cardiac death is the rupture of an atherosclerotic plaque. Most patients with acute myocardial infarction do not have severely stenosed arteries prior to the infarction. Figure 10.3 is from a review by Falk et al. (1995) where 68 % of patients with acute myocardial infarction had a stenosis diameter in the affected artery of less than 50 % before the plaque rupture occurred. A recent study by Stone et al. (2011) showed that previously untreated coronary segments that lead to cardiovascular events had a mean stenosis diameter of approximately 32 %, as detected by intravascular ultrasound. The fact that degree of stenosis alone is only a poor predictor for cardiovascular events shows that an integrated model of morphology and disease activity is needed. Table 10.3 shows the criteria that define an atherosclerotic lesion as vulnerable (Naghavi et al. 2003). All the listed criteria are associated with increased risk of plaque rupture and cardiovascular events and reflect morphologic aspects as well as molecular pathophysiology. Most of these criteria were derived from autopsy studies of patients with CAD. Invasive and noninvasive imaging techniques are capable of investigating features of vulnerable lesions in vivo. It is important to note that no imaging modality is ideal for looking at CAD; each has its advantages and limitations.