A biomarker is a substance that can be measured to evaluate normal biological processes, pathogenic processes, or pharmacological response to a therapeutic intervention [5]. Imaging and genetic testing can be considered biomarkers as well, but for this chapter biomarkers will refer only to blood markers. The desirable characteristics of a biomarker differ with the intended use [6]. Biomarkers may have value in improving global CVD risk assessment, monitoring response to therapy, or as targets for therapy [7]. Biomarkers can be classified as screening biomarkers (screening for subclinical disease), diagnostic biomarkers (recognizing overt disease), staging biomarkers (categorizing disease severity), or prognostic biomarkers (predicting future disease course, including recurrence and response to therapy, and monitoring efficacy of therapy) [8]. For screening biomarkers, features such as high sensitivity, specificity, and predictive values, large likelihood ratios, and low costs are important. For biomarkers to monitor the response to therapy, features such as narrow intraindividual variation and association with disease outcome are critical [8, 9]. A multimarker strategy may help us to understand the pathophysiological mechanisms of CVD and to develop new treatments in atherosclerosis. Inflammatory, hemodynamic, and vascular damage biomarkers are currently available and may be considered for the multimarker approach [5, 10, 11].

Given the complex pathophysiology of CVD, it is unlikely that any single biomarker will be able to serve as a universal surrogate for atherosclerosis. Lipoproteins have been used for a long time as biomarkers in CVD risk assessment and prevention. Biomarkers that can be measured in blood have the advantage of availability, lower cost, and repeatability, and hence they have value in risk stratification but may not prove as sensitive as imaging modalities for the detection or assessment of disease [12]. Although atherosclerosis is a generalized disease that involves most of the arterial bed, most deaths are caused by thrombotic occlusion secondary to a single plaque rupture. Thus, nonspecific biomarkers for the generalized process of atherosclerosis are less likely to help identify an individual vulnerable plaque in a disease that is often multifocal or even diffuse; however, such biomarkers may help in the identification of a vulnerable patient [13]. Atherosclerotic lesions or vulnerable plaques associated with thrombosis are frequently found to have a thin and/or fissured cap [14]. The risk is also higher if the plaque has a large lipid core, a history of rupture or remodeling, and is associated with inflammation [15, 16]. Soluble biomarkers may help in detecting systemic inflammation. For example, the inflammatory marker CRP is elevated in patients with unstable angina and more so in patients with acute myocardial infarction (MI) [17]. Moreover, CRP levels are predictive of risk for MI in patients with or without prevalent coronary heart disease (CHD) [17]. The caveat is that CRP is not specific for atherosclerosis and as a consequence can be elevated in other conditions, such as renal disease, infection, cancer, autoimmune diseases, liver and kidney disease, and trauma [13]. Other biomarkers for which assessment is currently available are similarly not specific in detecting atherosclerosis.

Ideally, we would need better approaches or biomarkers that would identify vulnerable plaques before they become culprit plaques. To evaluate plaque vulnerability, a combined approach capable of evaluating structural characteristics (morphology) as well as functional properties (activity) of plaque may be more informative and may provide higher predictive value than a single approach (Fig. 15.1). Many of these features can be detected by imaging modalities such as angiography, computed tomography (CT), magnetic resonance imaging (MRI), intravascular ultrasonography (IVUS), and molecular imaging [12, 18]. However, newer imaging technology may be limited by technical difficulty, availability, and cost. Therefore, a combined approach using both circulating biomarkers and imaging modalities may be more cost-effective. A number of biomarkers have been examined in conjunction with imaging data for noninvasive identification of high-risk atherosclerotic plaques [19, 20]. It should be noted, however, that circulating biomarkers may be weakly correlated with quantifiable imaging parameters, as shown in the Integrated Biomarker and Imaging Study (IBIS) [21]. Table 15.1 shows the applicability of biomarkers and imaging in CVD risk prediction, therapeutic monitoring, and treatment targets.

C-reactive protein (CRP) is a nonspecific inflammatory marker that has now been extensively studied in CVD. It is a member of the pentraxin family of innate immune response proteins [22]. CRP is postulated to have a role in atherosclerosis, as it has been shown to enhance expression of endothelial cell surface adhesion molecules, monocyte chemoattractant protein-1, endothelin-1, and endothelial plasminogen activator inhibitor-1 [23]. Many studies have shown that hs-CRP is associated with incident CVD events in healthy individuals as well as in patients with CVD [17, 24]. Inclusion of hs-CRP measurement has also been shown to improve CVD risk prediction as assessed by the area under the receiving operator characteristic curve (AUC), and hs-CRP is used in conjunction with other risk factors for cardiovascular risk prediction in the Reynolds risk score [25].

A number of studies have shown that statin therapy reduces the risk for CVD events in individuals with high concentrations of hs-CRP [26–28]. In the recent Justification for the Use of Statins in Primary Prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER), which enrolled subjects without known CVD who had hs-CRP ≥2 mg/L and low-density lipoprotein cholesterol (LDL-C) <130 mg/dL, CVD event rate was reduced with rosuvastatin versus placebo [26]. Based on the results from JUPITER, rosuvastatin is indicated for primary prevention of CVD in men aged 50 years or older and women aged 60 years or older who have hs-CRP ≥2 mg/L in conjunction with at least one additional cardiovascular risk factor, even without overt hyperlipidemia.

The American College of Cardiology (ACC)/American Heart Association (AHA) risk guideline recommendations include consideration of hs-CRP to inform treatment decisions in individuals whose risk is uncertain based on quantitative risk assessment, with hs-CRP ≥ 2 mg/L supporting increasing estimated risk [29]. In contrast, the US Preventive Task Force (USPTF) concluded that the current evidence is insufficient to assess the balance of benefits and risks of using hs-CRP to screen asymptomatic men and women with no history of CHD to prevent CHD events [30]. Several investigators have compared hs-CRP and plaque imaging data in an effort to assess which is better in identifying vulnerable individuals and whether combining biomarkers and imaging improves risk stratification.

Lp-PLA2 is another biomarker that is currently approved for use in CVD risk prediction. Lp-PLA2 is an enzyme that generates lysophosphatidylcholine and oxidized free fatty acids. Lysophosphatidylcholine in turn suppresses release of nitric oxide and up-regulates CD40 ligand expression in T lymphocytes [44]. Lp-PLA2 is associated with vascular inflammation and has relatively low biologic fluctuations [45]. Several large studies have demonstrated an association between Lp-PLA2 and incident CVD events [46–48], but other studies have shown only a modest increase in AUC when Lp-PLA2 was evaluated in risk prediction models [49, 50].

MPO is another soluble biomarker that is being investigated for possible use in CVD risk prediction. MPO, a protein produced by polymorphonuclear neutrophils and macrophages, is released in inflammatory conditions [61]. MPO is involved in oxidation of lipids contained within LDL and is thought to promote the formation of foam cells in atherosclerotic plaques [62]. Inflammatory cells producing MPO are found more frequently in ruptured plaques of patients with ACS than in patients with stable CHD [63, 64]. Therefore, MPO may be a marker of vulnerable plaque. Although several studies have shown an association of MPO and CVD events in healthy individuals as well as in patients with acute and chronic CVD [65–68], the additional predictive value of MPO levels in the stratification of cardiovascular risk in clinical practice is still not clear. Additional studies are necessary to evaluate the diagnostic and prognostic ability of MPO in the different forms of presentation of CVD.