Appendix 1. Description of Selected Inflammatory and Other Cellular Biomarkers that Have Been Evaluated in Clinical Studies to Assess Association with CVD Clinical Outcomes

C-reactive protein (hs-CRP)
CRP is produced by the liver, appears in peripheral blood, and is a sensitive marker of inflammation. Atherosclerotic plaques contain CRP, generally associated with accumulation of complement (a molecule that is activated during inflammation and which activates other inflammation molecules) and macrophages or foam cells (Zaman 1999). Multiple studies now suggest CRP as an independent risk factor for atherosclerotic vascular disease (Haverkate 1997, Zebrack 2002, Morrow 2000, Koenig 1999, Tracy 1997, Westhuyzen 2000, Ridker 1997). Several studies show that high hs-CRP levels predict poor prognosis for patients with unstable angina (Liuzzo 1994, Tomoda 2000, Heeschen 2000). However, the specifics of diagnostic potential for VP are still being defined.

The matrix metalloproteinases (MMPs)
MMPs are proteolytic enzymes produced by macrophages that digest extracellular matrix, eroding the fibrous cap of the atheromatic plaque resulting in its thinning and further weakening (Zaman 1999). Several MMPs have been identified in atherosclerotic plaque, playing key roles in vascular remodeling (Schwartz 2003).

Plasma MMP-9 concentration was identified as a novel risk marker of future cardiovascular mortality in a large cohort of patients with CAD independently of main clinical and therapeutic confounders (Blankenberg, 2003).

Cellular Adhesion Molecules (CAMs)
Specific adhesion molecules on the endothelial surface act as receptors for monocytes and T cells. They mediate adhesion of circulating leukocytes and their subsequent transendothelial migration (Zaman 1999). Such adhesion molecules include several selectins, intercellular adhesion molecules (ICAM), and vascular cellular adhesion molecules (VCAM).

The Physicians' Health Study showed that baseline sICAM-1 and sE-selectin correlated with cardiovascular risk (Ridker, Rifai, and Stampfer 2000). Furthermore, CAMs exhibited independent coronary and cerebrovascular risk in the Atherosclerosis Risk in Communities (ARIC) study (Hwang 1997).

sICAM-1 is predictive also in apparently healthy people, whereas sVCAM-1 and sE­selectin have a strong predictive value mainly in those patients with atherosclerotic lesions or at least risk factor-induced inflammation resulting from activated endothelium (Blankenberg 2001).

Interleukin-6 (IL-6)
Cytokine IL-6 is prominent early in focal inflammation. Its implication with vascular inflammation is consistent since it is the principal initiator of hepatocyte CRP expression (Schwartz 2003).

IL-6 appears to predict short-term (Biasucci, Liuzzo, and Grillo 1999) and long-term (Lindmark 2001) mortality of CAD patients having experienced one or more episodes of instability. Furthermore, several studies (deLemos 2000; Haverkate 1997; Haverkate 2000; Ridker, Rifai, and Stampfer 2000) of healthy adults have shown an association between elevated IL-6 levels and cardiovascular mortality and future MI.

Interleukin-18 (IL-18)
IL-18 induces interferon (IFN)-γ production in T lymphocytes and natural killer cells, which is believed to play a crucial role in atherosclerotic plaque rupture (Zaman 1999).  Baseline measurement of IL-18 provides powerful information for future fatal cardiovascular events across the entire spectrum of patients with stable or unstable CAD (Blankenberg 2002). IL-18 exhibited a weak correlation with hs-CRP, IL-6, and MMP-9. Combined determination of MMP-9 and IL-18 has been suggested to identify patients at very high risk (Gerdes 2002).

Tumor Necrosis Factor (TNF)-alpha
TNF-alpha is a proteolytic enzyme produced by macrophages that digest extracellular matrix, eroding the the fibrous cap of the atheromatic plaque resulting in its thinning and further weakening. Thus, it facilitates vessel wall damage and contributes to plaque vulnerability. 

TNF-alpha (the level increases following MI) and is a marker for increased cardiac event risk. It is suggested that since TNF-alpha has a short serum half-life, it might have limited value for long-term prognosis (Ridker, Rifai, Pfeffer et al. 2000).

Soluble CD40 Ligand (sCD40L)
SCD40L is a multi-potent immunomodulator expressed with its receptor on the vascular endothelial cells, smooth muscle cells, mononuclear phagocytes, and platelets. Its ligation on the surface of these cells triggers the expression of various pro-inflammatory mediators (Schonbeck and Libby 2001). In a prospective, nested case control analysis among participants in the Women's Health Study, high plasma concentrations of sCD40L appeared to be associated with increased vascular risk in apparently healthy women (Schonbeck, Varo, and Libby 2001).

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